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WO2025068714A1 - Pharmaceutical compositions comprising 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) - Google Patents

Pharmaceutical compositions comprising 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) Download PDF

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Publication number
WO2025068714A1
WO2025068714A1 PCT/GB2024/052500 GB2024052500W WO2025068714A1 WO 2025068714 A1 WO2025068714 A1 WO 2025068714A1 GB 2024052500 W GB2024052500 W GB 2024052500W WO 2025068714 A1 WO2025068714 A1 WO 2025068714A1
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Prior art keywords
dmt
meo
composition
patient
subject
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PCT/GB2024/052500
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French (fr)
Inventor
Cosmo FEILDING-MELLEN
Timothy Mason
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Beckley Psytech Ltd
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Beckley Psytech Ltd
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Priority claimed from GBGB2314911.5A external-priority patent/GB202314911D0/en
Priority claimed from GBGB2403419.1A external-priority patent/GB202403419D0/en
Priority claimed from GBGB2403721.0A external-priority patent/GB202403721D0/en
Priority claimed from GBGB2405965.1A external-priority patent/GB202405965D0/en
Application filed by Beckley Psytech Ltd filed Critical Beckley Psytech Ltd
Publication of WO2025068714A1 publication Critical patent/WO2025068714A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • compositions comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
  • This invention relates to dosage regimens of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), compositions of 5-MeO-DMT and uses thereof.
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • 5-MeO-DMT benzoate is the benzoate salt of the pharmacologically active compound of the tryptamine class, 5-MeO-DMT, and has the following structure:
  • 5-MeO-DMT a tryptamine alkaloid, is a short-acting serotonergic psychedelic that was first synthesised in 1936.
  • 5-MeO-DMT has been found in a large number of plants and has also been identified as the primary psychoactive component of the parotid gland venom of Incilius alvarius (formerly Bufo alvarius), the Sonoran Desert toad.
  • 5-MeO-DMT has been detected in blood, urine, and cerebrospinal fluid; however, its physiological role is unknown and more research is needed to definitively determine if 5-MeO-DMT is endogenously produced in humans.
  • 5-MeO-DMT is a serotonin (5-HT) receptor agonist with affinity to a variety of serotonin receptors. Its highest binding affinity is for the 5-HTIA receptor, with a 300-1000-fold higher selectivity compared with the 5-HT2A receptor.
  • the behavioural effects and safety margins of 5-MeO-DMT have been best characterised in rodents.
  • 5-MeO-DMT is rapidly metabolised by monoamine oxidase enzymes in the gut and liver, and is orally inactive. It is therefore usually administered parenterally through smoking or inhalation of vapour, or less commonly via intravenous, intramuscular, rectal, sublingual, or intranasal applications.
  • 5-MeO-DMT induces profound alterations in consciousness including mystical experiences, has minimal visual effects and higher rates of ego-dissolution compared to other psychedelics.
  • Data mainly derived from psilocybin and LSD studies, suggests that a profound psychedelic effect might be a necessary precursor for psychiatric efficacy of psychedelics, suggesting that 5-MeO-DMT, given at the right dose could be a beneficial alternative to current psychedelics in clinical development.
  • 5-MeO-DMT has a rapid onset and short duration of action, which might reduce the duration of treatment sessions and thus resource utilisation.
  • a rapid and sustained treatment of treatment resistant depression/major depressive disorder comprising the administration of 10 mg of 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
  • the terms “approximately” and “about” generally should be understood to encompass ⁇ 5% of a specified amount or value.
  • a pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT.
  • the composition is formulated for intranasal administration. In an embodiment, the composition is formulated as a dry powder. In an embodiment, the composition is formulated as a spray dried dry powder. In an embodiment, the composition comprises 5-MeO-DMT benzoate. In an embodiment, the composition comprises 5-MeO-DMT hydrochloride. In an embodiment, the composition comprises 5-MeO- DMT hydrobromide. In an embodiment, the composition comprises 5-MeO-DMT oxalate. In an embodiment, the 5-MeO-DMT is in crystalline form. In an embodiment, the composition is in crystalline form.
  • the composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20 as measured using an x-ray wavelength of 1.5406 A.
  • the composition comprises crystalline 5-MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5° ⁇ O.1°20 as measured using an x-ray wavelength of 1.5406 A.
  • the composition comprises crystalline 5- MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20 ⁇ O.1°20 as measured using an x-ray wavelength of 1.5406 A.
  • the composition comprises crystalline 5-MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20 ⁇ O.1°20 as measured using an x-ray wavelength of 1.5406 A.
  • the composition comprises one or more of: chitosan, chitosan derivatives, fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
  • ZOT zonula occludens toxin
  • ER143 human neutrophil elastase inhibitor
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition is for use in a method of treatment of depression/major depressive disorder.
  • the composition is for use in a method of treatment of depression/major depressive disorder.
  • the composition is for use in a method of treatment of depression/major depressive disorder.
  • the composition is for use in a method of treatment of depression/major depressive disorder.
  • an intranasal dry powder pharmaceutical composition comprising 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT, for use in a method of treatment.
  • the composition is for use in a method of treatment of depression/major depressive disorder.
  • the composition is for use in a method of treatment of treatment-resistant depression/major depressive disorder. In an embodiment, the composition is for use in a method of treatment of substance misuse disorder. In an embodiment, the composition is for use in a method of treatment of alcohol use disorder.
  • a method of treatment wherein a mystical experience is produced in a patient in need thereof by administration of a 10 mg dosage amount of 5-MeO-DMT.
  • 5- MeO-DMT is provided for use in the treatment of a mental health condition/disease, wherein 10 mg of 5-MeO- DMT is administered in a single intranasal dose.
  • the mental health condition/disease is depression/major depressive disorder.
  • the composition comprises a salt of 5-MeO-DMT. In an embodiment, the composition comprises a crystalline salt of 5-MeO-DMT. In an embodiment, there is provided a crystalline form of 5-MeO- DMT hydrobromide. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrobromide, characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT phosphate characterised by one or more peaks in an XRPD diffractogram at 12.9, 20.4 and 23.1°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT fumarate characterised by one or more peaks in an XRPD diffractogram at 13.0, 16.3 and 22.1°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT oxalate characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT tartrate characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.6, and 2O.7°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT benzenesulfonate characterised by one or more peaks in an XRPD diffractogram at 9.5, 21.2, and 23.6°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT tosylate characterised by one or more peaks in an XRPD diffractogram at 19.3, 23.6 and 24.1 °20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT glycolate characterised by one or more peaks in an XRPD diffractogram at 20.2, 21.1 and 23.4°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT ketoglutarate characterised by one or more peaks in an XRPD diffractogram at 14.4, 18.2 and 2O.9°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5- MeO-DMT malate characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.7 and 18.9°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT saccharinate characterised by one or more peaks in an XRPD diffractogram at 8.7, 15.2 and 2O.9°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT hydrochloride characterised by one or more peaks in an XRPD diffractogram at 9.2° ⁇ 0.1°, 12.2° ⁇ 0.1°, 14.1° ⁇ 0.1°, 15.0° ⁇ 0.1°, 18.5° ⁇ 0.1°, and 19.5° ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • a crystalline form of 5-MeO-DMT benzoate characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20 as measured using an x-ray wavelength of 1.5406 A.
  • the composition is formulated as a powder which is suitable for administration by inhalation/insufflation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurised metered dose inhaler.
  • the powder comprises particles, the particles having a median diameter of less than 2000 pm, 1000 pm, 500 pm, 250 pm, 100 pm, 50 pm, or 1 pm.
  • the powder comprises particles, the particles having a median diameter of greater than 500 pm, 250 pm, 100 pm, 50 pm, 1 pm or 0.5 pm.
  • the nature of the powder can be adjusted to suit needs. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.
  • the 5-MeO-DMT salt is amorphous or crystalline. In an embodiment, the 5-MeO-DMT salt is in a polymorphic crystalline form.
  • the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount of 5-MeO-DMT corresponds to 117 mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance).
  • the greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g/mol for the free base as compared to 254.8 g/mol for the salt).
  • the deuterated or triturated version of 5-MeO-DMT also considered within the scope of the invention, a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
  • X mg of a 5-MeO-DMT salt refers to the dosage amount of said salt which equates to X mg of the 5-MeO-DMT freebase. Therefore, a pharmaceutical composition comprising 12 mg 5-MeO-DMT benzoate refers to a pharmaceutical composition comprising 18.7 mg 5-MeO-DMT benzoate which equates to 12 mg of 5-MeO-DMT freebase. In an embodiment, there is provided the use of about 15.59 mg 5-MeO-DMT benzoate, or a pharmaceutical composition, thereof.
  • compositions comprise one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
  • the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-
  • TMC N,N,N-trimethyl chitosan
  • TMC N,N,N-trimethyl chitosan
  • n-butyl-(QuatButyl) and n-hexyl (QuatHexyl
  • composition disclosed herein is for use as a medicament. In an embodiment the composition disclosed herein is for use in a method of treatment of a human or animal patient/subject by therapy. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.05 mg to 100 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of
  • the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5 mg to 25 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5 mg to 10 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 10 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 8 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 3 mg to 15 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.005 mg to 100 mg.
  • the composition comprises a dosage amount of 5-MeO- DMT in the range of 0.001 mg to 100 mg. In an embodiment the composition comprises a dosage amount of 5- MeO-DMT in the range of 0.0005 mg to 100 mg.
  • the level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.
  • a pharmaceutical composition comprising 10-12 mg of 5-MeO-DMT.
  • a pharmaceutical composition capable of producing a complete mystical experience wherein said composition comprises 10-12 mg 5-MeO-DMT.
  • the 5-MeO-DMT is present as the benzoate salt.
  • the composition is for intranasal delivery.
  • the composition is a dry powder.
  • a pharmaceutical composition comprising: i) particles of 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or pharmaceutically acceptable salts or derivatives thereof; and ii) a pH-sensitive polymer, wherein the particles are nanoparticles or microparticles; and wherein the particles are encapsulated in the pH-sensitive polymer.
  • a pharmaceutically acceptable composition comprising 5-MeO-DMT, wherein administration of said composition to a patient/subject produces in said patient/subject a blood plasma Cmax (ng/mL) of about 4-39, of about 5-35 or of about 6-29.
  • administration of said composition to a patient/subject produces in said patient/subject a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or of about 0.1- 0.25. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or of about 0.25-0.44. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a AUCiast (h*ng/mL) of about 1.0-22, of about 1.2-20 or of about 1.5-18.5.
  • administration of said composition to a patient/subject produces in said patient/subject a AUCmt (h*ng/mL) of about 1.5-27, of about 1.7-25 or of about 1.9-24.
  • Cmax may refer to the maximum concentration (e.g., maximum blood plasma concentration) of a compound, as the result of the administration of a composition comprising the compound.
  • Tmax may refer to the time required for the concentration of the compound to reach Cmax, after the administration of the composition
  • ti/2 e.g., half-life
  • halve e.g., reach half of the Cmax
  • AUCiast may refer to an area under a curve representing plasma concentration as a function of time. The area may include the last measured plasma concentration. AUCmt may refer to an area under a curve representing plasma concentration as a function of time, extrapolated to where time approaches infinity.
  • the composition comprises 5-MeO-DMT benzoate. In an embodiment, the 5-MeO-DMT is present as the benzoate salt. In an embodiment, the 5-MeO-DMT composition is a composition for intranasal administration. In an embodiment, the 5-MeO-DMT composition is an intranasal composition. In an embodiment, the composition comprises 1-12 mg of 5-MeO-DMT benzoate.
  • the composition comprises 1 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-8, of about 5-7 or of about 6; a Tmax (h) of about 0.05-0.2, of about 0.06-0.15 or of about 0.1; a ti/2 (h) of about 0.1-0.4, of about 0.2-0.3 or of about 0.25; a AUCiast (h*ng/mL) of about 1.0-1.8, of about 1.2-1.6 or of about 1.5; or a AUCmt (h*ng/mL) of about 1.5-2.3, of about 1.7-2.0 or of about 1.9.
  • a Cmax ng/mL
  • Tmax of about 0.05-0.2, of about 0.06-0.15 or of about 0.1
  • a ti/2 (h) of about 0.1-0.4 of about 0.2-0.3 or of about 0.
  • the composition comprises 4 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or of about 9; a Tmax (h) of about 0.03-0.2, of about 0.09-0.16 or of about 0.12; a ti/2 (h) of about 0.27-0.53, of about 0.30-0.45 or of about 0.37; a AUCiast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or of about 4.5; or a AUCint (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or of about 5.
  • the composition comprises 8 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or of about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or of about 0.17; a ti/2 (h) of about 0.21-0.37, of about 0.25-0.35 or of about 0.30; a AUCiast (h*ng/mL) of about 9.25- 17.23, of about 11-15 or of about 13.1; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about
  • the composition comprises 10 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or of about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or of about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or of about 0.38; a AUCiast (h*ng/mL) of about 9.37- 20.41, of about 13-18 or of about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about
  • the composition comprises 12 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 20.9-39, of about 25-35 or of about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or of about 0.25; a ti/2 (h) of about 0.28-0.55, of about 0.40-0.50 or of about 0.44; a AUCiast (h*ng/mL) of about 14.45-22, of about 16-20 or of about 18.5; or a AUCmt (h*ng/mL) of about 19.10-27, of about 22-25 or of about
  • the composition is a dry powder composition.
  • the composition comprises one or more pharmaceutically acceptable carriers or excipients.
  • the composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC).
  • the composition comprises one or more of chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean levodo
  • the 5-MeO-DMT is present as crystalline 5-MeO-DMT benzoate as characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20.
  • a pharmaceutically acceptable dry powder intranasal composition comprising 1-12 mg of 5-MeO-DMT benzoate and HPMC.
  • intranasal administration of the composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4- 39, of about 5-35 or of about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or of about 0.1-0.25; a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or of about 0.25-0.44; a AUCiast (h*ng/mL) of about 1.0-22, of about 1.2-20 or of about 1.5-18.5; or a AUCmt (h*ng/mL) of about 1.5-27, of about 1.7-25 or of about 1.9-23.9.
  • the use of the composition for the treatment or prevention of a disease or condition is depression/major depressive disorder or treatment-resistant depression/major depressive disorder.
  • the formulation of 5-MeO-DMT benzoate is provided.
  • a pharmaceutically acceptable composition comprising 5-MeO-DMT (hereafter '5-MeO-DMT composition') comprising 1 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-8, of about 5-7 or about 6; a Tmax (h) of about 0.05-0.2, of about 0.06-0.15 or about 0.1; a ti/2 (h) of about 0.1-0.4, of about 0.2-0.3 or about 0.25; a AUCiast (h*ng/mL) of about 1.0-1.8, of about 1.2-1.6 or about 1.5; or a AUCint (h*ng/mL) of about 1.5-2.3, of about 1.7-2.0 or about 1.9.
  • a Cmax ng/mL
  • Tmax of about 0.05-0.2, of about 0.06-0.15 or about 0.1
  • a 5-MeO-DMT composition comprising 2.5 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-12, of about 6-10 or about 8; a Tmax (h) of about 0.1-0.3, of about 0.15-0.25 or about 0.18; a ti/2 (h) of about 0.1-0.4, of about 0.20-0.35 or about 0.32; a AUCiast (h*ng/mL) of about 2.3-6.5, of about 3.0- 4.4 or about 3.8; or a AUCmt (h*ng/mL) of about 2.9-6.8, of about 3.5-5.5 or about 4.4.
  • a 5-MeO-DMT composition comprising 4 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or about 9; a Tmax (h) of about 0.03-0.2, of about 0.09-0.16 or about 0.12; a ti/2 (h) of about 0.27-0.53, of about 0.30-0.45 or about 0.37; a AUCiast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or about 4.5; or a AUCmt (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or about 5.
  • a 5-MeO-DMT composition comprising 6 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 7.7-19.3, of about 12.5-17 or about 15; a Tmax (h) of about 0.07-0.27, of about 0.1-0.2 or about 0.15; a ti/2 (h) of about 0.32-0.42, of about 0.35-0.4 or about 0.37; a AUCiast (h*ng/mL) of about 4.6-12, of about 6-10 or about 8; or a AUCmt (h*ng/mL) of about 8.6-11, of about 9-10.5 or about 9.8.
  • a 5-MeO-DMT composition comprising 8 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or about 0.17; a ti/2 (h) of about 0.21-0.37, of about 0.25-0.35 or about 0.30; a AUCiast (h*ng/mL) of about 9.25-17.23, of about 11-15 or about 13.1; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • a 5-MeO-DMT composition comprising 10 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCiast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • a 5-MeO-DMT composition comprising 12 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 20.9-38.6, of about 25-35 or about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or about 0.25; a ti/2 (h) of about 0.28-0.55, of about 0.40-0.50 or about 0.44; a AUCiast (h*ng/mL) of about 14.45-22.23, of about 16-20 or about 18.5; or a AUCmt (h*ng/mL) of about 19.10-27.15, of about 22- 25 or about 23.9.
  • a 5-MeO-DMT composition comprising 1-12 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-38.6, of about 5-35 or about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or about 0.1-0.25; a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or about 0.25-0.44; a AUCiast (h*ng/mL) of about 1.0-22.23, of about 1.2-20 or about 1.5-18.5; or a AUCmt (h*ng/mL) of about 1.5-27.15, of about 1.7-25 or about 1.9-23.9.
  • the composition produces in a subject, per each 10 mg of 5-MeO-DMT present in the composition, one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCiast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
  • the 5-MeO-DMT composition comprises a mucoadhesive.
  • the 5-MeO- DMT composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC).
  • PVM/MA methyl vinyl ether and maleic anhydride
  • HPC hydroxypropyl cellulose
  • Na-CMC sodium carboxymethylcellulose
  • the 5-MeO-DMT composition comprises HPMC.
  • the 5-MeO-DMT composition comprises crystalline 5-MeO-DMT benzoate, as described subsequently or previously.
  • composition disclosed herein is for use as a medicament.
  • a composition as described previously or subsequently for the treatment of a disease or condition there is provided use of a composition as described previously or subsequently for the treatment of a disease or condition.
  • the disease or condition is depression/major depressive disorder. In an embodiment, the disease or condition is treatment-resistant depression/major depressive disorder. In an embodiment, the disease or condition is: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and shortlasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from antiinflammatory treatment, depression/major depressive disorder, treatment resistant depression/major depressive disorder, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA
  • the method of use is a method of treatment.
  • the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression/major depressive disorder and anxiety.
  • the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.
  • the further active agent is a psychedelic compound, optionally a tryptamine.
  • the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof.
  • the further active agent is an antidepressant compound.
  • the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
  • the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Ami
  • the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline).
  • one or more disorders or conditions in the patient have previously failed to be treated with one or more of the above treatments.
  • a method optionally a rapid and durable method, of improving one or more of: sexual functioning, anxiety, anhedonia, cognition and/or overall quality of life, in a patient in need thereof.
  • the improvement is assessed by one or more of: the Arizona Sexual Experiences Scale, the 7-item Generalised Anxiety Disorder Assessment (GAD-7), difference in self-reported anhedonia symptoms, assessed by Snaith-Hamilton Pleasure Scale (SHAPS), the Cognitive Test Battery, Patient Global Impression of Change and/or improvement in self-reported quality of life, assessed by EuroQoL- 5 Dimension-5 Level (EQ-5D-5L).
  • a method optionally a rapid and durable method, of treating a patient in need thereof, wherein the patient is aged 18 to 75 years old.
  • the patient has at least moderate major depressive disorder (MDD), (single or recurrent episode as informed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria; if single episode, duration of >3 months and ⁇ 2 years) based on medical records, clinical assessment, and documented completion of the version 7.0.2 Mini International Neuropsychiatric Interview (MINI).
  • MDD major depressive disorder
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria; if single episode, duration of >3 months and ⁇ 2 years
  • MINI Mini International Neuropsychiatric Interview
  • the patient is diagnosed with TRD defined as failure to respond to an adequate dose and duration of at least 2 pharmacological treatments, in the current episode, based on the MGH ATRQ assessment.
  • augmentation with an add-on treatment counts as a second treatment.
  • the patient has not failed more than 5 prior pharmacological treatments in the current episode.
  • psychotherapy is not counted towards treatment failure.
  • the patient has a Hamilton Depression Rating Scale (HDRS) (17 item) score >19 at baseline/prior to treatment.
  • the patient has a CGI-S >4 at baseline/prior to treatment.
  • the patient does not have a current or past history of schizophrenia, post- traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder.
  • the patient does not have a current or past history of schizophrenia, post-traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder as assessed by medical history and a structured clinical interview (MINI).
  • the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, - obsessive compulsive).
  • the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, -obsessive compulsive) assessed via McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), MINI, and clinical judgement.
  • the patient does not have a first-degree family history of schizophrenia, bipolar disorder, delusional disorder, or schizoaffective disorder.
  • the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine).
  • the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine) according to DSM-5 and assessed by the MINI.
  • the patient has not at any time been unresponsive to ketamine or esketamine.
  • the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT).
  • ECT electroconvulsive therapy
  • the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT) defined as at least 7 treatments with unilateral/bilateral ECT, or has received vagal nerve stimulation or has received deep brain stimulation.
  • the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment.
  • the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment, based on the C-SSRS, corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or any suicidal behavior prior to treatment.
  • the patient has not attempted suicide and/or any other self-injurious behaviour within 12 months prior to treatment.
  • the patient does not have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of transient and marked increases in blood pressure and heart rate.
  • the patient does not have atherosclerotic cardiovascular disease, obstructive coronary artery disease, myocardial infarction, hospitalisation for unstable angina, stroke, hospitalisation for transient ischemic attacks, known aortic or cerebral aneurysm or revascularization procedure within 12 months prior to treatment.
  • the patient does not have significant valvular heart disease, history of hospitalisation for heart failure and/or history of hospitalisation for atrial or ventricular arrhythmias.
  • the patient does not have a history of uncontrolled hypertension despite antihypertensive therapy and/or any past history of a hospital admission for hypertension.
  • the patient does not have controlled hypertension on antihypertensive therapy with repeated clinic seated or semi-recumbent systolic blood pressure >130 mmHg or diastolic blood pressure > 80 mmHg. In an embodiment, the patient does not have repeated clinic seated or semi-recumbent systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. In an embodiment, the patient does not have one or more of hypo/hyperthyroidism with abnormal thyroid stimulating hormone values, uncontrolled or insulin dependent diabetes with HbAlc >8, renal failure with Creatinine Clearance ⁇ 45 mL/min.
  • the patient does not have any seizure disorder and/or any seizure within 2 years of treatment. In an embodiment, the patient does not have any clinically significant results on ECG or a Q.T interval corrected using Fridericia's formula (QTcF) >450 msec for males or >470 msec for females prior to treatment. In an embodiment, the patient does not have any history of intolerance to 5-MeO-DMT or related compounds. In an embodiment, the patient does not have any nasal obstruction, blockage, or symptoms of congestion at the time of treatment. In an embodiment, the patient is not a female patient who is pregnant, lactating, or of childbearing potential who is not willing or able to use adequate forms of contraception during treatment.
  • QTcF Fridericia's formula
  • the patient is not a male patient who is not willing or able to use adequate forms of contraception during treatment.
  • the patient does not have a personal or family history of malignant hyperthermia.
  • the patient has discontinued one or more of the following at least 5 half-lives prior to treatment: Medications that antagonise the serotonin 2A receptor, Medications with serotonergic activity (e.g., SSRIs, SNRIs, efavirenz, lithium), Tramadol, Opioids, Antiviral Medications, St. John's Wort, Medications that inhibit UGT1A9 or UGT1A10 enzymes, Monoamine Oxidase Inhibitors (MAOIs) and/or Medications that inhibit aldehyde or alcohol dehydrogenase.
  • Medications that antagonise the serotonin 2A receptor Medications with serotonergic activity (e.g., SSRIs, SNRIs, efavirenz, lithium), Tramado
  • the patient does not inhale during the administration.
  • 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the 5-MeO-DMT of the present pharmaceutical compositions reaches the turbinates.
  • the plasma exposure is between 1-46 ng/mL, between 5-40 ng/mL, between 10-35 ng/mL, or between 25-32 ng/mL.
  • the plasma exposure is at least 25 ng/mL.
  • the licensed physician overseeing the administration to the patient uses the plasma exposure to adjust dosing.
  • the subsequent dose received by a patient is 12 mg of 5-MeO-DMT if the plasma exposure was less than 25 ng/mL at the 10 mg dose.
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: c) measuring the patient/subject's blood pressure; d) intranasally administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) intranasally administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
  • the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
  • the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
  • Figure 1 is a schematic of a one-step synthesis of 5-MeO-DMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal.
  • Figure 2 is a schematic of a three-step synthesis of 5-MeO-DMT.
  • the first step involves the reaction of 5- methoxyindole with oxalyl chloride.
  • the resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride.
  • Figure 3 is a schematic route for the formation of a powder form of 5-MeO-DMT using a spray drying process.
  • FIG. 4 is an overview of the slug mucosal irritation (SMI) test.
  • A First 15 minute contact period between slug and test item.
  • B Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • C Second 15 minute contact period between slug and test item.
  • D Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour.
  • E Third 15 minute contact period between slug and test item.
  • Figure 5 is a graph showing that the benzoate salt of 5-MeO-DMT has higher permeation compared with the hydrochloride salt, as per the experiment detailed in Example 7.
  • Figure 6 is an XRPD diffractogram of 5-MeO-DMT benzoate prior to particle size reduction.
  • Figure 7 is an XRPD diffractogram of 5-MeO-DMT benzoate following particle size reduction.
  • Figure 8 is an XRPD diffractogram of Figures 6 and 7 overlaid on one another.
  • Figure 9 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma linear concentration-time plot.
  • Figure 10 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma log concentration-time plot.
  • Figure 11 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma linear concentration-time plot.
  • Figure 12 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma log concentration-time plot.
  • Figure 13 shows Forced Swim Test results, Time Immobile, for 5-MeO-DMT benzoate at 0.5, 1.0, or 1.5 mg/kg doses, vehicle and imipramine.
  • Figure 14 shows Forced Swim Test results, Latency to Immobility, for 5-MeO-DMT benzoate at 0.5, 1.0, or 1.5 mg/kg doses, vehicle and imipramine.
  • Figure 15 shows a Dynamic Vapour Sorption (DVS) isotherm for 5-MeO-DMT benzoate.
  • Figure 16 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/20/126-FP).
  • Figure 17 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/45/006-FP).
  • Figure 18 shows mean ( ⁇ SD) plasma concentration-time curves of 5-MeO-DMT.
  • Figure 19 shows mean ( ⁇ SEM) subjective intensity ratings after single closes of placebo or 8 mg, 10 mg and 12 mg BPL-003 (SEM, Standard error of the mean).
  • Figure 20 shows mean ( ⁇ SEM) MEQ-30 scores after single doses of placebo or 8 mg, 10 mg and 12 mg BPL-003 (MEQ-30, Mystical Experience Questionnaire; SEM, Standard error of the mean. Dotted line indicates a meaningful threshold of >3).
  • Figure 21 shows the mean change from baseline in MADRS total score over time (per protocol population) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).
  • Figure 22 shows the particle size distribution of a 5-MeO-DMT SDD as Bulk Material (Red) and ExDevice (Green).
  • Figure 23 shows the nasal deposition profile for a 5-MeO-DMT SDD delivered via an active delivery nasal delivery device.
  • Figure 24 shows the nasal deposition profile for a 5-MeO-DMT SDD delivered via a passive delivery nasal delivery device.
  • Step 1 Add methyl tert-butyl ether (MTBE) (15 vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5- methoxyindole (1.0 eq) in THF (1 vol) to the reaction vessel, maintaining the temperature at no more than - 20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.
  • MTBE methyl tert-butyl ether
  • Step 2 Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2 vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5 vol) over no less than 1 hour while stirring at 0-5°C for no less than 1 hour.
  • Step 3 Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add IM Li Al H4 in THF (1.5 eq) in THF (8 vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.
  • Isopropyl acetate (IPAc) (15.8 vol) was added to the solids obtained above and the temperature was raised to about 73°C until the solid dissolved. The solution was allowed to cool to 0-5°C over 2 hours and this temperature was maintained for 1 hour with stirring. The resultant benzoate salt was filtered and vacuum dried at room temperature. Yield 68%.
  • the benzoate salt of 5-MeO-DMT has improved characteristics over the common hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability.
  • 5-MeO-DMT benzoate is a white to off white solid powder, soluble in water at >50 mg/ml with a pH of 7-8 at 50 mg/ml and a pKa of 9.71.
  • Spray drying a solution containing the substance(s) of interest (e.g. 5-MeO-DMT, or the salt, thereof inclusive of any excipients).
  • This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, and four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
  • a ProCepT spray dryer is used. In an embodiment, a ProCepT spray dryer with an ultrasonic nozzle is used.
  • the Slug Mucosal Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients.
  • the test utilises the terrestrial slug Arion lusitanicus.
  • the body wall of the slugs is a mucosal surface composed of different layers.
  • the outer single-layered columnar epithelium that contains cells with cilia, cells with microvilli and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface.
  • the test was validated using reference chemicals for eye irritation (ECETOC eye reference data bank).
  • ECETOC eye reference data bank reference chemicals for eye irritation
  • These studies have shown that the SMI assay can be used as an alternative to the in vivo eye irritation tests.
  • a multi-center prevalidation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative to predict the eye irritation potency of chemicals.
  • the purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below. Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).
  • Test System Slugs (Arion lusitanicus); 3 slugs per treatment group.
  • the parental slugs of Arion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatised room (18-20°C).
  • the slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.
  • Test Design A single study was performed. Treatment time was 15 minutes three times on the same day.
  • Slugs weighing between 3 and 6 g were isolated from the cultures two days before the start of an experiment. The body wall was inspected carefully for evidence of macroscopic injuries. Only slugs with clear tubercles and with a foot surface that shows no evidence of injuries were used for testing purposes. The slugs were placed in a plastic box lined with paper towel moistened with PBS and were kept at 18 - 20°C. Daily the body wall of the slugs was wetted with 300 pl PBS using a micropipette.
  • the stinging, itching or burning potency of the test item(s), was evaluated by placing 3 slugs per treatment group 3 times a day on 100 pL of test item in a Petri dish for 15 ⁇ 1 min. After each 15-min contact period the slugs were transferred for 60 min into a fresh Petri dish on paper towel moistened with 1 mL PBS to prevent desiccation. An overview of this can be seen in Figure 4.
  • the amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period.
  • the mucus production was expressed as % of the body weight.
  • the slugs were weighed before and after each 15-min contact.
  • test results were based upon the total amount of mucus production during 3 repeated contact periods with the test item.
  • the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period. The total mucus was calculated for each slug and then the mean per treatment group was calculated. The classification prediction model shown in the Table below was used to classify the compounds. Cut-off values for classification - potency for nasal mucosal discomfort
  • the negative control should be classified as causing no stinging, itching and burning (Total mucus production ⁇ 5.5%) the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production > 17.5%)
  • NC negative control
  • PC positive control
  • BAC benzalkonium chloride
  • the average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in the Table above. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce reactions in the slugs (mean total MP ⁇ 5.5%).
  • the positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP > 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions. The acceptance criteria were met and the experiment was considered valid.
  • test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) ⁇ sodium citrate (10% w/v) ⁇ disodium fumarate (10% w/v) ⁇ sodium phosphate (10% w/v).
  • NC negative control
  • PC positive control
  • BAC benzalkonium chloride
  • 5-MeO-DMT as a freebase compound is known to be highly irritating to the mucosal lining; therefore, it is commonly prepared as a salt for insufflation.
  • the hydrochloride (HCI) salt of 5-MeO-DMT is most commonly used due to ease of crystallisation. However, it is known that the HCI salt of 5-MeO-DMT is still quite irritating to the mucosal lining.
  • the 5-MeO-DMT benzoate produced 'mild' irritation compared to the 5-MeO-DMT HCI which scored as 'moderate' on testing.
  • less 5-MeO-DMT benzoate salt may be needed by inhalation to provide the same benefit as the HCI salt and the benzoate salt is less irritating, and so provides a synergistic benefit. Smaller amounts of compound also make inhalation easier to accomplish.
  • the XRPD pattern of 5-MeO-DMT benzoate salt was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material.
  • XRPD patterns of the benzoate salt prior to and following particle size reduction can be seen in Figures 6 and 7 respectively.
  • the XRPD patterns of the benzoate salt prior to and following particle size reduction overlaid on one another can be seen in Figure 8.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.1°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.1°20.
  • crystalline 5-MeO- DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.3°20.
  • crystalline 5-MeO- DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.1°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0,
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20 ⁇ O.3°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5,
  • crystalline 5-MeO- DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.2°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.3°20.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20 ⁇ O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
  • crystalline 5-MeO-DMT benzoate characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 6, 7 or 8.
  • Example 9 Spray drying parameters
  • composition of 5-MeO-DMT benzoate which is a dry powder.
  • this composition is presented in a single dose nasal applicator.
  • 5-MeO-DMT benzoate and HMPC input solutions are made up using sterile water and left to stir until fully dissolved.
  • the spray drying parameters used to produce a dry powder of 5-MeO-DMT benzoate and HPMC are selected from those set out in the Table below:
  • Example 10 A double-blind, randomised, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate (BPL-003) in healthy subjects
  • BPL-003 intranasal 5- MeO-DMT benzoate
  • the mean Cmax was 29 ng/mL for the 12 mg dosage.
  • the mean Tmax was 9.5 minutes whilst the mean half-life (ti/2) was 21 minutes.
  • Bufotenin the O-demethylated metabolite of 5-MeO-DMT, was only detected at very low levels at the 6 mg dose level after the 16 minutes time point.
  • Participants were screened within 56 days before their dose of the trial drug. All participants had 2 psychedelic preparatory visits (one online and one in-person) with a trained psychedelic monitor before being dosed (Day - 7 and Day -3) to prepare the participant for trial drug administration, provide information about 5-MeO-DMT and to establish rapport between the participant and the monitor.
  • Participants were at site from the day before dosing until the morning after dosing.
  • An indwelling intravenous catheter was inserted before trial drug administration, for the collection of PK samples.
  • a nurse and one psychedelic monitor were present in the room, to provide non-directive support and reassurance for participants.
  • dosing took place in a calm, decorated room and a prepared playlist with relaxing music was playing.
  • participants were instructed to do breathing exercises before dosing.
  • participant's psychedelic experience For up to 90 minutes post-dose, participants and the psychedelic monitor rated overall subjective drug intensity. After dosing, participants had a one-to-one guided interview with an independent researcher to discuss their psychedelic experience. Psychometric scales were administered to provide quantitative measures of the participant's psychedelic experience after the interview. All participants had their individual psychological wellbeing, including measures of suicidality, assessed by the trial psychiatrist before discharge from the ward.
  • Participants had an integration visit 2 days after dosing to discuss their experience on a one-to-one basis with the psychedelic monitor.
  • the session could either be done on the ward or conducted via video call, if deemed acceptable by the psychedelic monitor.
  • Trial Drug BPL-003 or matching placebo were administered as a single intranasal spray into 1 nostril by a trained member of the research team (usually a registered nurse), in the presence of a psychedelic monitor, using the Aptar Unidose dry powder delivery device.
  • TEAEs treatment-emergent adverse events
  • CCGs electrocardiograms
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • HPPD Hallucinogen Persisting Perception Disorder
  • Post Traumatic Stress Disorder can be caused by a traumatic experience and was assessed at follow-up via a checklist for DSM-5 (PCL-5) scores.
  • the PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. Subjects rate each item from 0 (not at all) to 4 (extremely) to indicate the degree to which they have been affected by that symptom over the past month.
  • Plasma and urine 5-MeO-DMT and bufotenine concentrations were quantified in a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Blood samples were taken pre-dose (dosing day) and at 0.5, 2, 4, 6, 10, and 16 minutes, and 0.5, 1, 1.5, 4, and 24-hours post-dose. Urine samples were collected continuously from 0-6 hours post-dose.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Urine PK parameters included the amount of unchanged drug excreted in urine at time t (Aet), fraction of administered drug excreted unchanged in urine (fe ), and renal clearance of drug from plasma (CLR), as well as metabolite Aet and CLR.
  • SDI Subjective Drug Intensity
  • the intensity of BPL-003 subjective effects were rated by the participant and psychedelic monitor using the SDI, a Likert Scale of 0-10, where 0 was 'definitely no effect' and 10 was 'the strongest effect imaginable for 5- MeO-DMT'.
  • the assessment was performed every 2 minutes for up to 90 minutes post-dose, and if the trial participants were not responsive, the psychedelic monitor would assess the rating to be 10.
