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WO2024231331A1 - Formulations pharmaceutiques injectables - Google Patents

Formulations pharmaceutiques injectables Download PDF

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Publication number
WO2024231331A1
WO2024231331A1 PCT/EP2024/062406 EP2024062406W WO2024231331A1 WO 2024231331 A1 WO2024231331 A1 WO 2024231331A1 EP 2024062406 W EP2024062406 W EP 2024062406W WO 2024231331 A1 WO2024231331 A1 WO 2024231331A1
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substituted
pharmaceutical formulation
salt
disorder
unsubstituted
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Inventor
Alex Nivorozhkin
Mohammed I. SHUKOOR
Ju FENG
Kenneth L. Avery
Pradip M. Pathare
Geoffrey B. VARTY
Michael E. Morgan
Michael Palfreyman
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Cybin IRL Ltd
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Cybin IRL Ltd
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Publication of WO2024231331A1 publication Critical patent/WO2024231331A1/fr
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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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

Definitions

  • FIELD 10 The present disclosure relates generally to injectable pharmaceutical formulations comprising a psychopharmaceutical agent and uses in the treatment of neuropsychiatric diseases or disorders or inflammatory diseases or disorders, such as a central nervous system (CNS) disorder and/or psychological disorder, including those associated with a 5-HT 2 receptor.
  • a psychopharmaceutical agent uses in the treatment of neuropsychiatric diseases or disorders or inflammatory diseases or disorders, such as a central nervous system (CNS) disorder and/or psychological disorder, including those associated with a 5-HT 2 receptor.
  • CNS central nervous system
  • the entactogen 25 methylenedioxymethamphetamine has recently passed the first phase-III trial in patients with PTSD [Mitchell JM, et al. MDMA-assisted therapy for severe PTSD: a randomized, double- blind, placebo-controlled phase 3 study. Nat Med. 2021;27: 1025–1033].
  • Lysergic acid diethylamide has shown clinical promise in alcohol use disorder [Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J 30 Neurol Sci. 2020, 411: 116715; Fuentes JJ, et al.
  • Psychedelic drugs neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 2020;21: 611–624; Barker SA. N,N-dimethyltryptamine (DMT), an endogenous hallucinogen:15 Past, present, and future research to determine its role and function. Front Neurosci.2018;12: 1– 17; and Strassman RJ, et al. Dose-response study of N,N-Dimethyltryptamine in humans II: Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994;51: 98–108] and potentially, addictions [Thomas G, et al.
  • Ayahuasca-assisted therapy for addiction results from a preliminary observational study in Canada. Curr Drug Abuse Rev.2013; Oliveira- 20 Lima AJ, et al. Effects of ayahuasca on the development of ethanol-induced behavioral sensitization and on a post-sensitization treatment in mice. Physiol Behav.2015;142: 28–36; Nolli LM, et al. Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction. Alcohol.2019; Fábregas JM, et al. Assessment of addiction severity among ritual users of ayahuasca. Drug Alcohol Depend.
  • DMT binding profile is well characterized. DMT acts on numerous ionotropic and 30 metabotropic receptors.
  • DMT is a potent agonist at the 5-HT2A receptor, through which (not unlike other serotonergic psychedelics) it exerts many subjective, visual, and potentially therapeutic effects [Cameron LP, Olson DE. Dark Classics in Chemical Neuroscience: N, N- Dimethyltryptamine (DMT). ACS Chem Neurosci. 2018;9: 2344–2357; Carbonaro TM, Gatch 5 MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull.2016;126: 74–88].5-HT2A activation has also been linked with increased synaptic plasticity [Ly C, et al.
  • DMT binds to other receptors, including trace amine-associated receptors (TAARs) and the sigma-1 receptor, potentially contributing to its neuroprotective plasticity enhancing effects [Carbonaro TM, Gatch MB. Neuropharmacology of N,N-dimethyltryptamine. Brain Res Bull. 2016;126: 74–88; Barker SA. N, N-dimethyltryptamine (DMT), an endogenous 15 hallucinogen: Past, present, and future research to determine its role and function. Front Neurosci. 2018;12: 1–17].
  • TAARs trace amine-associated receptors
  • Such MAO-mediated metabolism is also believed to contribute to high 25 variability in the pharmacokinetic (PK) profiles of various tryptamines in humans, including significant patient-to-patient pharmacokinetic variability after oral psilocybin administration and intravenous (IV) administration of DMT.
  • PK pharmacokinetic
  • IV intravenous
  • the duration of action time course of short-acting tryptamine psychedelics such as DMT and 5-MeO-DMT administered as a bolus to humans via inhalation or intravenous or intramuscular injection is brief—so short as to limit their use in effective therapies.
  • DMT the onset of 3
  • the injectable pharmaceutical 5 formulations extend the time the patient spends in the psychedelic state compared to bolus IV injection of the same tryptamine psychedelic, without overextending the release and the resulting duration of peak effects beyond about 120 minutes to avoid the prolonged supervised clinical observation requirements imposed by longer-acting psychopharmaceutical agents such as LSD and psilocybin.
  • an injectable pharmaceutical formulation comprising: a psychopharmaceutical agent; a hyaluronate salt; and an aqueous vehicle; wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a 25 compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof, 5
  • X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted 5 alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R 2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or 10 substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted ary
  • the psychopharmaceutical agent is an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); and
  • the injectable pharmaceutical formulation of (7), wherein the active salt mixture comprises (i) from 60% to 99% by weight of the pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8), based on a total weight of the active salt 25 mixture; and (ii) from 1% to 40% by weight, in sum, of the pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H- 9
  • total volume of the pharmaceutical formulation is about 10 mg/mL to about 50 mg/mL.
  • the injectable pharmaceutical formulation of any one of (1) to (18), wherein the 10 hyaluronate salt has a weight average molecular weight of about 1,000 kDa to about 1,800 kDa.
  • CNS central nervous system
  • 314 The method of (33), wherein the CNS disorder and/or psychological disorder is a 16
  • the method of (34), wherein the substance use disorder is alcohol use disorder.
  • the method of (33), wherein the CNS disorder and/or psychological disorder is an anxiety disorder.
  • the method of (36), wherein the anxiety disorder is generalized anxiety disorder (GAD).
  • the method of (37), wherein the generalized anxiety disorder is comorbid with depression.
  • the method of (36), wherein the anxiety disorder is social anxiety disorder.
  • the method of (33), wherein the CNS disorder and/or psychological disorder is a depressive disorder.
  • the method of (40), wherein the depressive disorder is major depressive disorder 20 (MDD) or treatment-resistant depression (TRD).
  • CNS disorder and/or psychological disorder is at least one selected from the group consisting of post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal 25 behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute psychedelic crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, Alzheimer’s disease, cluster headache and migraine, attention deficit hyperactivity 30 disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia nervosa, binge-eating disorder,
  • PTSD post-traumatic stress disorder
  • An injectable pharmaceutical formulation comprising: a psychopharmaceutical agent; a carboxymethyl cellulose salt; and an aqueous vehicle; 20 wherein the psychopharmaceutical agent is a pharmaceutically acceptable salt of a compound of Formula (I) or a stereoisomer, solvate, or prodrug thereof, wherein: X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, 18
  • R1 and Y2 are independently selected from the group consisting of hydrogen and 5 deuterium;
  • the method of (52), wherein the CNS disorder and/or psychological disorder is a substance use disorder.
  • the substance use disorder is alcohol use disorder.
  • the method of (52), wherein the CNS disorder and/or psychological disorder is an anxiety disorder.
  • 20 The method of (55), wherein the anxiety disorder is generalized anxiety disorder (GAD).
  • GAD generalized anxiety disorder
  • the method of (56), wherein the generalized anxiety disorder is comorbid with 25 depression.
  • the method of (55), wherein the anxiety disorder is social anxiety disorder.
  • the method of (52), wherein the CNS disorder and/or psychological disorder is a 30 depressive disorder.
  • the method of (59), wherein the depressive disorder is major depressive disorder 20
  • CNS disorder and/or psychological disorder is at least one selected from the group consisting of post-traumatic stress disorder (PTSD), major 5 depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar and related disorders, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute psychedelic crisis, social anxiety disorder, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use 10 disorder, Alzheimer’s disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain, aphantasia, childhood-onset fluency disorder, major neurocognitive disorder, mild neurocognitive disorder, chronic fatigue syndrome, Lyme disease, gambling disorder, anorexia nervosa, bulimia
  • PTSD post-traumatic stress disorder
  • MDD major 5 depressive disorder
  • TRD treatment-
  • concentration of the hyaluronate salt by weight per total volume of the pharmaceutical formulation is from about 0.1% to about 1% (w/v).
  • the injectable pharmaceutical formulation of any one of (66) to (77), wherein the aqueous vehicle comprises water and sodium chloride.
  • 25 The injectable pharmaceutical formulation of any one of (66) to (81), which has a viscosity of less than about 3,000 cP.
  • 15 Use of the injectable pharmaceutical formulation of any one of (1) to (31) for treating a patient with a central nervous system (CNS) disorder and/or psychological disorder.
  • 20 (90) Use of the injectable pharmaceutical formulation of any one of (47) to (50) for treating a patient with a central nervous system (CNS) disorder and/or psychological disorder.
  • FIG. 1 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds I-2 and I-6
  • Fig. 2 illustrates a general synthetic route for making Compounds of Formula (I), e.g., compounds I-1, I-4, I-5, and I-8
  • Fig.3 shows the percent drug release versus time profile of Formulations 1-6 compared to 10 control when subjected to the Dialysis—Drug Release Test
  • Fig. 4 shows the percent drug release versus time profile of Formulation 7 compared to control when subjected to the Dialysis—Drug Release Test
  • Fig. 5 shows the percent drug release versus time profile of Formulation 8 compared to control when subjected to the Dialysis—Drug Release Test
  • 15 Fig. 6 shows the percent drug release versus time profile of Formulation 9 compared to control when subjected to the Dialysis—Drug Release Test
  • Figs.7A and 7B show the percent drug release versus time profile of Formulations 10-12 compared to control when subjected to the Dialysis—Drug Release Test (Fig.
  • Figs.7A and 8B show the percent drug release versus time profile of Formulations 13-15 compared to control when subjected to the Dialysis—Drug Release Test (Fig. 8A) and the corresponding first order release kinetic plot (Fig.8B);
  • Figs.9A and 9B show the percent drug release versus time profile of Formulations 16-18 compared to control when subjected to the Dialysis—Drug Release Test (Fig. 9A) and the 25 corresponding first order release kinetic plot (Fig.9B);
  • Figs.10A and 10B show the percent drug release versus time profile of Formulations 19- 21 compared to control when subjected to the Dialysis—Drug Release Test (Fig.
  • Fig. 10A shows the corresponding first order release kinetic plot (Fig.10B);
  • Fig.11 shows the percent drug release versus time profile of Formulations 22-27 compared 30 to control when subjected to the Dialysis—Drug Release Test;
  • Figs. 12A and 12B show individual DMT-d10 plasma concentration-time curves in male B eagle dogs (animal IDs: 068M, 069M, 070M) after subcutaneous administration of DMT-d 10 at 25
  • Fig.12A 0.1 mg/kg from control
  • Fig.12B Formulation 28
  • Figs.13A and 13B show mean DMT-d 10 plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-d 10 at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively, in linear scale (Fig.13A) and log scale (Fig.13B);
  • 5 Fig.14 shows the dose proportionality of Cmax and AUCinf from the mean DMT-d10 plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-d 10 at 0.1, 0.5, and 1 mg/kg from Formulations 28-30, respectively;
  • Fig.15 shows the effect of sodium hyaluronate concentration on mean concentration-time profiles of DMT-d 10 after SC administration of DMT-d 10 at a dose of 1 mg/kg from Formulations 10 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg; Fig.
  • FIG. 16 shows the effect of sodium hyaluronate concentration on mean residence time (MRT inf ) of DMT-d 10 after SC administration of DMT-d 10 at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg; Fig. 17 shows the effect of sodium hyaluronate concentration on plasma half-life (t1/2) of 15 DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg; Fig.