  • the MEQ-30 is a 30-item questionnaire to evaluate mystical experiences, with subdomains to measure mystical, positive mood, transcendence, and ineffability factors. Participants rated the degree to which they experienced each of the 30 phenomena using the following scale: 0 (none; not at all), 1 (so slight cannot decide), 2 (slight), 3 (moderate), 4 (strong [equivalent in degree to any other strong experience]) or 5 (extreme [more than any other time in my life and stronger than 4]). Means were calculated for each subdomain and a total overall score. The % of participants experiencing a "complete mystical experience" in each dose cohort was assessed by calculating the number of participants that scored 3 and above (>60% of the attainable value) in all of the four subdomains of the MEQ-30.
  • CEQ Challenging Experience Questionnaire
  • AA African American
  • BMI body mass index
  • N number of participants
  • SD standard deviation.
  • composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved side effect profile.
  • pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved tolerability profile.
  • Post-dose heart rate above the reference range were recorded in 1 (7.7%) participants after placebo and 12 (38.7%) participants after BPL-OO3.
  • Post-dose diastolic blood pressures above the reference range were recorded in 1 (7.7%) participants after placebo (93 mmHg) and 15 (62.5%) participants after BPL-OO3 (ranging 91-109 mmHg).
  • Post-dose systolic blood pressures above the reference range were recorded in 4 (30.8%) participants after placebo (range 146-155 mmHg) and 14 (45.2%) participants after BPL-003 (range 141-181 mmHg).
  • Systolic blood pressure over time and the peak post-dose systolic blood pressure can be seen in the Tables below.
  • BPL-OO3 was rapidly absorbed, with a median Tmax of 4 to 15 minutes post-dose across all dose levels. Elimination of 5-MeO-DMT was rapid across all dose levels. Arithmetic mean t% ranged from 15 to 27 minutes across dose levels. Plasma 5-MeO-DMT concentrations were below the limit of detection by 4 hours after administration in all subjects. Variability between participants was generally low to moderate, where all participants in a group had quantifiable 5-MeO-DMT plasma concentrations.
  • Urinary PK parameters for 5-MeO-DMT are summarised in the Table above. Urine concentrations of 5-MeO- DMT were BLQ in most participants after 1 mg BPL-003, and in a few participants after higher doses of BPL- 003.
  • Urine excretion of 5-MeO-DMT appeared negligible.
  • the arithmetic mean fraction of 5-MeO-DMT excreted unchanged (fe- F) at 6 hours post-dose ranged between 0.06% to 0.38% across dose levels. Due to the low levels of 5-MeO-DMT detected in urine, PK parameters derived were highly variable.
  • Urine levels of bufotenine were all BLQ ( ⁇ 0.5 ng/mL).
  • composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved side effect profile and produces a complete mystical experience.
  • pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved tolerability profile and produces a complete mystical experience.
  • 5-MeO-DMT has a unique profile that, in addition to the activation of the 5-HT2A receptor, also shows a preferential receptor affinity to the 5-HT1A receptor.
  • One of the objectives of this study was to identify and explore a well-tolerated dose of BPL-003 that would reliably elicit profound mystical experiences in most trial participants, to evaluate whether progression into patient studies was appropriate.
  • a dose range of 10 to 12 mg was found to meet this requirement, with 60% of participants experiencing a complete mystical experience and/or ego dissolution events. The elicitation of full mystical experiences is thought to be an encouraging indicator for future therapeutic efficacy.
  • Psychedelic effects increased with BPL-003 dose, with a rapid onset of profound psychedelic effects that were short (45-90min) in duration.
  • the results of this single ascending dose study indicates that doses between 8-12 mg of BPL-003 are suitable for further pharmaceutical development in neuropsychiatric conditions with high unmet medical need, in particular the 10 mg dose which exhibited a particularly desirable side effect profile.
  • Example 11 A double-blind, randomised, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT HCI (BPL-002) in healthy subjects
  • BPL-002 A single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5- MeO-DMT HCI (BPL-002) was performed.
  • BPL-002 comprises 5-MeO-DMT HCI, HPMC, water for injection (WFI) and a sodium hydroxide solution to adjust pH.
  • An initial stock solution of 0.5% w/w HPMC was prepared using sterile water for injection which was further diluted with sterile water for injection to approximately 90% of the final weight required.
  • the required amount of drug substance (70 mg/ml or 140 mg/ml Freebase) was then dissolved in an aliquot of the 0.5% w/w HPMC stock solution with stirring and the pH of the active stock solution was then adjusted to 6.00 +/- 0.25 by adding sodium hydroxide (0.1 M solution). The IPC measurement was taken to ensure the pH is adjusted within the accepted range before making up to the final weight with sterile water for injection The concentration of the HPMC in the final solution was 0.1% w/w.
  • Placebo solutions of 0.1% w/w HPMC were made up by dissolving the required amount of HPMC in sterile water for injection (approximately 90% of final weight) and adjusted for pH 5.75 +/- 0.25 if necessary by the addition of sodium hydroxide solution (0.05 M). The in process check measurement was taken to ensure the pH is adjusted within the accepted range before making up to the final weight with sterile water for injection. The concentration of the HPMC in the final solution was 0.1% w/w.
  • mice Male CD-I mice from Charles River Laboratories (St. Constant, Quebec, Canada) served as test subjects in this study. Animals generally weighed 25-30 g at the time of testing.
  • mice received the appropriate dose of vehicle, test article, or positive control (treatments summarised above). Following the appropriate pretreatment time, animals were gently placed into tall glass cylinders filled with water (20-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture which is readily identifiable. The swim test involves scoring the duration of immobility. Over a 6-minute test session, the latency to first immobility is recorded (in seconds). The duration of immobility (in seconds) during the last 4 minutes of the test is also measured. Activity or inactivity from 0-2 minutes is not recorded.
  • Latency to immobility vehicle: 95.5 ⁇ 4.6 seconds - 5-MeO-DMT benzoate 121.8 ⁇ 22.0 seconds (0.5 mg/kg), 120.9 ⁇ 13.3 seconds (1.5 mg/kg), 85.0 ⁇ 9.5 seconds (5 mg/kg), imipramine 268.6 ⁇ 30.3 second, Figure 14).
  • Example 13 Dynamic Vapour Sorption (DVS) comparison of 5-MeO-DMT benzoate and HCI
  • the DVS profile for 5-MeO-DMT benzoate salt revealed reversible water uptake/loss over the humidity range and no hysteresis.
  • the water uptake/loss from 0 to 90% was gradual and amounted to a maximum of ca 0.20% and was a consequence of wetting of the solid.
  • the DVS isotherm can be seen in Figure 15.
  • the DVS isotherm of a 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 16) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23% w/w uptake is observed between 70-80% RH, whereas less than 0.3% w/w moisture uptake from 0-70% RH was observed. A further 20% w/w moisture uptake is observed up to and when held at 90% RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca. 6- 9% w/w above the minimum mass recorded at 0% RH, which indicates significant retention of moisture. Upon completion of the DVS cycle, the input material was noted to have been completely deliquesced.
  • a modified DVS isotherm of lot 20/45/006-FP (the same crystalline version) was undertaken to examine material behaviour from 60% RH and above.
  • DVS provides a versatile and sensitive technique for evaluating the stability of pharmaceutical formulations.
  • the DVS profiles show that the stability of the benzoate salt of 5-MeO-DMT is significantly higher than that of the hydrochloride salt and is therefore a more promising salt for development as a pharmaceutical composition.
  • the physical surroundings of the participant/patient/subject are of high importance in the character of many psychedelic experiences.
  • the space should be private, meaning that there should be no chance of intrusion by others. Ideally, sound from outside (e.g. the hallway, the street, etc.) will be minimal.
  • the dosing sessions should take place in rooms that feel like a living room or den rather than a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decor should be employed in creating a cosy and relaxing aesthetic. Artwork with any specific religious iconography, ideological connotation, or tendency to evoke negative emotions should be avoided.
  • the dosing room may also provide comfortable furniture for the participant and the therapists, who may sit on either side of the participant.
  • the room should shield the participant from sights and sounds of the world beyond the room, and the participant should not have any cause for concern of observation or interruption by anyone other than the therapists.
  • the space may also contain: The tools for safety procedures and medical devices necessary to respond in the unlikely event of a medical complication. The participant should be made aware of these procedures and the equipment, but as much as possible they should be hidden from view.
  • Audio and video-recording equipment If allowed in the study protocol the participant will have already consented to being recorded, and should be made aware of the equipment, but it should be placed to be as unobtrusive as possible. Participants may request the cessation of recording at any time.
  • the space may be large enough to accommodate chairs for two therapists, the stereo equipment and cabinet for storage of the participant's belongings and any extra supplies the therapists may need during the day.
  • the space may accommodate a bed or couch on which the participant can either sit up or lie down with a comfortable surroundings of pillows.
  • the space may be at least 100 2 feet or 10 2 metres so that participants do not feel cramped or too physically close to therapists. Participants should have room to explore a variety of positions including sitting on the floor or stretching their bodies without restriction. A bathroom should be either accessible directly from the session room or nearby.
  • 5-MeO-DMT sessions may use a pre-set playlist of nature sounds for creating a calm atmosphere. These nature sounds are considered to be a background element, helping drown out any noise from outside the room, and keep the participant focused on their experience. Participants are not instructed to listen to the sounds in any particular way, but may be asked to focus on it as a way of grounding their senses and relaxing before or after a session.
  • Medication discontinuation can be challenging for participants. Participants are to have discontinued all contraindicated medications and completed washout periods prior to Prep-1 with the therapist.
  • the study team members, including the therapist, may provide supportive check-in calls with the participant prior to this, as- needed during the washout period, but should not start Prep-1 until washout is complete and the participant confirms intention to continue with the therapy.
  • This treatment model includes three, 60-90 minute preparatory sessions with the therapist. These take place 7 days, 4 days, and 1 day before the 5-MeO-DMT session. Preparatory sessions are designed to take place via telemedicine, but can be in-person if possible.
  • the therapist will spend some of the preparation session time getting to know the participant.
  • the therapist may ask open-ended questions about:
  • the therapist should be listening for how the participant talks about themselves and their relationship to their depression/major depressive disorder, how they relate to the therapist and study environment, and stay attuned to establishing a sense of trust and rapport with the participant.
  • Clinical impressions of difficulty forming a trusting relationship with the therapist or any other clinical factors that could interfere with the participants' ability to engage in the treatment should be noted and discussed with the study team.
  • the therapist may learn more of the participant that could be reasons for study exclusion. Establishing the role of the therapist
  • the therapist should explain the therapeutic model used in this research study to the participant in the first preparation session.
  • the explanation should include:
  • Therapists may advise participants to take caution around posting about their experience on social media so as not to elicit excessive public commentary. Inadequate social support or use of social media in a way that may be disruptive to the therapeutic process may be discussed and resolved prior to 5-MeO-DMT administration.
  • the therapist should explain that on the day of the session that a member of the research team will enter the room briefly to administer the study drug.
  • the therapist should explain the participant positioning, e.g. they will be in a seated position on the bed or couch, that the research team member will insert the nasal spray device in one nostril, and that they will be asked to allow the therapist to assist them in lying down on the bed or couch immediately afterward.
  • Session procedures including boundaries, use of touch, safety, etc.
  • the therapist will explain the process of the session.
  • the session is contained by the timing of the dosing and the physical environment of the dosing room. It begins when the participant enters the room and engages with the therapist in the Session Opening. Session Opening is a formal moment in which the participant and therapist sit together in the room, all preparations having been made, and the playlist started.
  • the therapist may lead a breathing exercise of the participant's choice, if the participant is open to engaging in one, and ask the participant to reflect on the values they choose in the preparation session, or any other value or intention that is important to them.
  • a member of the research team will administer the nasal spray to the participant.
  • Trust and safety are not only communicated verbally, but also this may be nonverbally through how a therapist holds themselves in the presence of the participant. If a therapist is overly anxious, or fearful, this may be felt by the participant. It is important that the therapist is centred throughout the dosing session, particularly at times when a participant is expressing intense affect, unusual somatic expressions, or is asking for support.
  • Expectations can be defined as mental representations and beliefs of how something in the future will be. Sometimes expectations can be explicitly identified, and sometimes they are sub perceptual, taken for granted. Both kinds of expectations may be important to treatment.
  • the therapist should ask about explicit expectations and encourage the participant to acknowledge and set these aside such that they do not engage in comparing their experience to expectations. The therapist is also listening for sub perceptual expectations that may come into awareness through the therapy. Intentions are ways of relating to a behaviour or experience. In the 5-MeO- DMT treatment, it can be important for the therapist to elicit and understand the participant's intentions as these can vary greatly and may be taken for granted.
  • Therapists are to engage participants in a process of identifying and setting their intentions such that these are explicit and can be referenced later in integration. The purpose of the intention is for it to be identified and then let go of, with the knowledge that it can be part of the 5MED. Recurrence of acute effects
  • Therapeutic touch is touch that is intended to connect with, sooth, or otherwise communicate with the participant for therapeutic aims. It is always fully consensual, non-sexual, and the participant is encouraged to decline or cease therapeutic touch at any time.
  • Touch for safety reasons can include supporting a participant who is having trouble walking by offering an arm to hold, or blocking a patient back from leaving the room while under acute drug effects. This touch is agreed to in advance, is always non-sexual, and limited to specific safety concerns. Therapists should discuss both of these and establish boundaries with participants ahead of session.
  • Breathing practices include: Balancing Breath, Diaphragmatic Breath and Counted Breath.
  • the therapeutic protocol may use a customised Personal Values Card Sort to assist with the therapeutic focus on shift in sense of self. This is done by asking about how people relate to their chosen values before the session, and how they relate to them afterward, drawing attention to shifts, changes, and using these as a guide for the kind of changes the participant may desire to make. It is used as a way to elicit conversation about the participant's sense of self, beliefs about self, and changes in those senses/beliefs throughout the therapy. Therapists may engage participants in the card sort exercise in the third preparation session such that it occurs 1-2 days before the dosing session.
  • the session may be conducted by the therapist with an assistant therapist such that a second person is available to assist in case of any adverse event or physical complication in the participants safety.
  • the assistant who will be present for the session should be introduced in Prep Session 3 and included in a conversation such that they get to know the participant.
  • the therapist is present with the participant during the session — including pre-experience and post-experience times. This is the only session that must be conducted in-person.
  • the site and therapist should schedule about 3 hours for the session, including pre-experience and post-experience time. This does not include the time allotted to engage in baseline measures and enrolment confirmation prior to the session.
  • Local regulatory approvals will determine the minimum length of time a participant must be under observation following 5-MeO- DMT administration.
  • the Therapist, Assistant Therapist, and participant together in the room review all aspects of the room and safety procedures.
  • the therapist should introduce the participant to the team member administering the 5-MeO-DMT, to create a sense of familiarity.
  • Therapist introduces any Assistant Therapist and reviews safety features of the room and the equipment present.
  • Participant has time to ask any questions. The therapist will ask about any responses to the situation and how the participant is feeling about their session. The participant should not be rushed into the dosing by the therapists. The therapist will ask the participant to engage in a period of relaxation prior to dosing.
  • Participants will be asked to lie down, close their eyes, listen to the music, and, if willing, engage in at least one of the breathing exercises with the therapist's guidance.
  • the therapist will initiate the Session Opening. This practice helps contain and emphasise the specialness of the experience.
  • Therapists will contact the member of the research team to come to the room and administer the 5-MeO-DMT.
  • the team member should be aware not to disrupt the peaceful atmosphere of the room.
  • the participant should be in a seated position when insufflating the 5-MeO- DMT, as the effects may be felt quickly, the participant should be transitioned to a prone position and remain prone for the duration of the effect of the 5-MeO-DMT.
  • Experience (Around 60 Minutes)
  • This may be in the form of slow intentional inhaling and exhaling, or any other activity that helps the therapist ground and self-regulate. This is both for the therapist's benefit, as well as the participants', because a participant in a heightened non-ordinary state may be particularly attune to or pick up on their therapist's anxiety. It is optimal for the therapist to follow the participant's lead when choosing to verbally engage as the 5-MeO-DMT experience appears to be subsiding. Therapists may be eager to ask the participant about their experience, but it is preferable to wait until the participant is ready to share on their own. A participant may wish to remain in a period of silence, even after the apparent acute 5-MeO-DMT effect is gone. It is appropriate for therapists to greet participants with a friendly smile and welcoming nonverbal behaviour, and allow participants to take the lead on sharing when they feel ready.
  • BPL-003 was administered as a dry powder from a single-use FDA-approved intranasal delivery device.
  • the acute subjective experience in TRD patients was comparable to the findings of the Phase I clinical trial described in Example 10. Both groups of subjects were able to reach a score of equal to or greater than 3 out of 5 (as measured by the MEQ-30), which has previously been shown to correlate with short-term and longterm clinical symptom improvement.
  • PPP Per Protocol Population
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing apparent sadness in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing an inability to feel in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in in a patient in need thereof.
  • the patient is a depressed patient.
  • the patient is a treatment resistant depressed patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in a treatment resistant major depressive disorder patient.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder in a patient in need thereof, wherein the treatment resistant depression/major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and/or quetiapine.
  • the treatment resistant depression/major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and/or quetiapine, in the current episode.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the pharmaceutical composition is as described herein and wherein the method is a as described herein.
  • a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the depression/major depressive disorder or treatment resistant depression/major depressive disorder, is treated within 1 day of the single dose and wherein the response is sustained for 12 weeks or more.
  • the disease/condition to be treated has previously failed to be treated with one or more treatments.
  • the disease/condition has previously failed to be treated with one or more antidepressants, such as citalopram and/or sertraline.
  • the disease/condition has previously failed to be treated with one or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with two or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with three or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with four or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with five or more treatments, in the current episode of the disease/condition.
  • the one or more treatments were administered at an adequate dose for an adequate length of time.
  • the disease/condition has previously failed to be treated with one or more antidepressants, such as citalopram and/or sertraline.
  • the disease/condition has previously failed to be treated with one or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with two or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with three or more treatments, in the current episode of the disease/condition.
  • the disease/condition has previously failed to be treated with four or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with five or more treatments, in the current episode of the disease/condition. In an embodiment, the one or more treatments were administered at an adequate dose for an adequate length of time.
  • the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, not more often than once every 1, 2 or 3 months.
  • the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, once every three months.
  • a discharge questionnaire may be utilised by a professional.
  • this professional is a licensed medical professional.
  • a discharge questionnaire may include one or more of the following statements, which must be agreed with in order for a patient/subject to be assessed as ready for discharge: The patient/subject is fully responsive, aware of their surroundings, and reacts adequately; The acute psychedelic effects of the drug have completely subsided; The patient/subject is fully orientated (e.g. name, location, time); Blood pressure and pulse rate have returned to normal or only slightly elevated levels.
  • the breathing frequency and body temperature are normal;
  • the patient/subject has a stable gate and normal muscle coordination and can walk safely; Potential side effects are mild to moderate in intensity and do not need to be medically monitored;
  • the patient/subject has no acute suicidal ideations or suicidal intentions; Possible distress or feelings of being overwhelmed have sufficiently subsided to a degree that the patient/subject themselves feel safe to be discharged; In the opinion of the assessor, the patient/subject is safe to be discharged.
  • a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the patient/subject and wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration and wherein the clinical significant reduction is sustained for at least 12 weeks.
  • a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
  • a dry powder intranasal pharmaceutical composition comprising 5-MeO- DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
  • a pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
  • a dry powder intranasal pharmaceutical composition comprising 8 mg, 10 mg, 12 mg or 14 mg of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
  • a dry powder intranasal pharmaceutical composition comprising 8 mg, 10 mg, 12 mg or 14 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
  • the psychotherapy is provided prior to administration of the composition.
  • psychotherapy is provided during administration of the composition.
  • psychotherapy is provided after administration of the composition.
  • psychotherapy is provided prior to, during and after administration of the composition.
  • the psychological support is provided prior to administration of the composition.
  • the psychological support is provided during administration of the composition.
  • the psychological support is provided after administration of the composition.
  • the psychological support is provided prior to, during and after administration of the composition.
  • the method comprises the concurrent use of SSRIs.
  • a rational modification of such endpoint e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration may be applied.
  • Non-REM sleep may be divided into four stages (l-IV). These non-REM stages correspond to an increasing depth of sleep.
  • Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night.
  • non-REM sleep is deeper and occupies a disproportionately large amount of time, particularly within the first cycle of sleep.
  • non- REM sleep becomes shallow and more of each cycle is allocated to REM sleep.
  • sleep disturbance is frequently associated with mental disorders, such as depression.
  • treatment of depression does not necessarily lead to an improvement of the concomitant sleep disturbances.
  • antidepressants While most antidepressants have been proven to influence the sleep architecture, some classes of antidepressants improve sleep, but others may cause sleep impairment. Sleep may be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of awakenings throughout the night. The quantitative metrics may be measured using objective methods, including polysomnography, actigraphy, and the determination of sleep latency, or by way of self reported measures (questionnaires).
  • Polysomnography is a technique requiring that a patient/subject is monitored overnight at a specialised clinic. A variety of functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body positioning and movements, snoring, and heart rate. Another quantitative measurement is actigraphy. An actimetry sensor is worn to measure motor activity, which is recorded continually and used to assess sleep-wake cycles. This technique allows the patient/subject to continue normal routines while the required data are being recorded in a natural sleep environment.
  • Sleep latency may be measured by the multiple sleep latency test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep across a multiplicity of test naps. An average sleep latency of approximately 10 minutes is considered to be normal; less than eight minutes is indicative of sleep disturbance (excessive daytime sleepiness). Accompanying analysis of brain activity may assist in the further diagnosis of the sleep disturbance.
  • MSLT multiple sleep latency test
  • Sleep-rating questionnaires capture ratings of components of sleep quality, such as perceptions of sleep depth, rousing difficulties, and restfulness after sleep, in addition to other factors that could affect sleep quality, such as comorbid conditions and medication use.
  • the evaluation of the qualitative aspects of sleep experience is important, as sleep complaints may often persist despite normal values for quantitative measures of sleep.
  • Questionnaires not only facilitate a quick and accurate assessment of a complex clinical problem, but they are potentially also helpful for tracking a patient's progress.
  • indexes include examples of questionnaires to assess sleep in general and questionnaires to assess in particular insomnia, hypersomnia, circadian rhythm disorders and parasomnia, respectively.
  • the invention is, however, not limited to the use of a particular index or questionnaire.
  • recall periods recall windows
  • the recall period may be modified so that the scores obtained reflect a period after treatment.
  • Questionnaires specifically discussed herein to assess effects of a treatment on sleep in patients/subjects suffering from specific conditions rely on a recall period that does not start earlier than the time point when complete mystical experiences have subsided after the last administration. To meet this criterion, the normally applied recall period is modified if necessary.
  • the Sleep quality in general may be assessed, for instance, with the Sleep-50 questionnaire.
  • the SLEEP-50 questionnaire consists of 50 items designed to screen for a variety of sleep disorders in the general population.
  • the scale consists of nine subscales, reflecting some of the most common disorders and complaints related to sleep and the factors required for diagnosis such as sleep apnoea, insomnia, narcolepsy, restless legs/periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors influencing sleep, and the impact of sleep complaints on daily functioning.
  • respondents are provided with a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate the extent to which the statement has matched their experience over the previous month or another appropriate recall window.
  • a sleep disorder For diagnosing a sleep disorder not only the specific subscale (e.g., insomnia) must exceed a certain cut-off point, but respondents must also meet a cut-off of at least 3 or 4 ("rather much” or "very much", respectively) on the subscale evaluating the impact of sleep complaints on daily functioning. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value.
  • a common questionnaire assessing sleep disturbance is the Pittsburgh Sleep Quality Index.
  • Other instruments are the insomnia severity index, the Espie sleep disturbance questionnaire and the patient/subject Reported Outcomes Measurement Information System (PROMIS®) Sleep Disturbance.
  • the Pittsburgh Sleep Quality Index assesses overall sleep quality and disturbances.
  • the PSQI is a selfrated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window.
  • the 19 selfrated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) patient/subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction. Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances.
  • treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 5 or below.
  • the insomnia severity index is a short questionnaire relating to patient/subjective sleep quality, severity of symptoms, patient/subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how noticeable the respondent feels his or her insomnia is compared to others, and the overall level of distress created by the sleep problem.
  • a total score of 0-7 indicates "no clinically significant insomnia," 8-14 means “subthreshold insomnia," 15-21 is “clinical insomnia (moderate severity),” and 22-28 means “clinical insomnia (severe)".
  • the recall window is two weeks. Another appropriate recall window may also be used.
  • Treatment success may be indicated (i) by a decrease of the score, for instance, by >7 points, in particular >8 point; preferably (ii) by a decrease to below the cut-off value for clinically significant insomnia.
  • the Espie sleep disturbance questionnaire evaluates patient/subjective experiences of insomnia. With ratings on restlessness/agitation, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ is concerned specifically with beliefs about the sources of sleep issues. Respondents use a five-point scale to indicate how often certain statements about insomnia are representative of their experience. 1 means “never true,” while 5 means “very often true.” Higher scores are indicative of more dysfunctional beliefs about the causes and correlates of insomnia.
  • the Patient- Reported Outcomes Information System (PROMIS)® Sleep Disturbance instrument is a universal measure to evaluate sleep disturbances.
  • the instrument is available as a long form and 4 different short forms (e.g., 4-, 6-, and 8- items) and assesses selfreported perceptions of sleep quality, sleep depth, and any perceived difficulties related to getting and staying asleep over a 7-day period.
  • Each item on the measure is rated on a 5-point scale.
  • the raw scores on the items are summed to obtain a total raw score. Total raw scores are then converted into a standardised T-score using conversion tables.
  • Treatment success may be indicated by a decrease of the T-score.
  • Hypersomnia or hypersomnolence may be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity scale.
  • the Epworth Sleepiness Scale (ESS) evaluates overall daytime sleepiness.
  • the questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations representing a moment of relative inactivity, such as a nap in the afternoon or sitting in a car stopped in traffic. Using a scale of 0-3 (with 0 meaning "would never doze” and 3 meaning "high chance of dozing"), respondents rate their likelihood of falling asleep. Scoring ranges from 0-24; the higher the score, the higher the severity of daytime sleepiness.
  • a cut-off score of 10 identifies daytime sleepiness at a potentially clinical level. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 10 or below.
  • PADSS Paris Arousal Disorders Severity Scale
  • a common questionnaire that assesses sleep-related breathing disorders is the Berlin Questionnaire. An appropriate recall period may also be chosen. Treatment success may be indicated by a decrease of the score.
  • a common questionnaire that assesses sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale.
  • the 10-item questionnaire asks respondents to use Likert-type ratings to indicate how acutely the disorder has affected them over the course of the past week. Questions may be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep issues, disturbances in daily functioning, and resultant changes in mood.
  • Each of the ten questions requires respondents to rate their experiences with RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores may range from 0 to 40.
  • the instrument may be suitable for a variety of research and clinical purposes, including screening and assessment of treatment outcomes. Treatment response may be assessed by a decrease of the score.
  • Bipolar disorder has various aspects and is characterised by various symptoms.
  • the predominant psychopathology is depression, and the presentation of a patient/subject experiencing a depressive phase may initially result in the diagnosis of that patient/subject as having major depressive disorder (MDD).
  • MDD major depressive disorder
  • BD possesses multiple characteristics that define it as distinct from the latter even during the depressive phase.
  • Characteristic symptoms further include suicidal ideation. Still further, characteristic symptoms include mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).
  • BDRS Bipolar Depression Rating Scale
  • the Bipolar Depression Rating Scale is designed to measure the severity of depressive symptoms in bipolar depression.
  • the BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and/or mixed symptoms expressed by patients/subjects currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms.
  • the scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.
  • the questions address depressed mood; sleep disturbance; appetite disturbance; reduced social engagement; reduced energy and activity; reduced motivation; impaired concentration and memory; anxiety; anhedonia; affective flattening; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation.
  • Each of these aspects is assessed and assigned a score of 0, 1, 2 or 3.
  • Depressed mood is scored as 0 if there is no self-reported and/or observed depression as evidenced by gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) in case of brief or transient periods of depression, or mildly depressed mood; 2 (moderate) in case a depressed mood is clearly but not consistently present and other emotions are expressed, or depression is of moderate intensity; 3 (severe) in case of pervasive or continuous depressed mood of marked intensity.
  • Sleep disturbance is assessed based on the change in total amount of sleep over a 24- hour cycle, rated independent of the effect of external factors. It may either take the form of insomnia (reduction in total sleep time) or the form of hypersomnia (increase in total sleep time, inclusive of daytime sleep).
  • the rating for insomnia involves scores of 0 (no reduction in total sleep time); 1 (mild; reduction up to 2 hours); 2 (moderate; 2 - 4 hours); 3 (severe; more than 4 hours).
  • the alternative rating for hypersomnia involves scores of 0 (no increase in total sleep time, inclusive of daytime sleep); 1 (mild; less than 2 hours, or normal amount but nonrestorative); 2 (moderate; 2 - 4 hours); 3 (severe; greater than 4 hours).
  • Appetite disturbance is assessed based on the change in appetite and food consumption, rated independent of the effect of external factors. It may either take the form of loss of appetite or the form of increase in appetite.
  • the rating for loss of appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but has to push self to eat or reports that food has lost taste); 2 (moderate; some decrease in food intake); 3 (marked decrease in food intake, hardly eating).
  • the alternative rating for increase in appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but increased hunger); 2 (moderate; some increase in food intake, e.g., comfort eating); 3 (marked increase in food intake or cravings).
  • Reduced social engagement is scored as 0 if there are no patient/subjective reports of reduced social and interpersonal engagement or interactions; 1 (mild) in case of slight reduction in social engagement with no impairment in social or interpersonal function; 2 (moderate) in case of clear reduction in social engagement with some functional sequelae, e.g., avoiding some social engagements or conversations; and 3 (severe) in case of marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusing to answer the phone or see friends or family.
  • Reduced energy and activity is scored as 0 if there is no reduced energy, drive or goal directed behaviour; 1 (mild) in case of ability to engage in usual activities but with increased effort; 2 (moderate) in case of significant reduction in energy leading to reduction of some role-specific activities; and 3 (severe) in case of leaden paralysis or cessation of almost all role specific activities, (e.g., spending excessive time in bed, avoiding answering the phone, poor personal hygiene).
  • Impaired concentration and memory are scored as 0 if there are no patient/subjective reports of reduced attention, concentration, or memory, and consequent functional impairment; 1 (mild) in case of slight impairment of attention, concentration, or memory with no functional impairment; 2 (moderate) in case of significant impairment of attention, concentration, or forgetfulness with some functional impairment; 3 (severe) in case of marked impairment of concentration or memory with substantial functional impairment, e.g., unable to read or watch TV).

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Abstract

Pharmaceutical compositions comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients are described, as well as uses thereof as a medicament.

Description

Pharmaceutical compositions comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)
Field of the invention
This invention relates to dosage regimens of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), compositions of 5-MeO-DMT and uses thereof.
Background
5-MeO-DMT benzoate is the benzoate salt of the pharmacologically active compound of the tryptamine class, 5-MeO-DMT, and has the following structure:
Figure imgf000002_0001
5-MeO-DMT, a tryptamine alkaloid, is a short-acting serotonergic psychedelic that was first synthesised in 1936. 5-MeO-DMT has been found in a large number of plants and has also been identified as the primary psychoactive component of the parotid gland venom of Incilius alvarius (formerly Bufo alvarius), the Sonoran Desert toad. 5-MeO-DMT has been detected in blood, urine, and cerebrospinal fluid; however, its physiological role is unknown and more research is needed to definitively determine if 5-MeO-DMT is endogenously produced in humans.
5-MeO-DMT is a serotonin (5-HT) receptor agonist with affinity to a variety of serotonin receptors. Its highest binding affinity is for the 5-HTIA receptor, with a 300-1000-fold higher selectivity compared with the 5-HT2A receptor. The behavioural effects and safety margins of 5-MeO-DMT have been best characterised in rodents.
5-MeO-DMT is rapidly metabolised by monoamine oxidase enzymes in the gut and liver, and is orally inactive. It is therefore usually administered parenterally through smoking or inhalation of vapour, or less commonly via intravenous, intramuscular, rectal, sublingual, or intranasal applications.
5-MeO-DMT induces profound alterations in consciousness including mystical experiences, has minimal visual effects and higher rates of ego-dissolution compared to other psychedelics. Data, mainly derived from psilocybin and LSD studies, suggests that a profound psychedelic effect might be a necessary precursor for psychiatric efficacy of psychedelics, suggesting that 5-MeO-DMT, given at the right dose could be a beneficial alternative to current psychedelics in clinical development. Furthermore, 5-MeO-DMT has a rapid onset and short duration of action, which might reduce the duration of treatment sessions and thus resource utilisation. The high first-pass effect demands nonparenteral delivery options (i.v., inhalation, intranasal absorption) and the intranasal route disclosed herein provides benefits regarding the ease of use and the clear regulatory pathway of a broadly utilised drug-device combination. A comprehensive review of all published pre-clinical and clinical data concluded that 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of egodissolution and mystical experiences.
Controlled clinical studies with 5-MeO-DMT in humans are lacking and there remains a need in the art for further clinical exploration of formulations of 5-MeO-DMT benzoate.
Summary
Disclosed herein is a rapid and sustained treatment of treatment resistant depression/major depressive disorder, with an improved tolerability profile, said treatment comprising the administration of 10 mg of 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. As used herein, the terms "approximately" and "about" generally should be understood to encompass ± 5% of a specified amount or value. In an embodiment, there is provided a pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT.
In an embodiment, the composition is formulated for intranasal administration. In an embodiment, the composition is formulated as a dry powder. In an embodiment, the composition is formulated as a spray dried dry powder. In an embodiment, the composition comprises 5-MeO-DMT benzoate. In an embodiment, the composition comprises 5-MeO-DMT hydrochloride. In an embodiment, the composition comprises 5-MeO- DMT hydrobromide. In an embodiment, the composition comprises 5-MeO-DMT oxalate. In an embodiment, the 5-MeO-DMT is in crystalline form. In an embodiment, the composition is in crystalline form. In an embodiment, the composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A. In an embodiment, the composition comprises crystalline 5-MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°±O.1°20 as measured using an x-ray wavelength of 1.5406 A. In an embodiment, the composition comprises crystalline 5- MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A. In an embodiment, the composition comprises crystalline 5-MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A. In an embodiment, the composition comprises one or more of: chitosan, chitosan derivatives, fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid. In an embodiment, the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides. In an embodiment, the composition is for use in a method of treatment of depression/major depressive disorder. In an embodiment, the composition is for use in a method of treatment of depression/major depressive disorder. In an embodiment, the composition is for use in a method of treatment of depression/major depressive disorder. In an embodiment, the composition is for use in a method of treatment of depression/major depressive disorder. In an embodiment, there is provided an intranasal dry powder pharmaceutical composition comprising 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT, for use in a method of treatment. In an embodiment, the composition is for use in a method of treatment of depression/major depressive disorder.
In an embodiment, the composition is for use in a method of treatment of treatment-resistant depression/major depressive disorder. In an embodiment, the composition is for use in a method of treatment of substance misuse disorder. In an embodiment, the composition is for use in a method of treatment of alcohol use disorder.
In an embodiment, there is provided a method of treatment wherein a mystical experience is produced in a patient in need thereof by administration of a 10 mg dosage amount of 5-MeO-DMT. In an embodiment, 5- MeO-DMT is provided for use in the treatment of a mental health condition/disease, wherein 10 mg of 5-MeO- DMT is administered in a single intranasal dose. In an embodiment, the mental health condition/disease is depression/major depressive disorder.
In an embodiment, the composition comprises a salt of 5-MeO-DMT. In an embodiment, the composition comprises a crystalline salt of 5-MeO-DMT. In an embodiment, there is provided a crystalline form of 5-MeO- DMT hydrobromide. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrobromide, characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT phosphate, characterised by one or more peaks in an XRPD diffractogram at 12.9, 20.4 and 23.1°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT fumarate, characterised by one or more peaks in an XRPD diffractogram at 13.0, 16.3 and 22.1°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT oxalate, characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT tartrate, characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.6, and 2O.7°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT benzenesulfonate, characterised by one or more peaks in an XRPD diffractogram at 9.5, 21.2, and 23.6°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT tosylate, characterised by one or more peaks in an XRPD diffractogram at 19.3, 23.6 and 24.1 °20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT glycolate, characterised by one or more peaks in an XRPD diffractogram at 20.2, 21.1 and 23.4°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT ketoglutarate, characterised by one or more peaks in an XRPD diffractogram at 14.4, 18.2 and 2O.9°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5- MeO-DMT malate, characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.7 and 18.9°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT saccharinate, characterised by one or more peaks in an XRPD diffractogram at 8.7, 15.2 and 2O.9°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrochloride, characterised by one or more peaks in an XRPD diffractogram at 9.2°±0.1°, 12.2°±0.1°, 14.1°±0.1°, 15.0°±0.1°, 18.5°±0.1°, and 19.5°±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT benzoate, characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
In an embodiment the composition is formulated as a powder which is suitable for administration by inhalation/insufflation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurised metered dose inhaler. In an embodiment the powder comprises particles, the particles having a median diameter of less than 2000 pm, 1000 pm, 500 pm, 250 pm, 100 pm, 50 pm, or 1 pm. In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500 pm, 250 pm, 100 pm, 50 pm, 1 pm or 0.5 pm. In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of dl0=20-60 pm, and/or d50=80-120 pm, and/or d90=130-300 pm.