  • FIG. 19 shows the effect of sodium hyaluronate concentration on total exposure (AUC inf ) of DMT-d10 after SC administration of DMT-d10 at a dose of 1 mg/kg from Formulations 30-33; *Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg; Figs.20A and 20B show mean DMT-d 10 plasma concentration-time curves in male Beagle dogs after subcutaneous administration of DMT-d10 at 1 mg/kg free base from Formulation 34 25 (dose solution concentration of 20 mg/mL nominal delivered at dosing volume of 0.05 mL/kg) compared to control (dose solution concentration of 4 mg/mL nominal delivered at dosing volume of 0.25 mL/kg) in linear scale (Fig.20A) and log scale (Fig.20B); Figs.
  • FIG. 21A and 21B show mean DMT and DMT-d10 plasma concentration-time curves in male Beagle dogs after subcutaneous co-dose administration of DMT and DMT-d 10 at 0.5 30 mg/kg/analyte free base from Formulation 35 in linear scale (Fig.21A) and log scale (Fig.21B); and Fig.22 shows the percent drug release (ketamine) versus time profile of Formulations 36- 26
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 15 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl (t- Bu)((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • substituted alkyl refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -O-, -N- , -S-, -S(O) n - (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 10 substituents selected from the group consisting of deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, 25 acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy
  • 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10 - and the like.
  • This term includes, by way of example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n- propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), 5 (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like.
  • Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.
  • alkane refers to alkyl group and alkylene group, as defined herein.
  • alkylaminoalkyl refers to the 10 groups R ’ NHR ” - where R ’ is alkyl group as defined herein and R ” is alkylene, alkenylene or alkynylene group as defined herein.
  • alkaryl or “aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.
  • Alkoxy refers to the group –O-alkyl, wherein alkyl is as defined herein. Alkoxy includes,15 by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n- pentoxy, and the like.
  • alkoxy also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted 20 alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • alkoxyamino refers to the group –NH-alkoxy, wherein alkoxy is defined herein.
  • haloalkoxy refers to the groups alkyl-O- wherein one or more hydrogen atoms 25 on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • haloalkyl refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, 30 difluoromethyl, trifluoroethyl and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, 28
  • alkylthioalkoxy refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Alkenyl refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms, for example 2 to 4 carbon atoms and having at least 1, for example from 1 to 2 sites of double bond unsaturation.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 10 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms, for example, 2 to 3 carbon atoms and having at least 1 and for example, from 1 to 20 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH2C ⁇ CH).
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, 25 acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
  • Alkynyloxy refers to the group –O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like. 29
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and 5 substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
  • acyl includes the “acetyl” group CH3C(O) “Acylamino” refers to the groups –NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, N10 R 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, - NR 20 C(O)cycloalkenyl, -NR 20 C(O)substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O)alkenyl, - NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, -NR 20 C(O)substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20 C(O)heteroaryl, -NR
  • Aminocarbonyl or the term “aminoacyl” refers to the group -C(O)NR 21 R 22 , wherein R 21 20 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and 25 wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycl
  • Aminocarbonylamino refers to the group –NR 21 C(O)NR 22 R 23 where R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are 30 joined to form a heterocyclyl group.
  • alkoxycarbonylamino refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, 30
  • substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, 5 heteroaryl, and heterocyclyl are as defined herein.
  • Aminosulfonyl refers to the group –SO 2 NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted 10 heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted substituted
  • “Sulfonylamino” refers to the group –NR 21 SO2R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the atoms bound 20 thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, ary
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon 25 atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can 30 optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, 31
  • substituted cycloalkenyl amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2- 5 substituted alkyl, -SO2-aryl, -SO2-heteroaryl and trihalomethyl.
  • Aryloxy refers to the group –O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
  • Amino refers to the group –NH 2 .
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
  • the term “azido” refers to the group –N3. 15 “Carboxyl,” “carboxy” or “carboxylate” refers to –CO2H or salts thereof.
  • Carboxyl ester or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted 20 cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O
  • (Carboxyl ester)oxy” or “carbonate” refers to the groups –O-C(O)O- alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O- alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O- cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted 30 cycloalkenyl, -O-C(O)O-heteroaryl,
  • cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano or “nitrile” refers to the group –CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or 5 multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, 15 thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclocyclo
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms 20 having single or multiple rings and having at least one double bond and for example, from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, 25 acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thi
  • Cycloalkoxy refers to –O-cycloalkyl.
  • Cycloalkenyloxy refers to –O-cycloalkenyl.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Hydroxy or “hydroxyl” refers to the group –OH. 5
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
  • heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring 10 within the ring system is aromatic and at least one ring within the ring system is aromatic, provided that the point of attachment is through an atom of an aromatic ring.
  • a single ring such as, pyridinyl, imidazolyl or furyl
  • multiple condensed rings in a ring system for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • N ⁇ O N-oxide
  • sulfinyl N-oxide
  • sulfonyl moieties N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, 20 cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioaryloxy,
  • heteroarylkyl refers to the groups -alkylene-heteroaryl where alkylene and 25 heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • Heteroaryloxy refers to –O-heteroaryl.
  • Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and 30 spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of 34
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or – SO 2 - moieties.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, 5 imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4- 10 tetrahydroisoquinoline, phthal
  • such 15 heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted 20 thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamin
  • Heterocyclyloxy refers to the group –O-heterocyclyl.
  • heterocyclylthio refers to the group heterocyclic-S-. 25
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein.
  • hydroxyamino refers to the group -NHOH.
  • Niro refers to the group –NO2.
  • “Sulfonyl” refers to the group SO 2 -alkyl, SO 2 -substituted alkyl, SO 2 -alkenyl, SO 2 - substituted alkenyl, SO2-cycloalkyl, SO2-substituted cylcoalkyl, SO2-cycloalkenyl, SO2- s ubstituted cylcoalkenyl, SO 2 -aryl, SO 2 -substituted aryl, SO 2 -heteroaryl, SO 2 -substituted 35
  • heteroaryl SO2-heterocyclic, and SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Sulfonyl includes, by way of 5 example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.
  • “Sulfonyloxy” refers to the group –OSO 2 -alkyl, OSO 2 -substituted alkyl, OSO 2 -alkenyl, OSO2-substituted alkenyl, OSO2-cycloalkyl, OSO2-substituted cylcoalkyl, OSO2-cycloalkenyl, OSO2-substituted cylcoalkenyl, OSO2-aryl, OSO2-substituted aryl, OSO2-heteroaryl, OSO2- substituted heteroaryl, OSO 2 -heterocyclic, and OSO 2 substituted heterocyclic, wherein alkyl, 10 substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted ary
  • aminocarbonyloxy refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, 15 substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Alkylthio or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein.
  • sulfur may be oxidized to -S(O)-.
  • the sulfoxide may exist 20 as one or more stereoisomers.
  • substituted thioalkoxy refers to the group -S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
  • thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl 25 group is as defined herein including optionally substituted aryl groups as also defined herein.
  • heterocyclooxy refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
  • substituted when used to modify a specified 30 group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 ) 4 ; or an alkaline earth ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or 20 [Ba 2+ ] 0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the disclosure can serve as the counter ion for such divalent alkali earth ions).
  • an alkali ion such as K + , Na + , Li +
  • an ammonium ion such as + N(R 60 ) 4
  • -NR 80 R 80 is meant to25 include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N- morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, deuterium, -R 60 , halo, -O-M + , -OR 70 , -SR 70 , -S – M + , -NR 80 R 80 , 30 trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -SO 2 R 70 , -SO3 – M + , -SO3R 70 , -OSO2R 70 , -OSO3 – M + , -OSO3R 70 , -PO3 -2 (M + )2, -P(O)(OR 70 )O – M + , -P(O)(OR 70 )2, -C(O)R 70 ,
  • substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O-M + , -OR 70 , -SR 70 , -S-M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O-M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 , -OS(O) 2 10 O-M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )O-M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 ,
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further 20 substituted by a substituted aryl group, etc.) are not intended for inclusion herein, unless specified otherwise. In such cases, the maximum number of such substitutions is three.
  • serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.
  • substituent groups defined as e.g., polyethers may contain serial substitution greater than three, e.g., -O-(CH2CH2O)n-H, where n can be 1, 2, 3, 25 or greater.
  • the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
  • substituents or groups include all stereochemical isomers arising from the substitution of these compounds.
  • substituent or group “comprise(s) deuterium” or is “comprising deuterium,” it is to be understood that the substituent or group may itself be deuterium, or the substituent or group may contain at least one deuterium substitution in its chemical structure.
  • substituent “-R” when substituent “-R” is defined to comprise deuterium, it is to be understood that -R may be -D (-deuterium), or a group such as -CD 3 that is consistent with the other requirements set forth of -R.
  • fatty describes a compound with a long-chain (linear) hydrophobic portion made up of hydrogen and anywhere from 4 to 26 carbon atoms, which may 10 be fully saturated or partially unsaturated.
  • pharmaceutically acceptable “physiologically acceptable,” and the like, are employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or 15 complication, commensurate with a reasonable benefit/risk ratio.
  • the phrase “pharmaceutically acceptable salt” and the like means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime).
  • such salts can be derived from pharmaceutically acceptable inorganic or organic bases, by way of example, sodium, 20 potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, and when the molecule contains a basic functionality, addition salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate, perchlorate salts, and the like, and addition salts with organic acids, such as formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemi
  • salts designated as “hemi-” salts indicate that the stoichiometry of subject compound to counterion is about 2:1, whereas solid salt forms without the “hemi-” descriptor possess a subject compound to counterion stoichiometry of about 1:1.
  • DMT hemi- 30 fumarate indicates that the ratio of DMT to fumarate is 2:1
  • DMT fumarate indicates that the ratio of DMT to fumarate is 1:1.
  • Solvate refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice 5 of the crystalline solid.
  • the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
  • the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates.
  • solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.).
  • Exemplary solvates thus include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc.
  • Methods of solvation are generally known in the art. “Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space.
  • Stereoisomers include cis-trans isomers, 15 E and Z isomers, enantiomers, and diastereomers. All forms such as racemates and optically pure stereoisomers of the compounds are contemplated herein. Chemical formulas and compounds which possess at least one stereogenic center, but are drawn without reference to stereochemistry, are intended to encompass both the racemic compound, as well as the separate stereoisomers, e.g., R- and/or S-stereoisomers, each permutation of diastereomers so long as those diastereomers are 20 geometrically feasible, etc.
  • a “crystalline” solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules—with long range order—forming a crystal lattice, and thus displays sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern.
  • crystalline solids can exist in different crystalline forms 25 known as “polymorphs,” which have the same chemical composition, but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. As such, polymorphs may have different solid-state physical properties to affect, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility, etc.
  • amorphous refers to a solid material having substantially no long range order in the position of its molecules—the 40
  • Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points.
  • an amorphous material is a solid material having substantially no sharp characteristic 5 crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
  • an “amorphous” subject compound/material is one characterized as having substantially no crystallinity—less than 10% crystallinity, less than 8% crystallinity, less than 6% crystallinity, less than 4% crystallinity, less 10 than 2% crystallinity, less than 1% crystallinity, or 0% crystallinity—i.e., is at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined for example by XRPD.
  • the % crystallinity can in some embodiments be determined by measuring the intensity of one or more peaks in the XRPD diffractogram compared to a reference peak, which may be that of a known standard or an internal standard.
  • Other characterization techniques such 15 as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, may also be employed to determine the percent a subject compound/material is amorphous or crystalline, including quantitative methods which provide the above percentages in terms of weight percent.
  • XRPD X-ray powder diffraction
  • the phrase “characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from...” should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more (including all) of the recited characteristic XRPD diffraction peaks. Further, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited.
  • the compounds herein can exist in different salt, solvate, stereoisomer, crystalline/amorphous (including polymorphic) forms, and the present disclosure is intended to include all permutations thereof, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of the subject compound.
  • the language “tamper resistant” is art-recognized to describe aspects of a drug formulation 30 that make it more difficult to use the formulation to abuse the drug moiety of the formulation through e.g., extraction for intravenous use, or crushing for freebase use; and therefore, reduce the risk for abuse of the drug. 41
  • stable includes chemical stability and solid state (physical) stability.
  • chemical stability means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture with for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under 5 normal storage conditions, with little or no chemical degradation or decomposition.
  • Solid-state stability means the compound can be stored in an isolated solid form, or the form of a solid formulation in which it is provided in admixture with, for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no solid-state transformation (e.g., hydration, dehydration, solvatization, desolvatization, 10 crystallization, recrystallization or solid-state phase transition).
  • solid-state transformation e.g., hydration, dehydration, solvatization, desolvatization, 10 crystallization, recrystallization or solid-state phase transition.
  • composition is equivalent to the term “formulation.”
  • treating or “treatment” as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human) that includes: ameliorating the disease or medical condition, such as, eliminating or causing regression of the 15 disease or medical condition in a patient; suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or alleviating one or more symptoms of the disease or medical condition in a patient.
  • a treatment can provide a therapeutic benefit such as the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition, disease, or 20 disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be affected by the condition.
  • treatment may refer to prophylaxis, i.e., preventing the disease or medical condition from occurring or otherwise delaying the onset of the disease or medical condition in a patient.
  • a “patient” or “subject,” used interchangeably herein, can be any mammal including, for 25 example, a human.
  • a patient or subject can have a condition to be treated or can be susceptible to a condition to be treated.
  • a “psychopharmaceutical agent” is a chemical substance with the ability to cross the blood-brain barrier and act on the nervous system, resulting in alterations in perception, mood, consciousness, cognition, and/or behavior. Categories of psychopharmaceutical agents include 30 anxiolytics (e.g., benzodiazepines, barbiturates, etc.), empathogen-entactogens (e.g., MDMA, MDA, AMT, etc.), stimulants (e.g., amphetamines, modafinil, etc.), depressants (e.g., sedatives, 42
  • anxiolytics e.g., benzodiazepines, barbiturates, etc.
  • empathogen-entactogens e.g., MDMA, MDA, AMT, etc.
  • stimulants e.g., amphetamines, modafinil, etc.
  • depressants e.g., sedatives, 42
  • the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease, 5 disorder, or condition, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease, disorder, or condition.
  • the term “managing” encompasses treating a subject who had suffered from the particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition, or of one or more symptoms thereof.
  • “Therapeutically effective amount” refers to an amount of a compound(s) or its salt form sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder (prophylactically effective amount).
  • a “prophylactically effective amount” of an active agent is an amount sufficient to prevent a disease, disorder, or condition, or prevent its recurrence.
  • the term 15 “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • administration schedule is a plan in which the type, amount, period, procedure, etc. of the drug in the drug treatment are shown in time series, and the dosage, administration method, administration order, administration date, and the like of each drug are indicated.
  • the date 20 specified to be administered is determined before the start of the drug administration.
  • the administration is continued by repeating the course with the set of administration schedules as “courses”.
  • a “continuous” administration schedule means administration every day without interruption during the treatment course.
  • a “bolus” is where a discrete amount of active pharmaceutical ingredient 30 (API) (e.g., a psychopharmaceutical agent) is administered (e.g., by injection) within 30 minutes or less such that the concentration of the API in the body quickly increases.
  • API active pharmaceutical ingredient 30
  • Bolus injections are typically administered intravenously (directly into the vein), intramuscularly (within the muscle), 43
  • a bolus injection thus differs from an “infusion,” whereby a discrete amount of API (e.g., a psychopharmaceutical agent) is administered by single injection or multiple injections over a prolonged period of greater than 30 minutes, such that the concentration of the API in the body follows a more stable kinetic profile, 5 in some cases reaching a steady-state, with a prolonged exposure period.
  • API e.g., a psychopharmaceutical agent
  • toxic spikes is used herein to describe spikes in concentration of any compound described herein that would produce side-effects of sedation or psychotomimetic effects, e.g., hallucination, dizziness, and nausea; which can not only have immediate repercussions, but also influence treatment compliance.
  • side effects may become 10 more pronounced at blood concentration levels above about 300 ng/mL (e.g. above about 300, 400, 500, 600 or more ng/mL).
  • “osmolality” is the quotient of the negative natural logarithm of the rational activity of water and the molar mass of water.
  • osmolality is an expression of the number of osmotically active particles (the number of solute particles) in 1 kg of a solution, 15 represented herein as the number of milliosmoles (mOsm) per 1 kg of solution.
  • mOsm milliosmoles
  • one mole of a nondissociating substance e.g., glucose
  • a substance that dissociates into two separate species in solution e.g., sodium chloride
  • osmolality of 2 Osm/kg 2000 mOsm/kg
  • solutions are defined herein to be “isotonic” with one another, the solutions have the same osmolality.
  • a formulation is defined to be isotonic with human blood 25 serum
  • the formulation has the same osmolality as human blood serum.
  • Human blood serum typically has an osmolality of about 275 to about 300 mOsm/kg (L. Hooper et al., BMJ Open, 2015; 5(10):e008846).
  • “Syringeable” or “syringeability” refers to the force required to inject a given solution at a given rate via a chosen needle length and gauge, and relates to whether the formulation is30 administrable through a syringe. Flow through a hollow needle is characterized by the Hagen- Poiseuille equation (1): 44
  • ⁇ 128Q ⁇ LA ⁇ ⁇ 4 (1)
  • F syringe stopper (plunger) force
  • Q volumetric flow rate
  • ⁇ dynamic viscosity
  • L needle length
  • D needle bore diameter
  • A syringe area.
  • concentrations expressed in terms of weight per volume (w/v) are 5 calculated from grams (g) per milliliter (mL). These concentrations may be expressed as a percentage (% w/v), for example, the concentration of 1 g of solute in 100 mL of a solution is 1% w/v.
  • a “neuropsychiatric disease or disorder” is a behavioral or psychological problem associated with a known neurological condition, and 10 typically defined as a cluster of symptoms that co-exist.
  • Examples of neuropsychiatric disorders include, but are not limited to, schizophrenia, cognitive deficits in schizophrenia, attention deficit disorder, attention deficit hyperactivity disorder, cognitive deficit disorders, seizures, palsies, headache disorders, addictions, eating disorders, anger, bipolar and manic disorders, depression disorders, anxiety disorders, or any combinations thereof.
  • Inflammatory conditions and inflammatory diseases include, but are not limited to, rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, psoriatic arthritis); spondyloarthropathies (e.g., ankylosing spondylitis, reactive arthritis, Reiter's syndrome); crystal arthropathies (e.g., gout, pseudogout, calcium pyrophosphate 20 deposition disease); multiple sclerosis; Lyme disease; polymyalgia rheumatica; connective tissue diseases (e.g., systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, Sjogren's syndrome); vasculitides (e.g., polyarteritis nodosa, Wegener's granulomatosis, Churg- Strauss syndrome); inflammatory conditions including consequences of trauma or ischaemia, sarcoidosis;
  • adjunct therapy refers to a therapy that is given in addition to a primary or initial therapy to improve or maximize effectiveness.
  • a subject diagnosed with a depressive disorder that is taking one or more antidepressant medications e.g., an SSRI
  • an SSRI antidepressant medications
  • the adjunctive therapy may improve or maximize treatment effectiveness by reducing depressive symptom(s) compared to the primary or initial therapy alone.
  • the primary or initial therapy and 10 the adjunctive therapy involving the pharmaceutical formulation of the present disclosure can be, but need not be, prescribed and/or administered by the same person (e.g., clinician).
  • the primary or initial therapy e.g., SSRI therapy
  • the adjunctive therapy involving a pharmaceutical formulation of the present disclosure may be prescribed and/or administered by a second clinician.
  • the primary or initial therapy e.g., SSRI therapy
  • the adjunctive therapy involving a pharmaceutical formulation of the present disclosure may be prescribed and/or administered by the same (first) clinician.
  • the term “inadequate response” as used herein refers to a lack of clinically meaningful 20 improvement in symptoms, for example as measured by one or more of the rating scales described herein.
  • the inadequate response to an adequate course of treatment with an antidepressant medication(s) may be determined retrospectively or prospectively.
  • Prospective determination of inadequate response refers to a determination made by the prescribing clinician or therapist following administration of part of a course of treatment.
  • Retrospective determination refers to a 25 determination made by the prescribing clinician or therapist following administration of a full adequate course of treatment.
  • peak effects refer to subjective effects on perception and consciousness which are intense—peak effects normally correlate with a score of ⁇ 70 mm on the VAS any drug effect rating scale.
  • peak effects in humans are associated with a drug plasma concentration of ⁇ 40 ng/mL.
  • effect size refers to a statistical calculation that can be used to compare the efficacy of different agents by quantifying the size of the difference between treatments (“between- group”). It is a dimensionless measure of the difference in outcomes under two different treatment interventions. Effect sizes thus inform clinicians about the magnitude of treatment effects.
  • an effect size (Cohen’s d score) of zero means that the treatment and placebo have no differences in effect.
  • An effect size (Cohen’s d score) greater than zero indicates the degree to which treatment is more efficacious 15 than placebo. Conventionally, it is considered that an effect size (Cohen’s d score) of 0.2 is small, 0.5 is medium, and 0.8 or higher is large.
  • the term “and/or” includes any and all combinations of one or more of the associated listed items. As used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference as well as the singular reference 20 unless the context clearly dictates otherwise. The term “about” in association with a numerical value means that the value may vary up or down by 5%.
  • Pharmaceutical Formulation 25 Disclosed herein is an injectable pharmaceutical formulation comprising a psychopharmaceutical agent or drug, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral injection of the formulation through the skin or other external 30 boundary tissue, rather than through the alimentary canal, so that the active pharmaceutical ingredient(s) contained therein is administered, using gravity or force, directly into a blood vessel, 47
  • injectable or “injectability,” it is meant that the formulation is in accordance with Pharmacopeial requirements of injections, for example as set forth in The United States Pharmacopeial (USP) Convention, General Requirements/ ⁇ 1> Injections, 33.
  • the injectable pharmaceutical formulations are prepared by methods 5 designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants, and where appropriate, contain inhibitors of the growth of organisms (e.g., antimicrobial preservatives) and/or anti-oxidants.
  • Pharmacopeial requirements include, but are not limited to, USP Pyrogen Test ⁇ 151>, USP Bacterial Endotoxins Test ⁇ 85>, USP Antimicrobial Effectiveness Testing ⁇ 51>, USP Antimicrobial Agents—Content 10 ⁇ 341>, USP Sterilization and Sterility Assurance of Compendial Articles ⁇ 1211>, USP Particulate Matter in Injections ⁇ 788>, and USP Sterility Tests ⁇ 71>.
  • the endotoxin limit defined on the basis of dose is equal to K/M, where K is the threshold human pyrogenic dose of endotoxin per kg of body weight, and M is equal to the maximum recommended human dose of product per kg of body weight in a single hour period; Escherichia 15 coli should be absent in 1 g of formulation; the total aerobic microbial count (TAMC) should be under 1,000 colony forming units (CFU)/g; and the total yeast and mold count (TYMC) should not exceed 100 CFU/g.
  • K is the threshold human pyrogenic dose of endotoxin per kg of body weight
  • M is equal to the maximum recommended human dose of product per kg of body weight in a single hour period
  • Escherichia 15 coli should be absent in 1 g of formulation
  • the total aerobic microbial count (TAMC) should be under 1,000 colony forming units (CFU)/g
  • TYMC total yeast and mold count
  • injectable or “injectability,” it is further meant that the pharmaceutical formulation is characterized as having physiochemical properties, such as pH, 20 osmolality, and viscosity, which enables administration through the skin or other external boundary tissue via needle, syringe, canula, catheter, or other suitable injection device without causing excessive tissue necrosis, pain, or inflammation (e.g., phlebitis) at the injection site.
  • Injectable drug products generally have a pH of about 2 to 11 for IV and intramuscular injection, and a pH of about 3 to 9 for subcutaneous injection (Usach I, et al.
  • Injectable drug products generally have an osmolality of 150 to 600 mOsm/kg, with osmolalities closest to that of human blood serum (275 to about 300 mOsm/kg) being preferred.