The nature of the powder can be adjusted to suit needs. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet. In an embodiment the 5-MeO-DMT salt is amorphous or crystalline. In an embodiment, the 5-MeO-DMT salt is in a polymorphic crystalline form. For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount of 5-MeO-DMT corresponds to 117 mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g/mol for the free base as compared to 254.8 g/mol for the salt). Similarly, for the deuterated or triturated version of 5-MeO-DMT (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.
In an embodiment, X mg of a 5-MeO-DMT salt refers to the dosage amount of said salt which equates to X mg of the 5-MeO-DMT freebase. Therefore, a pharmaceutical composition comprising 12 mg 5-MeO-DMT benzoate refers to a pharmaceutical composition comprising 18.7 mg 5-MeO-DMT benzoate which equates to 12 mg of 5-MeO-DMT freebase. In an embodiment, there is provided the use of about 15.59 mg 5-MeO-DMT benzoate, or a pharmaceutical composition, thereof.
Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties. In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.
In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients. In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides. In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-
N,N-dimethyl chitosan, chitosan chloride), fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment the composition disclosed herein is for use as a medicament. In an embodiment the composition disclosed herein is for use in a method of treatment of a human or animal patient/subject by therapy. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.05 mg to 100 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of
O.1 mg to 50 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5 mg to 25 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5 mg to 10 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 10 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 8 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 3 mg to 15 mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.005 mg to 100 mg. In an embodiment the composition comprises a dosage amount of 5-MeO- DMT in the range of 0.001 mg to 100 mg. In an embodiment the composition comprises a dosage amount of 5- MeO-DMT in the range of 0.0005 mg to 100 mg. The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated. In an embodiment, there is provided a pharmaceutical composition comprising 10-12 mg of 5-MeO-DMT. In an embodiment, there is provided a pharmaceutical composition capable of producing a complete mystical experience wherein said composition comprises 10-12 mg 5-MeO-DMT. In an embodiment, the 5-MeO-DMT is present as the benzoate salt. In an embodiment, the composition is for intranasal delivery. In an embodiment, the composition is a dry powder. In an embodiment, there is provided a pharmaceutical composition comprising: i) particles of 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or pharmaceutically acceptable salts or derivatives thereof; and ii) a pH-sensitive polymer, wherein the particles are nanoparticles or microparticles; and wherein the particles are encapsulated in the pH-sensitive polymer. In an embodiment, there is provided a pharmaceutically acceptable composition comprising 5-MeO-DMT, wherein administration of said composition to a patient/subject produces in said patient/subject a blood plasma Cmax (ng/mL) of about 4-39, of about 5-35 or of about 6-29. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or of about 0.1- 0.25. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or of about 0.25-0.44. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a AUCiast (h*ng/mL) of about 1.0-22, of about 1.2-20 or of about 1.5-18.5. In an embodiment, administration of said composition to a patient/subject produces in said patient/subject a AUCmt (h*ng/mL) of about 1.5-27, of about 1.7-25 or of about 1.9-24. As used herein, Cmax may refer to the maximum concentration (e.g., maximum blood plasma concentration) of a compound, as the result of the administration of a composition comprising the compound. Tmax may refer to the time required for the concentration of the compound to reach Cmax, after the administration of the composition, ti/2 (e.g., half-life) may refer to the time it takes for the concentration of the compound to halve (e.g., reach half of the Cmax), after the administration of the composition. AUCiast may refer to an area under a curve representing plasma concentration as a function of time. The area may include the last measured plasma concentration. AUCmt may refer to an area under a curve representing plasma concentration as a function of time, extrapolated to where time approaches infinity. In an embodiment, the composition comprises 5-MeO-DMT benzoate. In an embodiment, the 5-MeO-DMT is present as the benzoate salt. In an embodiment, the 5-MeO-DMT composition is a composition for intranasal administration. In an embodiment, the 5-MeO-DMT composition is an intranasal composition. In an embodiment, the composition comprises 1-12 mg of 5-MeO-DMT benzoate.
In an embodiment, the composition comprises 1 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-8, of about 5-7 or of about 6; a Tmax (h) of about 0.05-0.2, of about 0.06-0.15 or of about 0.1; a ti/2 (h) of about 0.1-0.4, of about 0.2-0.3 or of about 0.25; a AUCiast (h*ng/mL) of about 1.0-1.8, of about 1.2-1.6 or of about 1.5; or a AUCmt (h*ng/mL) of about 1.5-2.3, of about 1.7-2.0 or of about 1.9.
In an embodiment, the composition comprises 4 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or of about 9; a Tmax (h) of about 0.03-0.2, of about 0.09-0.16 or of about 0.12; a ti/2 (h) of about 0.27-0.53, of about 0.30-0.45 or of about 0.37; a AUCiast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or of about 4.5; or a AUCint (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or of about 5.
In an embodiment, the composition comprises 8 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or of about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or of about 0.17; a ti/2 (h) of about 0.21-0.37, of about 0.25-0.35 or of about 0.30; a AUCiast (h*ng/mL) of about 9.25- 17.23, of about 11-15 or of about 13.1; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about
13.9.
In an embodiment, the composition comprises 10 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or of about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or of about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or of about 0.38; a AUCiast (h*ng/mL) of about 9.37- 20.41, of about 13-18 or of about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or of about
13.9.
In an embodiment, the composition comprises 12 mg of 5-MeO-DMT benzoate, wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 20.9-39, of about 25-35 or of about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or of about 0.25; a ti/2 (h) of about 0.28-0.55, of about 0.40-0.50 or of about 0.44; a AUCiast (h*ng/mL) of about 14.45-22, of about 16-20 or of about 18.5; or a AUCmt (h*ng/mL) of about 19.10-27, of about 22-25 or of about
23.9.
In an embodiment, the composition is a dry powder composition. In an embodiment, the powder is characterised by one or more of: particles having a median diameter of less than 2000 pm, 1000 pm, 500 pm, 250 pm, 100 pm, 50 pm, or 1 pm; particles having a median diameter of less than 15, 14, 13, 12, 11, or 10 pm; particles having a median diameter of less than 9 pm; particles having a median diameter of greater than 500 pm, 250 pm, 100 pm, 50 pm, 1 pm or 0.5 pm; and/or a particle size distribution of dl0=20-60 pm, and/or d50=80-120 pm, and/or d90=130-300 pm.
In an embodiment, the composition comprises one or more pharmaceutically acceptable carriers or excipients. In an embodiment, the composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC). In an embodiment, the composition comprises one or more of chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
In an embodiment, the 5-MeO-DMT is present as crystalline 5-MeO-DMT benzoate as characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20.
In an embodiment, there is provided a pharmaceutically acceptable dry powder intranasal composition comprising 1-12 mg of 5-MeO-DMT benzoate and HPMC. In an embodiment, intranasal administration of the composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4- 39, of about 5-35 or of about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or of about 0.1-0.25; a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or of about 0.25-0.44; a AUCiast (h*ng/mL) of about 1.0-22, of about 1.2-20 or of about 1.5-18.5; or a AUCmt (h*ng/mL) of about 1.5-27, of about 1.7-25 or of about 1.9-23.9.
In an embodiment, there is provided the use of the composition for the treatment or prevention of a disease or condition. In an embodiment, the disease or condition is depression/major depressive disorder or treatment-resistant depression/major depressive disorder. Herein disclosed, there is provided a formulation of 5-MeO-DMT benzoate. In an embodiment, there is provided a pharmaceutically acceptable composition comprising 5-MeO-DMT (hereafter '5-MeO-DMT composition') comprising 1 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-8, of about 5-7 or about 6; a Tmax (h) of about 0.05-0.2, of about 0.06-0.15 or about 0.1; a ti/2 (h) of about 0.1-0.4, of about 0.2-0.3 or about 0.25; a AUCiast (h*ng/mL) of about 1.0-1.8, of about 1.2-1.6 or about 1.5; or a AUCint (h*ng/mL) of about 1.5-2.3, of about 1.7-2.0 or about 1.9.
All pharmacokinetic values refer to, for example, the Cmax in blood plasma. In an embodiment, there is provided a 5-MeO-DMT composition comprising 2.5 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-12, of about 6-10 or about 8; a Tmax (h) of about 0.1-0.3, of about 0.15-0.25 or about 0.18; a ti/2 (h) of about 0.1-0.4, of about 0.20-0.35 or about 0.32; a AUCiast (h*ng/mL) of about 2.3-6.5, of about 3.0- 4.4 or about 3.8; or a AUCmt (h*ng/mL) of about 2.9-6.8, of about 3.5-5.5 or about 4.4.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 4 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 3-13, of about 7-11 or about 9; a Tmax (h) of about 0.03-0.2, of about 0.09-0.16 or about 0.12; a ti/2 (h) of about 0.27-0.53, of about 0.30-0.45 or about 0.37; a AUCiast (h*ng/mL) of about 1.9-7.2, of about 3.5-5.5 or about 4.5; or a AUCmt (h*ng/mL) of about 2.4-7.4, of about 3.5-6.5 or about 5.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 6 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 7.7-19.3, of about 12.5-17 or about 15; a Tmax (h) of about 0.07-0.27, of about 0.1-0.2 or about 0.15; a ti/2 (h) of about 0.32-0.42, of about 0.35-0.4 or about 0.37; a AUCiast (h*ng/mL) of about 4.6-12, of about 6-10 or about 8; or a AUCmt (h*ng/mL) of about 8.6-11, of about 9-10.5 or about 9.8.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 8 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 16.4-30.9, of about 19-25 or about 22; a Tmax (h) of about 0.1-0.27, of about 0.1-0.22 or about 0.17; a ti/2 (h) of about 0.21-0.37, of about 0.25-0.35 or about 0.30; a AUCiast (h*ng/mL) of about 9.25-17.23, of about 11-15 or about 13.1; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 10 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCiast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 12 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 20.9-38.6, of about 25-35 or about 29; a Tmax (h) of about 0.17-0.5, of about 0.2-0.3 or about 0.25; a ti/2 (h) of about 0.28-0.55, of about 0.40-0.50 or about 0.44; a AUCiast (h*ng/mL) of about 14.45-22.23, of about 16-20 or about 18.5; or a AUCmt (h*ng/mL) of about 19.10-27.15, of about 22- 25 or about 23.9.
In an embodiment, there is provided a 5-MeO-DMT composition comprising 1-12 mg 5-MeO-DMT benzoate wherein intranasal administration of said composition to a patient/subject produces in said patient/subject one or more of: a Cmax (ng/mL) of about 4-38.6, of about 5-35 or about 6-29; a Tmax (h) of about 0.05-0.5, of about 0.06-0.3 or about 0.1-0.25; a ti/2 (h) of about 0.1-0.55, of about 0.2-0.5 or about 0.25-0.44; a AUCiast (h*ng/mL) of about 1.0-22.23, of about 1.2-20 or about 1.5-18.5; or a AUCmt (h*ng/mL) of about 1.5-27.15, of about 1.7-25 or about 1.9-23.9.
In an embodiment, the composition produces in a subject, per each 10 mg of 5-MeO-DMT present in the composition, one or more of: a Cmax (ng/mL) of about 10.4-46.4, of about 25-39 or about 32; a Tmax (h) of about 0.03-0.27, of about 0.1-0.22 or about 0.14; a ti/2 (h) of about 0.24-0.59, of about 0.29-0.47 or about 0.38; a AUCiast (h*ng/mL) of about 9.37-20.41, of about 13-18 or about 15.4; or a AUCmt (h*ng/mL) of about 9.42-18.7, of about 11-16 or about 13.9.
In an embodiment, the 5-MeO-DMT composition comprises a mucoadhesive. In an embodiment, the 5-MeO- DMT composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM/MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC). In an embodiment, the 5-MeO-DMT composition comprises HPMC. In an embodiment, the 5-MeO-DMT composition comprises crystalline 5-MeO-DMT benzoate, as described subsequently or previously.
In an embodiment the composition disclosed herein is for use as a medicament. In an embodiment, there is provided use of a composition as described previously or subsequently for the treatment of a disease or condition.
In an embodiment, the disease or condition is depression/major depressive disorder. In an embodiment, the disease or condition is treatment-resistant depression/major depressive disorder. In an embodiment, the disease or condition is: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and shortlasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia), conditions benefiting from antiinflammatory treatment, depression/major depressive disorder, treatment resistant depression/major depressive disorder, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and/or SUNA, alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, opioid-related disorders, tobacco addiction, alcohol abuse and/or addiction.
In an embodiment there is provided a method of use of the composition disclosed herein. In an embodiment, the method of use is a method of treatment. In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression/major depressive disorder and anxiety. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine. In an embodiment the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof. In an embodiment the further active agent is an antidepressant compound. In an embodiment the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.
In an embodiment the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen/Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4), Triiodothyronine (T3).
In an embodiment the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline). In an embodiment, one or more disorders or conditions in the patient have previously failed to be treated with one or more of the above treatments.
In an embodiment, there is provided a method, optionally a rapid and durable method, of improving one or more of: sexual functioning, anxiety, anhedonia, cognition and/or overall quality of life, in a patient in need thereof. In an embodiment, the improvement is assessed by one or more of: the Arizona Sexual Experiences Scale, the 7-item Generalised Anxiety Disorder Assessment (GAD-7), difference in self-reported anhedonia symptoms, assessed by Snaith-Hamilton Pleasure Scale (SHAPS), the Cognitive Test Battery, Patient Global Impression of Change and/or improvement in self-reported quality of life, assessed by EuroQoL- 5 Dimension-5 Level (EQ-5D-5L).
In an embodiment, there is provided a method, optionally a rapid and durable method, of treating a patient in need thereof, wherein the patient is aged 18 to 75 years old. In an embodiment, the patient has at least moderate major depressive disorder (MDD), (single or recurrent episode as informed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria; if single episode, duration of >3 months and < 2 years) based on medical records, clinical assessment, and documented completion of the version 7.0.2 Mini International Neuropsychiatric Interview (MINI). In an embodiment, the patient is diagnosed with TRD defined as failure to respond to an adequate dose and duration of at least 2 pharmacological treatments, in the current episode, based on the MGH ATRQ assessment. In an embodiment, augmentation with an add-on treatment counts as a second treatment. In an embodiment, the patient has not failed more than 5 prior pharmacological treatments in the current episode. In an embodiment, psychotherapy is not counted towards treatment failure. In an embodiment, the patient has a Hamilton Depression Rating Scale (HDRS) (17 item) score >19 at baseline/prior to treatment. In an embodiment, the patient has a CGI-S >4 at baseline/prior to treatment. In an embodiment, the patient does not have a current or past history of schizophrenia, post- traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder. In an embodiment, the patient does not have a current or past history of schizophrenia, post-traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder as assessed by medical history and a structured clinical interview (MINI). In an embodiment, the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, - obsessive compulsive). In an embodiment, the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, -obsessive compulsive) assessed via McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), MINI, and clinical judgement. In an embodiment, the patient does not have a first-degree family history of schizophrenia, bipolar disorder, delusional disorder, or schizoaffective disorder. In an embodiment, the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine). In an embodiment, the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine) according to DSM-5 and assessed by the MINI. In an embodiment, the patient has not at any time been unresponsive to ketamine or esketamine. In an embodiment, the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT). In an embodiment, the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT) defined as at least 7 treatments with unilateral/bilateral ECT, or has received vagal nerve stimulation or has received deep brain stimulation. In an embodiment, the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment. In an embodiment, the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment, based on the C-SSRS, corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or any suicidal behavior prior to treatment. In an embodiment, the patient has not attempted suicide and/or any other self-injurious behaviour within 12 months prior to treatment. In an embodiment, the patient does not have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of transient and marked increases in blood pressure and heart rate. In an embodiment, the patient does not have atherosclerotic cardiovascular disease, obstructive coronary artery disease, myocardial infarction, hospitalisation for unstable angina, stroke, hospitalisation for transient ischemic attacks, known aortic or cerebral aneurysm or revascularization procedure within 12 months prior to treatment. In an embodiment, the patient does not have significant valvular heart disease, history of hospitalisation for heart failure and/or history of hospitalisation for atrial or ventricular arrhythmias. In an embodiment, the patient does not have a history of uncontrolled hypertension despite antihypertensive therapy and/or any past history of a hospital admission for hypertension. In an embodiment, the patient does not have controlled hypertension on antihypertensive therapy with repeated clinic seated or semi-recumbent systolic blood pressure >130 mmHg or diastolic blood pressure > 80 mmHg. In an embodiment, the patient does not have repeated clinic seated or semi-recumbent systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. In an embodiment, the patient does not have one or more of hypo/hyperthyroidism with abnormal thyroid stimulating hormone values, uncontrolled or insulin dependent diabetes with HbAlc >8, renal failure with Creatinine Clearance <45 mL/min. In an embodiment, the patient does not have any seizure disorder and/or any seizure within 2 years of treatment. In an embodiment, the patient does not have any clinically significant results on ECG or a Q.T interval corrected using Fridericia's formula (QTcF) >450 msec for males or >470 msec for females prior to treatment. In an embodiment, the patient does not have any history of intolerance to 5-MeO-DMT or related compounds. In an embodiment, the patient does not have any nasal obstruction, blockage, or symptoms of congestion at the time of treatment. In an embodiment, the patient is not a female patient who is pregnant, lactating, or of childbearing potential who is not willing or able to use adequate forms of contraception during treatment. In an embodiment, the patient is not a male patient who is not willing or able to use adequate forms of contraception during treatment. In an embodiment, the patient does not have a personal or family history of malignant hyperthermia. In an embodiment, the patient has discontinued one or more of the following at least 5 half-lives prior to treatment: Medications that antagonise the serotonin 2A receptor, Medications with serotonergic activity (e.g., SSRIs, SNRIs, efavirenz, lithium), Tramadol, Opioids, Antiviral Medications, St. John's Wort, Medications that inhibit UGT1A9 or UGT1A10 enzymes, Monoamine Oxidase Inhibitors (MAOIs) and/or Medications that inhibit aldehyde or alcohol dehydrogenase.
In an embodiment, the patient does not inhale during the administration. In an embodiment, the patient experiences greater than 5% 5-MeO-DMT exposure to the turbinates following administration of any of the pharmaceutical compositions described herein. In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the 5-MeO-DMT of the present pharmaceutical compositions reaches the turbinates. In an embodiment, the patient experiences a plasma exposure of between 1-46 ng/mL to 5-MeO-DMT. In some embodiments, the plasma exposure is between 1-46 ng/mL, between 5-40 ng/mL, between 10-35 ng/mL, or between 25-32 ng/mL. In some embodiments, the plasma exposure is at least 25 ng/mL. In some embodiments, the licensed physician overseeing the administration to the patient uses the plasma exposure to adjust dosing. In some embodiments, the subsequent dose received by a patient is 12 mg of 5-MeO-DMT if the plasma exposure was less than 25 ng/mL at the 10 mg dose.
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure a first time; b) administering to the patient/subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient/subject's blood pressure a second time; d) discharging the patient/subject if the patient/subject's blood pressure at the second time is about the same as the patient/subject 's blood pressure at the first time, wherein the patient/subject is discharged within 90 minutes of step (b).
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: c) measuring the patient/subject's blood pressure; d) intranasally administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) measuring the patient/subject's blood pressure; b) intranasally administering to the patient/subject 10 mg of 5-MeO-DMT if the patient/subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
In an embodiment, the pharmaceutical composition is for use in a method of treating depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
In an embodiment, the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a patient/subject in need thereof, wherein the method comprises: a) administering to the patient/subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient/subject for relapse of one or more depressive symptoms; c) administering to the patient/subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient/subject.
Brief description of the drawings
Figure 1 is a schematic of a one-step synthesis of 5-MeO-DMT from the reaction of 4-methoxyphenylhydrazine hydrochloride with (N,N)-dimethylamino)butanal dimethyl acetal.
Figure 2 is a schematic of a three-step synthesis of 5-MeO-DMT. The first step involves the reaction of 5- methoxyindole with oxalyl chloride. The resultant product is aminated with dimethylamine and then is reduced with lithium aluminium hydride.
Figure 3 is a schematic route for the formation of a powder form of 5-MeO-DMT using a spray drying process.
Figure 4 is an overview of the slug mucosal irritation (SMI) test. (A) First 15 minute contact period between slug and test item. (B) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (C) Second 15 minute contact period between slug and test item. (D) Slug is transferred onto a wet paper towel in a new Petri dish for 1 hour. (E) Third 15 minute contact period between slug and test item.
Figure 5 is a graph showing that the benzoate salt of 5-MeO-DMT has higher permeation compared with the hydrochloride salt, as per the experiment detailed in Example 7.
Figure 6 is an XRPD diffractogram of 5-MeO-DMT benzoate prior to particle size reduction.
Figure 7 is an XRPD diffractogram of 5-MeO-DMT benzoate following particle size reduction.
Figure 8 is an XRPD diffractogram of Figures 6 and 7 overlaid on one another.
Figure 9 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma linear concentration-time plot.
Figure 10 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL003) plasma log concentration-time plot.
Figure 11 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma linear concentration-time plot.
Figure 12 is a graph showing the mean (+/- SD) 5-MeO-DMT (BPL002) plasma log concentration-time plot.
Figure 13 shows Forced Swim Test results, Time Immobile, for 5-MeO-DMT benzoate at 0.5, 1.0, or 1.5 mg/kg doses, vehicle and imipramine.
Figure 14 shows Forced Swim Test results, Latency to Immobility, for 5-MeO-DMT benzoate at 0.5, 1.0, or 1.5 mg/kg doses, vehicle and imipramine.
Figure 15 shows a Dynamic Vapour Sorption (DVS) isotherm for 5-MeO-DMT benzoate.
Figure 16 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/20/126-FP).
Figure 17 shows a DVS isotherm of 5-MeO-DMT hydrochloride (lot 20/45/006-FP). Figure 18 shows mean (±SD) plasma concentration-time curves of 5-MeO-DMT.
Figure 19 shows mean (± SEM) subjective intensity ratings after single closes of placebo or 8 mg, 10 mg and 12 mg BPL-003 (SEM, Standard error of the mean).
Figure 20 shows mean (± SEM) MEQ-30 scores after single doses of placebo or 8 mg, 10 mg and 12 mg BPL-003 (MEQ-30, Mystical Experience Questionnaire; SEM, Standard error of the mean. Dotted line indicates a meaningful threshold of >3).
Figure 21 shows the mean change from baseline in MADRS total score over time (per protocol population) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).
Figure 22 shows the particle size distribution of a 5-MeO-DMT SDD as Bulk Material (Red) and ExDevice (Green).
Figure 23 shows the nasal deposition profile for a 5-MeO-DMT SDD delivered via an active delivery nasal delivery device.
Figure 24 shows the nasal deposition profile for a 5-MeO-DMT SDD delivered via a passive delivery nasal delivery device.
Detailed Description
The present disclosure includes the aspects described above and is further illustrated by the following examples. The examples are intended to illustrate the present disclosure without, however, being limiting in nature. It is understood that the present disclosure encompasses additional embodiments consistent with the foregoing description and following examples.
Examples
Example 1: Synthesis of 5-MeO-DMT (the free base) in one step (the free base)
A schematic representation of this reaction is shown in Figure 1.
Hydrazine (1.0 eq), diethyl acetal (1.2 eq), and aqueous sulfuric acid (0.1 eq) were heated together at 65-75°C for 18 hours. MTBE (10 vol) was added, followed by adjustment to about pHlO using 12% caustic (about 1.1 eq). The layers were separated and the aqueous fraction back extracted with MTBE (10 vol). The combined organic fractions were washed with water (10 vol) twice, then evaporated to dryness under vacuum. Yield 100%.
Example 2: Synthesis of 5-MeO-DMT (the free base) in three steps
A schematic representation of this reaction is shown in Figure 2.
Step 1 - Add methyl tert-butyl ether (MTBE) (15 vol) into the reaction vessel and cool to -20 to -30°C, before adding oxalyl chloride (1.5 eq), maintaining the temperature at no more than -20°C. Add a solution of 5- methoxyindole (1.0 eq) in THF (1 vol) to the reaction vessel, maintaining the temperature at no more than - 20°C. Allow the reaction to warm to 0-5°C and stir for at least 1 hour, ensuring that no more than 2% of the starting material indole remains.
Cool the reaction to between -20 to -30°C and add a solution of methanol (1 vol) and MTBE (1 vol), maintaining the temperature at no more than -20°C. Allow the reaction to warm to 0-5°C over no less than 30 minutes and stir for at least 1 hour.
Filter and wash the solids with MTBE cooled to 0-5°C. Add the washed filtered solids and methanol (20 vol) to a reaction vessel. Heat to 60-65°C and stir for no more than 30 minutes. Cool to 0-5°C over no less than 2 hours and stir for no less than 2 hours. Filter and wash the solids with MTBE cooled to 0-5°C. Dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 95%.
Step 2 - Add the compound obtained in step 1 (1.0 eq) to a reaction vessel together with dimethylamine hydrochloride (3.0 eq) and methanol (2 vol). Add 25% NaOMe in methanol (3.5 eq), to the reaction maintaining the temperature at no more than 30°C. Warm to and stir for no less than 5 hours, ensuring that no more than 0.5% of the starting material from step 1 remains. Adjust the temperature to 0-5°C over no less than 2 hours, then add water (5 vol) over no less than 1 hour while stirring at 0-5°C for no less than 1 hour.
Filter and wash the solids with water cooled to 0-5°C, and dry the solids obtained at no more than 40°C for no less than 12 hours. Yield 85%.
Step 3 - Add the compound obtained in step 2 (1.0 eq) to a reaction vessel. Add IM Li Al H4 in THF (1.5 eq) in THF (8 vol) to the reaction maintaining no more than 40°C. Heat at reflux for no less than 4 hours ensuring that no more than 2% of the starting material from step 2 remains.
Adjust to 0-5°C and add water (0.25 vol) in THF (0.75 vol) over no less than 30 minutes, maintaining no more than 10°C. Then add 15% caustic (0.25 vol) maintaining the temperature at no more than 10°C. Add water (0.65 vol) maintaining the temperature at no more than 10°C. Add THF (0.25 vol) as a vessel rinse and stir the contents at 0-5°C for no less than 30 minutes. Add sodium sulphate (100wt%) and stir contents at 0-5°C for no less than 30 minutes.
Filter and wash the solids with toluene (2x10 vol) and keep liquors separate. Recharge THF liquors to a clean vessel and distil under vacuum to minimum stir. Charge toluene liquors and distil under vacuum to about 10vol. Then add water (5 vol) and stir for no less than 15 minutes. Stop, settle and remove aqueous layer to waste. Charge with 4% HCI to a pH of between 1-2 (about 4 vol) and stir for no less than 15 minutes. Stop, settle and remove organic layers to waste. Charge MTBE (15 vol). Charge with 15% caustic to a pH between Ills (about 0.9 vol). Stir for no less than 15 minutes. Stop, settle and remove aqueous layer to waste. Charge with water (5 vol). Stir for no less than 15 minutes. Stop, settle and remove the aqueous layer to waste.
Example 3: Synthesis of 5-MeO-DMT benzoate salt
5-MeO-DMT (the free base) is dissolved in toluene (1 eq) and benzoic acid (1 eq) in toluene (10 vol) is added over a period of 20 minutes and stirred at room temperature for 2 hours. The resultant precipitation/crystallisation was filtered and washed with toluene (2.5vol) and dried under vacuum at room temperature.
Isopropyl acetate (IPAc) (15.8 vol) was added to the solids obtained above and the temperature was raised to about 73°C until the solid dissolved. The solution was allowed to cool to 0-5°C over 2 hours and this temperature was maintained for 1 hour with stirring. The resultant benzoate salt was filtered and vacuum dried at room temperature. Yield 68%.
The benzoate salt of 5-MeO-DMT has improved characteristics over the common hydrochloride salt, including reduced mucosal irritation, increased epithelial permeability and increased stability. 5-MeO-DMT benzoate is a white to off white solid powder, soluble in water at >50 mg/ml with a pH of 7-8 at 50 mg/ml and a pKa of 9.71.
Example 4: 5-MeO-DMT powder
A schematic route for the preparation of a powder form of 5-MeO-DMT (or the salt thereof) is shown in Figure 3. The three main steps in the process are:
1. Spray drying a solution containing the substance(s) of interest (e.g. 5-MeO-DMT, or the salt, thereof inclusive of any excipients). This can be done via an atomizing nozzle such as with rotary atomizers, pressure atomizers, twin fluid nozzles, ultrasonic atomizers, and four-fluid nozzles. This is done so as to form droplets capable of generating co-formed particles in the desired particle size range.
2. Drying of the atomized droplets (e.g. with nitrogen gas, optionally at an elevated temperature).
3. Separating and collecting the dried particles from the gas stream (e.g. using a cyclone separator to capture the required size fraction).
In an embodiment, a ProCepT spray dryer is used. In an embodiment, a ProCepT spray dryer with an ultrasonic nozzle is used.
In an embodiment, there is dissolution of 5-MeO-DMT benzoate and HPMC in water to make an input solution at a 50:50 ratio. Example 5: Slug Mucosal Irritation assay
The Slug Mucosal Irritation (SMI) assay was initially developed at the Laboratory of Pharmaceutical Technology (UGent) to predict the mucosal irritation potency of pharmaceutical formulations and ingredients. The test utilises the terrestrial slug Arion lusitanicus. The body wall of the slugs is a mucosal surface composed of different layers. The outer single-layered columnar epithelium that contains cells with cilia, cells with microvilli and mucus secreting cells covers the subepithelial connective tissue. Slugs that are placed on an irritating substance will produce mucus. Additionally tissue damage can be induced which results in the release of proteins and enzymes from the mucosal surface. Several studies have shown that the SMI assay is a useful tool for evaluating the local tolerance of pharmaceutical formulations and ingredients. A classification prediction model that distinguishes between irritation (mucus production) and tissue damage (release of proteins and enzymes) has been developed. Furthermore, several studies with ophthalmic preparations have shown that an increased mucus production is related to increased incidence of stinging, itching and burning sensations. In 2010 a clinical trial was set up to evaluate the stinging and burning sensations of several diluted shampoos. A 5% shampoo dilution or artificial tears were instilled in the eye and the discomfort was scored by the participants on a 5 point scale during several time points up to 30 min after instillation. The same shampoos were tested in the SMI assay using the Stinging, Itching and Burning (SIB) protocol. This study showed that an increased mucus production was related with an increased incidence of stinging and burning sensations in the human eye irritation test. The relevance of the assay to reliably predict nasal irritation and stinging and burning sensations was demonstrated using several OTC nasal formulations, isotonic, and hypertonic saline.
Furthermore, the test was validated using reference chemicals for eye irritation (ECETOC eye reference data bank). These studies have shown that the SMI assay can be used as an alternative to the in vivo eye irritation tests. Moreover, a multi-center prevalidation study with four participating laboratories showed that the SMI assay is a relevant, easily transferable and reproducible alternative to predict the eye irritation potency of chemicals. The purpose of this assay was to assess the stinging, itching or burning potential of the test item(s) defined below. Using the objective values obtained for the mucus production the stinging, itching or burning potential of the test item(s) can be estimated by means of the prediction model that is composed of four categories (no, mild, moderate and severe).
Control items:
• Negative control - Name: Phosphate buffered saline (PBS)
• Positive control - Name: 1% (w/v) Benzalkonium chloride in PBS
Test items:
Compound 1
Name: 10% (w/v) Disodium fumarate in PBS
CASRN: 17013-01-3
Batch: KBSJ-PO
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Compound 2
Name: 10% (w/v) Sodium phosphate monobasic in PBS
CASRN: 7558-80-7
Batch: 2A/220991
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment) Compound 3
Name: 10% (w/v) Sodium acetate in PBS
CASRN: 127-09-3
Batch: 5A/233258
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Compound 4
Name: 10% (w/v) Sodium citrate in PBS
CASRN: 68-04-2
Batch of vial: 5A/241516
Description: colourless solution
Storage condition: room temperature (compounded on the day of the experiment)
Test System: Slugs (Arion lusitanicus); 3 slugs per treatment group. The parental slugs of Arion lusitanicus collected in local gardens along Gent and Aalter (Belgium) are bred in the laboratory in an acclimatised room (18-20°C). The slugs are housed in plastic containers and fed with lettuce, cucumber, carrots and commercial dog food.
Test Design: A single study was performed. Treatment time was 15 minutes three times on the same day.
Preparation of Slugs:
Slugs weighing between 3 and 6 g were isolated from the cultures two days before the start of an experiment. The body wall was inspected carefully for evidence of macroscopic injuries. Only slugs with clear tubercles and with a foot surface that shows no evidence of injuries were used for testing purposes. The slugs were placed in a plastic box lined with paper towel moistened with PBS and were kept at 18 - 20°C. Daily the body wall of the slugs was wetted with 300 pl PBS using a micropipette.
Test Procedure:
The stinging, itching or burning potency of the test item(s), was evaluated by placing 3 slugs per treatment group 3 times a day on 100 pL of test item in a Petri dish for 15 ± 1 min. After each 15-min contact period the slugs were transferred for 60 min into a fresh Petri dish on paper towel moistened with 1 mL PBS to prevent desiccation. An overview of this can be seen in Figure 4.
Mucus Production:
The amount of mucus produced during each contact period was measured by weighing the Petri dishes with the test item before and after each 15-min contact period. The mucus production was expressed as % of the body weight. The slugs were weighed before and after each 15-min contact.
Classification prediction model
Based on the endpoint of the SMI assay the stinging, itching or burning potency of the test item(s) was estimated using a classification prediction model.
The evaluation of the test results was based upon the total amount of mucus production during 3 repeated contact periods with the test item.
For each slug, the mucus production was expressed in % of the body weight by dividing the weight of the mucus produced during each contact period by the body weight of the slug before the start of that contact period. The total mucus was calculated for each slug and then the mean per treatment group was calculated. The classification prediction model shown in the Table below was used to classify the compounds. Cut-off values for classification - potency for nasal mucosal discomfort
Figure imgf000017_0001
Acceptance criteria
Before a test was considered valid, the following criteria must be met: the negative control should be classified as causing no stinging, itching and burning (Total mucus production < 5.5%) the positive control item should be classified as causing severe stinging, itching and burning (Total mucus production > 17.5%)
Irritation Potential
Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced
Figure imgf000017_0002
NC: negative control; PC: positive control; BAC: benzalkonium chloride
1Mean ± SD, n=3
2 No: total MP < 5.5%; Mild: 5.5% < total MP < 10%; Moderate: 10% < total MP < 17.5%; Severe: total MP > 17.5%
The average amount of mucus produced during each 15-min contact period and total mucus production (total MP) is presented in the Table above. According to the classification prediction model of the SMI test, the negative control (untreated slugs) did not induce reactions in the slugs (mean total MP < 5.5%). The positive control on the other hand (DDWM/SLS 80/20) induced a high mucus production during each contact period (mean total MP > 17.5%) resulting in a classification as severe stinging, itching, and burning (SIB) reactions. The acceptance criteria were met and the experiment was considered valid.