  • Injectable drug products administered with common syringes and needle gauge generally have a viscosity of less than about 50 centipoise (cP), with higher viscosities sometimes requiring 5 injection forces too high for common syringes and gauge needles to withstand.
  • the drug may not even be administrable through a syringe (may not be “syringeable”).
  • injectable drug products with much higher viscosities can be administered by injection, for example, when administering non-Newtonian fluids or when using injection devices designed for high viscosity fluids such as auto-injectors for high viscosity fluids.
  • the pH, osmolality, and 10 viscosity of the pharmaceutical formulation of the present disclosure fall within the ranges reported to be suitable for injection, and suitable for subcutaneous injection in particular.
  • the pharmaceutical formulation is typically in the form of a solution, although other dosage forms are also contemplated such as suspensions, emulsions, micelles, liposomes, microspheres, and nanosystems which are suitable for injection.
  • Solid forms which are suitable for 15 solutions or suspensions in liquid prior to injection are also disclosed.
  • the pharmaceutical formulations are disclosed as ready-to-use sterile solutions.
  • the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry soluble products, including lyophilized powders and hypodermic tablets, reconstituted with an aqueous vehicle prior to use.
  • the pharmaceutical formulations are disclosed 20 as ready-to-use sterile suspensions.
  • the pharmaceutical formulations are disclosed as reconstituted solutions prepared from sterile dry insoluble products reconstituted with an aqueous vehicle prior to use.
  • the pharmaceutical formulations are disclosed as ready-to-use sterile emulsions.
  • the injectable pharmaceutical formulation is suitable for 25 intravenous administration (directly into the vein), i.e., is an intravenous pharmaceutical formulation.
  • the injectable pharmaceutical formulation is suitable for intramuscular administration (within the muscle), i.e., is an intramuscular pharmaceutical formulation.
  • the injectable pharmaceutical formulation is suitable for intradermal administration intradermally (beneath the skin), i.e., is an intradermal pharmaceutical 30 formulation.
  • the injectable pharmaceutical formulation is suitable for subcutaneous administration (within the fat or the layer of skin directly below the dermis and epidermis), i.e., is a subcutaneous pharmaceutical formulation. 49
  • Subcutaneous administration is a minimally invasive mode of administration.
  • Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, sustained rates of absorption, often with some amount of depot effect. Compared with other routes of administration, it is slower than intravenous and intramuscular injections but still faster than 5 intradermal injections. The convenience and speed of subcutaneous delivery allows increased patient compliance and quicker access to medication when needed.
  • Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed. Subcutaneous formulations are usually much easier to handle for both the 10 patient and practitioner.
  • a particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner to perform the administration in a rather short intervention with the patient, compared to intravenous infusion protocols associated with DMT-based therapy.
  • the patient can be trained to perform self-administration. Such self-administration may be particularly useful during maintenance 15 dosing where clinical observation and/or psychotherapy may play less prominent roles in the overall treatment.
  • injection volumes of up to about 3 mL are tolerated via the subcutaneous route, especially those given in the patient’s abdomen, with injection volumes of about 2 mL or less being well tolerated across various injection sites. Large subcutaneous injection volumes greater than about 3 mL are often associated with pain.
  • the pharmaceutical formulation may be suitable for bolus injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection within 30 minutes or less, 25 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less.
  • the bolus injection may involve a single injection or multiple injections performed within the above-described time range.
  • administering multiple bolus injections within the above-mentioned time range of 30 minutes or less would be considered a bolus administration herein.
  • the bolus injection involves a single injection within the above time range.
  • the pharmaceutical formulation may be suitable for 50
  • bolus subcutaneous injection such as a single bolus subcutaneous injection, i.e., the pharmaceutical formulation is a bolus subcutaneous pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intramuscular injection, such as a single bolus intramuscular injection, i.e., the pharmaceutical formulation is a bolus intramuscular 5 pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intradermal injection, such as a single bolus intradermal injection, i.e., the pharmaceutical formulation is a bolus intradermal pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for bolus intravenous injection, such as a single bolus intravenous injection, i.e., the pharmaceutical formulation is a bolus intravenous pharmaceutical formulation.
  • the pharmaceutical formulation may be suitable for infusion injection, in which a discrete amount of the psychopharmaceutical agent is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes.
  • the infusion injection may15 involve a single prolonged injection, or multiple injections (short or prolonged) within the above- described time range. Thus, administering multiple bolus injections over a prolonged period of greater than 30 minutes would be considered an infusion administration herein.
  • the infusion injection involves a single injection within the above time range.
  • the pharmaceutical formulation may be suitable for infusion subcutaneous injection.
  • the 20 pharmaceutical formulation may be suitable for infusion intramuscular injection.
  • the pharmaceutical formulation may be suitable for infusion intravenous injection.
  • Psychopharmaceutical agent The injectable pharmaceutical formulation comprises a psychopharmaceutical agent.
  • the 25 psychopharmaceutical agent may be an anxiolytic (e.g., benzodiazepines, barbiturates, etc.), an empathogen-entactogen (e.g., MDMA, MDA, AMT, etc.), a stimulant (e.g., amphetamines, modafinil, etc.), a depressant (e.g., sedatives, hypnotics, and opioids), and/or a hallucinogen such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant (e.g., psilocybin, LSD, DMT, mescaline, salvia divinorum, scopolamine, etc
  • the psychopharmaceutical agent is a dissociative, a dissociative hallucinogen, an anesthetic, an arylcyclo-hexylamine, a 1,2-diarylethylamine, a ⁇ -keto- arylcyclohexylamine, and/or a compound that modulates the NMDA receptor.
  • Examples of such psychopharmaceutical agents include, but are not limited to, ketamine, methoxetamine, 5 deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3-methoxyphencyclidine, methoxieticyclidine, ephenidine, lanicemine, dextromethorphan, dextrorphan, methoxyketamine, norketamine (e.g., (R)-norketamine, (S)-norketamine, or mixtures thereof), hydroxynorketamine (e.g., 2R,6R-hydroxynorketamine, 2S,6S-hydroxynorketamine, or mixtures thereof), or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination 10 thereof.
  • ketamine methoxetamine, 5 deschloroketamine, N-ethyl deschloroketamine (eticyclidone), 3-methoxyphencycl
  • the psychopharmaceutical agent is an opioid.
  • opioids include, but are not limited to, racemorphan, levorphanol, racemethorphan, buprenorphine, morphine, loperamide, morphine, codeine, hydrocodone, oxymorphone, buprenorphine, fentanyl, methadone, tramadol, alpha-methyl acetyl fentanyl, alfentanil, butyrfentanyl, carfentanil, 3-15 methylcarfentanil, 4-fluorofentanyl, beta-hydroxyfentanyl, alpha-methylfentanyl, cis-3- methylfentanyl, beta-hydroxy-3-methylfentanyl, remifentanil, sufentanil, 3-methylthiofentanyl, naloxone, and naltrexone, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or
  • the psychopharmaceutical agent is a cathinone, a 3,4- 20 methylenedioxyamphetamine compound, an aminoalkyl-substituted benzofuran, a substituted amphetamine, an aminoindane, a stimulant, diphenhydramine, hydroxazine, phenylephrine, dopamine, adrenaline, lidocaine, oxymetazoline, clemastine, chlorpheniramine, or 6-chloro-2- aminotetralin.
  • the pharmaceutical compound is a cathinone, an aminoalkyl- substituted benzofuran, and an aminoindane, or a pharmaceutically acceptable salt, a stereoisomer, 25 solvate, or prodrug thereof.
  • the psychopharmaceutical agent is a lysergamide.
  • lysergamides include, but are not limited to, methylisopropyllysergamide, ethylisopropyllysergamide, 6-allyl-6-nor-LSD, 6-ethyl-6-nor-lysergic acid diethylamide, 1-acetyl- LSD, 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide, 1-propionyl-lysergic acid 30 diethylamide, 1-cyclopropionyl-d-lysergic acid diethylamide, N1-butyryl-lysergic acid diethylamide, and 6-propyl-6-nor-lysergic acid diethylamide, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
  • the psychopharmaceutical agent is a phenethylamine.
  • phenethylamines include, but are not limited to, mescaline, 2,5-dimethoxy-4- bromophenethylamine (2C-B), 2-(4-iodo-2,5-dimethoxyphenyl)ethan-1-amine (2C-I), 2-(4- chloro-2,5-dimethoxyphenyl)ethan-1-amine (2C-C), 2,5-dimethoxy-4-iodoamphetamine, 2-[2,5- 5 dimethoxy-4-(propylsulfanyl)phenyl]ethan-1-amine, and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2- methoxyphenyl)methyl]ethanamine, or a pharmaceutically acceptable salt, a stereoisomer, solvate, or prodrug thereof, or a combination thereof.
  • the psychopharmaceutical agent is a tryptamine psychedelic.
  • tryptamine psychedelics include, but are not limited to, N,N-dimethyltryptamine,10 N,N-diethyltryptamine, N,N-dipropyltryptamine, N-Methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, 4-hydroxy-N-methyl-N-ethyltryptamine, 5- methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N-dimethyltryptamine, O-acetylpsilocin, psilocin, as well as those trypt
  • Examples of psychopharmaceutical agents which can be categorized as hallucinogens such as a psychedelic (e.g., a tryptamine psychedelic), a dissociative, or a deliriant include, but are not limited to, 9,10-didehydro-6-allyl-N,N-diethylergoline-8 ⁇ -carboxamide, 9,10-didehydro-6,N,N- triethylergoline-8 ⁇ -carboxamide, N,N-dimethyltryptamine, N,N-diethyltryptamine, 5-methoxy-20 N,N-dimethyltryptamine, N,N-dibutyltryptamine, N,N-diethyltryptamine, N,N- diisopropyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N,N-dial
  • dimethoxy-4-iodoamphetamine 2,5-dimethoxy-4-methylamphetamine, 2,6-dimethoxy-4- methylamphetamine, 2,5-dimethoxy-4-n-propylamphetamine, 3,5-dimethoxy-4- ethoxyphenethylamine, 2,4,5-triethoxyamphetamine, 2,4-diethoxy-5-methoxyamphetamine, 2,5- diethoxy-4-methoxyamphetamine, 4,5-dimethoxy-2-ethoxyamphetamine, N-hydroxy-N-methyl- 5 3,4-methylenedioxyamphetamine, 2,5-dimethoxy-3,4-(trimethylene)amphetamine, 3,6- dimethoxy-4-(2-aminopropyl)benzonorborane, 2,5-dimethoxy-3,4-dimethylamphetamine, 2,5- dimethoxy-4-ethylthio-N-hydroxyphenethylamine
  • the psychopharmaceutical agent is a tryptamine psychedelic.
  • Tryptamine psychedelics generally share a basic core structure of an indole (a fused a fused benzene and pyrrole ring), and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen), as represented below.
  • Many tryptamine 5 psychedelics are 5-HT2A receptor agonists, i.e., they increase the activity of a 5-HT2A receptor, which is a subtype of the 5-HT 2 receptor that belongs to the serotonin receptor family, and includes both partial and full agonists.
  • the tryptamine psychedelic is optionally substituted on the 10 tryptamine ring.
  • the tryptamine psychedelic is an N,N-dialkyltryptamine.
  • the tryptamine psychedelic is N,N-dimethyltryptamine, N,N- diethyltryptamine, N,N-dipropyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N- isopropyltryptamine, N,N-diallyltryptamine, N-methyl-N-allyltryptamine, N-methyl-N- ethyltryptamine, N,N-diisopropyltryptamine, wherein the tryptamine is optionally substituted, or 15 a combination thereof.
  • the tryptamine psychedelic is substituted with one or more deuterium atoms. In some embodiments, the tryptamine psychedelic is optionally substituted at the 4- or 5-position of the tryptamine ring with a substituent selected from hydroxy, acetoxy, or methoxy. In some embodiments, the tryptamine is 4-hydroxy-N-methyl-N- ethyltryptamine, psilocin, 5-methoxy-N,N-diisopropyltryptamine, 5-methoxy-N,N- 20 dimethyltryptamine, or O-acetylpsilocin (4-acetoxy-N,N-dimethyltryptamine), or a combination thereof.
  • the tryptamine psychedelic may be a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), defined hereinafter.
  • the tryptamine psychedelic may be a pharmaceutically acceptable salt of a single compound of the 25 present disclosure or a pharmaceutically acceptable salt of a mixture of compounds of the present 56
  • the injectable pharmaceutical formulation comprises (as the tryptamine psychedelic) a pharmaceutically acceptable salt of a compound of the present disclosure, e.g., a compound of Formula (I) through (III), when it comprise ions (protonated forms) of the compounds of the present disclosure and ions that counter the charge of the compounds of the present disclosure 5 (counterions) in solution.
  • the pharmaceutically acceptable salt of a compound of the present disclosure e.g., e.g., a compound of Formula (I) through (III)
  • the injectable pharmaceutical formulation may be prepared from a 10 pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)).
  • the pharmaceutically acceptable salt of a compound of the present disclosure within the pharmaceutical formulation may be formed in-situ, for example, by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base 15 with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the compounds of the present disclosure.
  • the pharmaceutical formulation While a distribution of free base and protonated species (salt form) of the compound may exist in solution depending on the pH of the pharmaceutical formulation, the pharmaceutical formulation generally contains a molar proportion of protonated compound (salt form) of least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 20 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%. In most cases, the pharmaceutical formulation contains a molar proportion of protonated compound (salt form) of least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, at least 99.9% for most favorable aqueous solubility.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of 25 a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof, 57
  • X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted 5 alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R 2 is selected from the group consisting of hydrogen, deuterium, halogen, unsubstituted or 10 substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted ary
  • X 1 and X 2 may be the same, or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 are hydrogen. In some embodiments, X 1 and X 2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or 5 deuterium, and X2 is a substituted or unsubstituted C1-C6 alkyl.
  • X2 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n- propyl, preferably methyl.
  • X2 is a substituted C1-C6 alkyl.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may 10 be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • one of X1 and X2 is deuterium while the other is hydrogen. In some embodiments, one or more of X1 and X2 is a substituted or unsubstituted C 3 -C 10 cycloalkyl. In some embodiments, one or more of X 1 and X 2 is an unsubstituted C 3 -C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • one or more of X1 and X2 is a substituted C3-C10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • X1 and/or X2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl.
  • Y 1 and Y 2 may be the same, or different. In some embodiments, Y 1 and Y 2 are the same.
  • Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y 1 and Y 2 are different. In some embodiments, one of Y 1 and Y 2 is deuterium while the other is hydrogen. In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some 25 embodiments, R2 is a halogen, e.g., fluoro, chloro, bromo, and iodo.
  • R2 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R2 is a substituted C1-C6 alkyl.
  • R2 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar 30 substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R2 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl.
  • R 2 is an unsubstituted or substituted alkynyl.
  • R 2 is a substituted or unsubstituted C 3 -C 10 cycloalkyl.
  • R 2 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, 5 adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R 2 is a substituted C 3 -C 10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R 2 is an unsubstituted or substituted heterocycloalkyl.
  • R2 is an unsubstituted or substituted aryl.
  • R2 is an unsubstituted or substituted heteroaryl.
  • R 4 and R 5 may be the same, or different.
  • R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is hydroxyl. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n- 15 propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R 4 is a substituted C 1 -C 6 alkyl.
  • R 4 is a substituted C 1 -C 6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy.
  • R 4 is a substituted alkoxy.
  • preferred substituents may include, but are not limited to, deuterium, halogen 25 (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkoxy group may contain one, or more than one, substituent.
  • the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc.
  • R4 is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n- 30 butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio.
  • R4 is a substituted alkylthio.
  • the alkylthio group may contain one, or more t han one, substituent.
  • R 4 is an alkylthio group substituted with one or more 60
  • the alkylthio group may contain one, or more than one, deuterium substituent.
  • the alkylthio group is a C 1 alkylthio group (i.e., a methylthio group)
  • the deuterium substituted C 1 alktlthio group may be -SCDH 2 , -SCD 2 H, and -SCD 3 .
  • R 4 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which 5 include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH 2 CH 2 CH 2 F, -SCH 2 CH 2 CHF 2 , -SCH 2 CH 2 CF 3 , -SCH 2 CH 2 CH 2 F, -SCH 2 CH 2 CH 2 CHF 2 , and -SCH2CH2CH2CF3, with particular mention being made to -SCH2F, -SCHF2, -SCF3.
  • 5 include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, -SCH 2 CH 2 CH 2 F, -SCH 2 CH 2 CHF 2 , -SCH2CH2CH2CF3, with particular mention being made
  • R4 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH 3 ), propionoxy (-OCOCH 2 CH 3 ), and butyroxy (- 10 OCOCH2CH2CH3).
  • R5 is deuterium.
  • R5 is hydrogen.
  • R 5 is hydroxyl.
  • R 5 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R5 is a substituted C1-C6 15 alkyl.
  • R5 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R 5 is an unsubstituted 20 alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy.
  • R 5 is a substituted alkoxy.
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkoxy group may contain one, or 25 more than one, substituent.
  • the substituted C 1 alkoxy group may be -OCDH 2 , -OCD 2 H, -OCD 3 , -OCFH 2 , - OCF2H, -OCF3, etc.
  • R5 is an unsubstituted alkylthio, examples of which include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, t-butylthio, n-pentylthio, neopentylthio, and hexylthio.
  • R 5 is a substituted alkylthio.
  • the alkylthio group may contain one, or more than one, substituent.
  • R5 is an alkylthio group substituted with one or more deuterium.
  • the alkylthio group may contain one, or more than one, deuterium substituent.
  • the deuterium substituted C 1 alktlthio group may be -SCDH 2 , -SCD 2 H, and -SCD 3 .
  • R 5 is a haloalkylthio (an alkylthio substituted with one or more halogen atoms), examples of which include, but are not limited to, -SCH2F, -SCHF2, -SCF3, -SCH2CH2F, -SCH2CHF2, -SCH2CF3, 5 -SCH2CH2CH2F, -SCH2CH2CHF2, -SCH2CH2CF3, -SCH2CH2CH2CH2F, -SCH2CH2CH2CHF2, and -SCH 2 CH 2 CH 2 CF 3 , with particular mention being made to -SCH 2 F, -SCHF 2 , -SCF 3 .
  • R5 is an unsubstituted or substituted acyloxy, examples of which include, but are not limited to, acetoxy (-OCOCH3), propionoxy (-OCOCH2CH3), and butyroxy ( -OCOCH 2 CH 2 CH 3 ).
  • R6 and R7 may be the same, or different. In some embodiments, R6 and R7 are the same. In some embodiments, R6 and R7 are different. In some embodiments, R6 is hydrogen. In some embodiments, R 6 is deuterium. In some embodiments, R 6 is a halogen, e.g., fluoro, chloro, bromo, and iodo.
  • R 6 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C1-C6 alkyl).
  • R6 is an unsubstituted C1-C6 alkyl, examples15 of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, neopentyl, and hexyl.
  • R 6 is a substituted C 1 -C 6 alkyl.
  • R6 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc.
  • R6 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R 6 is an unsubstituted or substituted alkynyl. In some embodiments, R 6 is an unsubstituted or substituted C3-C10 cycloalkyl. In some embodiments, R6 is an unsubstituted C3-C10 cycloalkyl, examples of 25 which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R 6 is a substituted C 3 -C 10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R 6 is an unsubstituted or substituted 30 heterocycloalkyl.
  • R 6 is an unsubstituted or substituted aryl.
  • R6 is an unsubstituted or substituted heteroaryl.
  • R7 is hydrogen. In some embodiments, R7 is deuterium. In some 62
  • R7 is a halogen, e.g., fluoro, chloro, bromo, and iodo.
  • R7 is an unsubstituted or substituted alkyl (e.g., an unsubstituted or substituted a C 1 -C 6 alkyl).
  • R 7 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and 5 hexyl.
  • R7 is a substituted C1-C6 alkyl.
  • R7 is a substituted C1-C6 alkyl
  • preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the alkyl group may contain one, or more than one, substituent.
  • the substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R7 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R7 is an unsubstituted or substituted alkynyl. In some embodiments, R 7 is an unsubstituted or substituted C 3 -C 10 cycloalkyl. In some embodiments, R 7 is an unsubstituted C 3 -C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R7 is a substituted C3-C10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain one, or more than one, substituent.
  • R7 is an unsubstituted or substituted heterocycloalkyl.
  • R 7 is an unsubstituted or substituted aryl.
  • R 7 is an 20 unsubstituted or substituted heteroaryl.
  • R8 and R9 may be the same, or different.
  • R8 and R9 are the same. In some embodiments, R 8 and R 9 are hydrogen. In some embodiments, R 8 and R 9 are deuterium. In some embodiments, R 8 and R 9 are unsubstituted or substituted alkyl, such as an unsubstituted or substituted C1-C6 alkyl. In some embodiments, R8 and R9 are different. In some embodiments, R8 25 is hydrogen, and R9 is an unsubstituted or substituted C1-C6 alkyl.
  • R 8 and/or R 9 is an unsubstituted C 1 -C 6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl, preferably methyl.
  • R8 and/or R9 is a substituted C1-C6 alkyl.
  • the alkyl group may contain one, or more than one, substituent. For example, when the alkyl group is a C 1 alkyl group (i.e., methyl group), 30 the substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, -CD 3 , -CFH 2 , -CF 2 H, -CF 3 , etc.
  • R8 and/or R9 is an alkyl substituted with one or more deuterium, e.g., a C1-C6 alkyl group substituted with one or more deuterium.
  • the alkyl group may contain one, or more than one, 63
  • the deuterium substituted C 1 alkyl group may be -CDH 2 , -CD 2 H, and -CD 3 , with particular mention being made to -CD 3 .
  • R 8 and/or R 9 is a haloalkyl, examples of which include, but are not limited to, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CH2F, -CH2CH2CHF2, - 5 CH2CH2CF3, -CH2CH2CH2CH2F, -CH2CH2CH2CHF2, and -CH2CH2CH2CF3, with particular mention being made to -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , and -CH 2 CH 2 CF 3 .
  • R8 and/or R9 is an unsubstituted or substituted alkenyl, e.g., an unsubstituted or substituted allyl. In some embodiments, R8 and/or R9 is an unsubstituted or substituted alkynyl. In some embodiments, R 8 and/or R 9 is a substituted or unsubstituted C 3 -C 10 cycloalkyl.
  • R8 and/or R9 is an unsubstituted C3-C10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
  • R 8 and/or R 9 is a substituted C 3 -C 10 cycloalkyl.
  • Preferred substituents may include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, etc.
  • the cycloalkyl group may contain 15 one, or more than one, substituent.
  • R8 and/or R9 is an unsubstituted or substituted heterocycloalkyl.
  • R 8 and/or R 9 is an unsubstituted or substituted aryl.
  • R8 and/or R9 is an unsubstituted or substituted heteroaryl.
  • R8 and R9 together with the nitrogen atom attached thereto are joined to form an unsubstituted or substituted heterocycloalkyl.
  • R 8 and R 9 20 together with the nitrogen atom attached thereto are joined to form an unsubstituted heterocycloalkyl.
  • the unsubstituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4- membered ring, 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s).
  • the unsubstituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R8 and R9), and may 25 optionally contain at least one additional hetero-ring atom, which may be one or more of nitrogen, sulfur, or oxygen, for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom).
  • Examples of unsubstituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to, , , , , , , 64
  • R 8 and R 9 together with the nitrogen atom attached thereto are 5 joined to form a substituted heterocycloalkyl.
  • the substituted heterocycloalkyl group may be, e.g., a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, etc., which may be optionally fused to other ring(s).
  • the substituted heterocycloalkyl group contains a minimum of one nitrogen ring atom (the nitrogen atom intervening R8 and R9), and may optionally contain additional hetero-ring atoms (e.g., nitrogen, 10 sulfur, or oxygen) for a total of 1, 2, 3, or 4 hetero-ring atoms (at least one of which is a nitrogen ring atom).