In total, 4 different solutions were tested. The amount of mucus produced during each 15-min contact period was between 10% and 17.5%, indicating moderate SIB reactions. The test items can be ranked according to increasing total mucus production: sodium acetate (10% w/v) < sodium citrate (10% w/v) < disodium fumarate (10% w/v) < sodium phosphate (10% w/v). Numerical Data
Figure imgf000018_0001
Amount of mucus produced (MP) during each 15-min contact period (CP) and total amount of mucus produced
Figure imgf000018_0002
NC: negative control; PC: positive control; BAC: benzalkonium chloride
1Mean ± SD, n=3
2 No: total MP < 5.5%; Mild: 5.5% < total MP < 10%; Moderate: 10% < total MP < 17.5%; Severe: total MP > Amount of mucus produced (MP) during each 30-min contact period (CP) and total amount of mucus produced (Code 00E04)
Figure imgf000019_0001
Amount of mucus produced (MP) during each 60-min contact period (CP) and total amount of mucus produced
Figure imgf000019_0002
Amount of mucus produced (MP) during a 60-min contact period (CP)
Figure imgf000019_0003
Results The total MP for a 60-min treatment (historical data) was compared with the total MP of the SIB protocol (3x 15-min treatment; current data). In the Table below a ranking is proposed from least SIB reactions to highest SIB reactions:
Figure imgf000019_0004
Sodium oxalate appears to be the most irritating salt since a 1% concentration results in 11.2% total MP after 1 hour of contact. Sodium benzoate is the least irritating salt. Example 6: Further slug mucosal irritation (SMI) testing
5-MeO-DMT as a freebase compound is known to be highly irritating to the mucosal lining; therefore, it is commonly prepared as a salt for insufflation. The hydrochloride (HCI) salt of 5-MeO-DMT is most commonly used due to ease of crystallisation. However, it is known that the HCI salt of 5-MeO-DMT is still quite irritating to the mucosal lining.
Following the results above indicating that sodium benzoate is the least irritating salt of those studied; further SMI testing was performed on 5-MeO-DMT benzoate and the common 5-MeO-DMT HCI salt according to the previously described methods (of the previous Example). The results of this are shown below:
Figure imgf000020_0001
The 5-MeO-DMT benzoate produced 'mild' irritation compared to the 5-MeO-DMT HCI which scored as 'moderate' on testing.
Exgmple 7: Permegtion dgtg
The use of ovine nasal epithelium to study nasal drug absorption is a technique which is well known to the person skilled in the art. The permeation of 5-MeO-DMT benzoate and 5-MeO-DMT HCI has been studied by the current applicants. Dosing solutions corresponding to 1.25% concentration were prepared in water and applied to ovine nasal epithelium. The average cumulative (pg/cm2) of permeation of the benzoate and hydrochloride salt are shown in the Table below (mean ± SD, n=5):
Figure imgf000020_0002
The cumulative amount of 5-MeO-DMT benzoate and 5-MeO-DMT hydrochloride which permeated through ovine nasal epithelium per unit area following application of 1.25% dosing solutions prepared in water (mean ± SD, n=5) can be seen in Figure 5. As can be seen, the benzoate salt has higher permeation across the epithelium. The above data obtained in the above test show that the 5-MeO-DMT benzoate salt gives higher permeation with less mucosal irritation than the commonly used HCI salt; and so this combination of properties makes the benzoate salt an ideal candidate for mucosal delivery. For example, less 5-MeO-DMT benzoate salt may be needed by inhalation to provide the same benefit as the HCI salt and the benzoate salt is less irritating, and so provides a synergistic benefit. Smaller amounts of compound also make inhalation easier to accomplish.
Exgmple 8: X-Rgy Powder Diffraction (XRPD) of 5-MeO-DMT benzoate
The XRPD pattern of 5-MeO-DMT benzoate salt was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material. XRPD patterns of the benzoate salt prior to and following particle size reduction can be seen in Figures 6 and 7 respectively. The XRPD patterns of the benzoate salt prior to and following particle size reduction overlaid on one another can be seen in Figure 8.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO- DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO- DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0,
11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20 as measured by x- ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5,
17.7. 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.1°20. In an embodiment, there is provided crystalline 5-MeO- DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.1°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A.
In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram as substantially illustrated in Figures 6, 7 or 8. Example 9: Spray drying parameters
In an embodiment, there is provided a composition of 5-MeO-DMT benzoate which is a dry powder. In an embodiment, this composition is presented in a single dose nasal applicator.
In an embodiment, 5-MeO-DMT benzoate and HMPC input solutions are made up using sterile water and left to stir until fully dissolved.
In an embodiment, the spray drying parameters used to produce a dry powder of 5-MeO-DMT benzoate and HPMC are selected from those set out in the Table below:
Figure imgf000022_0001
Example 10: A double-blind, randomised, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate (BPL-003) in healthy subjects
A single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5- MeO-DMT benzoate (BPL-003) was performed. The doses tested were 1 mg, 2.5 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg.
The pharmacokinetics were shown to be approximately dose linear. No dose exceeded the maximum exposure limits defined by previous preclinical work in dogs: Cmax: 421 ng/mL or AUC 220 h*ng/mL. The mean (+/- SD) 5- MeO-DMT plasma linear concentration-time plot and plasma log concentration-time plot are shown in Figures 9 and 10, respectively.
The mean Cmax was 29 ng/mL for the 12 mg dosage. The mean Tmax was 9.5 minutes whilst the mean half-life (ti/2) was 21 minutes. Bufotenin, the O-demethylated metabolite of 5-MeO-DMT, was only detected at very low levels at the 6 mg dose level after the 16 minutes time point.
Summary statistics for the plasma 5-MeO-DMT, bufotenin PK concentrations, excluding a patient/subject that had a complete profile below the limit of quantification (BLQ) (1 mg), can be seen in the Table below:
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Summary statistics for the derived plasma 5-MeO-DMT, bufotenin PK concentrations, excluding a patient/subject that had a complete profile below the limit of quantification (BLQ) (1 mg), can be seen in the Table below:
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Trial Participants:
Forty-four healthy adult male and female participants aged between 25-55 years with a body mass index of 18.0-30.9 kg/m2 were enrolled in the trial. All participants were psychedelic-naive. Participants were recruited via online advertisements and word of mouth.
Trial Design:
This was a Phase I, double-blind, randomised, and placebo-controlled trial in psychedelic-naive healthy participants to evaluate the safety, tolerability, PK, and PD of single ascending intranasal doses of BPL-003 (5- MeO-DMT benzoate salt, dry powder formulation; Beckley Psytech Ltd, Oxford, UK).
Participants were divided into 7 cohorts of up to 7 participants per cohort. In each cohort, 4 (Cohorts 1-4) or 5 participants (Cohorts 5-7) received single intranasal doses of BPL-003 (1, 2.5, 4, 6, 8, 10, or 12 mg in Cohorts 1-7, respectively), and up to 2 participants per cohort received matching placebo (Table 1). BPL-003 or placebo were administered using an Aptar Unidose dry powder intranasal spray device. Sentinel dosing was used with 2 participants in each cohort (one active and one placebo), dosed at least 23 hours before the remaining participants. After each dose level, a Safety Review Committee reviewed safety, tolerability, PK, and PD (Mystical Experience Questionnaire [MEQ-30]) data and the dose was escalated only if deemed acceptable.
Screening and Preparation:
Participants were screened within 56 days before their dose of the trial drug. All participants had 2 psychedelic preparatory visits (one online and one in-person) with a trained psychedelic monitor before being dosed (Day - 7 and Day -3) to prepare the participant for trial drug administration, provide information about 5-MeO-DMT and to establish rapport between the participant and the monitor.
Dosing Visit:
Participants were at site from the day before dosing until the morning after dosing. An indwelling intravenous catheter was inserted before trial drug administration, for the collection of PK samples. During the session, a nurse and one psychedelic monitor were present in the room, to provide non-directive support and reassurance for participants. To ensure optimal setting for the psychedelic session, dosing took place in a calm, decorated room and a prepared playlist with relaxing music was playing. To ensure psychological comfort and aid relaxation, participants were instructed to do breathing exercises before dosing.
For up to 90 minutes post-dose, participants and the psychedelic monitor rated overall subjective drug intensity. After dosing, participants had a one-to-one guided interview with an independent researcher to discuss their psychedelic experience. Psychometric scales were administered to provide quantitative measures of the participant's psychedelic experience after the interview. All participants had their individual psychological wellbeing, including measures of suicidality, assessed by the trial psychiatrist before discharge from the ward.
Psychedelic Integration Visit:
Participants had an integration visit 2 days after dosing to discuss their experience on a one-to-one basis with the psychedelic monitor. The session could either be done on the ward or conducted via video call, if deemed acceptable by the psychedelic monitor.
Follow-up Visit:
All participants returned to the ward for a follow-up visit around 7 days after administration of the trial drug.
Lifestyle Restrictions:
Participants were required to adhere to several lifestyle restrictions before the study, during the study, and whilst awaiting follow-up.
Compliance with Ethical Standards:
This trial was conducted in accordance with International Council for Harmonisation Good Clinical Practice guidelines and ethical principles that have their origin in the Declaration of Helsinki. Protocols were approved by the Medicines and Healthcare Products Regulatory Agency and an independent recognised NHS research ethics committee before eligibility screening. Written informed consent was obtained from each participant before any trial-related procedures were performed.
Trial Drug: BPL-003 or matching placebo were administered as a single intranasal spray into 1 nostril by a trained member of the research team (usually a registered nurse), in the presence of a psychedelic monitor, using the Aptar Unidose dry powder delivery device.
Safety Assessments:
Safety and tolerability were evaluated by recording the incidence and severity of treatment-emergent adverse events (TEAEs) throughout the trial, review of clinical laboratory tests, vital signs (blood pressure, heart rate and temperature), electrocardiograms (ECGs), physical examinations and Columbia-Suicide Severity Rating Scale (C-SSRS) questionnaire responses. A nasal examination was performed pre- and post-dose to determine if there were any nasal site reactions following study drug administration.
Hallucinogen Persisting Perception Disorder (HPPD) is a rare clinical condition in which patients who have had previous exposure to a hallucinogenic substance may experience perceptual distortions after cessation of the initial substance use. In this trial, HPPD was assessed at follow-up.
Post Traumatic Stress Disorder (PTSD) can be caused by a traumatic experience and was assessed at follow-up via a checklist for DSM-5 (PCL-5) scores. The PCL-5 is a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. Subjects rate each item from 0 (not at all) to 4 (extremely) to indicate the degree to which they have been affected by that symptom over the past month.
Pharmacokinetic Assessments:
Plasma and urine 5-MeO-DMT and bufotenine concentrations were quantified in a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. Blood samples were taken pre-dose (dosing day) and at 0.5, 2, 4, 6, 10, and 16 minutes, and 0.5, 1, 1.5, 4, and 24-hours post-dose. Urine samples were collected continuously from 0-6 hours post-dose.
Plasma PK parameters evaluated included maximum plasma concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC) from time 0 to time of the last quantifiable concentration (AUCiast), AUC extrapolated to infinity (AUGnt), terminal half-life (ti/2), and terminal elimination rate constant (Az) for both analytes, plus volume of distribution (Vz/F) and clearance (CL/F) for 5-MeO-DMT only.
Urine PK parameters included the amount of unchanged drug excreted in urine at time t (Aet), fraction of administered drug excreted unchanged in urine (fe ), and renal clearance of drug from plasma (CLR), as well as metabolite Aet and CLR.
Pharmacodynamic Assessments:
Subjective Drug Intensity (SDI)
The intensity of BPL-003 subjective effects were rated by the participant and psychedelic monitor using the SDI, a Likert Scale of 0-10, where 0 was 'definitely no effect' and 10 was 'the strongest effect imaginable for 5- MeO-DMT'. The assessment was performed every 2 minutes for up to 90 minutes post-dose, and if the trial participants were not responsive, the psychedelic monitor would assess the rating to be 10.
Mystical Experiences Questionnaire (MEQ-30)
The MEQ-30 is a 30-item questionnaire to evaluate mystical experiences, with subdomains to measure mystical, positive mood, transcendence, and ineffability factors. Participants rated the degree to which they experienced each of the 30 phenomena using the following scale: 0 (none; not at all), 1 (so slight cannot decide), 2 (slight), 3 (moderate), 4 (strong [equivalent in degree to any other strong experience]) or 5 (extreme [more than any other time in my life and stronger than 4]). Means were calculated for each subdomain and a total overall score. The % of participants experiencing a "complete mystical experience" in each dose cohort was assessed by calculating the number of participants that scored 3 and above (>60% of the attainable value) in all of the four subdomains of the MEQ-30.
Subjective Experience Data via Qualitative Interview
A description of the BPL-003 subjective experience data was gained from a qualitative interview utilising the "micro-phenomenology" interview technique. Participants were asked to take part in this optional qualitative interview. If they agreed, the interview commenced on cessation of the psychedelic experience and before any post-dose questionnaires were completed.
Challenging Experience Questionnaire (CEQ) The CEQ has been used to characterise challenging experiences with psilocybin and is used in this trial to characterise and quantify any potentially challenging experiences with BPL-OO3. The questionnaire is grouped into 7 factors with 26 questions rated 0 (none/not at all) to 5 (extreme/more than ever before). Means % scores were calculated for each factor and total overall % score.
Statistical Analysis:
This trial was exploratory, with no null hypotheses to be tested. No formal sample size determination was made. Summary statistics (arithmetic mean, standard deviation [SD], geometric mean, minimum and maximum) were produced for plasma and urine concentrations of 5-MeO-DMT and bufotenine at each timepoint available. Actual times were used to derive PK parameters, and missing data were not imputed.
Results
Baseline Characteristics:
44 participants enrolled in the trial, of which 13 received placebo and 31 received a single dose of BPL-OO3. All 31 participants (100%) who received a dose of BPL-003 were included in all PK and PD populations. Participant demographic characteristics are summarised in the Table below; most participants were male (73%) and white (59%).
Table: Participant demographic characteristics
Figure imgf000032_0001
AA, African American; BMI, body mass index; N, number of participants; SD, standard deviation.
Safety and Tolerability:
Overall, 21 participants (47.7%) had TEAEs across all cohorts; 19 participants (61.3%) that received BPL-003 and 2 participants (15.4%) that received placebo. The incidence of TEAEs in participants that received BPL-003 did not appear to correlate with dose. Most TEAEs 34 out of 38 (89.5%) were mild in severity; 4 out of 38 (10.5%) were moderate in severity. There were no severe or serious TEAEs, or any TEAEs leading to withdrawal from the trial. All TEAEs and the number of times each event occurred are shown in the Table below. The most frequently reported TEAEs were nasal discomfort (10 participants [26.3%]; all taking BPL-003 [2.5-8 mg and 12 mg]), nausea (7 participants [18.4%]; all taking BPL-003 [4-12 mg]), vomiting (5 participants [13.2%]; all taking BPL- 003 [4, 8 and 12 mg]), and headache (4 participants [10.5%]; 1 [7.7%] taking placebo vs. 3 [9.7%] taking BPL- 003 [4 and 8 mg]).
It was surprisingly found that the number of reported TEAEs for the 10 mg dose were half that reported for the 8 mg dose. No participants receiving the 10 mg dose reported nasal discomfort, whereas nasal discomfort was reported in at least 1 participant receiving any of the 2.5 mg, 4 mg, 6 mg, 8 mg and 12 mg doses. No vomiting was reported for participants receiving the 10 mg dose, whereas vomiting was reported for 40% of those receiving the 12 mg dose and 20% of those receiving the 8 mg dose.
There is therefore provided a pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved side effect profile. There is therefore provided a pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved tolerability profile.
Table: Summary of treatment-emer ent adverse events.
Figure imgf000034_0001
There were no clinically significant findings for laboratory parameters, vital signs, ECGs, or physical examinations. There were transient increases in blood pressure and heart rate which began soon after BPL-OO3 treatment but recovered within the 90-minute observation period without intervention. None were considered clinically significant or assessed as AEs by the Investigator.
Post-dose heart rate above the reference range were recorded in 1 (7.7%) participants after placebo and 12 (38.7%) participants after BPL-OO3. Post-dose diastolic blood pressures above the reference range were recorded in 1 (7.7%) participants after placebo (93 mmHg) and 15 (62.5%) participants after BPL-OO3 (ranging 91-109 mmHg). Post-dose systolic blood pressures above the reference range were recorded in 4 (30.8%) participants after placebo (range 146-155 mmHg) and 14 (45.2%) participants after BPL-003 (range 141-181 mmHg). Systolic blood pressure over time and the peak post-dose systolic blood pressure can be seen in the Tables below.
Table: Mean systolic blood pressure over time
Figure imgf000035_0001
Time points selected to reflect peak elevations and return to baseline.
Max, maximum; min, minimum.
Table: Post-dose peak systolic blood pressure
Figure imgf000035_0002
There were transient increases in systolic blood pressure >160 mmHg in 5 participants. These occurred at the height of the psychedelic experience when there were also substantial arm and body movements.
No participant reported any suicide-related thoughts or behaviours. No HPPD (clinical assessment) or PTSD symptoms (PCL-5 scale) were evident at follow-up for any participant treated with placebo or BPL-003.
Pharmacokinetics
Plasma 5-MeO-DMT Pharmacokinetics
Mean plasma concentration-time curves of 5-MeO DMT are presented in Figure 18 and PK parameters are summarised in the Table below.
Figure imgf000036_0001
+n=2; *n=3; *n=4. a Geometric mean. b Arithmetic mean. 5-MeO-DMT, 5-Methoxy-N,N-dimethyltryptamine benzoate; Aee, amount excreted unchanged in urine up to 6 h post-dose; AUC, area under the plasma concentration-time curve; AUGnf, AUC extrapolated to infinity; AUCiast, AUC up to the last measurable concentration; AUCs, AUC up to 6 h post-dose; Cl, confidence intervals; CL/F, apparent total clearance from plasma after intranasal administration; CLR,6, renal clearance of drug from plasma based on urine/plasma concentration data up to 6 h post-dose; Cmax, maximum (peak) plasma concentration; %CVb, between-participant coefficient of variation; fe,6-F, fraction of dose excreted unchanged in urine up to 6 h post-dose; N, number of participants; PK, pharmacokinetic; SD, standard deviation; Tmax, time of Cmax; ti/2, terminal elimination half-life; Vz/F, apparent volume of distribution after intranasal administration; Az, terminal rate constant.
BPL-OO3 was rapidly absorbed, with a median Tmax of 4 to 15 minutes post-dose across all dose levels. Elimination of 5-MeO-DMT was rapid across all dose levels. Arithmetic mean t% ranged from 15 to 27 minutes across dose levels. Plasma 5-MeO-DMT concentrations were below the limit of detection by 4 hours after administration in all subjects. Variability between participants was generally low to moderate, where all participants in a group had quantifiable 5-MeO-DMT plasma concentrations.
Systemic exposure to 5-MeO-DMT (Cmax and AUC parameters) generally increased with BPL 003 dose. Geometric mean Cmax was 5.74 ng/mL after 1 mg BPL 003 and 28.2 ng/mL after 12 mg. Arithmetic mean CL/F and Vz/F were 522 to 953 L/h and 207 to 526 L, respectively, across all dose levels. There did not appear to be a correlation between BPL-003 dose and CL/F and Vz/F. No dose exceeded the pre-defined toxicokinetic thresholds of 421 ng/mL for Cmax and 220 h*ng/mL for AUCint.
Plasma Bufotenine Pharmacokinetics
All bufotenine plasma concentrations were below the limit of quantification (BLQ) (<0.5 ng/mL) except in one sample for 1 participant.
Urine 5-MeO-DMT Pharmacokinetics
Urinary PK parameters for 5-MeO-DMT are summarised in the Table above. Urine concentrations of 5-MeO- DMT were BLQ in most participants after 1 mg BPL-003, and in a few participants after higher doses of BPL- 003.
Urine excretion of 5-MeO-DMT appeared negligible. The arithmetic mean fraction of 5-MeO-DMT excreted unchanged (fe- F) at 6 hours post-dose ranged between 0.06% to 0.38% across dose levels. Due to the low levels of 5-MeO-DMT detected in urine, PK parameters derived were highly variable.
Urine Bufotenine Pharmacokinetics
Urine levels of bufotenine were all BLQ (<0.5 ng/mL).
Pharmacodynamics
BPL-003 SDI
Overall, both monitor and participant drug intensity ratings increased with BPL-003 dose, indicating stronger subjective experience of BPL-003 with increasing dose. SDI onset was rapid, generally within 2-10 minutes and short-lasting, generally resolving completely within 45-90 minutes. Mean subjective intensity scores of participants in the placebo and the highest four BPL-003 doses are shown in Figure 19. The SDI scale has a maximum score of 10, and the mean maximum SDI score achieved by participants increased up to 6 mg BPL- 003, after which it plateaued.
Effects by M EQ-30
Generally, the Mystical Experience Questionnaire-30 subdomain and total scores increased with BPL-003 dose, with the highest total score of 3.7 at the highest (12 mg) BPL-003 dose level and the lowest total score of 0.58 with placebo (Figure 20 and the Table below). A complete mystical experience, defined by reaching or exceeding a score of 3 on all four subdomains of the scale, was reported in 3 out of 5 participants (60%) at both the 10 mg and 12 mg doses; for lower doses a maximum of 1 participant had a complete mystical experience (<25%). Table: Summary of MEQ-30 scores
Figure imgf000038_0002
Figure imgf000038_0001
MEQ, mystical experience questionnaire; SEM, standard error of the mean
There is therefore provided a pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved side effect profile and produces a complete mystical experience. There is therefore provided a pharmaceutical composition comprising 10 mg 5-MeO-DMT wherein said composition has an improved tolerability profile and produces a complete mystical experience.
Effects by CEQ
Challenging Experience Questionnaire scores were generally less than 40% across the 7 subdomains, with total CEQ scores ranging from 20-37% for BPL-003 of 4 mg to 12 mg (Table 8).
BPL-003 Subjective Experiences by Qualitative Interview
The common psychedelic experiences that were reported during the qualitative interviews highlighted the dynamic temporal progression of the subjective effects. Generally, participants described a rapid onset of the psychedelic effects, followed by inward focussed attention, altered sense of time, intense emotions, with various degrees of fear or discomfort, as well as a psychological struggle to "let go and surrender" to the experience. If participants were able to relax into the experience and "let go", the sensation of floating in space, an ocean or void often followed, with feelings of peacefulness, calmness, relaxation or bliss. At the higher doses (10 mg and 12 mg of BPL-003) most participants appeared to experience a complete mystical experience. Gradually external awareness returned, and participants stated this allowed them to reflect on their experiences, often recounting meaningful insights.
Many participants emphasised the importance of the psychological preparation, and the rapport and trust they built with the psychedelic monitors which they said helped participants to feel safer during the experience. Even participants who had challenging experiences, reported having benefited from these, as new insights or learnings about overcoming difficulties, or processing repressed or avoided memories justified the challenge.
Discussion
Several psychedelic compounds are currently undergoing clinical trials to assess their utility for diverse neuropsychiatric indications, and some have shown encouraging efficacy signals in larger controlled clinical trials. The compounds differ not only in their receptor occupancy profiles but also their PK and PD parameters and subjective effects. There is a wealth of evidence that implicates the 5 HT1A receptor in the pathophysiology of depression/major depressive disorder and it is a therapeutic target for many antidepressants. 5-MeO-DMT has a unique profile that, in addition to the activation of the 5-HT2A receptor, also shows a preferential receptor affinity to the 5-HT1A receptor.
The mode of administration of psychedelic compounds influences the variability and absorption characteristics, and for parenteral applications the intranasal delivery route seems to be a promising approach. This study investigated a proprietary formulation of synthetic 5-MeO-DMT benzoate salt given as a dry power in an intranasal Unidose spray device. Results demonstrated predictable PK parameters; dose-proportional increase in exposure levels, a rapid absorption, and brief Tmax of around 10 minutes, and a short t% of around 20 minutes, which corresponded with profound and short-lasting consciousness-altering effects of 45-90 minutes in duration. Most TEAEs were mild in severity (89.5%) and resolved within minutes after BPL-OO3 exposure, and all other TEAEs were moderate in severity (10.5%). There were no SAEs, otherwise significant TEAEs, or TEAEs leading to participant withdrawal during the trial. The most frequently reported TEAEs (>5%) were nasal discomfort, nausea, vomiting, and headache. Generally, less AEs were observed in this study when compared to psychedelic use in uncontrolled circumstances, reinforcing 5-MeO-DMT administration is safer in a clinical setting.
There were no clinically significant laboratory, vital sign, ECG, or physical examination findings. Participants experienced no increase in suicidal thoughts, intentions or behaviour as measured by the C-SSRS. Additionally, there were no HPPDA and PTSD assessment concerns. Transient increases in heart rate and blood pressure were observed with BPL-003 treatment; however, these resolved rapidly without treatment. This is in line with literature reports of other short-lasting psychedelics, e.g. trials with DMT in healthy volunteers.
One of the objectives of this study was to identify and explore a well-tolerated dose of BPL-003 that would reliably elicit profound mystical experiences in most trial participants, to evaluate whether progression into patient studies was appropriate. A dose range of 10 to 12 mg was found to meet this requirement, with 60% of participants experiencing a complete mystical experience and/or ego dissolution events. The elicitation of full mystical experiences is thought to be an encouraging indicator for future therapeutic efficacy.
We observed a clear relationship between plasma 5-MeO-DMT concentration and the reported drug intensity. The onset, length, and intensity of the psychedelic experience after administration of 8, 10, and 12 mg BPL-003 followed the plasma concentration closely, indicating a close relationship between pharmacokinetic and pharmacodynamic measures.
A significant strength of this study was that all participants enrolled were evaluated and no participants were lost to follow-up, resulting in a complete data set for analysis. None of the participants had experience with using psychedelics prior to the study which may also be viewed as a strength, as it reduces the likelihood of a positive bias and is likely representative of future clinical populations, where the reported lifetime use of psychedelic substances is reported to be between 13.4-13.6%.
Conclusion
Psychedelic effects increased with BPL-003 dose, with a rapid onset of profound psychedelic effects that were short (45-90min) in duration. The results of this single ascending dose study indicates that doses between 8-12 mg of BPL-003 are suitable for further pharmaceutical development in neuropsychiatric conditions with high unmet medical need, in particular the 10 mg dose which exhibited a particularly desirable side effect profile.
Example 11: A double-blind, randomised, Phase 1, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT HCI (BPL-002) in healthy subjects
A single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5- MeO-DMT HCI (BPL-002) was performed. BPL-002 comprises 5-MeO-DMT HCI, HPMC, water for injection (WFI) and a sodium hydroxide solution to adjust pH. An initial stock solution of 0.5% w/w HPMC was prepared using sterile water for injection which was further diluted with sterile water for injection to approximately 90% of the final weight required. The required amount of drug substance (70 mg/ml or 140 mg/ml Freebase) was then dissolved in an aliquot of the 0.5% w/w HPMC stock solution with stirring and the pH of the active stock solution was then adjusted to 6.00 +/- 0.25 by adding sodium hydroxide (0.1 M solution). The IPC measurement was taken to ensure the pH is adjusted within the accepted range before making up to the final weight with sterile water for injection The concentration of the HPMC in the final solution was 0.1% w/w. Placebo solutions of 0.1% w/w HPMC were made up by dissolving the required amount of HPMC in sterile water for injection (approximately 90% of final weight) and adjusted for pH 5.75 +/- 0.25 if necessary by the addition of sodium hydroxide solution (0.05 M). The in process check measurement was taken to ensure the pH is adjusted within the accepted range before making up to the final weight with sterile water for injection. The concentration of the HPMC in the final solution was 0.1% w/w.
The mean (+/- SD) 5-MeO-DMT plasma linear concentration-time plot and plasma log concentration-time plot are shown in Figures 11 and 12, respectively. Summary statistics for the plasma 5-MeO-DMT, bufotenin PK concentrations, can be seen in the Table below:
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Summary Statistics for Derived Plasma 5-MeO-DMT, Bufotenine PK Parameters can be seen in the Table below:
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000046_0001
Example 12: Mouse Forced Swim Test
This study aimed to assess the effect of 5-MeO-DMT Benzoate at three doses in the mouse Forced Swim Test (FST). Husbandry
Housing and Acclimation
Animals received a 72-hour period of acclimation to the test facility prior to the commencement of testing.
Animals were housed four per cage in polycarbonate cages bedded with %" bed-o'cob. Cages were changed, and enrichment provided according to standard operating procedures. Animals were maintained on a 12-hour light/12-hour dark cycle with all experimental activity occurring during the animals' light cycle. All animal use procedures were performed in accordance with the principles of the Canadian Council on Animal Care (CCAC).
Food and Water
Certified Rodent Diet (LabDiet® 5001) was offered ad libitum. Animals were not fasted prior to, or after the experiment was initiated. Water was provided ad libitum in glass bottles with stainless steel sippers. Study Design
Test Subjects
Male CD-I mice from Charles River Laboratories (St. Constant, Quebec, Canada) served as test subjects in this study. Animals generally weighed 25-30 g at the time of testing.
Schedule of Events
Figure imgf000046_0002
Figure imgf000047_0001
Treatment Groups
Animals were randomly allocated into the following treatment groups:
Figure imgf000047_0002
Pre-FST Behavioural Test
On day 0, in addition to the forced swim test animals were evaluated for signs of 5-HT (serotonin) syndrome. Animals were exposed to activity chambers for 10 minutes at two timepoints post dose: (1) 5-15 minutes post dose, and (2) 2.5 hours post dose.
Forced Swim Test
Male CD-I mice received the appropriate dose of vehicle, test article, or positive control (treatments summarised above). Following the appropriate pretreatment time, animals were gently placed into tall glass cylinders filled with water (20-25°C). After a period of vigorous activity, each mouse adopted a characteristic immobile posture which is readily identifiable. The swim test involves scoring the duration of immobility. Over a 6-minute test session, the latency to first immobility is recorded (in seconds). The duration of immobility (in seconds) during the last 4 minutes of the test is also measured. Activity or inactivity from 0-2 minutes is not recorded.
Test Articles
5-MeO-DMT Benzoate
BEW: 1.59 (Benzoate salt form)
MW: 340.40 g/mol
Doses: 0.5, 1.5, 5 mg/kg (doses corrected to base)
Route of administration, dose volume: SC., 10 mL/kg
Pre-treatment time: 3 hr
Vehicle: 0.9% Saline
Imipramine
BEW: 1.13
MW: 280.415 g/mol
Doses: 30 mg/ kg (doses corrected to base)
Route of administration, dose volume: IP., 10 mL/kg
Pre-treatment time: 3 hr
Vehicle: 0.9% Saline Results
At 3-hour post-dose, over the 6-minute test session, there is a positive trend in reducing the duration of immobility and increasing latency to immobility by the low doses of 5-MeO-DMT benzoate (0.5 and 1.5 mg/kg), compared to vehicle-treated mice (time immobile 2-6 minutes, vehicle: 190.4 ± 7.7 seconds - 5-MeO-DMT benzoate: 133.2 ± 24.9 seconds (0.5 mg/kg), 137.6 ± 17.0 seconds (1.5 mg/kg), 156.8 ± 18.7 seconds (5 mg/kg) - Imipramine 46.8 ± 16.6 seconds, Figure 13. Latency to immobility, vehicle: 95.5 ± 4.6 seconds - 5-MeO-DMT benzoate 121.8 ± 22.0 seconds (0.5 mg/kg), 120.9 ± 13.3 seconds (1.5 mg/kg), 85.0 ± 9.5 seconds (5 mg/kg), imipramine 268.6 ± 30.3 second, Figure 14).
Example 13: Dynamic Vapour Sorption (DVS) comparison of 5-MeO-DMT benzoate and HCI
The DVS profile for 5-MeO-DMT benzoate salt, revealed reversible water uptake/loss over the humidity range and no hysteresis. The water uptake/loss from 0 to 90% was gradual and amounted to a maximum of ca 0.20% and was a consequence of wetting of the solid. There was no evidence of form/version modification as a consequence of exposure of 5-MeO-DMT benzoate salt to variable humidity. The DVS isotherm can be seen in Figure 15.
The DVS isotherm of a 5-MeO-DMT Hydrochloride, lot 20/20/126-FP (Figure 16) was found to undergo significant moisture uptake upon the first sorption cycle from 70%RH. Approximately 23% w/w uptake is observed between 70-80% RH, whereas less than 0.3% w/w moisture uptake from 0-70% RH was observed. A further 20% w/w moisture uptake is observed up to and when held at 90% RH before commencement of the second desorption cycle. Subsequent sorption and desorption cycles follow a similar profile with some observed hysteresis between operations that do not match the original desorption step. These return to ca. 6- 9% w/w above the minimum mass recorded at 0% RH, which indicates significant retention of moisture. Upon completion of the DVS cycle, the input material was noted to have been completely deliquesced.
A modified DVS isotherm of lot 20/45/006-FP (the same crystalline version) was undertaken to examine material behaviour from 60% RH and above. A 2 cycle DVS with desorption beginning from 40-0% RH with sorption from 0-60% RH in 10% RH intervals, followed by incremental 5% RH increases to 65, 70, 75, 80 and finally 85% RH. This was to obtain in-depth profiling of the material towards humidity at these elevated levels.
No significant moisture uptake/loss in the first desorption-sorption profile between 0-70% RH was noted (Figure 17) followed by a ca. 0.46% w/w increase from 70-75% RH. A further ca. 7% uptake is observed from 75-80% RH, then ca. 40% from 80-85% w/w. Complete deliquescence of the solids was observed upon isolation of the material post DVS analysis, which had likely occurred above 80% RH.
Temperature and humidity are important factors in the processing and storage of pharmaceuticals. DVS provides a versatile and sensitive technique for evaluating the stability of pharmaceutical formulations. The DVS profiles show that the stability of the benzoate salt of 5-MeO-DMT is significantly higher than that of the hydrochloride salt and is therefore a more promising salt for development as a pharmaceutical composition.
Example 14: Administration of 5-MeO-DMT
The physical surroundings of the participant/patient/subject are of high importance in the character of many psychedelic experiences. The space should be private, meaning that there should be no chance of intrusion by others. Ideally, sound from outside (e.g. the hallway, the street, etc.) will be minimal. The dosing sessions should take place in rooms that feel like a living room or den rather than a clinical setting. Artwork, plants, flowers, soft furniture, soft lighting, and related decor should be employed in creating a cosy and relaxing aesthetic. Artwork with any specific religious iconography, ideological connotation, or tendency to evoke negative emotions should be avoided. The dosing room may also provide comfortable furniture for the participant and the therapists, who may sit on either side of the participant. Participants under the effect of 5-MeO-DMT may exhibit spontaneous movement or slide off of the bed or couch in their prone position. It is therefore important to make sure no sharp or hard objects are nearby that the participant may fall on. Additionally, pillows may be useful to physically support participants who are mobile during the experience. A therapist can provide physical support to the participant by placing a pillow between their hands and the participant's body.
Music may accompany the experience, so the dosing room should be equipped with a stereo. The room should shield the participant from sights and sounds of the world beyond the room, and the participant should not have any cause for concern of observation or interruption by anyone other than the therapists.
The space may also contain: The tools for safety procedures and medical devices necessary to respond in the unlikely event of a medical complication. The participant should be made aware of these procedures and the equipment, but as much as possible they should be hidden from view.
A secured and locked space for study materials and documentation in the session room or nearby.
An approved safe for storing the 5-MeO-DMT in the session room or nearby.
Audio and video-recording equipment: If allowed in the study protocol the participant will have already consented to being recorded, and should be made aware of the equipment, but it should be placed to be as unobtrusive as possible. Participants may request the cessation of recording at any time.
Physical Space
The space may be large enough to accommodate chairs for two therapists, the stereo equipment and cabinet for storage of the participant's belongings and any extra supplies the therapists may need during the day. The space may accommodate a bed or couch on which the participant can either sit up or lie down with a comfortable surroundings of pillows. The space may be at least 1002 feet or 102 metres so that participants do not feel cramped or too physically close to therapists. Participants should have room to explore a variety of positions including sitting on the floor or stretching their bodies without restriction. A bathroom should be either accessible directly from the session room or nearby.
Music
5-MeO-DMT sessions may use a pre-set playlist of nature sounds for creating a calm atmosphere. These nature sounds are considered to be a background element, helping drown out any noise from outside the room, and keep the participant focused on their experience. Participants are not instructed to listen to the sounds in any particular way, but may be asked to focus on it as a way of grounding their senses and relaxing before or after a session.
Medication Discontinuation
Medication discontinuation can be challenging for participants. Participants are to have discontinued all contraindicated medications and completed washout periods prior to Prep-1 with the therapist. The study team members, including the therapist, may provide supportive check-in calls with the participant prior to this, as- needed during the washout period, but should not start Prep-1 until washout is complete and the participant confirms intention to continue with the therapy.
Preparatory Sessions
This treatment model includes three, 60-90 minute preparatory sessions with the therapist. These take place 7 days, 4 days, and 1 day before the 5-MeO-DMT session. Preparatory sessions are designed to take place via telemedicine, but can be in-person if possible.
Preparatory Session 1
The following topics may be covered in the first preparatory session.
Getting to know the participant
The therapist will spend some of the preparation session time getting to know the participant. The therapist may ask open-ended questions about:
How they found out about the treatment and what their expectations are;
Current life situation with regards to living situation, work, school, and important relationships;
Understanding of their own depression/major depressive disorder;
Key life events that the participant feels might be of relevance
The therapist should be listening for how the participant talks about themselves and their relationship to their depression/major depressive disorder, how they relate to the therapist and study environment, and stay attuned to establishing a sense of trust and rapport with the participant. Clinical impressions of difficulty forming a trusting relationship with the therapist or any other clinical factors that could interfere with the participants' ability to engage in the treatment should be noted and discussed with the study team. Although in the preparatory session stage, the therapist may learn more of the participant that could be reasons for study exclusion. Establishing the role of the therapist
Therapists in the 5-MeO-DMT-assisted therapy treatment model form a relationship with study participants which becomes part of the container in which the 5MDE (subjective experience of 5-MeO-DMT) takes place. This formation of this relationship is deliberate on the therapists part and characterised by the therapist establishing transparency and trust, taking clinical responsibility for the patient's wellbeing, and relational and emotional safety for the patient. The therapeutic relationship is understood as a critical component of the set and setting for the therapeutic use of the 5MDE. The communication and establishment of this relationship is both explicit (overt) and implicit (covert) in the therapists behaviours and mannerisms throughout the treatment.
Explaining the therapeutic model with participant as active participant in their process
The therapist should explain the therapeutic model used in this research study to the participant in the first preparation session. The explanation should include:
Practical aspects:
How many meetings with the therapist will occur, and for how long.
That the therapy is thought to work by:
Creating a safe container for the experience so that the participant knows what to expect and can fully let go into their experience,
Helping the participant focus on and explore their own responses to the experience,
Facilitating a process of the participant determining for themselves how they will put their insights into practice in their life.
That the therapist's role is:
Supporting the participant through the session, engaging in a series of activities to elicit the participant's unique experience and insights, fostering the participant's process of implementing the resulting changes in their life.
That the therapy is:
Not a full deep dive into a participant's personal history, not a place to do specific problem solving or engage in CBT, Psychodynamic interpretations, get general advice, or receive other interventions the participant may be familiar with.
Establishing physical, emotional, and psychological/relational safety
Beginning in the first preparatory session the therapist establishes the environment of physical, emotional, and psychological safety. The therapist explains the safety of 5-MeO-DMT and the safety procedures relevant to the participants physical health for the session. With regards to emotional safety the therapist states that all emotional experiences are welcomed, that there is no area of experience that the participant is not welcome to share. Safety can also be established through the calm reassuring presence of the therapist, which does not always require the use of language.
The use of self-disclosure is not prohibited, but should be used very sparingly. A participant may be seeking safety by asking personal questions of the therapist. If the therapist chooses to disclose, it should be brief and under the condition the participant shares why this personal information is important to them.
Psychological/relational safety is established by assuring the participant that their wishes will be respected with regards to the use of touch. Also, the participant is to be reassured that if they choose not to participate in the 5MDE experience they may do so at any point up until drug administration and that this will be respected, and that the therapy sessions will still be available to them if they make that choice.
The therapist can use the following techniques to establish safety with the participant:
Ask open-ended questions that invite the expression of doubts, hesitancies, or concerns:
What questions do you have for me?
What more would you like to know about 5-MeO-DMT?
What would you find helpful in the event ... ?
How could I be of assistance to you if you feel ... ? Encourage and engage with the full range of participant's emotions and experiences without trying to fix or resolve them:
Participant expresses scepticism about the 5-MeO-DMT Experience: I appreciate you sharing that doubt with me. What do you make of that in light of your presence here at this time?
Participant expresses fear about the 5MDE Experience: What more can you tell me about your fear and how it manifests for you? How could I be helpful to you as you experience this?
Use affirmations to establish an environment of valuing the participant's time and effort:
I really appreciate the time you are putting into this treatment and your willingness to participate in research.
Your experience is unique to you and I appreciate the opportunity to see you through this process.
Expected potential subjective drug effects (unity, "feeling like dying", "the void",)
It may be helpful to discuss the concept of "non-ordinary state of consciousness" with participants. In the past, "altered state of consciousness" was often associated with experiences engendered by psychedelic compounds. However, alterations of consciousness are experienced on a daily basis, as moods or feelings shift, or when people shift from awake alertness to feeling tired and drowsy. "Non-ordinary state of consciousness" emphasises the quality of an experience that is not ordinarily had on a daily occurrence, but can still be within human experience.
The therapist may begin this conversation by asking the participant about their existing knowledge of 5-MeO- DMT effects, and listen for specific expectations or ideas about it. The therapist is to encourage an attitude of openness toward the experience, encouraging participants to explore what kinds/ideas they may have and be open to the possibility that it will not be possible to imagine what this will be like. Participants may have specific expectations based on the media, prior experience with 5-MeO-DMT or other psychedelics, or other kinds of non-ordinary states of consciousness. It is important for therapists to provide a balanced description of what the participant may experience.
Different people have different levels of comfort with "not knowing" what something will be like, or what to expect. The therapist may explore the participant's level of comfort with the unknown, their relationship to the idea of the future not being fully knowable in any situation, and how they generally relate to this. Among participants with depression/major depressive disorder there may be deep fear of the unknown, anticipation of what is expected in the future (more negative experiences), resulting in a feedback loop of feeling fearful and depressed. Therapists should elicit and explore this area during preparation.
Common 5-MeO-DMT Experiences: The therapist should also introduce a few key terms and commonly reported experiences known to occur under 5-MeO-DMT. These include a feeling of unity, a feeling of dying, and a feeling of entering or experiencing a "void" (absence of material reality). Some participants may have an existing spiritual, philosophical, or religious belief system through which they will interpret or make meaning of these experiences. Therapists should enquire about this and work with the participant's own explanation and terms, without taking a stance as to whether these are correct or erroneous..
Social Support and Social Media
Participant's social support may be assessed during preparation sessions and be determined by the therapist to be adequate to support the patient through the process of change, especially in the event of either disappointment or dramatic symptom reduction. In the event the participant has a psychotherapist outside of the study the study therapist may, with the participant's permission, have a phone call with the participants therapist to describe the nature of the study and therapeutic approach and answer any questions the therapist may have. The study therapist may also educate any friends or family members who are close to the participant and have questions regarding the nature of the study, the 5-MeO-DMT experience, and what to expect. The therapist should discuss social support with the participant including preparing the participant for the variety of reactions their friends and family may have.
Therapists may advise participants to take caution around posting about their experience on social media so as not to elicit excessive public commentary. Inadequate social support or use of social media in a way that may be disruptive to the therapeutic process may be discussed and resolved prior to 5-MeO-DMT administration.
Preparatory Session 2
The following topics may be covered in the second preparatory session. Drug experience preparation: trust, surrender (let go), embrace, transcendence.
There are several key attitudes towards psychedelic experiences that are considered to be conducive to a positive and clinically helpful experience. The more participants can embody a relaxed stance toward their experience the less likely they are to struggle, inadvertently creating a loop of stress and distress that heightens attention to negative aspects and interpretations. The therapist may educate the participant on the purpose of deliberately generating an attitude of trust, surrendering to the experience, and letting go of attempts to control the experience. Therapists may encourage participants to develop an attitude of welcoming and embracing all experiences they may have as part of their 5-MeO-DMT experience. The therapist may suggest to a participant that all aspects of the experience (feelings, sensations, and thoughts) can be welcomed. Previous research with psychedelics has demonstrated that a capacity to be absorbed by the experience can contribute to the potency of a mystical experience.
The Drug Administration
The therapist should explain that on the day of the session that a member of the research team will enter the room briefly to administer the study drug. The therapist should explain the participant positioning, e.g. they will be in a seated position on the bed or couch, that the research team member will insert the nasal spray device in one nostril, and that they will be asked to allow the therapist to assist them in lying down on the bed or couch immediately afterward.
Session procedures including boundaries, use of touch, safety, etc.
The therapist will explain the process of the session. The session is contained by the timing of the dosing and the physical environment of the dosing room. It begins when the participant enters the room and engages with the therapist in the Session Opening. Session Opening is a formal moment in which the participant and therapist sit together in the room, all preparations having been made, and the playlist started. The therapist may lead a breathing exercise of the participant's choice, if the participant is open to engaging in one, and ask the participant to reflect on the values they choose in the preparation session, or any other value or intention that is important to them. Once the participant signals that they are ready, a member of the research team will administer the nasal spray to the participant. Trust and safety are not only communicated verbally, but also this may be nonverbally through how a therapist holds themselves in the presence of the participant. If a therapist is overly anxious, or fearful, this may be felt by the participant. It is important that the therapist is centred throughout the dosing session, particularly at times when a participant is expressing intense affect, unusual somatic expressions, or is asking for support.
Somatic changes and shifts in one's sense of their body
Some participants may experience an intensified awareness of their body such as feeling their heart rate more strongly or physical sensations in their temple. Other participants may be aware of a tingling in their body, changes or perceived difficulty breathing, or other unusual physiological experiences. It is important for the therapist to communicate that these changes in perception are normal and should not be a focus of preoccupation or fear. If these sensations arise, the participant should be encouraged to communicate these to the therapist, if they so desire. The therapist should reassure the participant that these sensations are expected and are normal to have. The therapist can inform and remind the participant that naturally occurring 5-MeO- DMT has been consumed in other settings for hundreds of years with no indication that it is physically harmful, and that these changes are expected and will resolve shortly.
Discussing expectations and intentions
Expectations can be defined as mental representations and beliefs of how something in the future will be. Sometimes expectations can be explicitly identified, and sometimes they are sub perceptual, taken for granted. Both kinds of expectations may be important to treatment. The therapist should ask about explicit expectations and encourage the participant to acknowledge and set these aside such that they do not engage in comparing their experience to expectations. The therapist is also listening for sub perceptual expectations that may come into awareness through the therapy. Intentions are ways of relating to a behaviour or experience. In the 5-MeO- DMT treatment, it can be important for the therapist to elicit and understand the participant's intentions as these can vary greatly and may be taken for granted. Therapists are to engage participants in a process of identifying and setting their intentions such that these are explicit and can be referenced later in integration. The purpose of the intention is for it to be identified and then let go of, with the knowledge that it can be part of the 5MED. Recurrence of acute effects
Some individuals who used 5-MeO-DMT in non-clinical contexts have reported re-experiencing 5-MeO-DMT's subjective effects in the days after. The dose used, purity, and other factors were not monitored in these cases. The likelihood of these reactivations occurring in a controlled clinical study context is not known, but estimated to be less likely. Nonetheless, it is important for participants to be made aware of this phenomenon. The experience of reactivations are often reported as pleasant, brief (lasting a few moments to minutes), and do not occur with enough frequency to interfere with a person's life. These reactivations are thought by some as part of the integration process. If a participant notices certain activities trigger reactivations, such as certain meditative states, stimulants, or other drugs, and the participant finds these reactivations unpleasant, it should be suggested to the participant that they avoid such triggers. Processing the 5-MeO-DMT experience in therapy, as part of integration, may also be helpful.
Discussing the use of touch
Therapists in this modality may engage in two types of touch: therapeutic touch, and touch for safety reasons. During preparation the therapist should explain and define each. Therapeutic touch is touch that is intended to connect with, sooth, or otherwise communicate with the participant for therapeutic aims. It is always fully consensual, non-sexual, and the participant is encouraged to decline or cease therapeutic touch at any time. Touch for safety reasons can include supporting a participant who is having trouble walking by offering an arm to hold, or blocking a patient back from leaving the room while under acute drug effects. This touch is agreed to in advance, is always non-sexual, and limited to specific safety concerns. Therapists should discuss both of these and establish boundaries with participants ahead of session.
Preparing for after the session (what to expect, what to do, setting aside time for integration)
Participants should be encouraged to take some time to rest and integrate their experience after their session day. Study therapists should ask participants to plan for time off after their session, at least the full day of the session and the day after the session. Therapists should explain that after the acute effects of the 5-MeO-DMT have worn off they will stay together in the room for a while. This period of time will be for the participant to readjust to their experience after the acute effects. They will be asked to share what they can recall about their experience and any reactions they have. They will not be asked to share anything they don't want to share, and are welcome to keep their experience private. They may choose to write or draw about their experience, art supplies and writing supplies will be available. They may be encouraged to spend some time continuing to stay with their experience, with the therapist's support, for around an hour. They will then meet with the study team for a safety assessment before going home. Once at home they are encouraged to rest and continue to stay with the experience and the insights, ideas, or new understanding they may have from it. Participants should be reminded that they do not need to share their experience with others unless they want to, and are encouraged to continue to focus on it in whatever way they find most helpful. Participants should refrain from returning to work, from driving, drinking alcohol, drug use, or being a sole caregiver for a child or dependent for the rest of the day.
Therapist teaches Breathing Exercise for dosing session
When stressed, breaths become shorter and shallower, and when relaxed, the breath becomes longer and slower. Working with the breath is a way of modulating and regulating one's mental state. The therapist may teach and practise two breathing techniques with the participant. These are designed to help the participant relax their body and mind, tolerate stressful or uncomfortable experiences, and develop autonomy through practice on their own. These are not for use during the acute effects of 5-MeO-DMT, but can be used prior to dosing and afterward.
When teaching the practices, the therapist elicits the participant's individual response to each practice to assess suitability of using it. Breathing practices include: Balancing Breath, Diaphragmatic Breath and Counted Breath.
Preparatory Session 3
Values card sort with prompts
The therapeutic protocol may use a customised Personal Values Card Sort to assist with the therapeutic focus on shift in sense of self. This is done by asking about how people relate to their chosen values before the session, and how they relate to them afterward, drawing attention to shifts, changes, and using these as a guide for the kind of changes the participant may desire to make. It is used as a way to elicit conversation about the participant's sense of self, beliefs about self, and changes in those senses/beliefs throughout the therapy. Therapists may engage participants in the card sort exercise in the third preparation session such that it occurs 1-2 days before the dosing session.
The Values Card Sort Instructions are:
1. Place five anchor cards in order from 1-5 in front of the participant from left to right in order of least to most important.
2. Shuffle the 100 value cards; keep the 2 blank cards separate.
3. Instruct the participant to sort the cards using the following script: "I placed five title cards in front
Figure imgf000054_0001
4. When the participant is finished sorting, thank them and invite them to look at the "most important" category, removing the other cards from the table.
5. Read the following: "For the second task, I'd like you to focus on the top values you put in the "most important" category and choose the top five."
6. When the participant has chosen their top five cards, thank them and read the following: "For the third task, I'd like you to focus on the top five values you chose and rank them in order from most to least important."
7. When the participant indicates they are finished ordering, check to make sure you understand how the cards were sorted (ascending or descending). Point to the #1 spot and say, "I want to make sure I have this right— is this your number one value?"
8. Record values on a scoring sheet, journal or by taking a picture of the cards. Participants should keep a record of their card selections as well.
Debriefing and discussion:
Next, invite the participant to engage in a structured discussion of each value using a few of the following open- ended prompts, or similar prompts depending on the context of your work:
You selected as your # value?;
Please tell me more about what means to you?
What are some ways has been represented in your life?
What are some ways you'd like to see more of in your life?
How does your decision to or not relate to this value?
How much would you like to have in your life?
How would you know if was increasing or decreasing in your life?
How does relate to the change you are trying to make (or considering making)?
Invite the participant to journal about their answers to the same questions with the remaining cards afterwards. In later sessions it can be helpful to check in on the values and revisit these questions, see how answers have changed, and how participants are currently relating to their values.
Assistant Therapist
The session may be conducted by the therapist with an assistant therapist such that a second person is available to assist in case of any adverse event or physical complication in the participants safety. The assistant who will be present for the session should be introduced in Prep Session 3 and included in a conversation such that they get to know the participant.
Session-Specific Therapeutic Tasks
Therapists should aim to complete the therapeutic tasks outlined above according to the chart below, while acknowledging that some variation will occur based on individual participant needs.
Figure imgf000055_0001
5-MeO-DMT Experience Session
The therapist is present with the participant during the session — including pre-experience and post-experience times. This is the only session that must be conducted in-person. The site and therapist should schedule about 3 hours for the session, including pre-experience and post-experience time. This does not include the time allotted to engage in baseline measures and enrolment confirmation prior to the session. Local regulatory approvals will determine the minimum length of time a participant must be under observation following 5-MeO- DMT administration.
Pre-experience (Around 30 Minutes)
After the participant has completed all enrolment confirmation and randomization procedures and is cleared to participate, the Therapist, Assistant Therapist, and participant together in the room review all aspects of the room and safety procedures. The therapist should introduce the participant to the team member administering the 5-MeO-DMT, to create a sense of familiarity. Therapist introduces any Assistant Therapist and reviews safety features of the room and the equipment present. Participant has time to ask any questions. The therapist will ask about any responses to the situation and how the participant is feeling about their session. The participant should not be rushed into the dosing by the therapists. The therapist will ask the participant to engage in a period of relaxation prior to dosing. Participants will be asked to lie down, close their eyes, listen to the music, and, if willing, engage in at least one of the breathing exercises with the therapist's guidance. When the participant is settled and comfortable, the therapist will initiate the Session Opening. This practice helps contain and emphasise the specialness of the experience. Therapists will contact the member of the research team to come to the room and administer the 5-MeO-DMT. The team member should be aware not to disrupt the peaceful atmosphere of the room. The participant should be in a seated position when insufflating the 5-MeO- DMT, as the effects may be felt quickly, the participant should be transitioned to a prone position and remain prone for the duration of the effect of the 5-MeO-DMT. Experience (Around 60 Minutes)
It is expected that the onset of acute effects will occur very rapidly after administration. Therapists should be aware of the time of administration so they can be aware of the participant's response in relation to the expected course of duration. Some participants may want to know how long they experienced the effects of the 5-MeO-DMT and it is appropriate to share this information if asked. A significant portion of the time the participant may be nonverbal, focused inward, and engaging in their experience. It is important for the therapist to be mindfully aware of the participant, but not interfering with the participant's experience, unless it is clear that the participant is seeking the therapist's support. Therapists are encouraged to engage in self-regulation techniques while the participant is undergoing their experience. This may be in the form of slow intentional inhaling and exhaling, or any other activity that helps the therapist ground and self-regulate. This is both for the therapist's benefit, as well as the participants', because a participant in a heightened non-ordinary state may be particularly attune to or pick up on their therapist's anxiety. It is optimal for the therapist to follow the participant's lead when choosing to verbally engage as the 5-MeO-DMT experience appears to be subsiding. Therapists may be eager to ask the participant about their experience, but it is preferable to wait until the participant is ready to share on their own. A participant may wish to remain in a period of silence, even after the apparent acute 5-MeO-DMT effect is gone. It is appropriate for therapists to greet participants with a friendly smile and welcoming nonverbal behaviour, and allow participants to take the lead on sharing when they feel ready.
Post-experience (around 90 minutes)
Therapist will encourage the participant to stay with their experience for a period of time of at least one hour after the acute effects of the 5-MeO-DMT have worn off and the participant is once again aware of their surroundings and situation in the treatment room. To stay with the experience means to continue directing attention toward it in whatever way feels most appropriate to the participant, without turning to engagement in distractions, entertainment, or the concerns of daily life. During this time the therapist will invite the participant to describe their experience, if they choose to, and respect the choice not to if the participant is unready. If the participant does describe their experience the therapist is to listen and encourage the participant to express whatever they would like to share without interpretation or attempts to make meaning. The therapist practices simply listening, encouraging the participant to describe what they can about the experience. The therapist also offers the participant the option of resting and listening to the music, or to write about or draw any aspects of the experience they desire. At the end of this time period, the therapist will verify with the participant that they feel ready to close the session, will engage in the Session Closing, and contact the study team for exit assessment.
Integration Sessions
The key principle of integration sessions is to help the participant focus on shifts in their perception of themselves and the implications of these as they relate to their depression/major depressive disorder. Self, for the purpose of this study, is broadly defined as the narrative or historical self, the sense of a coherent "I" that moves through experiences, and the self-identities one may use. It is key to remember that the sense of self, or the "I," is reflected in both the experiencer's self-experience and experience of the object of experience, therefore descriptions may, on the surface, be of changes in the perception of the external world, but reflect shifts in the internal processes. To this end, the following therapeutic tasks will guide the integration sessions.
These sessions are less structured than preparatory sessions to accommodate variations in participant responses. There are three tasks: The first should occur at all sessions, the second and third may be introduced and engaged in if and when the participant is ready and willing. The tasks are:
Listening and hearing about the participant's experience
Therapists ask open-ended questions about the participant's experience and listen with non-judgmental curiosity to the participant's descriptions. Therapists ask only that participants focus on the 5MDE and related material, such that their time together is focused on the treatment. Therapists should focus inquiry on the participant's experience, asking them to tune into any aspect of the three types of sense of self they can identify.
Reintroducing the values and discussing relationship to each
The therapist will reintroduce the values identified in the Values Card Sort from preparation and bring discussion back to them if and when appropriate in the integration sessions. There is by no means a requirement to engage in the structured discussion of the values, but it serves as a framework where needed to direct the focus of sessions toward participants' shift in sense of self. The therapist may ask for example, to reintroduce the values:
Therapist: Before your 5MDE we discussed a list of Values you hold and how you were relating to each of those. I'd like to draw our attention back to that and ask for a little detail about how those ways of relating might have shifted. For instance you named "Family" as one thing that was important to you, but you were concerned that you weren't feeling well enough to be present for family relationships. You said you were isolating yourself from your family a lot by working on your computer from your makeshift office in the garage every evening. How do you relate to the value of "Family" now?
In the dialogue, the therapist can for example continue to focus on shifts in how the participant is relating to his value of "Family" by enquiring about what he is noticing in this area.
Create ways the participant can act to enhance their relationship to their chosen values; identify value-oriented action in their life as an integration practice. Integration can be understood as a process of embodying or living out the insights one has. In at least one of the integration sessions, the earliest the therapist feels the participant can engage in this stage, the therapist should introduce the idea of identifying value-oriented actions they can take in their lives as integration practices. Explaining the concept as above, the therapist can invite the participant to recall the values they identified (or any other that is important to them), recall the insights or experiences of their 5-MeO-DMT session, and think creatively about things they might try intentionally doing differently in order to implement positive change in their relationship to the values based on those insights and experiences
Items:
Item 1: A method of administering 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof to a patient who is diagnosed with depression/major depressive disorder, the method comprising: the discontinuation of the use by the patient of any mood-altering substance or any other substance, medications or preparation which may affect serotonergic function; the relaxation of the patient, such as the patient is instructed to lay down, close their eyes, and listen to music and/or engage in one or more breathing exercises guided by a therapist; optionally, the clearing of their nasal passages, by blowing their nose, by the patient e.g. whilst sat down; the administration of 5-MeO-DMT, optionally by via insufflation, and optionally wherein the patient is in a prone position for the duration of the effects of 5-MeO- DMT. Item 2: The method of item 1, wherein the patient has discontinued the use of monoamine oxidase (MAO) inhibitors, CYP2D6 inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), lithium, antipsychotics, triptans, tramadol, 5- hydroxytryptophan, herbal preparations which may contain 5-HTP, St John's Wort and any benzodiazepines prior to administration of 5-MeO-DMT. Item 3:The method of item 1 or item 2, wherein the 5-MeO-DMT is administered via the Aptar Unidose (UDS) liquid or dry powder delivery system. Item 4: The method of item 1, item 2 or item 3, wherein the 5-MeO-DMT is the benzoate salt, optionally a polymorph of the benzoate salt. Item 5: The method of any one of items 1 to 4, wherein the patient participates in at least one psychological support session before administration of the 5-MeO-DMT. Item 6: The method of item 5, wherein the patient participates in at least three psychological support sessions before administration of the 5-MeO-DMT. Item 7:The method of item 6, wherein the patient participates in three psychological support sessions, wherein these sessions take place 7 days, 4 days and 1 day before the administration of the 5-MeO-DMT. Item 8: The method of any one of items 5 to 7, wherein the psychological support sessions are 60-90 minutes in length. Item 9:The method of any one of items 5 to 8, wherein at least one therapeutic intention is discussed during the psychological support session. Item 10: The method of any one of items 5 to 9, wherein self-directed inquiry and experiential processing are practised during the psychological support session. Item 11: The method of any one of items 1 to 10, wherein the patient participates in at least one psychological support session after administration of the 5-MeO-DMT. Item 12: The method of item 11, wherein the patient participates in at least three psychological support sessions after administration of the 5-MeO-DMT. Item 13: The method of item 11 or item 12, wherein the patient participates in three psychological support sessions, wherein these sessions take place 1 day, 4 days and 7 days after the administration of the 5-MeO-DMT. Item 14: The method of any one of items 11 to 13, wherein the psychological support sessions are 60-90 minutes in length. Item 15: The method of any one of items 1 to 14, wherein the 5-MeO-DMT is administered to the patient in a room with a substantially non-clinical appearance. Item 16: The method of item 15, wherein the room comprises soft furniture. Item 17: The method of item 15 or 16, wherein the room is decorated using muted colours. Item 18: The method of any one of items 15 to 17, wherein the room comprises a high- resolution sound system. Item 19: The method of any one of items 15 to 18 wherein the room comprises food and drink for the patient and therapist. Item 20: The method of any one of items 15 to 19 wherein the room comprises an approved safe for storing 5-MeO-DMT. Item 21: The method of any one of items 15 to 20 wherein the room is insulated such that the patient is shielded from sights and sounds of the world beyond the room. Item 22: The method of any one of items 15 to 21 wherein the room does not contain any artwork or decoration with any specific religious iconography, ideological connotation, or other such artwork or decoration which may evoke negative emotions in a patient. Item 23: The method of any one of items 15 to 22, wherein the room comprises a bed or a couch. Item 24: The method of item 23, wherein the patient lies in the bed or on the couch for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT. Item 25: The method of any one of items 1 to 24, wherein the patient listens to music for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT. Item 26: The method of any one of items 1 to 25, wherein the patient wears an eye mask for approximately 0.5-8 hours, or a substantial fraction thereof, after administration of the 5-MeO-DMT. Item 27: The method of any one of items 1 to 26, wherein a therapist provides psychological support to the patient for approximately 0.5-8 hours after administration of the 5-MeO-DMT. Item 28: The method of any one of items 1 to 27, wherein the therapist uses guided imagery and/or breathing exercises to calm the patient and/or focus the patient's attention. Item 29: The method of any one of items 1 to 28, wherein the therapist provides reassuring physical contact with the patient. Item 30: The method of item 29, wherein the therapist holds the hand, arm, or shoulder of the patient. Item 31: The method of any one of items 1 to 30, wherein the therapist encourages the patient to perform self-directed inquiry and experiential processing. Item 32: The method of item 31, wherein the therapist reminds the patient of at least one therapeutic intention. Item 33: The method of any one of items 1 to 32, wherein the therapist counsels the patient to do one or more of the following: (1) to accept feelings of anxiety, (2) to allow the experience to unfold naturally, (3) to avoid psychologically resisting the experience, (4) to relax, and/or (5) to explore the patient's own mental space. Item 34: The method of any one of items 1 to 33, wherein the therapist does not initiate conversation with the patient. Item 35: The method of item 34, wherein the therapist responds to the patient if the patient initiates conversation. Item 36: The method of any one of items 5 to 35, wherein psychological support is provided remotely to the patient. Item 37: The method of item 36, wherein the psychological support is provided via a digital or electronic system. Item 38: The method of item 37, wherein the digital or electronic system is a mobile phone app. Item 39: The method of item 38, wherein the digital or electronic system is a website.
Example 15: Results of a Phase Ila study into 5-MeO-DMT for Treatment Resistant depression/major depressive disorder (TRD)
In an open-label Phase Ila study, patients with moderate-to-severe TRD symptoms who were not taking concomitant antidepressants were given a single 10 mg dose of BPL-003 (5-MeO-DMT benzoate) alongside psychological support in order to explore the safety, efficacy and pharmacokinetics of the treatment. 12 subjects were dosed, and 11 met the criteria for per-protocol analysis.
12 patients, 83% male, 83% white, with a mean age of 42 (31-55) years received 10 mg BPL-003. The mean number of failed antidepressants in the current episode was 3.2 (range of 2-5), with citalopram and sertraline the most frequently failed antidepressants. 2 (17%) of the patients washed out their antidepressants during screening.
Patients were followed for 12 weeks post-dosing, with assessments conducted at multiple points throughout the period.
A single dose of BPL-003 was shown to deliver a rapid response in 55% of patients with TRD by day 2, with 55% of patients in remission at day 29 and 45% of patients in remission at day 85. This is the longest-known followup of improvement in depression/major depressive disorder outcomes for a clinical study of 5-MeO-DMT.
75% of subjects were assessed as being ready for discharge at the first assessment time of 90 minutes, confirming the potential for a short treatment duration, fast discharge and low resource burden with BPL-003.
Analysis of the per-protocol population (n=ll) shows that a single 10 mg dose of BPL-003 rapidly induced a clinically significant 12.7 point mean reduction in the Montgomery-Asberg depression/major depressive disorder Rating Scale (MADRS) score in TRD patients from as early as 1 day post-dose and a response was sustained up to day 85 post-dose (13 point mean reduction from baseline). BPL-003 demonstrated good tolerability, with convenient nasal administration and no serious adverse events reported. Most reported events were mild-to-moderate and resolved themselves within the dosing session, which is broadly consistent with Phase I findings (see Example 10).
BPL-003 was well tolerated with no serious adverse events (AEs) or withdrawals due to AEs. Overall, 10 patients (83%) reported 22 treatment-emergent AEs (TEAEs); 10 TEAEs were rated mild, 11 moderate, and 1 severe. The most frequently reported TEAEs were nasal discomfort (4 patients; 33%), nausea (4 patients; 33%s), vomiting (2 patients; 17%) and headache (2 patients; 17%). 9 patients (75%) reported 16 TEAEs on Day 1, with the remaining 6 TEAEs reported on Day 2 or later.
BPL-OO3 was also shown to produce a rapid onset and timely offset of psychedelic experiences, which have previously been shown to correlate with positive clinical improvement. 9/12 subjects were assessed as being ready for discharge at the first assessment time of 90 minutes, with a mean readiness for discharge time for all 12 subjects of 107 minutes. This signals the potential for a shorter treatment duration and reduced resource burden for healthcare systems compared to other psychedelic treatments currently under development.
The mean change from baseline in MADRS total score over time (per protocol population) can be seen in Figures 21. The mean MADRS total score of 27.5±0.97 at Baseline was reduced to 14.8± 8.99 at Day 2 and to 14.5111.54 at Day 85. This represents a reduction of 12.6 MADRS points at Day 2, and 13.0 MADRS points at Day 85. The responder rate was 55% at Day 2, which was sustained at 55% at Day 85. The remitter rate was 36% at Day 2 and increased to 45% by Day 85,
BPL-003 was administered as a dry powder from a single-use FDA-approved intranasal delivery device. The acute subjective experience in TRD patients was comparable to the findings of the Phase I clinical trial described in Example 10. Both groups of subjects were able to reach a score of equal to or greater than 3 out of 5 (as measured by the MEQ-30), which has previously been shown to correlate with short-term and longterm clinical symptom improvement.
The results for each of the 10-items of the MADRS for the per protocol population (PPP) can be seen in the Tables below. As can be seen, a single administration of BPL-003 leads to reductions in the scores of each of the 10-items, said reductions being present from day 2 and being sustained out to day 85. Surprisingly, it can be seen that reductions in each of "inability to feel", "reduced sleep", "reduced appetite", "apparent sadness", "lassitude" and "concentration" are larger at day 85 compared with day 2.
Tables: Per Protocol Population (PPP) Mean MADRS Scores Measured For Single Dose BPL-003 Administration.
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0001
In an embodiment, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients and wherein following a single dose of 5-MeO-DMT, an antidepressant response is sustained. In an embodiment, an antidepressant response may be an improvement in one or more of the 10-items of the MADRS.
In an embodiment, an antidepressant response is sustained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or more weeks. In an embodiment, an antidepressant response is defined as a reduction in MADRS score (from baseline) of 5, 6, 7, 8, 9, 10, 11, 12 or 13 points or more. In an embodiment, the antidepressant response is defined by one or more of the alternative measures known to the person skilled in the art for the definition of antidepressant response. In an embodiment, a rapid method of treatment of depression/major depressive disorder is a treatment wherein a patient/subject reports a reduction in MADRS score (from baseline) of 5, 6, 7, 8, 9, 10, 11, 12 or 13 points or more, within 1, 2, 3, 4, 5, 6 or 7 days of treatment. In an embodiment, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients and wherein following a single dose of 5-MeO-DMT, an antidepressant response is sustained for 12 weeks or more.
In an embodiment, the composition comprises 5-MeO-DMT benzoate. In an embodiment, the composition comprises amorphous 5-MeO-DMT benzoate. In an embodiment, the composition comprises crystalline 5- MeO-DMT benzoate. In an embodiment, the composition comprises 10 mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. In an embodiment, the composition comprises 10 mg of 5-MeO-DMT benzoate.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving concentration in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving concentration in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing apparent sadness in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing apparent sadness in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing an inability to feel in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing an inability to feel in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in a treatment resistant major depressive disorder patient.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression/major depressive disorder in a patient in need thereof, wherein the treatment resistant depression/major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and/or quetiapine.
In an embodiment, the treatment resistant depression/major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and/or quetiapine, in the current episode.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the pharmaceutical composition is as described herein and wherein the method is a as described herein.
In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression/major depressive disorder, or treatment resistant depression/major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the depression/major depressive disorder or treatment resistant depression/major depressive disorder, is treated within 1 day of the single dose and wherein the response is sustained for 12 weeks or more.
In an embodiment, there is provided a method as disclosed herein wherein the disease/condition to be treated has previously failed to be treated with one or more treatments. In an embodiment, the disease/condition has previously failed to be treated with one or more antidepressants, such as citalopram and/or sertraline. In an embodiment, the disease/condition has previously failed to be treated with one or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with two or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with three or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with four or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with five or more treatments, in the current episode of the disease/condition. In an embodiment, the one or more treatments were administered at an adequate dose for an adequate length of time.
In an embodiment, there is provided the use of a pharmaceutical composition as described herein wherein the disease/condition to be treated has previously failed to be treated with one or more treatments. In an embodiment, the disease/condition has previously failed to be treated with one or more antidepressants, such as citalopram and/or sertraline. In an embodiment, the disease/condition has previously failed to be treated with one or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with two or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with three or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with four or more treatments, in the current episode of the disease/condition. In an embodiment, the disease/condition has previously failed to be treated with five or more treatments, in the current episode of the disease/condition. In an embodiment, the one or more treatments were administered at an adequate dose for an adequate length of time.
In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, not more often than once every 1, 2 or 3 months. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, once every three months. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, at a frequency of once per three months.
In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, not more often than once every 4, 8 or 12 weeks. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, once every 12 weeks. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, at a frequency of once per 12 weeks.
In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 90 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 100 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 110 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 120 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 130 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 140 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 150 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 160 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 170 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 180 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 190 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient/subject is ready for discharge within 200 minutes post-dose.
In an embodiment, the patient/subject is assessed as being ready for discharge depending on the results of one or more discharge questionnaires. In an embodiment, a discharge questionnaire may be utilised by a professional. In an embodiment, this professional is a licensed medical professional. In an embodiment, a discharge questionnaire may include one or more of the following statements, which must be agreed with in order for a patient/subject to be assessed as ready for discharge: The patient/subject is fully responsive, aware of their surroundings, and reacts adequately; The acute psychedelic effects of the drug have completely subsided; The patient/subject is fully orientated (e.g. name, location, time); Blood pressure and pulse rate have returned to normal or only slightly elevated levels. The breathing frequency and body temperature are normal; The patient/subject has a stable gate and normal muscle coordination and can walk safely; Potential side effects are mild to moderate in intensity and do not need to be medically monitored; The patient/subject has no acute suicidal ideations or suicidal intentions; Possible distress or feelings of being overwhelmed have sufficiently subsided to a degree that the patient/subject themselves feel safe to be discharged; In the opinion of the assessor, the patient/subject is safe to be discharged.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the patient/subject and wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration and wherein the clinical significant reduction is sustained for at least 12 weeks.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 5-MeO- DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10 mg of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 8 mg, 10 mg, 12 mg or 14 mg of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 8 mg, 10 mg, 12 mg or 14 mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression/major depressive disorder in a patient/subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient/subject is ready for discharge within 90 minutes post-administration.
In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein said method further comprises psychotherapy. In an embodiment, the psychotherapy is provided prior to administration of the composition. In an embodiment, psychotherapy is provided during administration of the composition. In an embodiment, psychotherapy is provided after administration of the composition. In an embodiment, psychotherapy is provided prior to, during and after administration of the composition.
In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein said method further comprises psychological support. In an embodiment, the psychological support is provided prior to administration of the composition. In an embodiment, the psychological support is provided during administration of the composition. In an embodiment, the psychological support is provided after administration of the composition. In an embodiment, the psychological support is provided prior to, during and after administration of the composition.