  • additional hetero-ring atoms e.g., nitrogen, 10 sulfur, or oxygen
  • substituted heterocycloalkyl group examples include, but are not limited to, aziridine, azetidine, pyrrolidine, isoindole, indole, dihydroindole, indazole, purine, carbazole, carboline, imidazolidine, imidazoline, piperidine, piperazine, indoline, 1,2,3,4- tetrahydroisoquinoline, thiazolidine, morpholine, or thiomorpholine, which is substituted with at 15 least one substituent.
  • the substituent(s) may be any recited herein, including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, oxo, unsubstituted alkoxy, substituted alkoxy (e.g., polyether groups), unsubstituted alkyl, substituted alkyl, unsubstituted alkenyl, substituted alkenyl, unsubstituted alkynyl, substituted alkynyl, unsubstituted cycloalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, substituted heterocycloalkyl, unsubstituted 20 aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl.
  • halogen e.g., fluorine
  • polar substituents such as hydroxyl, oxo, unsubstituted alkoxy,
  • the substituted heterocycloalkyl formed from joining R 8 and R 9 together with the nitrogen atom attached thereto contains a heterocycloalkyl group substituted with one, two, three, four, or more substituents.
  • the substituent may be located on a carbon ring atom or on a hetero-ring atom.
  • substituted heterocycloalkyl groups formed from joining R8 and R9 together with the nitrogen atom attached thereto include, but are not limited to, , , , , , , , 5 , , , and .
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I), or a stereoisomer, solvate, or prodrug thereof, wherein any one or more of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 optionally comprises deuterium.
  • At least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R8, and R9 comprises deuterium.
  • at least one of X 1 , X 2 , Y 1 , Y 2 , R 5 , R 8 , and R 9 comprises deuterium.
  • at least one of X1, X2, Y1, Y2, R8, and R9 comprises deuterium.
  • X1, X2, R8, and R9 comprise deuterium.
  • X1, X2, Y1, Y2, R8, and R 9 comprise deuterium.
  • X 1 , X 2 , and R 5 comprise deuterium.
  • X1, X2, Y1, Y2, R5, R8, and R9 comprise deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (II), or a stereoisomer, solvate, or prodrug thereof 66
  • X1 and X2 are independently hydrogen or deuterium, Y1 and Y2 are independently hydrogen or deuterium, 5 each Z 1 is independently hydrogen or deuterium, each Z 2 is independently hydrogen or deuterium, and R2, R4, R5, R6, and R7 are independently hydrogen or deuterium.
  • X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X 1 and X 2 are hydrogen. In some embodiments, X 1 and X 2 are deuterium. 10 In some embodiments, X1 and X2 are different. In some embodiments, X1 is deuterium and X2 is hydrogen. Y 1 and Y 2 may be the same, or different.
  • Y 1 and Y 2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, Y1 is deuterium and Y2 is 15 hydrogen. In some embodiments, X1, X2, Y1, and Y2 are hydrogen. In some embodiments, X1, X2, Y1, and Y2 are deuterium. In some embodiments, each Z 1 is hydrogen. In some embodiments, each Z 1 is deuterium. In some embodiments, one Z 1 is hydrogen, while the other two Z 1 ’s are deuterium.
  • one Z1 is deuterium, while the other two Z1’s are hydrogen.
  • each Z2 is hydrogen.
  • each Z2 is deuterium.
  • one Z2 is hydrogen, while the other two Z 2 ’s are deuterium.
  • one Z 2 is deuterium, while the other two Z2’s are hydrogen.
  • each Z1 and Z2 is hydrogen. In some 67
  • each Z1 and Z2 is deuterium.
  • R 2 is deuterium. In some embodiments, R 2 is hydrogen.
  • R 4 is deuterium. In some embodiments, R 4 is hydrogen.
  • R 5 is deuterium. In some embodiments, R5 is hydrogen.
  • R6 is deuterium. In 5 some embodiments, R6 is hydrogen.
  • R7 is deuterium. In some embodiments, R 7 is hydrogen.
  • R 2 , R 4 , R 5 , R 6 , and R 7 may be the same, for example, R 2 , R 4 , R 5 , R 6 , and R7 may each be hydrogen, or alternatively, R2, R4, R5, R6, and R7 may each be deuterium.
  • at least one of R2, R4, R5, R6, and R7 is deuterium, or at least two of R2, R4, R5, R 6 , and R 7 are deuterium, or at least three of R 2 , R 4 , R 5 , R 6 , and R 7 are deuterium, or at least four 10 of R2, R4, R5, R6, and R7 are deuterium.
  • At least one of X1, X2, Y1, Y2, Z1, Z2, R2, R4, R5, R6, and R7 is deuterium.
  • X 1 , X 2 , Z 1 and Z 2 are deuterium.
  • X 1 , X 2 , Y 1 , and Y 2 are deuterium.
  • X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of 15 a compound of Formula (III), or a stereoisomer, solvate, or prodrug thereof wherein: X 1 and X 2 are independently hydrogen or deuterium, Y 1 and Y 2 are independently hydrogen or deuterium, 20 each Z1 is independently hydrogen or deuterium, each Z2 is independently hydrogen or deuterium, each Z 3 is independently hydrogen or deuterium, and R2, R4, R6, and R7 are independently hydrogen or deuterium. 68
  • X1 and X2 may be the same, or different. In some embodiments, X1 and X2 are the same. In some embodiments, X 1 and X 2 are hydrogen. In some embodiments, X 1 and X 2 are deuterium. In some embodiments, X 1 and X 2 are different. In some embodiments, X 1 is deuterium and X 2 is hydrogen. 5 Y1 and Y2 may be the same, or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y 1 and Y 2 are hydrogen. In some embodiments, Y 1 and Y 2 are deuterium. In some embodiments, Y1 and Y2 are different.
  • Y1 is deuterium and Y2 is hydrogen.
  • X 1 , X 2, Y 1 , and Y 2 are hydrogen.
  • X 1 , X 2, Y 1 , 10 and Y2 are deuterium.
  • each Z1 is hydrogen.
  • each Z1 is deuterium.
  • one Z 1 is hydrogen, while the other two Z 1 ’s are deuterium.
  • one Z 1 is deuterium, while the other two Z 1 ’s are hydrogen.
  • each Z2 is hydrogen.
  • each Z2 is deuterium.
  • one Z2 15 is hydrogen, while the other two Z2’s are deuterium. In some embodiments, one Z2 is deuterium, while the other two Z 2 ’s are hydrogen. In some embodiments, each Z 1 and Z 2 is hydrogen. In some embodiments, each Z1 and Z2 is deuterium. In some embodiments, each Z3 is hydrogen. In some embodiments, each Z3 is deuterium. In some embodiments, one Z 3 is hydrogen, while the other two Z 3 ’s are deuterium. In some 20 embodiments, one Z 3 is deuterium, while the other two Z 3 ’s are hydrogen. In some embodiments, each Z1, Z2, and Z3 is hydrogen.
  • each Z1 and Z2 is hydrogen and each Z3 is deuterium. In some embodiments, each Z 1 , Z 2 , and Z 3 is deuterium. In some embodiments, each Z 1 and Z 2 is deuterium, and each Z 3 is hydrogen. In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some 25 embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R6 is deuterium. In some embodiments, R 6 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R7 is hydrogen.
  • R2, R4, R6, and R7 may be the same, for example, R2, R4, R6, and R7 may each be hydrogen, or alternatively, R2, R4, R6, and R7 may each be deuterium.
  • at least one of R 2 , R 4 , R 6 , and R 7 is deuterium, or at least two of R 2 , R 4 , R 6 , and R 7 30 are deuterium, or at least three of R 2 , R 4 , R 6 , and R 7 are deuterium.
  • at least one of X1, X2, Y1, Y2, Z1, Z2, Z3, R2, R4, R6, and R7 is deuterium.
  • X1, X2, Z1 and Z2 are deuterium and each Z3 is hydrogen.
  • X1, X2, Y1, and Y2 are deuterium and each Z3 is hydrogen.
  • X 1 , X 2 , Y 1 , Y 2 , Z 1 , and Z 2 are deuterium and each Z 3 is hydrogen.
  • X 1 , X 2 , and Z 3 are deuterium.
  • X 1 , X 2 , Z 1 , Z 2 , and Z 3 are deuterium.
  • X1, X2, Y1, Y2, and Z3 are deuterium.
  • 5 X1, X2, Y1, Y2, Z1, Z2, and Z3 are deuterium.
  • the tryptamine psychedelic is a pharmaceutically acceptable salt of a compound of Formula (I) through (III), which include, but are not limited to, the following exemplary compounds (I-1), (I-2), 10 (I-3), (I-4), (I-5), (I-6), 70
  • the compound e.g., a compound of Formula (I) or (II), is a deuterated analog of DMT, examples of which include, but are not limited to,
  • the deuterated analog of DMT is one or more of 2-(1H-indol-3-yl)- N,N-dimethylethan-1-amine-1,1-d 2 (I-2); 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine- 1,1,2,2-d4 (I-8); 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10); 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1-d 2 (I-6);
  • the deuterated analog of 5-MeO-DMT is one or more of 2-(5- methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-20); 2-(5-methoxy-1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-22); 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-23); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1-d 2 (I-18); 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-106
  • any position in the compounds defined herein as having deuterium have a minimum deuterium incorporation that is greater than that found naturally occurring in hydrogen (about 0.016 atom %).
  • any position in the compound defined as having deuterium 15 has a minimum deuterium incorporation of at least 10 atom %, at least 20 atom %, at least 25 atom %, at least 30 atom %, at least 40 atom %, at least 45 atom %, at least 50 atom %, at least 60 atom %, at least 70 atom %, at least 80 atom %, at least 90 atom %, at least 95 atom %, at least 99 atom % at the site of deuteration.
  • the compounds described herein may 20 contain a stereogenic center.
  • the compounds may exist as different stereoisomeric forms, even though Formula (I) through (III) are drawn without reference to stereochemistry.
  • the present disclosure includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and their non-racemic mixtures as 25 well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art.
  • the compounds described herein, e.g., compounds of Formula (I) 30 through (III), are non-stereogenic.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are racemic.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are enantiomerically enriched (one 107
  • the compounds described herein, e.g., compounds of Formula (I) through (III), are provided as a single diastereomer.
  • the compounds described herein, e.g., compounds of Formula (I) through (III) are provided as a mixture of diastereomers.
  • the mixtures may include equal mixtures, or mixtures which are enriched with a particular diastereomer (one diastereomer is present in a higher percentage than another).
  • a racemic compound e.g., a compound of Formula (I) through (III) may contain about 50% of the R- and S-stereoisomers based on a molar ratio (about 48 to about 10 52 mol %, or about a 1:1 ratio)) of one of the isomers.
  • a pharmaceutical formulation, medicament, or method of treatment may involve combining separately produced compounds of the R- and S-stereoisomers in an approximately equal molar ratio (e.g., about 48 to 52%).
  • a medicament or pharmaceutical formulation may contain a mixture of separate compounds of the R- and S-stereoisomers in different ratios.
  • the pharmaceutical formulation contains an excess (greater than 50%) of the R-enantiomer.
  • Suitable molar ratios of R/S may be from about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher.
  • a pharmaceutical formulation may contain an excess of the S-enantiomer, with the ratios provided for R/S reversed.
  • Other suitable amounts of R/S may be selected.
  • the R-enantiomer may be enriched, e.g., may be present in amounts of at least about 55% to 100%, or 20 at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%.
  • the S-enantiomer may be enriched, e.g., in amounts of at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all these exemplary embodiments as well as greater than and less than them while still within the disclosure, all are included.
  • Pharmaceutical formulations may 25 contain a mixture of the racemate and a separate compound of Formula (I) through (III), in salt form.
  • the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2 receptor.
  • the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT 2A receptor. In some embodiments, the compound of Formula (I) 30 through (III) is an agonist of a serotonin 5-HT 1A receptor. In some embodiments, the compound of Formula (I) through (III) is an agonist of a serotonin 5-HT2C receptor.
  • the tryptamine psychedelic used in the preparation of the pharmaceutical formulation is chemically pure, for example has a purity of greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% by UPLC or HPLC.
  • the tryptamine psychedelic has no single impurity of greater than 1%, greater than 0.5%, greater than 0.4%, 5 greater than 0.3%, or greater than 0.2%, measured by UPLC or HPLC.