In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein the method does not comprise the concurrent use of other antidepressant treatments. In an embodiment, the method does not comprise the concurrent use of SSRIs.
In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein the method comprises the concurrent use of other antidepressant treatments. In an embodiment, the method comprises the concurrent use of SSRIs.
In an embodiment, there is provided a rapid method of treating one or more mental health diseases or conditions as described herein, in a patient/subject in need thereof, wherein the rapid method produces a sustained/durable treatment from a single administration, the method comprising the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject.
In an embodiment, there is provided a rapid method of treating one or more mental health diseases or conditions as described herein, in a patient/subject in need thereof, wherein the rapid method produces a sustained/durable treatment from a single administration, the method comprising the induction of a complete mystical experience in the patient/subject by the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject.
In an embodiment, there is provided a rapid and sustained/durable treatment method of one or more mental health diseases or conditions as described herein, in a patient/subject in need thereof, said treatment method comprising the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject.
In an embodiment, the rapid method comprises the administration of a single dose of 10 mg 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject. In an embodiment, the rapid method comprises the administration of 10 mg 5-MeO-DMT benzoate. The skilled person will understand that 10 mg of a 5-MeO-DMT salt, as described herein, refers to the weight of such a salt required to provide a 10 mg free base when the salt is taken/administered. In an embodiment, there is therefore provided a rapid method that comprises the administration of about 15.59 mg 5-MeO-DMT benzoate, which is equivalent to 10 mg 5-MeO-DMT freebase. In an embodiment, there is provided a method of rapidly treating one or more mental health conditions or diseases, as described herein, in a patient/subject in need thereof, comprising inducing a complete mystical experience in a patient/subject by the single administration of a pharmaceutical composition comprising 10 mg 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, wherein said rapid treatment is sustained for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks following the single administration.
In an embodiment, there is provided a method of rapidly treating one or more of cognitive dysfunction, negative thinking, bipolar disorder, postnatal depression/major depressive disorder, postpartum depression/major depressive disorder, social/emotional withdrawal of detachment, psychomotor retardation, anxiety and/or sleep disturbance.
In an embodiment, there is provided a method of rapidly treating a sleep disturbance, such as insomnia, hypersomnia, circadian rhythm disorder, parasomnia, sleep-related breathing disorder, sleep-related movement disorder, and/or an idiopathic sleep disturbance. In an embodiment, the patient is suffering from: one or more mental or nervous system disorders associated with the sleep disturbance, or a treatment resistant form thereof, selected from one or more of: a disorder characterised by depressive episodes associated with the sleep disturbance, major depressive disorder (MDD) associated with the sleep disturbance, postpartum depression (PPD) associated with the sleep disturbance, compromised maternal functioning, compromised maternal functioning wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 80 or below, such as 65 or below, compromised maternal functioning wherein the treatment improves maternal functioning, compromised maternal functioning wherein the treatment improves maternal functioning reflected by an improvement of the BIMF total score by 10% or more, preferably by 20 % or more, compromised maternal functioning wherein the treatment improves maternal functioning reflected by at least an improvement in the BIMF total score on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT, by at least an improvement in the BIMF total score on day 1, 2, 3, 4, 5, 6 and/or 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT, bipolar disorder associated with the sleep disturbance, bipolar II disorder associated with the sleep disturbance, bipolar I disorder associated with the sleep disturbance, a current major depressive episode, seasonal affective disorder associated with the sleep disturbance, persistent depressive disorder associated with the sleep disturbance, anxiety disorder associated with the sleep disturbance, separation anxiety disorder associated with the sleep disturbance, agoraphobia associated with the sleep disturbance, generalised anxiety disorder (GAD) associated with the sleep disturbance, social anxiety disorder (SAD) associated with the sleep disturbance, panic disorder associated with the sleep disturbance, phobia associated with the sleep disturbance, substance/medication induced anxiety disorder associated with the sleep disturbance, somatic symptom disorder associated with the sleep disturbance, an obsessive compulsive or related disorder associated with the sleep disturbance, body dysmorphic disorder (BDD) associated with the sleep disturbance, post-traumatic stress disorder (PTSD) associated with the sleep disturbance, a pain disorder associated with the sleep disturbance, chronic pain associated with the sleep disturbance, fibromyalgia associated with the sleep disturbance, migraine associated with the sleep disturbance, a mental and behavioural disorder due to psychoactive substance use associated with the sleep disturbance, substance use disorder (SUD) associated with the sleep disturbance, a psychotic disorder associated with the sleep disturbance, schizophrenia associated with the sleep disturbance, Huntington's disease associated with the sleep disturbance, Parkinson's disease associated with the sleep disturbance, dementia associated with the sleep disturbance, Alzheimer's dementia associated with the sleep disturbance, Parkinson's disease dementia associated with the sleep disturbance, dementia with Lewy Bodies associated with the sleep disturbance, vascular dementia associated with the sleep disturbance, frontotemporal dementia associated with the sleep disturbance, eating disorder associated with the sleep disturbance, an eating disorder suffers from a treatment resistant form of the disorder, attention deficit hyperactivity disorder (ADHD) associated with the sleep disturbance, a personality disorder associated with the sleep disturbance, schizotypal personality disorder associated with the sleep disturbance, a borderline personality disorder (BPD) associated with the sleep disturbance, an autism spectrum disorder (ASD) associated with the sleep disturbance and/or chronic fatigue syndrome associated with the sleep disturbance.
In an embodiment, there is provided a method of rapidly treating bipolar disorder in a patient in need thereof. In an embodiment, the bipolar disorder is bipolar I or bipolar II. In an embodiment, the patient: suffers from a current major depressive episode, the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37, the patient has a Bipolar Depression Rating Scale (BDRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37, the patient had no adequate improvement after at least two adequate courses of therapy, the patient had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy, the patient has a Young Mania Rating Scale (YM S) total score less than or equal to 8 and/or the 5-MeO-DMT or salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a complete mystical experience.
In an embodiment, there is provided a method of rapidly treating anxiety in a patient in need thereof. In an embodiment, the patient: is suffering from is a subthreshold anxiety, has a comorbidity of anxiety and a further diagnosed disorder, is also suffering from a mental or nervous system disorder, is also suffering from a mental or nervous system disorder suffers from a treatment resistant form of the disorder, is also suffering from a disorder characterised by depressive episodes, is also suffering from major depressive disorder (MDD), is also suffering from postpartum depression (PPD), suffers in addition from compromised maternal functioning, has a Barkin Index of Maternal Functioning (BIMF) score of 80 or below, such as 65 or below. In an embodiment, the patient is suffering from a treatment resistant form of one or more of the above conditions or disorders.
In an embodiment, there is provided a method of rapidly treating one or more as disorders characterised by depressive episodes for example, Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Dis-order and Bipolar II Disorder; Anxiety Disorder, for example Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobias, and Substance/Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain, Fibromyalgia and Migraine; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Parkinson's Disease; Dementia, for example Alzheimer's Dementia (AD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies , Vascular Dementia, Fronto-Temporal Dementias; Eating Disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality Disorders, for example Schizotypal Personality Disorder and Borderline Personality Disorder; Autism Spectrum Disorder; Chronic Fatigue Syndrome; or a medical health condition leading to an associated mental or nervous system condition, for example anxiety due to Traumatic Brain Injury (TBI), HIV infection, or post COVID condition.
Treatment as indicated herein with 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof (or a pharmaceutical composition comprising said compound or salt) leads to a clinical response. The response may be assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, which improvement preferably occurs not later than about 2 hours after the single administration of 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks after the single administration of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof.
The clinical response may also be assessed by improvement of the MADRS or HAM-D score, compared to the respective score prior to the single administration of 5-MeO-DMT. The clinical response may be assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to the single administration of 5-MeO-DMT.
This response preferably occurs not later than about 2 hours after the single administration of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. Further, a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, preferably occurs not later than about 2 hours after the single administration of 5- MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. The clinical response, as may be assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, preferably persists until at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks after the single administration of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. As used in the context of the present invention, a "patient" to be treated is a human subject who is diagnosed as suffering from one or more of the diseases/conditions/disorders, as disclosed herein, by a licensed professional in accordance with accepted medical practice.
Diagnosis of one or more of the diseases/conditions/disorders, as disclosed herein, optionally a mental disorder or a nervous system disorder can, for instance, be in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. In some instances, as is apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or patient groups particularly benefiting from a treatment according to the invention. The diagnosis will in any event be by a physician or a psychologist. It is not sufficient that the human subject himself/herself considers that he/she is suffering from the disorder.
As used in the context of the present invention, unless otherwise noted, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms of the disease or eliminate the disease, condition, or disorder. "Treatment of one or more of the diseases/conditions/disorders, as disclosed herein" shall include the management and care of a patient for the purpose of combating negative thinking and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms of the one or more of the diseases/conditions/disorders, as disclosed herein.
The patient may suffer from treatment resistant disease. Treatment resistance means that the patient had no adequate improvement after at least two adequate courses of therapy. The patient in particular had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy; for instance, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy. The at least two prior courses of treatment were in particular administered in the current episode of the disease, for instance, if the patient suffers from a disorder characterised by depressive episodes, in the current episode of depression.
As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" shall mean the amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of the signs and/or symptoms of the one or more of the diseases/conditions/disorders, as disclosed herein.
As used herein, "Clinical response" and/or "clinically significant reduction" and/or "clinically significant response" includes, but is not limited to, improvements on rating scales such as the Clinical Global Impression - Severity scale (CGI-S), the Patient Global Impression - Severity scale (PGI-S), the Clinical Global Impression - Improvement scale (CGI-I) or the Patient Global Impression - Improvement scale (PGI-I) and further includes, but is not limited to, endpoints such as the Montgomery-Asberg depression/major depressive disorder Rating Scale (MADRS) or the 17-item Hamilton depression/major depressive disorder Rating Scale (HAM-D) for depression/major depressive disorder and persistent depressive disorder, anxiety symptoms e.g. as measured by the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Scale (HAM-A) or the State-Trait Anxiety Inventory (STAI) for anxiety disorder, the Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS) for posttraumatic stress disorder, the Yale-Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder (BDD-YBOCS) for body dysmorphic disorder, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for obsessive-compulsive disorder, weight gain for anorexia nervosa, frequency of binge-purge episodes for bulimia nervosa, frequency of binge episodes for binge eating disorder, duration of abstinence or reduced substance use in psychoactive substance abuse and suicidality rating scales such as the Columbia-Suicide Severity Rating Scale (C-SSRS) or the suicidal thoughts item of the MADRS for suicidal ideation or the Clinical Global Impression - Severity of Suicidality - Revised (CGI-SS-R) scale (the CGI-SS-R is derived from the CGI-S, and is scored 0 = Normal, Not At All Suicidal; 1 = Questionably Suicidal; 2= Mildly Suicidal; 3 = Moderately Suicidal; 4 = Markedly Suicidal; 5 = Severely Suicidal; 6 = Extremely Suicidal). When assessing a clinical response at an early time point after drug administration (e.g. at 2 hours) based on endpoints which have been developed for a longer recall period, a rational modification of such endpoint (e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied.
The severity of a condition as well as changes of the severity can be assessed by the Clinical Global Impression (CGI) rating scales which are measures of symptom severity, treatment response and the efficacy of treatments. The CGI rating scales were developed to provide a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after a treatment (Busner, J. and Tagrum, S. D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).
The CGI-Severity (CGI-S) is based on one question the clinician has to answer: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" This is rated on the following seven-point scale: l=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.
The CGI-S can be used to assess treatment success by comparing scores before and after treatment.
A clinical response may be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 . Preferably, the CGI-S is reduced by at least 2 and/or to a score of 0. It is especially preferred if the CGI-S is reduced by at least 3 and/or to a score of 0.
Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which is similarly simple in its format. After the treatment, the clinician compares the patient's overall clinical condition to the one prior to the treatment (the so-called baseline value). Again, only one query is rated on a seven-point scale: "Compared to the patient's condition at admission to the project [prior to medication initiation], this patient's condition is: l=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6=much worse; 7=very much worse since the initiation of treatment."
The Patient Global Impression scale (PGI), also known as Subject Global Impression (SGI), is the counterpart to the Clinical Global Impressions scale (CGI). It consists of one item based on the CGI and adapted to the patient. It can measure disease severity (PGI- S) or disease improvement (PGI-I).
Individual items of scales as described herein as well as sub-combinations of individual items may be used to assess specific disease aspects.
Numerous scales have been suggested to assess severity of one or more conditions or disorders, such as one or more conditions or disorders, such as one or more conditions or disorders, such as a mental disorder or a nervous system disorder. Such scales are based on tests which may be self-administered or administered by a clinician/physician. Scales which may be used according to the invention include those known in the art for diagnosis and/or monitoring the one or more conditions or disorders, such as a mental disorder or a nervous system disorder are discussed in more detail herein. Treatment outcome is assessed by using one or more indices or scales at one or more time points after completion of a treatment course.
The assessment may be carried out after the complete mystical experience has subsided. An appropriate point in time for an early assessment is generally about 2 to 3 hours after the last administration. An early assessment may generally be carried out, for instance, about 2 hours or about 3 hours after the last administration. An assessment of an effect on, for example, sleep disturbance can, however, be carried out at the earliest on the day after the treatment (i.e., on day 1) so that the treated patient/subject had the opportunity to sleep for at least one night.
Thus, an assessment at day 1 or on day 1 means an assessment on the day following the administration. The assessment may be carried out not earlier than 12 hours after the last administration and in any event optionally not earlier than one night after the last administration and not later than 36 hours after the last administration. The assessment may be carried out after about 24 hours. An assessment at day 7 or on day 7 means an assessment on the seventh day following the administration (the day of administration is day 0). Analogous definitions apply for other assessment timings measured in days.
When assessing a clinical response, for instance, using one of the scales to assess severity of one or more conditions or disorders, such as a mental disorder or a nervous system disorder, at an early time point after drug administration (e.g. at 1, 2 or 3 hours) based on endpoints which have been developed for a longer recall period (e.g. normally 7 days for the MADRS), a rational modification of such endpoint (e.g. changing the MADRS recall period to 1, 2 or 3 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied. The same applies with respect to any other scale applied herein, unless a recall period is specifically indicated. The considerations outlined apply for early time points because, on the one hand, in order to assess a clinical response, the influence of the patient's status before the treatment on any score recorded after treatment should be kept as low as possible, whereas on the other hand the sleep item cannot be assessed 1, 2 or 3 hours after drug administration. At later time points, for instance, on day 1 or later, typically all items of the relevant scales to assess a clinical response may be assessed, using, if necessary, an adapted recall period, so that it is not necessary to carry forward any pre-treatment score.
There are two fundamental types of sleep: rapid eye movement (REM) sleep and non- REM sleep. Non-REM sleep may be divided into four stages (l-IV). These non-REM stages correspond to an increasing depth of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. During the earlier proportion of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, particularly within the first cycle of sleep. As the night progresses, non- REM sleep becomes shallow and more of each cycle is allocated to REM sleep.
Normal healthy sleep consists of different phases as outlined above that proceed in successive, tightly regulated order through the night. Disruption of this tight regulation results in sleep disturbances. Sleep disturbance refers to conditions, whether idiopathic or occurring in the context of a medical condition such as for example one or more conditions or disorders, such as one or more conditions or disorders, such as a mental disorder or a nervous system disorder, that affect sleep quality, timing, or duration. It impacts a person's ability to properly function while the person is awake.
Common forms of sleep disturbances encompass disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep wake schedule (circadian rhythm disorders), dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia), disorders characterised by respiratory disturbance during sleep (sleep-related breathing disorders) and disorders characterised by abnormal movements during sleep (sleep-related movement disorders). Insomnia is a sleep disturbance where people have difficulty falling or staying asleep. People with insomnia have difficulty falling asleep; wake up often during the night and have trouble going back to sleep; wake up too early in the morning; have unrefreshing sleep; and/or have at least one daytime problem such as fatigue, sleepiness, problems with mood, concentration, accidents at work or while driving, etc. due to poor sleep.
Hypersomnia is characterised by excessive daytime sleepiness, and/or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomnia patients/subjects. It is a difficulty transitioning from sleep to wake. Individuals experiencing sleep drunkenness report waking with confusion, disorientation, slowness and repeated returns to sleep.
Circadian rhythm disorders are characterised by chronic or recurring sleep disturbances due to alterations of the individual's internal circadian rhythm or due to misalignments between their circadian rhythm and their desired or required work or social schedule. This dyssynchrony may be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during the desired waking state is impaired, and temporary opportunities to revert to a regular sleep schedule are unsuccessful.
Parasomnia designates various forms of sleep disturbance characterised by abnormal behavioural or physiological activity (such as sleepwalking or nightmares) that people experience prior to falling asleep, while asleep, or during the arousal period between sleep and wakefulness. There are considerable variations in terms of characteristics, severity, and frequency. Parasomnia may compromise the quality of sleep.
Sleep-related breathing disorders are characterised by abnormal and difficult respiration during sleep.
Respiration is a complex process that relies heavily on the coordinated action of the muscles of respiration and the (control centre in the) brain. One form of a sleep-related breathing disorder is central sleep apnoea. It occurs when the brain stops sending signals that control breathing, for instance, based on an underlying health condition. Central sleep apnoea has a potentially serious impact on sleep and the balance of oxygen and carbon dioxide in the blood. The reduction of airflow leads to intermittent hypoxia which in leads to sleep fragmentation due to microarousals or awakenings. A consequence may be excessive daytime sleepiness.
In sleep-related movement disorders repetitive, relatively simple, usually stereotyped, movements interfere with sleep or its onset. The most common of these are restless leg syndrome (RLS) and periodic limb movement disorder (PLMD). Not getting the proper amount or quality of sleep may lead to personality changes and may not only exacerbate existing mental illness, but also be a trigger for the development of mental illness. Sleep disturbance may also interfere with cognitive function and lead to memory impairment. A patient/subject who is deprived of sleep may experience difficulty making decisions, irritability, have problems with performance, and may have slower reaction times. Sleep loss may also adversely affect life by contributing to the development of obesity, diabetes, and heart disease.
Treatment of sleep disorders varies depending on the type and underlying cause. Maintenance of good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered as first-line treatment. If not successful, treatment also involves pharmacotherapy or psychotherapy. Available treatments are not successful in all patients/subjects, may be associated with side effects and/or require treatment over a long period of time to achieve a relevant treatment effect. In patients/subjects suffering from sleep disturbance in association with one or more conditions or disorders, such as a mental disorder or a nervous system disorder known treatments of the mental or nervous system disorder do not necessarily improve the sleep disturbance.
For instance, sleep disturbance is frequently associated with mental disorders, such as depression. However, treatment of depression does not necessarily lead to an improvement of the concomitant sleep disturbances. While most antidepressants have been proven to influence the sleep architecture, some classes of antidepressants improve sleep, but others may cause sleep impairment. Sleep may be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of awakenings throughout the night. The quantitative metrics may be measured using objective methods, including polysomnography, actigraphy, and the determination of sleep latency, or by way of self reported measures (questionnaires).
Polysomnography is a technique requiring that a patient/subject is monitored overnight at a specialised clinic. A variety of functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body positioning and movements, snoring, and heart rate. Another quantitative measurement is actigraphy. An actimetry sensor is worn to measure motor activity, which is recorded continually and used to assess sleep-wake cycles. This technique allows the patient/subject to continue normal routines while the required data are being recorded in a natural sleep environment.
Sleep latency may be measured by the multiple sleep latency test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep across a multiplicity of test naps. An average sleep latency of approximately 10 minutes is considered to be normal; less than eight minutes is indicative of sleep disturbance (excessive daytime sleepiness). Accompanying analysis of brain activity may assist in the further diagnosis of the sleep disturbance.
Sleep-rating questionnaires capture ratings of components of sleep quality, such as perceptions of sleep depth, rousing difficulties, and restfulness after sleep, in addition to other factors that could affect sleep quality, such as comorbid conditions and medication use. The evaluation of the qualitative aspects of sleep experience is important, as sleep complaints may often persist despite normal values for quantitative measures of sleep. Questionnaires not only facilitate a quick and accurate assessment of a complex clinical problem, but they are potentially also helpful for tracking a patient's progress.
Various sleep quality indexes are known. The following indexes include examples of questionnaires to assess sleep in general and questionnaires to assess in particular insomnia, hypersomnia, circadian rhythm disorders and parasomnia, respectively. The invention is, however, not limited to the use of a particular index or questionnaire.
Some questionnaires rely on recall periods (recall windows) of several days or even weeks. While this may be appropriate for diagnosing sleep disturbances, it is not always appropriate for assessing treatment effects, in particular rapid onset of effect after treatment. For several of the questionnaires the recall period may be modified so that the scores obtained reflect a period after treatment. Questionnaires specifically discussed herein to assess effects of a treatment on sleep in patients/subjects suffering from specific conditions rely on a recall period that does not start earlier than the time point when complete mystical experiences have subsided after the last administration. To meet this criterion, the normally applied recall period is modified if necessary.
Sleep quality in general may be assessed, for instance, with the Sleep-50 questionnaire. The SLEEP-50 questionnaire consists of 50 items designed to screen for a variety of sleep disorders in the general population. The scale consists of nine subscales, reflecting some of the most common disorders and complaints related to sleep and the factors required for diagnosis such as sleep apnoea, insomnia, narcolepsy, restless legs/periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors influencing sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate the extent to which the statement has matched their experience over the previous month or another appropriate recall window.
For diagnosing a sleep disorder not only the specific subscale (e.g., insomnia) must exceed a certain cut-off point, but respondents must also meet a cut-off of at least 3 or 4 ("rather much" or "very much", respectively) on the subscale evaluating the impact of sleep complaints on daily functioning. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value. A common questionnaire assessing sleep disturbance is the Pittsburgh Sleep Quality Index. Other instruments are the insomnia severity index, the Espie sleep disturbance questionnaire and the patient/subject Reported Outcomes Measurement Information System (PROMIS®) Sleep Disturbance.
The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a selfrated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window. The 19 selfrated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) patient/subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction. Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances.
The seven component scores are then summed to yield one global score, with a range of 0-21 points, "0" indicating no difficulty and "21 " indicating severe difficulties in all areas. A global score cut-off of 5 distinguishes poor from good sleepers. A global score > 5 indicates that a patient/subject is having severe difficulties in at least two areas, or moderate difficulties in more than three areas. If treatment outcome is assessed using the PSQI, treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 5 or below.
The insomnia severity index (ISI) is a short questionnaire relating to patient/subjective sleep quality, severity of symptoms, patient/subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how noticeable the respondent feels his or her insomnia is compared to others, and the overall level of distress created by the sleep problem. Individual responses may be scored from 0 (=none) to 4 (=very); a higher total score corresponds to more severe insomnia. A total score of 0-7 indicates "no clinically significant insomnia," 8-14 means "subthreshold insomnia," 15-21 is "clinical insomnia (moderate severity)," and 22-28 means "clinical insomnia (severe)". The recall window is two weeks. Another appropriate recall window may also be used. Treatment success may be indicated (i) by a decrease of the score, for instance, by >7 points, in particular >8 point; preferably (ii) by a decrease to below the cut-off value for clinically significant insomnia.
The Espie sleep disturbance questionnaire (SDQ) evaluates patient/subjective experiences of insomnia. With ratings on restlessness/agitation, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ is concerned specifically with beliefs about the sources of sleep issues. Respondents use a five-point scale to indicate how often certain statements about insomnia are representative of their experience. 1 means "never true," while 5 means "very often true." Higher scores are indicative of more dysfunctional beliefs about the causes and correlates of insomnia.
Treatment success may be indicated by a decrease of the score. The Patient- Reported Outcomes Information System (PROMIS)® Sleep Disturbance instrument is a universal measure to evaluate sleep disturbances. The instrument is available as a long form and 4 different short forms (e.g., 4-, 6-, and 8- items) and assesses selfreported perceptions of sleep quality, sleep depth, and any perceived difficulties related to getting and staying asleep over a 7-day period. Each item on the measure is rated on a 5-point scale. The raw scores on the items are summed to obtain a total raw score. Total raw scores are then converted into a standardised T-score using conversion tables. Treatment success may be indicated by a decrease of the T-score.
Hypersomnia or hypersomnolence may be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity scale. The Epworth Sleepiness Scale (ESS) evaluates overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations representing a moment of relative inactivity, such as a nap in the afternoon or sitting in a car stopped in traffic. Using a scale of 0-3 (with 0 meaning "would never doze" and 3 meaning "high chance of dozing"), respondents rate their likelihood of falling asleep. Scoring ranges from 0-24; the higher the score, the higher the severity of daytime sleepiness. A cut-off score of 10 identifies daytime sleepiness at a potentially clinical level. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 10 or below.
The Stanford Sleepiness Scale is a patient/subjective measure of sleepiness, evaluating sleepiness at specific moments in time. Consisting of only one item, the scale requires respondents to select one of seven statements best representing their current level of perceived sleepiness. A scale from 1 (=Feeling active and vital; alert; wide awake) to 7 (=Almost in reverie; sleep onset soon; lost struggle to remain awake) is used to assess the level of sleepiness. Treatment success may be indicated by a decrease of the score. Parasomnias may be evaluated by the Paris Arousal Disorders Severity Scale (PADSS). The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale listing parasomniac behaviours, assessing their frequency and includes an evaluation of consequences. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value.
A common questionnaire that assesses sleep-related breathing disorders is the Berlin Questionnaire. An appropriate recall period may also be chosen. Treatment success may be indicated by a decrease of the score. A common questionnaire that assesses sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire asks respondents to use Likert-type ratings to indicate how acutely the disorder has affected them over the course of the past week. Questions may be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep issues, disturbances in daily functioning, and resultant changes in mood. Each of the ten questions requires respondents to rate their experiences with RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores may range from 0 to 40. As a brief scale with excellent psychometric qualities, the instrument may be suitable for a variety of research and clinical purposes, including screening and assessment of treatment outcomes. Treatment response may be assessed by a decrease of the score.
Bipolar disorder (BD) has various aspects and is characterised by various symptoms. The predominant psychopathology is depression, and the presentation of a patient/subject experiencing a depressive phase may initially result in the diagnosis of that patient/subject as having major depressive disorder (MDD). However, BD possesses multiple characteristics that define it as distinct from the latter even during the depressive phase.
Of particular interest here are the symptoms that are more strongly associated with BD compared to other psychiatric disorders, as these are the metrics against which patient/subject treatment is assessed. Notwithstanding that many symptoms may be said to straddle multiple disorders, much work has been done to identify several symptoms that present strongly in BD patients/subjects: sleep disturbance, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory) and social/emotional withdrawal or detachment (anhedonia, emotional withdrawal and affective flattening). Characteristic symptoms further include suicidal ideation. Still further, characteristic symptoms include mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).
Clinical assessment tools such as the Bipolar Depression Rating Scale (BDRS) have been developed and validated for use in BD, which take into account these symptoms. The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and/or mixed symptoms expressed by patients/subjects currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms. The scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.
The questions address depressed mood; sleep disturbance; appetite disturbance; reduced social engagement; reduced energy and activity; reduced motivation; impaired concentration and memory; anxiety; anhedonia; affective flattening; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation. Each of these aspects is assessed and assigned a score of 0, 1, 2 or 3.
Depressed mood is scored as 0 if there is no self-reported and/or observed depression as evidenced by gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) in case of brief or transient periods of depression, or mildly depressed mood; 2 (moderate) in case a depressed mood is clearly but not consistently present and other emotions are expressed, or depression is of moderate intensity; 3 (severe) in case of pervasive or continuous depressed mood of marked intensity.
Sleep disturbance (sleep dysregulation) is assessed based on the change in total amount of sleep over a 24- hour cycle, rated independent of the effect of external factors. It may either take the form of insomnia (reduction in total sleep time) or the form of hypersomnia (increase in total sleep time, inclusive of daytime sleep). The rating for insomnia involves scores of 0 (no reduction in total sleep time); 1 (mild; reduction up to 2 hours); 2 (moderate; 2 - 4 hours); 3 (severe; more than 4 hours). The alternative rating for hypersomnia involves scores of 0 (no increase in total sleep time, inclusive of daytime sleep); 1 (mild; less than 2 hours, or normal amount but nonrestorative); 2 (moderate; 2 - 4 hours); 3 (severe; greater than 4 hours).
Appetite disturbance is assessed based on the change in appetite and food consumption, rated independent of the effect of external factors. It may either take the form of loss of appetite or the form of increase in appetite. The rating for loss of appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but has to push self to eat or reports that food has lost taste); 2 (moderate; some decrease in food intake); 3 (marked decrease in food intake, hardly eating). The alternative rating for increase in appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but increased hunger); 2 (moderate; some increase in food intake, e.g., comfort eating); 3 (marked increase in food intake or cravings).
Reduced social engagement is scored as 0 if there are no patient/subjective reports of reduced social and interpersonal engagement or interactions; 1 (mild) in case of slight reduction in social engagement with no impairment in social or interpersonal function; 2 (moderate) in case of clear reduction in social engagement with some functional sequelae, e.g., avoiding some social engagements or conversations; and 3 (severe) in case of marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusing to answer the phone or see friends or family.
Reduced energy and activity is scored as 0 if there is no reduced energy, drive or goal directed behaviour; 1 (mild) in case of ability to engage in usual activities but with increased effort; 2 (moderate) in case of significant reduction in energy leading to reduction of some role-specific activities; and 3 (severe) in case of leaden paralysis or cessation of almost all role specific activities, (e.g., spending excessive time in bed, avoiding answering the phone, poor personal hygiene).
Reduced motivation is scored as 0 if there are no reports of patient/subjective reduction in drive, motivation, and consequent goal directed activity; 1 (mild) in case of a slight reduction in motivation with no reduction in function; 2 (moderate) in case of a reduced motivation or drive with significantly reduced volitional activity or requiring substantial effort to maintain usual level of function; and 3 (severe) in case of reduced motivation or drive such that goal directed behaviour or function is markedly reduced.
Impaired concentration and memory are scored as 0 if there are no patient/subjective reports of reduced attention, concentration, or memory, and consequent functional impairment; 1 (mild) in case of slight impairment of attention, concentration, or memory with no functional impairment; 2 (moderate) in case of significant impairment of attention, concentration, or forgetfulness with some functional impairment; 3 (severe) in case of marked impairment of concentration or memory with substantial functional impairment, e.g., unable to read or watch TV).
Anxiety is scored as 0 if there are no patient/subjective reports of worry, tension, and/or somatic anxiety symptoms e.g., tremor, palpitations, dizziness, light-headedness, pins and needles, sweating, dyspnoea, butterflies in the stomach, or diarrhoea; 1 (mild; transient worry or tension about minor matters); 2 (moderate; significant anxiety, tension, or worry, or some accompanying somatic features); 3 (severe; marked continuous anxiety, tension, or worry that interferes with normal activity; or panic attacks).
Anhedonia is scored as 0 (no patient/subjectively reduced ability to experience pleasure in usual activities); 1 (mild; slight reduction in pleasure from usually pleasurable activities); 2 (moderate; significant reduction in pleasure from usually pleasurable activities; some pleasure from isolated activities retained); or 3 (severe; complete inability to experience pleasure). Affective flattening is scored as 0 if there is no patient/subjective sense of reduced intensity or range of feelings or emotions; 1 (mild) in case of slight constriction of range of affect, or transient reduction in range or intensity of feelings; 2 (moderate) in case of significant constriction of range or intensity of feelings with preservation of some emotions, e.g., inability to cry; and 3 (severe) in case of marked and pervasive constriction of range of affect or inability to experience usual emotions.
Feelings of worthlessness (also simply referred to as worthlessness) are scored as 0 (no patient/subjective sense, or thoughts, of decreased self-value or self-worth); 1 (mild; slight decrease in sense of self-worth); 2 (moderate; some thoughts of worthlessness and decreased self-worth) 3 (severe; marked, pervasive, or persistent feelings of worthlessness, e.g., feels others better off without them, unable to appreciate positive attributes).
Feelings of helplessness and hopelessness (also simply referred to as helplessness and hopelessness) characterise the patient/subjective sense of pessimism or gloom regarding the future, inability to cope, or sense of loss of control. If this is absent, the score is 0. The score is 1 (mild) in case of occasional and mild feelings of not being able to cope as usual, or pessimism; it is 2 (moderate) in case the patient/subject often feels unable to cope, or has significant feelings of helplessness or hopelessness which lift at times; it is 3 (severe) if there are marked and persistent feelings of pessimism, helplessness, or hopelessness.
Suicidal ideation relates to thoughts or feelings that life is not worthwhile; thoughts of death or suicide and is scored 0 if such thoughts are absent; 1 (mild) in case of thoughts that life is not worthwhile or is meaningless; 2 (moderate) in case of thoughts of dying or death, but with no active suicide thoughts or plans; 3 (severe) in case of thoughts or plans of suicide. Feelings of guilt (also simply referred to as guilt) are scored as 0 if there is no patient/subjective sense of self blame, failure, or remorse for real or imagined past errors; 1 (mild) in case of slight decrease in self-esteem or increased self-criticism; 2 (moderate) in case of significant thoughts of failure, self-criticism, inability to cope, or ruminations regarding past failures and the effect on others; able to recognise as excessive; 3 (severe) in case of marked, pervasive, or persistent guilt, e.g., feelings of deserving punishment; or does not clearly recognise as excessive.
Psychotic symptoms are scored as 0 if overvalued ideas, delusions, or hallucinations are absent; 1 (mild) in case of mild overvalued ideas, e.g., self-criticism or pessimism without clear effect on behaviour; 2 (moderate) in case of significant overvalued ideas with clear effect on behaviour, e.g., strong guilt feelings, clear thoughts that others would be better off without them; 3 (severe) in case of clear psychotic symptoms, e.g., delusions or hallucinations.
Irritability reports uncharacteristic patient/subjective irritability, short fuse, easily angered, manifested by verbal or physical outbursts and is scored 0 if absent; 1 (mild) in case of slight patient/subjective irritability which may not be overtly present; 2 (moderate) in case of verbal snappiness and irritability that is clearly observable in the interview; 3 (severe) in case of reports of physical outbursts, e.g., throwing/breaking objects, or markedly abusive verbal outbursts. Lability is scored 0 if there are no observed mood lability or reported mood swings. It is scored 1 (mild) in case of patient/subjective reports of mild increase in mood lability; 2 (moderate) if mood lability is clearly observable, moderate in intensity; 3 (severe) in case of marked and dominant mood lability, frequent or dramatic swings in mood.
Increased motor drive relates to patient/subjective reports and objective evidence of increased motor drive and motor activity. It is scored 0 in case of normal motor drive: 1 (mild) in case of a slight increase in drive, not observable in the interview; 2 (moderate) in case of clear and observable increase in energy and drive; 3 (severe) if there is a marked or continuous increase in drive. Increased speech relates to an observed increase in either the rate or quantity of speech, or observed flight of ideas. This item is scored 0 if such observations are absent; 1 (mild) if there is a slight increase in the rate or quantity of speech; 2 (moderate) in case of racing thoughts, or if the patient/subject is significantly more talkative, clearly distractible, or in case of some circumstantiality; wherein this does not impede the interview; 3 (severe) in case of flight of ideas; which interferes with the interview.
Agitation is scored 0 if there is no observed restlessness or agitation; 1 (mild) in case of slight restlessness; 2 (moderate) in case of clear increase in level of agitation; 3 (severe) in case of marked agitation, e.g., near continuous pacing or wringing hands. While a higher score on the BDRS scale indicates more severe disease, there are no generally accepted limits for when a patient/subject is to be considered moderately or severely ill. BDRS score ranges used herein for indicating the severity of depressive episodes in patients/subjects with bipolar disorder are 13-18 for "mildly ill", 19-23 for "moderately ill", 24-36 for "markedly ill", 37-39 for "severely ill", and >40 for "extremely ill". Various other scales are also useful to assess the severity of disease as well as the clinical outcome of treatments.
Anxiety is sometimes defined as an "apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic symptoms of tension". Anxiety is characterised by an intense, excessive, and persistent worry and fear about a situation that is only patient/subjectively seen as menacing and is often accompanied by muscular tension, restlessness, fatigue, inability to catch one's breath, tightness in the abdominal region, nausea, and problems in concentration.
In anxiety disorders or other mental or nervous system disorders associated with anxiety, the feelings of anxiety are difficult to control and interfere with daily activities. Anxiety is a core feature of anxiety disorders, including separation anxiety disorder, specific phobia, social anxiety disorder (social phobia), panic disorder, generalised anxiety disorder (GAD), agoraphobia, and substance/medication-induced anxiety disorder. Anxiety is moreover associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disturbance. Several rating scales to assess anxiety are known on the art, and anxiety symptoms are furthermore assessed as part of various rating scales used to assess mental and nervous system disorders. The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. The scale is clinician/physician-administered. It has 14 items which may be divided into a group of psychic items (1 -6 and 14) measuring in particular mental agitation and psychological distress and into a group of somatic items (items 7-13) measuring in particular physical complaints related to anxiety. Each item is rated by the interviewer on a scale from 0 to 4: 0 = Not present, 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Very severe. A total score is obtained by summing the 14 items. The total score range is 0-56. Higher scores indicate more anxiety. A score <7 is considered to represent no or minimal anxiety; a score of 8-14 mild anxiety; a score of 15-23 moderate anxiety; a score >24 severe anxiety.
The Beck Anxiety Inventory (BAI) is a 21 -item self-report questionnaire developed to assess anxiety, with a focus on somatic symptoms. The items are rated on a four-point Likert scale ranging from zero (not at all) to three (severely: I could barely stand it). The total score ranges from 0 to 63. Subthreshold anxiety as the term is used herein in particular means that the patient/subject has a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 but of less than 18 and/or a Beck Anxiety Inventory (BAI) score of at least 11 but of less than 16.
Negative thinking or individual aspects thereof, such as worthlessness, helplessness and hopelessness, and guilt, may be evaluated by different instruments, such as questionnaires or scales.
Questionnaires assess the mental status of a patient/subject based on observations made by the patient/subject himself/herself, caregivers or the clinician/physician administering the questionnaire. Questionnaires used to assess whether a patient/subject suffers from a particular mental or nervous system disorder may comprise items related to negative thinking. Instruments evaluating relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule - Expanded Form (PANAS-X) or the State Hope Scale (SHS).
The State Shame and Guilt Scale (SSGS) is a self-rating scale of in-the-moment (state) feelings of shame, and guilt experiences. It comprises two subscales, a shame and a guilt subscale. The shame subscale comprises items 1, 3, 5, 7, 9. The guilt subscale comprises items 2, 4, 6, 8, 10. All items are scored in a positive direction and are rated on a 5-point Likert scale. It contains some statements which may or may not describe how the patient/subject is feeling right now. A higher score indicates a more intense feeling of shame or guilt. The Positive and Negative Affect Schedule - Expanded Form (PANAS-X) is a 60-item, expanded version of the PANAS. The PANAS-X measures 11 specific affects: Fear, Sadness, Guilt, Hostility, Shyness, Fatigue, Surprise, Joviality, Self-Assurance, Attentiveness, and Serenity. The PANAS-X thus provides for mood measurement at two different levels. The basic negative emotion scales are fear, hostility, guilt and sadness, while the scale of guilt encompasses six items: guilty, ashamed, blameworthy, angry at self, disgusted with self, dissatisfied with self. Each answer should be scored as 1 = very slightly or not at all; 2 = a little; 3 = moderately; 4 = quite a bit; or 5 = extremely. However, investigators facing more severe time constraints may select and assess only those scales that are most relevant to their research.
More intense feelings of guilt are reflected by a higher score on the guilt scale. The PANAS-X is simple and easy to administer. Most patients/subjects complete the entire 60- item schedule in 10 minutes or less. This scale consists of a number of words and phrases that describe different feelings and emotions. While it should be indicated to what extent the patient/subject has felt this way during the past few weeks, it has been found that the trait scores on the PANAS-X scales are stable over time, including "at the present moment", "today" and during "the past few days", indicating that an appropriate shorter recall period may be applied.
The State Hope Scale (SHS) has three agency and three pathways items to which respondents describe themselves in terms of how they are "right now." The agency subscale score is derived by summing items 2, 4 and 6, relating to the perceived capacity to use one's pathways to reach desired goals; the pathways subscale score is derived by adding the items 1, 3 and 5, relating to thinking that is used to identify possible ways to achieve a goal. The total State Hope Scale score is derived by summing the three agency and the three pathways items. Scores may range from a low of 6 to a high of 48, wherein higher hope is reflected by a higher score on this scale. Negative thinking or aspects thereof are also reflected in other scales such as HAM-D, the MADRS, the BPRS or the BDRS, wherein relevant items thereof may be commonly applicable for assessing negative thinking or aspects thereof.
Cognition includes the skills needed for thinking, remembering, paying attention, and solving problems. Loss or decline of these skills leads to cognitive dysfunction, a term used herein to refer to a deficit in, or an impairment of, any domain of cognition. Cognitive dysfunction may be one of the manifestations of a patient's underlying condition.
The DSM-5 defines six key domains of cognitive function, namely complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. Cognitive dysfunction may impact one or more of those domains. In fact, cognitive abilities are highly interrelated, and it is not unusual that more than one domain is affected. For instance, the domain complex attention has the subdomains sustained attention (commonly referred to as 'concentration' or 'focus'), divided attention, selective attention, and processing speed.
Thus, complex attention evidently encompasses aspects which are critical for a variety of cognitive tasks, such as executive function and learning and memory. Cognitive control or executive function is intrinsically attentional. Also, perception, and decision-making are profoundly influenced by attention abilities. As a consequence, attention is not only tested for in isolation, but for example, also tested by cognitive control tasks/executive function. If attention is impaired, other types of cognitive abilities will likely also be impaired. Before language may be comprehended, visual- spatial relationships perceived, information remembered or problems solved, the stimuli must be attended to.
Cognitive dysfunction, which term herein means an acquired condition and thus represents a decline from a previously attained level of functioning, may be associated with various processes. In a healthy individual, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained upon ageing and may even improve over time. However, even in the absence of any pathological condition, ageing leads to declines in abilities like thinking abstractly, reasoning, and decision-making. These deteriorations are linked to underlying age-related deficits in processing speed, attention, memory, and executive function, which are indicative of cognitive ageing.
Independent of normal ageing, cognitive dysfunction may be associated with one or more conditions or disorders, such as a mental disorder or a nervous system disorder or some other medical conditions. Mental or nervous system disorders which lead to, or are associated with, cognitive dysfunction include disorders characterised by depressive episodes, for example, Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Anxiety Disorder, for example Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobia, and Substance/Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); PostTraumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain, Fibromyalgia and Migraine; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Huntington's Disease; Parkinson's Disease; Dementia, for example Alzheimer's Dementia (AD), Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies, Vascular Dementia, FrontoTemporal Dementia; Eating Disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality Disorders, for example Schizotypal Personality Disorder and Borderline Personality Disorder; Chronic Fatigue Syndrome; one or more conditions or disorders, such as a mental disorder or a nervous system disorder associated with HIV, Traumatic Brain Injury or Post COVID Condition. The cognitive dysfunction may also occur in a patient/subject suffering from sleep disturbance, for instance, insomnia.
Cognitive dysfunction furthermore occurs in disorders showing symptoms characteristic of a neurocognitive disorder that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any aetiology-related disorder. Cognitive dysfunction may take the form of a neurocognitive disorder. Mild neurocognitive disorder, also referred to as mild cognitive impairment, is characterised by a modest cognitive decline from a previous level of performance in one or more of the cognitive domains. Affected patients/subjects are still able to stay independent and do daily tasks. However, the patient/subject usually functions at a suboptimal level. Everyday tasks become more effortful owing to the engagement of compensatory strategies to maintain independence. In major neurocognitive disorder, a significant cognitive decline from a previous level of performance in one or more of the cognitive domains is observed. The cognitive deficits interfere with independence in everyday activities.
Cognitive dysfunction may be evaluated by questionnaires or by neuropsychological assessments. Questionnaires assess the mental status of a patient/subject based on observations made by the patient/subject himself, caregivers or the clinician/physician administering the questionnaire. Questionnaires used to assess whether a patient/subject suffers from a particular mental or nervous system disorder may comprise items related to cognitive function. A neuropsychological assessment is a process by which a person's cognitive, psychological/emotional and behavioural functioning is comprehensively evaluated. A core part of neuropsychological assessment is the administration of neuropsychological tests for the formal assessment of cognitive function.
Performance in these tests is compared with norms appropriate to the patient's age, educational attainment, and cultural background. Testing often uses a set of performance-based questions, also known as a neuropsychological test battery. The abilities tested include language processing, visuospatial processing, attention/concentration, verbal learning and memory, visual learning and memory, executive functions, speed of processing, and sensory-perceptual functions.
Common tests that assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), the MiniMental State Examination (MMSE), the Mini-Cog™, the Screen for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB). The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses different cognitive domains: shortterm memory; visuospatial abilities; executive functions; attention, concentration and working memory; language; orientation to time and space. The total possible score is 30 points; a score of 26 or above is considered normal; a score of 18-25 is considered mild cognitive impairment, a score of 10-17 is considered moderate cognitive impairment and a score less than 10 is considered severe cognitive impairment.
The Mini-Mental State Examination (MMSE) is an 11 -question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. The raw score may also need to be corrected for educational attainment and age. Four cut-off levels are employed herein to classify the severity of cognitive impairment: 24-30 means no cognitive impairment; 19-23 means mild cognitive impairment; 10-18 means moderate cognitive impairment; and <9 means severe cognitive impairment. Used repeatedly, the MMSE is suitable to measure changes in cognitive status. The Mini-Cog™ is a short cognitive impairment screening questionnaire. It combines a 3-word recall with a clock drawing test. The clock drawing test assesses many cognitive areas that may be affected, such as executive function, visuospatial abilities, motor programming, and attention. One point is given for each of the three words correctly recalled after performing the clock drawing test; a correctly drawn clock is worth two points. A score of <4 indicates cognitive impairment.
The Screen for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening instrument for the examination of cognitive performance in psychiatric patients/subjects. The SCIP consists of five subscales: verbal learning test - immediate (VLT-I), working memory test (WMT), verbal fluency test (VFT), verbal learning test - delayed (VLT-D) and processing speed test (PST). There are three different test forms to facilitate test repetition and therefore reducing learning effect. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score of less than 70 indicates cognitive dysfunction.
Cognitive dysfunction may also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of the various subtests. The subtests are: Trail Making Test, Part A (testing speed of processing); Brief Assessment of Cognition in Schizophrenia, symbol coding subtest (speed of processing); Hopkins Verbal Learning Test-Revised, immediate recall, three learning trials only (verbal learning); Wechsler Memory Scale, 3rd ed., spatial span subtest (working memory (nonverbal)); Letter-Number Span test (working memory (verbal)); Neuropsychological Assessment Battery, mazes subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category fluency test, animal naming (speed of processing); Mayer-Salovey-Ca-ruso Emotional Intelligence Test, managing emotions branch (social cognition); and Continuous Performance Test, Identical Pairs version (attention/vigilance). The test battery is appropriate to measure cognitive change. Further tests are the Verbal Recognition Memory (VRM) test, the Rapid Visual information Processing (RVP) test, the Spatial Working Memory (SWM) test and the Digit Symbol Substitution Test (DSST).
Postpartum depression (PPD) is a complex mix of physical, emotional, and behavioural changes that happen in some women after giving birth. PPD is also known as major depressive disorder with peripartum onset. According to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when major depressive disorder (MDD) symptoms begin during pregnancy or within four weeks of delivery. A patient/subject treated according to the present invention is preferably a woman diagnosed with PPD and >4 weeks postpartum. Further, the patient/subject will preferably be <9 months postpartum. Depressive aspects of PPD may be assessed by the HAM-D or the MADRS score. The Edinburgh Postnatal Depression Scale (EPDS) may also be used. The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients/subjects with mood disorders (Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p.382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which would be more sensitive to the changes brought on by antidepressants and other forms of treatment. Higher MADRS score indicates more severe depression. The items considered are apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60.
A patient/subject may suffer from moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 16 or more. It is further considered that the patient/subject may suffer from severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or more or by a Hamilton Depression Rating Scale (HAM- D) score of 27 or more. The patient/subject may be diagnosed with a treatment-resistant form of PPD. A patient/subject treated according to the invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.
Further, a patient/subject treated according to the invention may have a MADRS score of 28 or more or a HAM-D score of 22 or more. Still further, a patient/subject treated according to the invention may have a MADRS score of 35 or more or a HAM-D score of 25 or more. In addition to the above, PPD compromises maternal functioning. In particular the first year after childbirth marks a critical window for both mother and child. In most cases, mothers are the primary caregivers and are, therefore, responsible for the majority of the work related to infant care tasks.
Maternal functioning includes aspects of maternal competence relating to interactions with the infant(s) as well as maternal self-care. Maternal functioning, including the emotional aspect of mothering, is also important for the child's development. In fact, the quality of mother-child interaction in the year after birth affects infant development. High levels of maternal functioning are likely to correlate with positive infant development outcomes. Likewise, impaired functioning in the postpartum period might impede optimal infant development.
The Barkin Index of Maternal Functioning (BIMF) was designed to measure functioning in the year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score between 0 and 6 so that the maximum total score is 120. The higher the score, the better maternal functioning is rated. The BIMF identifies the key functional domains of a mother during the postnatal period as: self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
A BIMF score of 95 or below is considered herein as representing slightly compromised maternal functioning, score of 80 or below is considered herein as representing compromised maternal functioning, a score of 65 or below is considered herein as representing severely compromised maternal functioning. The invention in particular allows improving maternal functioning in patients/subjects having a score of 80 or below before treatment and in patients/subjects having a score of even 65 or below.
Symptoms such as anhedonia; emotional withdrawal and affective flattening are clustered together here as social/emotional withdrawal or detachment. Reduced social engagement is a further aspect associated with social/emotional withdrawal or detachment.
Anhedonia is the inability to experience pleasure. The patient/subject does not suffer from anhedonia if there is patient/subjectively no reduced ability to experience pleasure in usual activities. Anhedonia is mild in the case of slight reduction in pleasure from usually pleasurable activities; moderate in the case of significant reduction in pleasure from usually pleasurable activities or some pleasure from isolated activities retained; or severe in the case of complete inability to experience pleasure.
Anhedonia comprises consummatory (or liking) and anticipatory (or wanting) components. Consummatory pleasure refers to the "in the moment" pleasure experienced by the patient/subject directly engaged in an enjoyable activity, whereas anticipatory pleasure refers to the experience of pleasure related to future activities. Affective flattening characterises the patient/subjective sense of reduced intensity or range of feelings or emotions. The patient/subject does not show affective flattening if there is no sense of reduced intensity or range of feeling or emotions. It is mild in the case of slight constriction of range of affect, or transient reduction in range or intensity of feelings; moderate in the case of significant constriction of range or intensity of feelings with preservation of some emotions, e.g., inability to cry; and severe in the case of marked and pervasive constriction of range of affect or inability to experience usual emotions.
Emotional withdrawal or detachment is an inability or unwillingness to connect with other people on an emotional level. For example, the BPRS contains an item relating to emotional withdrawal, which is characterised as the deficiency in the patient/subject's ability to relate emotionally during the interview situation. According to the description of this BPRS item, there is no emotional withdrawal if there is no lack of emotional involvement shown by occasional failure to make reciprocal comments, occasionally appearing preoccupied, or smiling in a stilted manner, but spontaneously engages the interviewer most of the time.
There is a mild form of emotional withdrawal if there is a lack of emotional involvement shown by noticeable failure to make reciprocal comments, appearing preoccupied, or lacking in warmth, but responds to the interviewer when approached. It is moderate if the emotional contact is not present much of the interview because the patient/subject does not elaborate responses, fails to make eye contact, does not seem to care if the interviewer is listening, or may be preoccupied with psychotic material. It is moderately severe if, in addition, emotional contact is not present most of the interview. Severe forms are present if emotional participation is actively avoided by the patient/subject or if the patient/subject is frequently unresponsive or responds with yes/no answers or responds with only minimal affect. It is extremely severe if the patient/subject consistently avoids emotional participation, is unresponsive or responds with yes/no answers or may leave during the interview or just not respond at all.
Reduced social engagement characterises patient/subjective reports of reduced social and interpersonal engagement or interactions. There is no reduced social engagement if there are no reports of reduced social and interpersonal engagement or interactions. It is mild in the case of slight reduction in social engagement with no impairment in social or interpersonal function; moderate in the case of clear reduction in social engagement with some functional sequelae, e.g., avoiding some social engagements or conversations; and severe in the case of marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusing to answer the phone or see friends or family.
Social/emotional withdrawal or detachment may be associated with one or more conditions or disorders, such as a mental disorder or a nervous system disorder or some other medical conditions. Mental or nervous system disorders which lead to, or are associated with, social/emotional withdrawal or detachment include disorders characterised by depressive episodes, for example Major Depressive Disorder (MDD), Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder, Postpartum Depression (PPD), Seasonal Affective Disorder and Persistent Depressive Disorder; Anxiety Disorders, for example Generalised Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD); Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); PostTraumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain and Fibromyalgia; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DLB); Vascular Dementia and Fronto-Temporal Dementia (FTD); Parkinson's Disease (PD); Eating Disorders; Autism Spectrum Disorder (ASD); Attention Deficit Hyperactivity Disorder (ADHD); and Personality Disorders, for example Schizotypal Personality Disorder and Borderline Personality Disorder (BPD).
The social/emotional withdrawal or detachment may also occur in a patient/subject suffering from sleep disturbance, for instance, insomnia. The social/emotional withdrawal or detachment may also occur in a patient/subject suffering from medical health conditions leading to an associated mental or nervous system condition including Traumatic Brain Injury (TBI).
Social/emotional withdrawal or detachment or individual aspects thereof, such as anhedonia, emotional withdrawal and affective flattening, may be evaluated by different instruments, such as questionnaires or scales. Questionnaires assess the mental status of a patient/subject based on observations made by the patient/subject himself/herself, caregivers or the clinician/physician administering the questionnaire. Questionnaires used to assess whether a patient/subject suffers from a particular mental or nervous system disorder may comprise items related to social/emotional withdrawal or detachment.
The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, i.e., the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Either of the "disagree" responses score one point, and either of the "agree" responses score 0 points. Thus, the final score ranges from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used for measuring anhedonia in depression, but it is also frequently used to assess anhedonia in other patient/subject groups.
In principle, the SHAPS measures hedonic tone during the last few days with 14 hypothetically formulated items. However, due to the hypothetical nature of the items an appropriate shorter recall period may also be applied for an earlier assessment time point. Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS) measuring interest, motivation, effort and consummatory pleasure across four domains: hobbies, food/drink, social activities and sensory experience may be used for the assessment of anhedonia. It comprises 17 items assessing state anhedonia right now. The DARS is rated on a five-point Likert scale from 0 (not at all) to 4 (very much), higher values indicating less anhedonia. All items are summed up to a total score in the range of 0 to 68. For each of the four hedonic domains, hobbies (four items, sum score 0-16), food/drink (four items, sum score 0-16), social activities (four items, sum score 0-16) and sensory experiences (5 items, sum score 0- 20), patients/subjects/patient/subjects are asked to provide two or three of their own favourite examples.
The Personality Inventory for DSM-5 (PID-5) - Adult is a 220 item self-rated personality trait assessment scale for adults age 18 and older. It assesses 25 personality trait facets including Anhedonia, Anxiousness, Attention Seeking, Callousness, Deceitfulness, Depressivity, Distractibility, Eccentricity, Emotional Lability, Grandiosity, Hostility, Impulsivity, Intimacy Avoidance, Irresponsibility, Manipulativeness, Perceptual Dysregulation, Perseveration, Restricted Affectivity, Rigid Perfectionism, Risk Taking, Separation Insecurity, Submissiveness, Suspiciousness, Unusual Beliefs and Experiences, and Withdrawal, with each trait facet consisting of 4 to 14 items.
The trait facet Anhedonia contains the items 1, 23, 26, 30R, 124, 155R, 157, 189 (reverse scored items are marked with the letter "R"), the trait facet Withdrawal contains the items 10, 20, 75, 82, 136, 146, 147, 161 , 182, 186 and the trait facet Intimacy Avoidance contains the items 89, 97R, 108, 120, 145, 203. These three trait facets may be combined to yield the broader trait domain designated Detachment. The measure is completed by the individual prior to a visit with the clinician/physician. Each item asks the individual to rate how well the item describes him or her generally. Each item on the measure is rated on a 4-point scale. The response categories for the items are 0 = very false or often false; 1 = sometimes or somewhat false;
2 = sometimes or somewhat true; 3 = very true or often true. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131 , 142, 155, 164, 177, 210, and 215, the items are reverse-coded prior to entering into scale score computations.
The scores on the items within each trait facet should be summed and entered in the appropriate raw facet score box. In addition, the clinician/physician is asked to calculate and use average scores for each facet and domain. The average scores reduce the overall score as well as the scores for each domain to a 4-point scale, which allows the clinician/physician to think of the individual's personality dysfunction relative to observed norms. The average facet score is calculated by dividing the raw facet score by the number of items in the facet (e.g., if all the items within the "Anhedonia" facet are rated as being "sometimes or somewhat true," then the average facet score would be 16/8 = 2, indicating moderate anhedonia). An average domain score is calculated by summing and then averaging the 3 facet scores contributing primarily to the specific domain. For example, if the average facet scores on Anhedonia, Intimacy Avoidance and Withdrawal (scales primarily indexing Detachment) are all 2, then the sum of these scores would be 6, and the average domain score would be 6/3 = 2. Higher average scores indicate greater dysfunction in a specific personality trait facet or domain. High scores on a facet or domain may indicate significant and problematic areas for the individual receiving care that might warrant further assessment, treatment, and follow up.
Key aspects observed with patients/subjects suffering from psychomotor retardation are reduced energy and activity and reduced motivation. Psychomotor retardation involves a slowing down of thought and a reduction of physical movements in an individual. Psychomotor impairment may cause a visible slowing of physical and emotional reactions. Psychomotor retardation may be associated with one or more conditions or disorders, such as a mental disorder or a nervous system disorder or some other medical conditions.
Mental or nervous system disorders which lead to, or are associated with, psychomotor retardation include disorders characterised by depressive episodes, for example, Major Depressive Disorder (MDD); Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Postpartum Depression (PPD); Seasonal Affective Disorder and Persistent Depressive Disorder; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example Substance Use Disorder (SUD); Psychotic Disorder, for example Schizophrenia; Dementia, for example Alzheimer's Dementia (AD); Dementia with Lewy Bodies (DLB) ; Vascular Dementia and Parkinson's Disease Dementia; Parkinson's Disease; Chronic Fatigue Syndrome. Psychomotor retardation may also occur in a patient/subject suffering from sleep disturbance, for instance, insomnia.
Psychomotor retardation may be assessed by measuring various aspects. These may include for instance various types of drawing tasks and tests, such as the trail making test (TMT), the digit symbol substitution test (DSST), or the Gibson Spiral Maze Test (GSM) and others which are known in the art. In the trail making test (TMT), for instance, patients/subjects must connect 25 circles that contain either numbers (TMT A) or a combination of numbers and letters (TMT B) in ascending order. Task requirements are similar for TMT-B, except that the patient/subject must alternate between numbers and letters (1, A, 2, B, 3, C and so on). The test thus evaluates processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the amount of time required to complete the task.
Another test that involves graphomotor ability is the Gibson Spiral Maze (GSM) assessing psychomotor speed only, and is not influenced by cognitive abilities, patients/subjects who complete the GSM must correctly trace through a spiral maze from a starting point to an endpoint without touching bordering lines. The digit symbol substitution test (DSST) also measures psychomotor speed and consists of digit-symbol pairs followed by a list of digits. Under each digit, the patient/subject should write down the corresponding symbol as fast as possible. The score consists in the number of symbols correctly reported in 90 s. A further example for a motor test is the finger tapping test.
Thus, certain tests combine measurements of both motor and cognitive aspects of psychomotor retardation, while further others assess only motor aspects.
Analysis of speech may be a further indicator of psychomotor retardation. Major scales available to assess and measure include the severity of psychomotor retardation, the Salpetriere Retardation Rating Scale (SRRS) and the Motor Agitation and Retardation Scale (MARS). The Salpetriere Retardation Rating Scale (SRRS), developed by Widlocher assesses cognitive and motor aspects by fifteen items. The first three measure movement, specifically the quality of stride and slowness of limb, trunk, head, and neck movement. The next three items focus on speech including verbal flow, tone of voice, and length of response. Two items are designed to objectively measure cognitive function. These questions are based on the interview conversation and measure the patient's ability to approach and expand on topics. The further items are patient/subjective and assess rumination, fatigue, level of interest, perception of time, memory, and concentration. The last item of the scale relates to an overall assessment of the patient's psychomotor retardation. The items are scaled from 0 (symptom absence) to 4 (severe) based on the severity of the presenting symptom, for a total score range of 0 to 60.
The Motor Agitation and Retardation Scale (MARS) assesses motor aspects only. It was designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five major body categories including eyes, face, voice, limbs, and trunk with a total of 19 items on the scale. Items of the eyes category include direction of gaze, amount of blinking, staring, and eye movement. Items associated with the face category include facial expression and facial expressivity. The category of voice has items that include volume, slurring, tone and time for onset. Items under the limbs category include hand, foot, and leg movement, stride, motor slowness, and tension in hands. The trunk category items include posture, immobility, and axial movement. The severity of each item ranges from a 1 to a 4, with 4 being the most severe. Of the 19 items 9 relate to motor agitation and 10 items assess motor retardation. The retardation items include abnormal gait, immobility of trunk / proximal limbs, postural collapse, motor slowness (i.e. the limb and trunk category); lack of facial expressivity, downcast gaze (i.e. the eyes and face category); and reduced voice volume, slurring of speech, delayed speech onset, monotone speech (i.e. the voice category). The MARS scale offers a rapid clinical assessment of motor signs.
In an embodiment, the pharmaceutical composition of the invention is for use in the treatment of a patient with a AES-S score of at least 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in AES-S score of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in AES-S score of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 or 72 points. In an embodiment, the pharmaceutical composition of the invention is for use in the treatment of a patient with a MADRS score of at least 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in MADRS score of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in MADRS score of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 points. In an embodiment, the pharmaceutical composition of the invention is for use in the treatment of a patient with a GAD-7 score of at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 points. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in GAD-7 score of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in GAD-7 score of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 points. In an embodiment, the pharmaceutical composition of the invention is for use in the treatment of a patient with a PHQ-9 score of at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 points. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in PHQ-9 score of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, treatment of a patient with the pharmaceutical composition of the invention results in a decrease in PHQ-9 score of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 points.
The skilled person will appreciate that references herein to pharmaceutically acceptable salts of 5-MeO-DMT include within their scope those salts, and crystalline forms thereof, as described herein.
Example 16: Blinding in psychedelic studies: comparison of placebo and sub-perceptual dose of intranasal 5- MeO-DMT (BPL-003) in healthy volunteers
Previous clinical studies indicate that 5-MeO-DMT induces profound alterations in consciousness, including mystical experiences, with putative benefit in mood and substance use disorders. The potential unblinding of the treatment assignment is a known limitation of studies investigating psychedelics and we have explored different comparators to assess their ability to unmask participants.
A randomised, Phase 1 study to evaluate the safety, tolerability and pharmacodynamics of single doses of intranasal BPL-003 (5-MeO-DMT benzoate) in healthy, psychedelic-naive subjects was conducted. Psychedelic effects were evaluated using the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). We assessed the subjective drug intensity (SDI) rating every 2 minutes for up to 90 minutes post-dose to determine the subject's perception of the drug effect. SDI was scored as 0 (definitely no effect), 1-2 (possible effect), 3-9 (definite effect) or 10 (the strongest effect imaginable).
BPL-003 was safe and well tolerated at doses up to 12 mg; the most frequently reported treatment emergent adverse events (TEAEs) were nasal discomfort, nausea, headache and vomiting. 15% of placebo, 60% of 0.3 mg BPL-003 and 80% of 12 mg BPL-003 subjects had TEAEs; the most common TEAE of nasal discomfort being observed in 0 out of 13, 2 out of 5 and 3 out of 5 subjects respectively. Nasal discomfort was mild for all events. The mean total MEQ-30 was 0.58, 0.15 and 3.69 for placebo, 0.3 mg and 12 mg BPL-003 respectively; no meaningful effect being reported for placebo or 0.3 mg BPL-003. Similar effects were observed with the EDI. Within the dose range evaluated psychedelic effects increased with dose, the onset was rapid and shortlasting. The peak SDI was scored as definitely no effect for 50% of placebo, 20% of 0.3 mg BPL-003, 0% of 12 mg BPL-003; possible effect for 33% of placebo, 80% of 0.3 mg BPL-003, 0% 12 mg BPL-003; definite effect for 17% of placebo, 0% for 0.3 mg BPL-003, 20% of 12 mg BPL-003; the strongest effect possible for 0% for placebo, 0% of 0.3 mg BPL-003 and 80% of 12 mg BPL-003.
Identification of a suitable comparator is essential to try to minimise any potential unblinding in psychedelic studies. The psychedelic effects of the very low dose of BPL-003 were similar to placebo, however the TEAE of nasal discomfort documented in this Phase 1 study might help mitigate potential unmasking of treatments. This was confirmed by the SDI results, where 80% of subjects receiving 0.3 mg of BPL-003 thought they had a possible effect. Based on these results 0.3 mg of BPL-003 is well suited to be used as a sub-perceptual dose (i.e active placebo) in future clinical trials.
In an embodiment, there is provided a pharmaceutical composition for use to prevent unblinding in psychedelic studies, wherein the pharmaceutical composition comprises a dose of a psychedelic compound. In an embodiment, the dose is 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0% of the dose of the psychedelic compound under investigation. In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, for the purposes of preventing unblinding, wherein the pharmaceutical composition is as described herein.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises 0.3 mg of a psychedelic compound. In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 mg of a psychedelic compound. In an embodiment, the psychedelic may be 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises a dosage amount of a psychedelic compound which corresponds to 2.5% of a dosage amount of the psychedelic compound which is being investigated in the clinical trial. In an embodiment, the psychedelic may be 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises a dosage amount of 5-MeO- DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, which corresponds to 2.5% of a dosage amount of the psychedelic compound which is being investigated in the clinical trial.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises a dosage amount of 5-MeO- DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, which corresponds to 2.5% of a dosage amount of the psychedelic compound which is being investigated in the clinical trial, wherein said psychedelic is 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises a dosage amount of a psychedelic compound which corresponds to 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0% of a dosage amount of the psychedelic compound which is being investigated in the clinical trial. In an embodiment, the psychedelic may be 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises 0.3 mg of a psychedelic compound and the dosage amount of the psychedelic compound which is being investigated in the clinical trial is 12 mg. In an embodiment, the psychedelic may be 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, there is provided a pharmaceutical composition for use as an active placebo in a psychedelic clinical trial, wherein said pharmaceutical composition comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 or 0.8 mg of a psychedelic compound and the dosage amount of the psychedelic compound which is being investigated in the clinical trial is 8, 9, 10, 11, 12, 13, 14, 15 or 16 mg. In an embodiment, the psychedelic may be 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
In an embodiment, the pharmaceutical composition for use as an active placebo in a psychedelic clinical trial comprises 5-MeO-DMT benzoate. In an embodiment, the 5-MeO-DMT benzoate is in crystalline form, as described herein. In an embodiment, the pharmaceutical composition is an intranasal composition.
In an embodiment, there is provided a pharmaceutical composition for use in a method of treating one or more diseases/conditions, said pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, wherein the pharmaceutical composition comprises a dosage amount of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, which was determined following one or more clinical trials wherein said one or more clinical trials comprised the use, as an active control, of a pharmaceutical composition comprising a dosage amount of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, which corresponded to 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5.0% of one or more of the 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, dosages under clinical investigation.
In an embodiment, the clinical trial may be a phase 0, 1, la, lb, 2, 2a, 2b, 3 or 4 clinical trial. In an embodiment, the clinical trial is a randomised, double-blind clinical trial. In an embodiment, the clinical trial is a quadruple masked clinical trial.
Example 17: Targeted Nasal Delivery
The nasal cavity is recognised as a promising systemic drug delivery route due to the highly vascularised capillary bed within the nasal mucosa. There is therefore a need for formulations or compositions as described herein with an optimised particle size distribution which show turbinate deposition. There is also a need for delivery devices which can selectively deliver a formulation or composition as described herein to the nasal turbinates, for the uses as described herein.
Materials
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) Benzoate, Hydroxypropyl methylcellulose (HPMC) ((Pharmacoat 606 - substitution 2910, viscosity 6 cP) ShinEtsu Chemical, Japan), HPLC grade 99% ethanol, HPLC grade 99% methanol, HPLC grade water, Glycerol and Brij-35 (Fisher Scientific, United Kingdom). Ultrapure water 18.2 MQ (Veolia Elga LabWater system, in house) Active devices (UDSp, Aptar Pharma, France).
Preparation of 5-MeO-DMT Spray Dried Dispersion (5-MeO-DMT SDD)
Feed solution was prepared at 50% w/w 5-MeO-DMT Benzoate loading (32.1% 5-MeO-DMT). Both polymers were dissolved in water under ambient stirring overnight. D-sorbitol and 5-MeO-DMT Benzoate were added to solution and dissolved under ambient stirring, producing a clear, lightly straw-coloured solution. Feed solution was spray dried using the ProCepT 4M8-Trix Spray Dryer fitted with a 25 kHz Ultrasonic nozzle (ProCepT,
Figure imgf000085_0001
Particle Size Distribution (PSD) was determined using a Sympatec HELOS H4459 particle size analyser equipped with an R5 lens (Sympatec GmbH, Germany) in triplicate. Bulk powder was analysed using the RODOS dry powder dispersion unit at 3 bar dispersal pressure and powder from active devices (ExDevice) were manually actuated into the laser diffractor with the tip of the device positioned 3 cm from the mid-point of the laser.
Methodology - summary
The Alberta Idealised Nasal Inlet (Al N I) and Stage 1 collection cup of the Next Generation Impactor (NGI) was coated with a solution containing 12 g Brij-35, 20 g glycerol and 80 mL ethanol. Once dried, AINI and NGI were assembled with the addition of a pre-separator with 15 mL 50:50 (v/v) methanokwater diluent in the reservoir. The UDSp loaded with 37.4 mg formulation was positioned at either 30, 45 or 60° to the horizontal and inserted 1 cm into the nasal orifice of the AINI. A 7.5 L/min airflow was applied for 15 seconds upon actuation of the UDSp, delivering 1.875 L of air. After actuation, the configuration was disassembled and 15 mL diluent used to dissolve material on the UDSp's exterior, deposited in the AINI and the NGI collection cup, with the addition of a secondary dilution. Analysis was performed in triplicate and analysed by HPLC, with Two-way ANOVA statistical analysis.
Methodology - detailed Nasal deposition was measured using the Alberta Idealised Nasal Inlet (AIN I) with the Copley Next Generation Impactor (NGI) from an Aptar Unidose Powder Nasal spray system (UDSp)
A) Coating of AINI and NGI collection cups
12 g Brij-35, 20 g glycerol and 80 mL ethanol were mixed until dissolved to form a coating solution. Bottom of the AINI was sealed and a 20 mL coating solution was added through the vestibule while the AINI was inverted. The AINI was slowly rotated horizontally 360° clockwise and anticlockwise then rotated vertically 360° clockwise and anticlockwise. Excess coating solution was drained and the AINI was placed on its left side, back and right side for 15 minutes each. AINI was positioned upright for 30 minutes to allow any further excess coating solution to drain and for the coat to dry. 2 mL of coating solution was pipetted onto the NGI Stage 1 collection cup and rocked for 5 minutes using the NGI rocker in order to coat. Excess solution was drained and the cup was allowed to dry.
B) NGI assembly
NGI was assembled with the coated Stage 1 collection cup and uncoated collection cups for states 2-7 and micro-orifice collector. The pre-separator and throat piece were attached and a leak test was performed using the critical flow controller and high-capacity pump. The flowmeter was attached to the throat piece and the flowrate set to 7.5 L/min. The throat piece was removed and 15 mL 50:50% v/v HPLC grade water: HPLC grade methanol (diluent) was added to the pre-separator insert cup. The AINI was then installed on the preseparator.
C) Actuation
The UDSp containing 5-MeO-DMT was weighed to obtain a pre-actuation mass. The UDSp was then clamped into position such that the tip of the UDSp was inserted 1 cm into the vestibule of the AINI. The angle of insertion was set using an electronic protractor. The UDSp was actuated using 7.5 L/min flow rate for 15 seconds.
D) HPLC Sample collection
UDSp was then removed and weighed to obtain a post-actuation mass. The exterior of the UDSp was washed with 15 mL diluent in a glass dish and the washings were collected for HPLC analysis. AINI was disassembled and each component was thoroughly washed in separate glass dishes with 15 mL diluent. These washings were then collected for HPLC analysis. The pre-separator was removed from the NGI, the top and bottom were then covered and the pre-separator was inverted to wash the interior with the previously added 15 mL diluent. These washings were then collected for HPLC analysis. 15 mL diluent was added to the Stage 1 collection cup and the cup was rocked for 10 minutes using the NGI rocker to wash. These washings were then collected for HPLC analysis.