  • the tryptamine psychedelic has a chemical purity of greater than 97 area %, greater than 98 area %, or greater than 99 area % by UPLC or HPLC.
  • the tryptamine psychedelic has no single impurity greater than 1 area %, greater than 0.5 area %, greater than 0.4 area %, greater than 0.3 area %, or greater than 0.2 area % as measured by UPLC or HPLC.
  • Acids which may be used to form the pharmaceutically acceptable (acid addition) salts of the compounds disclosed herein, e.g., compounds of Formula (I) through (III), include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-15 hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5- disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic
  • 5 preferred salt forms of the compounds disclosed herein are those that possess one or more of the following characteristics: are easy to prepare in high yield with a propensity towards salt formation; are stable and have well-defined physical properties such as crystallinity, lack of polymorphism, and high melting/enthalpy of fusion; have slight or no hygroscopicity; are free flowing, do not cohere/adhere to surfaces, and possess a 10 regular morphology; have acceptable aqueous solubility for the intended route of administration; and/or are physiologically acceptable, e.g., do not cause irritation when administered to mammals.
  • the pharmaceutically acceptable salt of the compound of the present disclosure may be crystalline or amorphous, 15 preferably crystalline, as determined e.g., by X-ray powder diffraction (XRPD).
  • the pharmaceutically acceptable salt of the compound of the present disclosure is amorphous, e.g., as determined by XRPD and/or DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable amorphous form.
  • a highly pure amorphous form of a pharmaceutically acceptable salt of a compound of the present 20 disclosure is provided, wherein at least 92%, at least 94%, at least 96%, at least 98%, at least 99%, or at least 99.5% by weight of the pharmaceutically acceptable salt of the compound of the present disclosure is in amorphous form, e.g., as determined by X-ray powder diffraction and/or DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure is crystalline. Crystalline forms are advantageous in terms of e.g., stability and 25 providing well-defined physical properties, which is desirable for pharmaceutical preparation and administration.
  • the pharmaceutically acceptable salt of the compound of the present disclosure can be in a stable crystalline form.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a percent crystallinity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or at least 99.5%, and up to 100%, 30 as determined by XRPD and/or DSC analysis.
  • a highly pure crystalline form of a pharmaceutically acceptable salt of a compound of the present disclosure is provided, wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the 110
  • the divergence and scattering slit widths can be set at 2 mm and the detector slit width can be set at 0.2 mm.
  • Diffracted radiation can be detected by a NaI scintillation detector.
  • a theta-two theta 10 continuous scan from 2.0 to 40° (4 seconds per step; 0.01° step size) can be used.
  • advantageous salt forms of the compounds of the present disclosure are those that readily afford a crystalline solid on crystallization in acceptable yield without proceeding via an oil, and with favorable volume factors, making them suitable for mass production.
  • Salts forms of the compound of the present disclosure can in some cases exist in different polymorphs (i.e., forms having a different crystal structure), however, preferred salt forms of the present disclosure are those which can be crystallized into a single crystalline form or single polymorph, as determined by XRPD and/or differential scanning calorimetry (DSC). It is also generally desirable for the salt forms to be free 20 flowing, not cohere/adhere to surfaces, and possess a regular morphology.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a melt onset of from about 100°C, from about 110°C, from about 120°C, from about 130°C, from about 140°C, from about 150°C, from about 160°C, from about 170°C, from about 25 180°C, from about 190°C, and up to about 250°C, up to about 225°C, up to about 210°C, up to about 200°C, as determined by DSC.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has an enthalpy of fusion of from about 90 J ⁇ g -1 , from about 100 J ⁇ g -1 , from about 110 J ⁇ g -1 , from about 120 J ⁇ g -1 , from about 130 J ⁇ g -1 , from about 140 J ⁇ g -1 , from about 150 J ⁇ g -1 , from 30 about 160 J ⁇ g -1 , and up to about 190 J ⁇ g -1 , up to about 180 J ⁇ g -1 , up to about 170 J ⁇ g -1 , as determined by DSC.
  • 111 the pharmaceutically acceptable salt of the compound of the present disclosure has an enthalpy of fusion of from about 90 J ⁇ g -1 , from about 100 J ⁇ g -1 , from about 110 J ⁇ g -1 , from about 120 J ⁇ g -1 , from about 130 J ⁇ g -1 , from about 140 J ⁇ g -1 , from about 150 J ⁇ g -1 , from 30 about 160 J ⁇ g -1 ,
  • Pre-formed pharmaceutically acceptable salts of the compound of the present disclosure suitable for pharmaceutical manufacture may also be characterized as non-hygroscopic or slightly hygroscopic, preferably non-hygroscopic.
  • the hygroscopicity may be measured herein by performing a moisture adsorption-desorption isotherm using a dynamic vapor sorption (DVS) 5 analyzer with a starting exposure of 30% relative humidity (RH), increasing humidity up to 95% RH, decreasing humidity to 0%, and finally increasing the humidity back to the starting 30% RH, and classified according to the following: non-hygroscopic: ⁇ 0.2%; slightly hygroscopic: ⁇ 0.2% and ⁇ 2%; hygroscopic: ⁇ 2% and ⁇ 15%; very hygroscopic: ⁇ 15%; deliquescent: sufficient water is absorbed to form a 10 liquid; all values measured as weight increase (w/w due to acquisition of water) at >95% RH and 25°C.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a weight increase at >95% RH of less than 1% w/w, less than 0.8% w/w, less than 0.6% w/w, less than 0.5% w/w, less than 0.4% w/w, less than 0.3% w/w, less than 0.2% w/w, less 15 than 0.1% w/w, less than 0.08% w/w, less than 0.06% w/w, less than 0.05% w/w, less than 0.02% w/w, as determined by DVS.
  • Pre-formed pharmaceutically acceptable salts of the compounds of the present disclosure can be maintained/stored in open or closed environments, such as in open or closed flasks/vials, under ambient or stress conditions e.g., 25°C/60% RH, 25°C/90+% RH, 40°C/75% RH, etc. 20 without appreciable degradation (e.g., without appreciably diminished chemical purity) or physical changes (e.g., changed forms, deliquesced, etc.).
  • dry powder samples of salt forms disclosed herein may have a purity change or form change of less than 10%, less than 5%, less than 1%, when stored under ambient conditions or stress conditions (e.g., increased temperature, e.g., 40°C, and/or humidity).
  • Suitable salt forms of the compounds of the present disclosure are physiologically acceptable and do not cause excessive irritation or tissue damage at the injection site.
  • preferred pharmaceutical salts of the compounds of the present disclosure are those formed with an organic acid, preferably an organic acid with 30 a mild acidity, for example an organic acid with a pK a in water of no less than 1.0, no less than 1.5, no less than 2.0, no less than 2.5, no less than 3.0, no less than 3.5, no less than 4.0, no less than 4.5, for example, from 3.0 to 6.5. 112
  • aqueous solubility of the pharmaceutical salts of the compounds of the present disclosure can be determined by equilibrating excess solid with 1 mL of water for 24 hours at 22° C. A 200 uL aliquot can be centrifuged at 15,000 revolutions per minute (rpm) for 15 minutes. 5 The supernatant can be analyzed by UPLC or HPLC and the solubility can be expressed as its free base equivalent (mg FB/mL). For example, pharmaceutically acceptable salt forms of the compounds of the present disclosure can be prepared and the solubility and solution pH can be measured.
  • the pharmaceutically acceptable salt of the compound of the present 10 disclosure e.g., a compound of Formula (I) through (III)
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility of from about 1 mg/mL, from about 2 mg/mL, from about 3 mg/mL, from about 5 mg/mL, from about 10 mg/mL, from about 20 mg/mL, from about 30 mg/mL, from about 40 mg/mL, from about 50 mg/mL, from about 60 15 mg/mL, from about 70 mg/mL, from about 80 mg/mL, from about 90 mg/mL, from about 100 mg/mL, from about 110 mg/mL, from about 120 mg/mL, from about 130 mg/mL, from about 140 mg/mL, from about 150 mg/mL, and up to about 400 mg/mL, up to about 380 mg/mL, up to about 360 mg/mL, up to about 340 mg/mL, up to about 320 mg/mL, up to about 300 mg/mL, up to about 280 mg/mL, up to about 260 mg/mL
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 200 mg/mL to about 400 mg/mL. In some embodiments, the pharmaceutically acceptable salt of the compound of the present disclosure has a water solubility from about 150 mg/mL to about 250 mg/mL.
  • the pharmaceutically acceptable salt of the compound of the present disclosure has a 25 water solubility of greater than about 1 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, or 150 mg/mL.
  • the pharmaceutically acceptable salt of the compound of the present disclosure is a fumarate, a benzoate, a salicylate, 30 a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt.
  • preferred pharmaceutically acceptable salts are fumarate salts, hemi-fumarate salts, benzoate salts, 113
  • the pharmaceutically acceptable salt of the compound of the present disclosure e.g., the compound of Formula (I) through (III)
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of N,N- dimethyltryptamine (DMT).
  • DMT N,N- dimethyltryptamine
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT).
  • the 10 pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d10).
  • the 15 pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan- 1-amine-1,1-d2 (a DMT-d8).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- 20 amine-1,1-d 2 (a DMT-d 2 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi- fumarate salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (5- MeO-DMT-d 10 ).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt 25 of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5).
  • the pharmaceutically acceptable salt is a fumarate, a benzoate, a salicylate, a succinate, an oxalate, a glycolate, a hemi-oxalate, or a hemi-fumarate salt of 2-(5-(methoxy-d3)- 1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d13).
  • the pharmaceutically acceptable salt of DMT or a deuterated analog 30 of DMT is a crystalline solid as disclosed in PCT/EP2023/050702, which is incorporated herein by reference in its entirety.
  • DMT-d 10 a deuterated analog 30 of DMT
  • Table 1 Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (II) are provided in Table 1. Table 1.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1a) (i.e., a fumarate salt of compound I-1, depicted below).
  • salt I-1a when salt I-1a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 10 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 10 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1b) (i.e., a 5 benzoate salt of compound I-1 depicted above).
  • salt I-1b when salt I-1b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1c) (i.e., a salicylate salt of compound I-1 depicted above).
  • salt I-1c when salt I-1c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 15 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a succinate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1d) (i.e., a succinate salt of compound I-1 depicted above).
  • salt I-1d when salt I-1d is in a 20 crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuK ⁇ radiation source. 25
  • the pharmaceutically acceptable salt of a compound of the present 116 the pharmaceutically acceptable salt of a compound of the present 116
  • oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (i.e., an oxalate salt of compound I-1 depicted above).
  • salt I-1e when salt I-1e is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 5 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a glycolate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1f) (i.e., a glycolate salt of compound I-1 depicted above).
  • salt I-1f when salt I-1f is in a 10 crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present 15 disclosure is a hemi-oxalate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1g) (i.e., a hemi-oxalate salt of compound I-1 depicted above).
  • salt I-1g when salt I-1g is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 23.5°, 24.5°, 25.0°, 20 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a hemi-fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-1h) (i.e., a hemi-fumarate salt of compound I-1 depicted above).
  • salt I-1h when salt I-1h is in 25 a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 22.3°, 22.7°, 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I- 8a) (i.e., a fumarate salt of compound I-8 depicted below).
  • salt I-8a 117 when salt I-8a 117 is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°, 26.2°, 26.8°, 27.3°, 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 5 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°,
  • salt I-8a when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 10 33.6°, and 34.9°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8a when salt I-8a is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I- 8b) (i.e., a benzoate salt of compound I-8 depicted above).
  • salt I-8b 20 when salt I-8b 20 is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8b when salt I-8b is in a crystalline 25 solid form it is characterized by an X-ray powder diffraction pattern containing at least three 118
  • salt I-8b when salt I-8b is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern 5 containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1° as determined by XRPD using a CuK ⁇ radiation source.
  • the pharmaceutically acceptable salt of a compound of the present disclosure is a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I- 10 8c) (i.e., a salicylate salt of compound I-8 depicted above).
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°, 25.2°, 25.6°, 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 15 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°, as determined by XRPD using a CuK ⁇ radiation source.