E) HPLC
HPLC was carried out on the samples to quantify 5-MeO-DMT content. Where necessary samples were diluted to stay within the linearity of the quantification method.
Results
Pharmacopoeia guidelines state that a nasal powder should demonstrate that deposition of the products is localised within the nasal cavity, and the current method requires that most of the particles are larger than 10 pm as determined by laser diffraction. Analysis was performed on the 5-MeO-DMT SDD with the Sympatec, and the particle size distribution shown in Figure 22. Using the ultrasonic nozzle an optimised nasal powder was achieved in which the mean particle diameter was close to the diameter recommended while maintaining minimal particles below 10 pm, passing acceptance criteria requested by the European Medicines Agency (EMA).
The AINI was used to assess the deposition profile of the 5-MeO-DMT SDD formulation with the method outlined above. The AINI consists of four components for the nasal cavity - the vestibule (nostril), turbinates, olfactory and nasopharynx - which is assembled and attached to a pre-separator. The pre-separator is incorporated to capture any deposition that would falsely land on Stage 1 due to particle bounce in the internal surfaces of the AINI. Minimal deposition was seen in the vestibule compared to commercially available nasal sprays. Minimal deposition was also seen in the lung analogue. The majority of the formulation was found in the turbinates and the olfactory region showed deposition from 5-11% - which is advantageous as it is theorised that a minimum of 0.01-1% of the oral dose is effective for nose-to-brain absorption. The results of the AINI can be seen in Figure 23. There is therefore provided an advantageous method for the delivery of a 5-MeO-DMT SDD. The same 5- MeO-DMT SDD was filled into the passive nasal delivery device at a loading suitable to deliver 12 mg 5-MeO- DMT free base equivalent. The passive device was positioned into an adapter and drawn through the AINI/NGI with a flow rate of 30 L/min to deliver either 1 L or 2 L of air respectively. The nasal deposition profile produced can be seen in Figure 24. It can be readily seen that very little drug product was deposited in the desired locations of the turbinates and olfactory region.
There is therefore provided an advantageous method for the delivery of a 5-MeO-DMT wherein 5-MeO-DMT is delivered by an active nasal delivery device. In an embodiment, there is provided the use of a formulation or composition as described herein in a method of treating a patient in need thereof, wherein the formulation or composition is administered intranasally via an active delivery nasal device, as described herein, and wherein more than 30%, 40%, 50%, 60%, 70%, 80% or 90% of the formulation or composition is deposited to the turbinates and/or olfactory region of the nasal cavity. In an embodiment, the method of treating a patient in need thereof is a method of treating one or more of the conditions or diseases described herein.
In an embodiment, there is provided the use of a formulation or composition as described herein in a method of treating a patient in need thereof, wherein the formulation or composition is administered intranasally via an active delivery nasal device and wherein less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% is deposited in the lungs. In an embodiment, there is provided a nasal delivery device for delivering a formulation or composition as described herein to an olfactory region of a nasal cavity, the device comprising a formulation or composition as described herein. In an embodiment, the device is an active nasal delivery device wherein a plunger style actuator, or similar, is depressed to administer a dose. In an embodiment, the nasal delivery device is not a breath actuated delivery device. In an embodiment, the device comprises a dose volume up to 140 mm3.
In an embodiment the device is an Aptar device (UDS -Unidose Solid) as commercially available in the UK as of 1 June 2023. In an embodiment, the dry powder is administered to the subject using a dry powder device as described in U.S. Publication 2016/0296957, which is hereby incorporated by reference in its entirety. Dry powder devices described in U.S. Publication No. 2022/0362491, International Publication No. WO 2022/123128, International Publication No. WO 2022/171969; and International Publication No. WO 2022/208014 are incorporated herein by reference.
In an embodiment, the nasal delivery device may be as described in any one of W021005308; WO22123128; WO22171969; and W022208014 (the contents of which are incorporated by reference). In an embodiment, there is provided a dispenser device, optionally for dispensing a formulation or composition as described herein, the dispenser device comprising: a formulation or composition as described herein; a dispenser outlet (10); an air expeller (20) for generating a flow of air while the device is being actuated, said air expeller (20) including a piston (21) that slides in an air chamber (22) between a rest position and a dispensing position, said air chamber (22) including a cylindrical body (222) in which said piston (21) slides in airtight manner; and at least one reservoir (30) that contains a single dose of composition, said reservoir (30) including an air inlet (31) that is connected to said air expeller (20), and a composition outlet (32) that is connected to said dispenser outlet (10), said air inlet (31) including a composition retainer member (40) for retaining the composition in the reservoir (30) until the composition is dispensed, and said composition outlet (32) being closed by a closure element (50) that is force fitted in the composition outlet (32) of the reservoir (30); said device further including a mechanical opening system (61, 62) that co-operates with said closure element (50) so as to expel it mechanically from its closed position while the device is being actuated, said mechanical opening system comprising a rod assembly (61, 62), a first rod portion (61) being part of said air expeller (20) and sliding in said air chamber (22) during actuation of the device, and a second rod portion (62) pushed by said first rod portion (61) during actuation of the device, said rod assembly (61, 62) cooperating at the end of the actuation stroke with said closure element (50) to expel it mechanically from its closed portion, said piston (21) of said air expeller (20), when in its rest position, co-operating in non-airtight manner with said air chamber (22), in such a manner that said air chamber (22) is in communication with the atmosphere in the rest position, said piston (21) including an inner lip (215) that slides in airtight manner on said cylindrical surface (614) during actuation of the device, and that co-operates in non-airtight manner with fluting (615) formed on said cylindrical surface (614) in the rest position to put the air chamber (22) in communication with the atmosphere in the rest position, said piston 21) co-operating in airtight manner with said cylindrical body (222) in any positions, and co-operating in non-airtight manner with said cylindrical surface (614) only in the rest position.
In an embodiment, there is provided a dispenser device, optionally for dispensing a formulation or composition as described herein, the dispenser device comprising: a formulation or composition as described herein; a dispenser outlet; an air expeller for generating a flow of air while the device is being actuated, said air expeller including a piston that slides in an air chamber between a rest position and a dispensing position, said air chamber including a cylindrical body in which said piston slides in airtight manner; and at least one reservoir that contains a single dose of composition, said reservoir including an air inlet that is connected to said air expeller, and a composition outlet that is connected to said dispenser outlet, said air inlet including a composition retainer member for retaining the composition in the reservoir until the composition is dispensed, and said composition outlet being closed by a closure element that is force fitted in the composition outlet of the reservoir; said device further including a mechanical opening system that co-operates with said closure element so as to expel said closure element mechanically from a closed position while the device is being actuated, said piston of said air expeller, when in the rest position, co-operating in non-airtight manner with said air chamber, in such a manner that said air chamber is in communication with the atmosphere in the rest position, wherein said piston includes an inner lip configured to cooperate with a cylindrical surface of a cylindrical member extending inside the cylindrical body, said cylindrical surface including fluting that cooperates in non-airtight manner with said inner lip of the piston in the rest position.
In an embodiment, said piston comprises one or more markings which are visible only when the piston is in the rest position and not visible when the piston is in the dispensing position. In an embodiment, a method comprising the use of the dispenser device comprises the actuation of the piston from the rest position to the dispensing position such that the one or more markings are no longer visible. In an embodiment, successful actuation of the dispensing device occurs when the one or more markings are no longer visible. In an embodiment, the one or more markings may be: one or more coloured lines, one or more coloured shapes, one or more words or written text or one or more physical features.
In an embodiment, there is provided an active nasal delivery device as described herein comprising one or more markings, said markings being visible when the active nasal delivery device is in the resting state and not visible following successful actuation of said active nasal delivery device. In an embodiment, the absence from view of said markings represents successful actuation of the active nasal delivery device. In an embodiment, the one or more markings may be as described herein.
A method of intranasally delivering a powder pharmaceutical formulation comprising a psychedelic and one or more pharmaceutically acceptable carriers or excipients, to a patient, wherein 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more or 99% or more of the formulation reaches the turbinates and olfactory region, wherein the psychedelic is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, and the formulation is delivered via a nasal powder dispenser device which may comprise one or more of: a nasal dispenser head for inserting into a patient's nostril, the nasal dispenser head including a dispenser orifice; and an air expeller that, during actuation of the nasal powder dispenser device, generates a flow of compressed air so as to dispense a dose of the powder pharmaceutical formulation into the nostril through the dispenser orifice.
In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of:
Figure imgf000088_0001
a spray pattern of: a particle size distribution (at 40mm) of: D10 = 13 to 17, D50 = 35 to 60, D90 = 650 to 700, %<10 pm = <0.1, 1,
2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70mm) of: DIO = 13 to 17, D50 = 24 to 30, D90 = 540 to 610, %<10pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution of: DIO = 13 to 17, D50 = 22 to 27, D90 = 35 to 56, %<9 pm = <0.1-10%; or
% particles of equal to or less than 11.7pm size of: 0.5 to 5%.
In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 20 to 45 degrees; width: 25 to 55 mm;
Figure imgf000089_0001
a spray pattern of: a particle size distribution (at 40mm) of: D10 = 13 to 17, D50 = 35 to 60, D90 = 650 to 700, %<10 pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70mm) of: D10 = 13 to 17, D50 = 24 to 30, D90 = 540 to 610, %<10pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or
% particles of equal to or less than 11.7pm size of: 0.5 to 5%.
In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 20 to 35 degrees; width: 25 to 45 mm;
Figure imgf000089_0002
a spray pattern of: a particle size distribution of: D10 = 13 to 17, D50 = 22 to 27, D90 = 35 to 56, %<9 pm = <0.1-10%; or
% particles of equal to or less than 11.7 pm size of:0.5 to 5%.
In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 27 or 40 degrees; width: 33 or 50 mm;
Figure imgf000090_0001
a spray pattern of: a particle size distribution (at 40 mm) of: DIO = 15 or 16, D50 = 38 or 54, D90 = 684 or 685, %<10 pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70 mm) of: D10 = 15 or 16, D50 = 27 or 28, D90 = 558 or 596, %<10 pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution of: D10 = 13 to 17, D50 = 22 to 27, D90 = 35 to 56, %<9 pm = <0.1-10%; or
% particles of equal to or less than 11.7 pm size of: 0.5 to 5%.
In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a plume geometry of: angle: 22 to 35 degrees; width: 27 to 55 mm; or plume geometry of: angle: 22 to 33 degrees; width: 27 to 42 mm; or a plume geometry of: angle: 25 to 30 degrees; width: 29 to 39 mm; or a plume geometry of: angle: 26 to 28 degrees; width: 32 to 35 mm; or a plume geometry of: angle: 27.5 degrees; width: 34.33 mm; or a plume geometry of: angle: 24.4 degrees; width: 30.30 mm; or a plume geometry of: angle: 24.8 degrees; width: 30.76 mm; or a plume geometry of: angle: 27.4 degrees; width: 34.13 mm; or a plume geometry of: angle: 30.5 degrees; width: 38.29 mm; or a plume geometry of: angle: 39.2 degrees; width: 50.35 mm; or a plume geometry of: angle: 33.43 degrees; width: 52.25 mm; or a plume geometry of: angle: 28 degrees; width: 34 mm; or a plume geometry of: angle: 24 degrees; width: 30 mm; or a plume geometry of: angle: 25 degrees; width: 31 mm; or a plume geometry of: angle: 27 degrees; width: 34 mm; a plume geometry of: angle: 31 degrees; width: 38 mm or a plume geometry of: angle: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46 degrees; width: 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56 mm.
In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a
Figure imgf000090_0002
spray pattern of:
Figure imgf000090_0003
or
In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a spray pattern of:
Figure imgf000091_0001
Figure imgf000091_0002
or
Figure imgf000091_0003
or
Figure imgf000091_0004
or
In an embodiment, the particle size distribution of the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is: DIO = 15.54 or 15.05 or 15.89 or 15.31, D50 = 26.8 or 28.21 or 38.27 or 53.92, D90 = 558.4 or 595.9 or 683.8 or 385.3, %<10 pm = 5.45 or 3.01 or 3.90 or 3.79; or DIO = 10.4 or 10.7, D50 = 21.0 or 22.8, D90 = 38.4 or 14.9, %<10 pm = 8.65% or 8.35%; or D10 = 13, 14, 15, 16 or 17, D50 = 22, 23, 24, 25, 26 or 27, D90 = 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 or 56, %<9 pm = <0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%. In an embodiment, the % particles of equal to or less than 11.7 pm size of the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is: 0.5 to 5%, 0.6 to 4%, 0.7 to 3%, 0.8 to 2%, 0.9 to 1%. In an embodiment, the active nasal delivery has an actuation force of between 30 and 60 N. In an embodiment, the actuation force is between 40 and 50 N. In an embodiment, the actuation force is 41, 42, 43, 44, 45, 46, 47, 48 or 49 N. In an embodiment, the actuation force is 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,
66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80 N. In an embodiment, the actuation force is 36 N. In an embodiment, the actuation force is 37 N. In an embodiment, the actuation force is 38 N. In an embodiment, the actuation force is 39 N. In an embodiment, the actuation force is 36 N.
In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, comprises a crystalline form of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, as described herein.
In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a moisture content of <5%, <4%, <3%, <2%, or <1%. In an embodiment, the moisture content is <2%, <1.9%, <1.8%, <1.7%, <1.6%, <1.5%, <1.4%, <1.3%, <1.2% or <1.1%. In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% by weight of a hydroxyl impurity. In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% of by weight of any one impurity.
In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% of by weight of any impurity. In an embodiment, the impurity profile is determined by RP-HPLC. In an embodiment, the % particles of equal to or less than 11. 7pm size of the powder plume is determined by Next Generation Impactor and HPLC. In an embodiment, the moisture content is determined by Karl Fisher coulometric titration.
In an embodiment, the plume geometry is analysed using the Proveris SprayVIEW apparatus (or equivalent) in conjunction with the Proveris automated actuation device. In an embodiment, Analysis is performed at one distance (7.0 cm). In an embodiment, the settings are as follows: Orifice tip distance (cm): 7.0, Frame rate (Hz): 500, Number of images 250, Lens aperture 2.0, Camera position from horizontal (cm): 27.0, Camera height (cm): 8.0, Laser position (cm): 5.2, Laser depth (cm): 5.3, Laser height (cm): 13.2, Actuator position (cm): 7.0, Plume orientation: 0 deg, Palette: Gradient, Arm 1/Arm 2 (%): 20 - 30%, Evacuation time (ms): 1000, Setting time (ms): 1000. In an embodiment, the spray pattern is determined using the Proveris SprayVIEW apparatus (or equivalent) in conjunction with the Proveris automated actuation device. In an embodiment, analysis is performed at two distances (4.0 cm and 7.0 cm). In an embodiment, the settings are as above for the 7.0 cm distance and as follows for the 4.0 cm distance (where different from the settings used for 7.0 cm): Orifice tip distance (cm): 4.0, Camera position from horizontal (cm): 8.0 and Camera height (cm): 22.
In an embodiment, the particle size distribution is determined by laser diffraction using a Malvern Mastersizer (or equivalent). In an embodiment, the settings are as follows: Instrument: Malvern Mastersizer 3000 with Malvern software (or equivalent), Sampling handling Unit: Hydro MV dispersion unit, Material Refractive Index: 1.590, Absorption Refractive Index: 0.001, Dispersant Refractive Index: 1.391 (2,2,4-trimethylpentane), Obscuration Limits: 10-20%, Sonification time: Externally sonicated for 120 secs during sample preparation prior to addition to Hydro MV, Stirrer Speed: 3000 rpm, Measurement time: 30 secs, Background time: 30 secs, Dispersant: 2,2,4 - trimethylpentane ( Rl =1.391) and Lecithin 0.05% w/w, degassed and equilibrated to ambient temperature.
In an embodiment, the aerodynamic particle size distribution (DISP) is determined by a method based on USP <601>, using the Proveris Sprayview and a Copley Next Generation Impactor (NGI) or equivalent, complying with USP/Ph.Eur. In an embodiment, standard solutions are prepared based on the label claim for the drug product (x mg per 100ml diluent) where x=label claim. In an embodiment, the settings are as follows: Actuation acceleration: 5000 mm/s2, Actuation velocity: 70 mm/s, Symmetric: Yes, Initial delay: 0 ms, Hold time: 100 ms, Final delay: 0 ms, Stroke length: 14 mm, One shot is fired into the NGI. Weigh the device prior to (Wl) and after firing (W2) to calculate shot weight (W3). W1 - W2 = shot weight (W3), Add 5 ml of test solvent to each NGI cup then place on the NGI gentle rocker for 5 minutes. Quantitatively wash the expansion chamber, bungs, inlet cone, all cups and the Proveris collar with diluent into the correct flask size and make to volume. Assay is determined via HPLC.
In an embodiment, the particle size distribution (PSD) is determined by laser diffraction. In an embodiment, the analysis is performed using Sympatec instrumentation with R5 lens and a dispersal pressure of 3 bar. The intranasal delivery system/device is held in a clamp stand and positioned central with the extractor and so the tip of the device is 3 cm from the mid-point of the laser. After referencing, the device is manually/hand actuated so the powder passes through the laser beam, which takes a reading. Readings are performed with an R5 lens, in triplicate and then an average calculated.
Example 18: Items
1. A pharmaceutical composition comprising 10 mg 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treating depression/major depressive disorder/treatment-resistant major depressive disorder in a patient/subject in need thereof, the method comprising the single administration of the composition to the subject, wherein a clinically significant reduction in MADRS score is present within 1, 2, 3, 4, 5, 6 or 7 days of the administration and wherein, optionally, previous treatment of the depression/major depressive disorder/treatment-resistant major depressive disorder has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
2. The pharmaceutical composition for use of item 1, wherein the clinically significant reduction in MADRS score is a reduction from baseline of at least 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 points.
3. The pharmaceutical composition for use of item 1, wherein the clinically significant reduction in MADRS score is a reduction from baseline of at least 12 points.
4. The pharmaceutical composition for use of any one of items 1 to 3, wherein the clinically significant reduction in MADRS score is sustained following the administration.
5. The pharmaceutical composition for use of any one of items 1 to 4, wherein the reduction is sustained for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration.
6. The pharmaceutical composition for use of any one of items 1 to 4, wherein the reduction is sustained for 12 or more weeks following the administration.
7. The pharmaceutical composition for use of any one of items 1 to 6, wherein the patient/subject is ready for discharge within 90, 100, 110 or 120 minutes following administration.
8. The pharmaceutical composition for use of any one of items 1 to 7, wherein the patient/subject is ready for discharge within 90 minutes following administration.
9. The pharmaceutical composition for use of any one of items 1 to 8, wherein the composition is formulated for intranasal administration.
10. The pharmaceutical composition use of any one of items 1 to 9, wherein the composition is formulated as a dry powder.
11. The pharmaceutical composition for use of any one of items 1 to 10, wherein the composition is formulated as a spray dried dry powder.
12. The pharmaceutical composition for use of any one of items 1 to 11, wherein the composition comprises an amount of 5-MeO-DMT benzoate equivalent to 10 mg 5-MeO-DMT freebase.
13. The pharmaceutical composition for use of any one of items 1 to 12, wherein the composition comprises an amount of 5-MeO-DMT hydrochloride equivalent to 10 mg 5-MeO-DMT freebase.
14. The pharmaceutical composition for use of any one of items 1 to 13, wherein the composition comprises an amount of 5-MeO-DMT hydrobromide equivalent to 10 mg 5-MeO-DMT freebase.
15. The pharmaceutical composition for use of any one of items 1 to 14, wherein the composition comprises an amount of 5-MeO-DMT oxalate equivalent to 10 mg 5-MeO-DMT freebase.
16. The pharmaceutical composition for use of any one of items 1 to 15, wherein the 5-MeO-DMT is in crystalline form.
17. The pharmaceutical composition for use of any one of items 1 to 16, wherein the composition is in crystalline form.
18. The pharmaceutical composition for use of item 12, wherein the composition comprises crystalline 5- MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A. 19. The pharmaceutical composition for use of item 13, wherein the composition comprises crystalline 5- MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
20. The pharmaceutical composition for use of item 14, wherein the composition comprises crystalline 5- MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
21. The pharmaceutical composition for use of item 15, wherein the composition comprises crystalline 5- MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
22. The pharmaceutical composition for use of any one of items 1 to 21, wherein the composition comprises one or more of: chitosan, chitosan derivatives, fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
23. The pharmaceutical composition for use of any one of items 1 to 22, wherein the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
24. The pharmaceutical composition for use of any one of items 1 to 23, wherein the method is a rapid and sustained method of treatment of treatment resistant depression/major depressive disorder/major depressive disorder.
25. A dry powder intranasal pharmaceutical composition comprising an amount of 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) benzoate equivalent to 10 mg 5-MeO-DMT freebase, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treating treatment-resistant depression/major depressive disorder/major depressive disorder in a patient/subject in need thereof, the method comprising the single intranasal administration of the composition to the subject, wherein: the patient/subject is ready for discharge within 90 minutes post-dose; a clinically significant reduction in MADRS score of at least 12 points from baseline is present within 1 day of the administration; the clinically significant reduction in MADRS score of at least 12 points from baseline is sustained for at least 12 weeks following the administration; and wherein, optionally, previous treatment of the depression/major depressive disorder/treatment- resistant major depressive disorder has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
26. The composition for use of item 25, wherein the method comprises the provision to the patient/subject of psychological support.
27. A pharmaceutical composition comprising:
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof; and one or more pharmaceutically acceptable carriers or excipients; for use in rapidly treating depression/major depressive disorder or treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with depression/major depressive disorder or treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the depression/major depressive disorder or treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the depression/major depressive disorder/treatment- resistant major depressive disorder has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
28. The pharmaceutical composition for use as in item 27, wherein the pharmaceutical composition comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
29. The pharmaceutical composition for use as in item 27, wherein the pharmaceutical composition comprises 8, 9, 10, 11, 12, 13 or 14 mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
30. The pharmaceutical composition for use as in item 27, wherein the pharmaceutical composition comprises 10, 11 or 12 mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.
31. The pharmaceutical composition for use as in item 27, wherein the pharmaceutical composition comprises 10 mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof.
32. The pharmaceutical composition for use as in any one of items 27 to 31, wherein the disorder is diagnosed in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association.
33. The pharmaceutical composition for use as in any one of items 27 to 32, wherein the patient suffers from moderate or severe depression/major depressive disorder as indicated by a Montgomery-Asberg depression/major depressive disorder Rating Scale (MADRS) score of 20 or more or by a 17-item Hamilton depression/major depressive disorder Rating Scale (HAM-D) score of 17 or more.
34. The pharmaceutical composition for use as in any one of items 27 to 33, wherein the patient suffers from severe depression/major depressive disorder as indicated by a MADRS score of 35 or more or by a HAM-D score of 25 or more.
35. The pharmaceutical composition for use as in items 27 to 34, wherein the patient is diagnosed with a treatment-resistant form of depression/major depressive disorder.
36. The pharmaceutical composition for use as in items 27 to 35, wherein the patient suffers in addition from suicidal ideation.
37. The pharmaceutical composition for use as in item 36, wherein the patient suffers from suicidal ideation with intent to act.
38. The pharmaceutical composition for use as in items 27 to 37, wherein the patient is at imminent risk for suicide.
39. The pharmaceutical composition for use as in items 27 to 38, wherein the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, optionally crystalline 5-MeO-DMT benzoate, optionally crystalline 5-MeO-DMT benzoate as described herein, equivalent to 10 mg 5-MeO-DMT freebase.
40. The pharmaceutical composition for use as in items 27 to 39, wherein the single dose of the pharmaceutical composition produces a rapid sustained/durable treatment for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks following the single administration.
41. The pharmaceutical composition for use as in items 27 to 40, wherein the pharmaceutical composition produces a rapid sustained/durable treatment within 1, 2, 3, 4, 5, 6 or 7 days following the single administration.
42. The pharmaceutical composition for use as in items 27 to 41, wherein the patient/subject is ready for discharge within 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 minutes of the administration of the pharmaceutical composition.
43. The pharmaceutical composition for use as in items 27 to 42, wherein the pharmaceutical composition is administered under the supervision of one or more professionals.
44. The pharmaceutical composition for use as in items 27 to 43, wherein the pharmaceutical composition is administered under the supervision of one or more licensed professionals.
45. The pharmaceutical composition for use as in items 27 to 44, wherein the pharmaceutical composition is administered in combination with one or more of therapy, psychotherapy, psychological support or support. 46. The pharmaceutical composition for use as in items 27 to 45, wherein the pharmaceutical composition is administered in combination with one or more of therapy, psychotherapy, psychological support or support, wherein said one or more of therapy, psychotherapy, psychological support or support is provided to the patient/subject prior to the single administration of the pharmaceutical composition.
47. The pharmaceutical composition for use as in items 27 to 46, wherein the pharmaceutical composition is administered in combination with one or more of therapy, psychotherapy, psychological support or support, wherein said one or more of therapy, psychotherapy, psychological support or support is provided to the patient/subject during the single administration of the pharmaceutical composition.
48. The pharmaceutical composition for use as in items 27 to 47, wherein the pharmaceutical composition is administered in combination with one or more of therapy, psychotherapy, psychological support or support, wherein said one or more of therapy, psychotherapy, psychological support or support is provided to the patient/subject following the single administration of the pharmaceutical composition.
49. The pharmaceutical composition for use as in items 27 to 48, wherein administration of the pharmaceutical composition to the patient/subject induces a complete mystical experience.
50. The pharmaceutical composition for use as in items 27 to 49, wherein administration of the pharmaceutical composition to the patient/subject induces a complete mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30) and/or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, optionally the complete mystical experience is induced within 5, 10, 15, 20, 25, or 30 minutes of administration of the pharmaceutical composition and optionally the complete mystical experience is resolved within 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 minutes of administration of the pharmaceutical composition.
51. The pharmaceutical composition for use as in any of items 27 to 50, wherein the composition is administered via inhalation delivery, intranasal delivery, intravenous delivery, intramuscular delivery or subcutaneous delivery.
52. The pharmaceutical composition for use as in items 27 to 51, wherein a rapid clinically significant response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, occurs not later than about 2 hours after the single administration of the pharmaceutical composition
53. The pharmaceutical composition for use as in items 27 to 52, wherein the rapid clinically significant response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, persists until at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks after the single administration of the pharmaceutical composition.
54. The pharmaceutical composition for use as in items 27 to 53, wherein a rapid clinically significant response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the single administration of the pharmaceutical composition.
55. The pharmaceutical composition for use as in items 27 to 54, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs not later than about 2 hours after the single administration of the pharmaceutical composition.
56. The pharmaceutical composition for use as in items 27 to 55, wherein a rapid clinically significant response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 20 weeks after the single administration of the pharmaceutical composition.
57. The pharmaceutical composition for use as in items 27 to 56, wherein the pharmaceutical composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
58. A pharmaceutical composition comprising: 10 mg 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof; and one or more pharmaceutically acceptable carriers or excipients; for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
59. The pharmaceutical composition for use as in item 58, wherein the pharmaceutical composition is a dry powder intranasal pharmaceutical composition.
60. A pharmaceutical composition comprising:
10 mg 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof; and one or more pharmaceutically acceptable carriers or excipients; for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
61. The pharmaceutical composition for use as in item 60, wherein the pharmaceutical composition is a dry powder intranasal pharmaceutical composition.
62. A pharmaceutical composition comprising: an amount of 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate equivalent to 10 mg 5-MeO-DMT freebase; and one or more pharmaceutically acceptable carriers or excipients; for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
63. The pharmaceutical composition for use as in item 62, wherein the pharmaceutical composition is a dry powder intranasal pharmaceutical composition.
64. A pharmaceutical composition comprising: an amount of crystalline 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate equivalent to 10 mg 5-MeO-DMT freebase; and one or more pharmaceutically acceptable carriers or excipients; for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
65. The pharmaceutical composition for use as in item 64, wherein the pharmaceutical composition is a dry powder intranasal pharmaceutical composition.
66. A single use dry powder intranasal pharmaceutical composition comprising an amount of 5-MeO-DMT benzoate equivalent to 10 mg 5-MeO-DMT freebase and one or more pharmaceutically acceptable carriers or excipients, for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
67. The pharmaceutical composition for use of any one of items 58 to 66, wherein administration of the pharmaceutical composition to the patient/subject induces a complete mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30) and/or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, optionally the complete mystical experience is induced within 5, 10, 15, 20, 25, or 30 minutes of administration of the pharmaceutical composition and optionally the complete mystical experience is resolved within 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 300 minutes of administration of the pharmaceutical composition.
68. The pharmaceutical composition for use of item 67, wherein a rapid clinically significant response, as assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, occurs not later than about 2 hours after the single administration of the pharmaceutical composition.
69. The pharmaceutical composition for use of item 68, wherein the single dose of the pharmaceutical composition produces a rapid sustained/durable treatment for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks following the single administration.
70. The pharmaceutical composition for use of item 69, wherein the pharmaceutical composition produces a rapid sustained/durable treatment within 1, 2, 3, 4, 5, 6 or 7 days following the single administration.
71. A pharmaceutical composition comprising about 15.59 mg 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT) benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treating depression/major depressive disorder/treatment-resistant major depressive disorder in a patient/subject in need thereof, the method comprising the single administration of the composition to the subject, wherein a clinically significant reduction in MADRS score is present within 1, 2, 3, 4, 5, 6 or 7 days of the administration and wherein, optionally, previous treatment of the depression/major depressive disorder/treatment-resistant major depressive disorder has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
72. A dry powder intranasal pharmaceutical composition comprising about 15.59 mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treating treatment-resistant depression/major depressive disorder/major depressive disorder in a patient/subject in need thereof, the method comprising the single intranasal administration of the composition to the subject, wherein: the patient/subject is ready for discharge within 90 minutes post-dose; a clinically significant reduction in MADRS score of at least 12 points from baseline is present within 1 day of the administration; the clinically significant reduction in MADRS score of at least 12 points from baseline is sustained for at least 12 weeks following the administration;, and wherein, optionally, previous treatment of the depression/major depressive disorder/treatment- resistant major depressive disorder has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
73. A single use dry powder intranasal pharmaceutical composition comprising about 15.59 mg 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) benzoate and one or more pharmaceutically acceptable carriers or excipients, for use in rapidly treating treatment resistant depression/major depressive disorder in a patient/subject who is diagnosed with treatment resistant depression/major depressive disorder by a licensed professional in accordance with accepted medical practice, wherein administration of a single dose of the pharmaceutical composition produces a rapid and sustained/durable treatment of the treatment resistant depression/major depressive disorder and wherein, optionally, previous treatment of the condition/disease has failed, wherein, optionally said treatment comprises treatment with one or more antidepressant pharmaceutical compositions and/or therapies, such as one or more selective serotonin reuptake inhibitors (SSRIs), such as citalopram and sertraline.
74. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours prior to treatment.
75. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour prior to treatment.
76. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour following treatment.
77. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours following treatment.
78. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is administered by the patient.
79. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is not administered by the patient.
80. A pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is administered by a physician.
81. The pharmaceutical composition for use as described in item 80, wherein the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is administered by a physician and the method comprises the steps of: the patient sits in an upright position; the patient blows their nose; the pharmaceutical composition is administered by a physician to a single nostril; and the patient does not inhale through their nose during the administration.
82. The pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 40 and 80 days after the first administration.
83. The pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 50 and 70 days after the first administration.
84. The pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 55 and 65 days after the first administration.
85. The pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place 64 days, ±1, 2, 3, 4, 5, 6 or 7 days, after the first administration.
86. The pharmaceutical composition for use as described in any one preceding item, wherein the patient has not taken one or more of the following for at least 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.
87. The pharmaceutical composition for use as described in any one preceding item, wherein the patient has not taken one or more of the following for at least 1, 2, 3, 4, 5 or 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.
88. The pharmaceutical composition for use as described in any one preceding item, wherein the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device.
89. The pharmaceutical composition for use as described in item 88, wherein the single use intranasal delivery device is an active delivery device.
90. The pharmaceutical composition for use as described in item 88, wherein the single use intranasal delivery device is an active delivery device which does not require the patient to inhale through the nose to deliver the pharmaceutical composition.
91. The pharmaceutical composition for use of any one of items 1 to 90, wherein the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) measuring the subject's blood pressure a first time; b) administering to the subject 10 mg of 5-MeO-DMT intranasally; c) measuring the subject's blood pressure a second time; d) discharging the subject if the subject's blood pressure at the second time is about the same as the subject's blood pressure at the first time, wherein the subject is discharged within 90 minutes of step (b).
92. The pharmaceutical composition for use of any one of items 1 to 90, wherein the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) measuring the subject's blood pressure; b) intranasally administering to the subject 10 mg of 5-MeO-DMT if the subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
93. The pharmaceutical composition for use of any one of items 1 to 90, wherein the pharmaceutical composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) administering to the subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the subject for relapse of one or more depressive symptoms; c) administering to the subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the subject.

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT.
2. The composition of claim 1, wherein the composition is formulated for intranasal administration.
3. The composition of claim 1 or claim 2, wherein the composition is formulated as a dry powder.
4. The composition of any one of claims 1 to 3, wherein the composition is formulated as a spray dried dry powder.
5. The composition of any one of claims 1 to 4, wherein the composition comprises 5-MeO-DMT benzoate.
6. The composition of any one of claims 1 to 4, wherein the composition comprises 5-MeO-DMT hydrochloride.
7. The composition of any one of claims 1 to 4, wherein the composition comprises 5-MeO-DMT hydrobromide.
8. The composition of any one of claims 1 to 4, wherein the composition comprises 5-MeO-DMT oxalate.
9. The composition of any one of claims 1 to 8, wherein the 5-MeO-DMT is in crystalline form.
10. The composition of any one of claims 1 to 8, wherein the composition is in crystalline form.
11. The composition of claim 5, wherein the composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
12. The composition of claim 6, wherein the composition comprises crystalline 5-MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1, 15.0, 18.5 and 19.5°±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
13. The composition of claim 7, wherein the composition comprises crystalline 5-MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
14. The composition of claim 8, wherein the composition comprises crystalline 5-MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A.
15. The composition of any one of claims 1 to 14, wherein the composition comprises one or more of: chitosan, chitosan derivatives, fJ-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alchohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.
16. The composition of any one of claims 1 to 15, wherein the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.
17. The composition of claim 1, for use in a method of treatment of depression.
18. The composition of claim 5, for use in a method of treatment of depression.
19. The composition of claim 9, for use in a method of treatment of depression.
20. The composition of any one of claims 1 to 16, for use in a method of treatment of depression.
21. An intranasal dry powder pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10 mg 5-MeO-DMT, for use in a method of treatment.
22. The composition for use of claim 21, for use in a method of treatment of depression.
23. The composition for use of claim 21, for use in a method of treatment of treatment-resistant depression.
24. The composition for use of claim 21, for use in a method of treatment of substance misuse disorder.
25. The composition for use of claim 21, for use in a method of treatment of alcohol use disorder.
26. The composition for use of any one of claims 1 to 16, wherein the composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) measuring the subject's blood pressure a first time; b) administering to the subject 10 mg of 5-MeO-DMT intranasally; c) measuring the subject's blood pressure a second time; d) discharging the subject if the subject's blood pressure at the second time is about the same as the subject's blood pressure at the first time, wherein the subject is discharged within 90 minutes of step (b).
27. The composition for use of any one of claims 1 to 16, wherein the composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) measuring the subject's blood pressure; b) intranasally administering to the subject 10 mg of 5-MeO-DMT if the subject's systolic blood pressure is less than 130 mmHg and/or subject's diastolic blood pressure is less than 80 mmHg.
28. The composition for use of any one of claims 1 to 16, wherein the composition is for use in a method of treating treatment-resistant depression in a subject in need thereof, wherein the method comprises: a) administering to the subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the subject for relapse of one or more depressive symptoms; c) administering to the subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the subject.
PCT/GB2024/052500 2023-09-28 2024-09-27 Pharmaceutical compositions comprising 5-methoxy-n,n-dimethyltryptamine (5-meo-dmt) Pending WO2025068714A1 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GBGB2314911.5A GB202314911D0 (en) 2023-09-28 2023-09-28 Dosing of 5-MeO-DMT
GB2314911.5 2023-09-28
GB2403419.1 2024-03-08
GBGB2403419.1A GB202403419D0 (en) 2024-03-08 2024-03-08 Dosing of 5-MeO-DMT
GBGB2403721.0A GB202403721D0 (en) 2024-03-14 2024-03-14 Dosing of 5-meo-dmt
GB2403721.0 2024-03-14
GBGB2405965.1A GB202405965D0 (en) 2024-04-29 2024-04-29 Dosing of 5-meO-DMT
GB2405965.1 2024-04-29

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