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined 20 by XRPD using a CuK ⁇ radiation source.
  • salt I-8c when salt I-8c is in a crystalline solid form it is characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2 ⁇ ⁇ 0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuK ⁇ radiation source. 25
  • Non-limiting examples of pharmaceutically acceptable salts of compounds of Formula (I) and (III) are provided in Table 2. 119 Table 2.
  • the pharmaceutically acceptable salt is hydrochloride salt of N,N- dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a 5 hydrochloride salt of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (DMT-d 10 ).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(1H-indol-3-yl)- 10 N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (a DMT-d8). In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt of 2-(1H-indol-3-yl)-N,N-dimethylethan- 1-amine-1,1-d 2 (a DMT-d 2 ).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ).
  • the pharmaceutically acceptable salt is a hydrochloride 15 salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d 2 (5-MeO-DMT-d 5 ).
  • the pharmaceutically acceptable salt is a hydrochloride salt of 2-(5- (methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d13).
  • Various methods and procedures may be used to prepare pre-formed pharmaceutically acceptable salts of the compounds of the present disclosure, such methods and procedures being 20 generally known to those of ordinary skill in the art.
  • the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure is prepared by: (a) suspending or dissolving a free base of the compound of the present disclosure (e.g., a compound of Formula (I) through (III) in a solvent or mixture of solvents; (b) contacting an acid with the compound of the present disclosure to provide a mixture; 25 (c) optionally heating the mixture; (d) optionally cooling the mixture; and (e) isolating the salt. 121
  • solvents may be used, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof.
  • the solvent(s) is a protic solvent(s).
  • the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxanes (1,4-dioxane), water, tetrahydrofuran 5 (THF), acetonitrile (MeCN), ether solvents (e.g., t-butylmethyl ether (TBME)), hexane, heptane, and octane, and combinations thereof.
  • the solvent is ethanol.
  • Suitable acids for use during the contacting step may include those described heretofore.
  • the acid may be an inorganic acid (e.g., hydrochloric acid) or an organic acid, with organic acids being preferred.
  • the acid is an organic acid selected from the group 10 consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid.
  • the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred.
  • a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the compound of the present disclosure.
  • a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the compound of the present disclosure.
  • the use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt.
  • the mixture is heated, e.g., refluxed, prior to cooling.
  • the mixture is cooled and the salt is precipitated out of the solution.
  • the salt is precipitated out of solution in crystalline form.
  • the salt is precipitated out of solution in amorphous form. Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like.
  • the isolating step includes filtering 25 the mixture. After isolation, additional crystallization and/or recrystallization steps may also optionally be performed, if desired, for example to increase purity, crystallinity, etc.
  • the pharmaceutical formulation may comprise, as the psychopharmaceutical agent, a 30 pharmaceutically acceptable salt of a single compound of the present disclosure (e.g., a single of compound of Formula (I) through (III)) or a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)).
  • the pharmaceutical formulation may contain an isotopologue mixture of compounds of the present disclosure in salt form as the psychopharmaceutical agent.
  • a subject compound of Formula (I) through (III) in salt form may be present in the pharmaceutical formulation at a purity of at least 20% by weight, at least 30% by weight, at least 5 40% by weight, at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, based on a total weight of the isotopologue mixture of compounds of Formula (I) through (III) in salt form present in the pharmaceutical formulation.
  • a pharmaceutical formulation formulated with a DMT-d 10 salt (salt form of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 ), 10 as the subject compound in salt form, may additionally contain isotopologues of the subject compound in salt form, e.g., DMT-d9 salt, a DMT-d8 salt, etc.
  • the pharmaceutical formulation is substantially free of other isotopologues of the subject compound in salt form, e.g., the pharmaceutical formulation has less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 or 0.5 mole percent of other isotopologues of the subject compound in salt form.
  • the injectable pharmaceutical formulation comprises, as the psychopharmaceutical agent, a pharmaceutically acceptable salt of a mixture of compounds of the present disclosure (e.g., a mixture of compounds of Formula (I) through (III)), that mixture may be referred to herein an “active salt mixture”.
  • the active salt mixture is a fumarate salt mixture, wherein the salt forms recited are fumarate salts.
  • the active salt mixture is 20 a benzoate salt mixture, wherein the salt forms recited are benzoate salts.
  • the active salt mixture is a salicylate salt mixture, wherein the salt forms recited are salicylate salts.
  • the active salt mixture is a succinate salt mixture, wherein the salt forms recited are succinate salts.
  • the pharmaceutical formulation comprises an active salt mixture 25 comprising: (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol- 3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a pharmaceutically30 acceptable salt of
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt 5 mixture, of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8).
  • a pharmaceutically acceptable salt of DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 10 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • a pharmaceutically acceptable salt of DMT-d9 i.e., a pharmaceutically acceptable salt of one or more
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by 15 weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I- 6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)- 20 N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d 4 (I-8); and (ii) a pharmaceutically acceptable salt of DMT-d 9 , i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 25 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a pharmaceutically acceptable salt of DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) from 90% to 99% by weight of a pharmaceutically acceptable salt of DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 1,1,2,2-d 4 (I-8), or any range therebetween, based on a total weight of the active salt mixture; and 30 (ii) from 1% to 10% by weight, in sum, of a pharmaceutically acceptable salt of DMT-d 9 , i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- a mine-1,2,2-d 3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11), 124
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of: (1) a pharmaceutically acceptable salt of DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(1H-indol-3-yl)-N,N- 5 bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine- 2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12); (2) a pharmaceutically acceptable salt of DMT-d7; (3) a pharmaceutically acceptable salt of DMT-d6 (a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N,N
  • a weight, in sum, of pharmaceutically acceptable salts of isotopologues of DMT not listed in (i) or (ii), such as those listed in (1) through (9), is less than 1% by weight, less than 0.75% by weight, less than 0.5% by weight, less than 0.4% by weight, less than 0.3% by weight, less than 0.25% by weight, less than 0.2% by weight, less than 0.1% by weight, or 0% by weight, based on a total weight of the active 20 salt mixture.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a fumarate salt of DMT-d 10 , i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a fumarate salt of DMT-d 9 , i.e., a fumarate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- 25 (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a fumarate salt of DMT-d 8 , i.e., a fumarate salt of one or more of 2-(1H-indol
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 30 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a fumarate salt 125
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% 5 by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a fumarate salt of DMT-d 9 , i.e., a fumarate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-ind
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less 10 than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a fumarate salt of DMT-d 8 , i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a fumarate salt of DMT-d 10 , i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a fumarate salt of DMT-d9, i.e., a fumarate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • DMT-d 10 i.e., a fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a benzoate salt of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a benzoate salt of DMT-d 9 , i.e., a benzoate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11); and optionally (iii) a benzoate25 salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by 30 weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a benzoate salt o f DMT-d 10 , i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- 126
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the 5 active salt mixture, of (ii) a benzoate salt of DMT-d9, i.e., a benzoate salt of one or more of 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a benzoate salt of DMT-d9 i.e., a benzoate salt of one or more of 2-
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, 10 less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a benzoate salt of DMT-d8, i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a benzoate salt15 of DMT-d10, i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d 4 (I-8); and (ii) a benzoate salt of DMT-d 9 , i.e., a benzoate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a benzoate salt15 of DMT-d10 i.e., a benzoate salt of 2-(1H-indol-3-yl)-N,N-bis
  • the pharmaceutical formulation comprises an active salt mixture20 comprising: (i) a salicylate salt of DMT-d 10 , i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-8); (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3-yl)
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, 30 or any range therebetween, based on a total weight of the active salt mixture, of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2- d4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by 127
  • a salicylate salt of DMT-d9 i.e., a salicylate salt of one or more of 2- 5 (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt10 mixture, of (iii) a salicylate salt of DMT-d8, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d 2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2-d 2 (I-12).
  • the active salt mixture consists of or consists essentially of (i) a salicylate salt of DMT-d10, i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-15 d4 (I-8); and (ii) a salicylate salt of DMT-d9, i.e., a salicylate salt of one or more of 2-(1H-indol-3- yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d3)ethan-1-amine-1,1,2-d3 (I-11).
  • a salicylate salt of DMT-d10 i.e., a salicylate salt of 2-(1H-indol-3-yl)-N,N-bis
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a succinate salt of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N- 20 bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-8); (ii) a succinate salt of DMT-d 9 , i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-11); and optionally (iii) a succinate salt of DMT-d 8 , i.e., a succinate salt of one or more of 2-(1H-indol-3-yl)-N,
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a succinate salt30 of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8).
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 128
  • a succinate salt of DMT-d 9 i.e., a succinate salt of one or more of 2- (1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N- 5 bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-11).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a succinate salt of DMT-d 8 , i.e., a succinate salt of one or more of 2-(1H-indol-3-10 yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-2,2-d2 (I-7), and/or 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2 (I-12).
  • a succinate salt of DMT-d 8
  • the active salt mixture consists of or consists essentially of (i) a succinate salt of DMT-d 10 , i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2- d4 (I-8); and (ii) a succinate salt of DMT-d9, i.e., a succinate salt of one or more of 2-(1H-indol-3-15 yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-10) and/or 2-(1H-indol-3-yl)-N,N-bis(methyl- d 3 )ethan-1-amine-1,1,2-d 3 (I-11).
  • a succinate salt of DMT-d 10 i.e., a succinate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan- 1-amine-1,1-d 2 (I-6); (ii) a pharmaceutically acceptable salt of DMT-d 7 , i.e., a pharmaceutically 20 acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1-d; and optionally (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2-(1H- indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine (I-4).
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% 25 to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6).
  • the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 30 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d7, i.e., a pharmaceutically acceptable salt of 2-(1H- 129
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of 5 (iii) a pharmaceutically acceptable salt of DMT-d6, i.e., a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine (I-4).
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-6); and (ii) a pharmaceutically acceptable salt of DMT-d 7 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- 10 amine-1-d.
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1- amine-1,1-d 2 (I-2); (ii) a pharmaceutically acceptable salt of DMT-d 1 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d; and optionally (iii) a15 pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol- 3-yl)-N,N-dimethylethan-1-amine.
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween,20 based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 2- (1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-2).
  • the active salt mixture comprises from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range 25 therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of DMT-d 1 , i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine-1-d.
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any 30 range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of DMT, i.e., a pharmaceutically acceptable salt of 2-(1H-indol-3-yl)-N,N- dimethylethan-1-amine.
  • the active salt mixture consists of or consists 130
  • the pharmaceutical formulation comprises an active salt mixture 5 comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I- 20); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23); and 10 optionally (iii) a pharmaceutically acceptable salt of 5-Me
  • the active salt mixture comprises from 60% to 99% by weight, from 60% to 98% 15 by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d10, i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-20).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d10 i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d9, i.e., a pharmaceutically acceptable25 salt of one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I- 22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based30 on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO- DMT-d8, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol-3-yl)- N ,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-18), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- 131
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d8, i.e., a pharmaceutically acceptable salt of 5 one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (I-18), 2- (5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-2,2-d 2 (I-19), and 2-(5-methoxy- 1H-indol-3-yl)-N,N-bis(methyl-d3)e
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO- DMT-d 10 , i.e., a pharmaceutically acceptable salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-10 bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (I-20); and (ii) a pharmaceutically acceptable salt of 5- MeO-DMT-d9, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-methoxy-1H-indol- 3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-22) and/or 2-(5-methoxy-1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,1,2-d 3 (I-23).
  • a pharmaceutically acceptable salt of 5-MeO- DMT-d 10 i.e
  • the pharmaceutical formulation comprises an active salt mixture 15 comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (I-34); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,2,2-d 3 (I-36) and/or 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1- 20 amine-1,1,2-d 3 (I-37);
  • the active salt mixture comprises from 60% to 99% 25 by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d13, i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan- 30 1-amine-1,1,2,2-d 4 (I-34).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d13 i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, 132
  • a pharmaceutically acceptable salt of 5-MeO-DMT- d 12 i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)- N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 (I-36) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- 5 bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I-37).
  • the active salt mixture comprises, in sum, from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 11 , i.e., a pharmaceutically10 acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1-d2 (I-32), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d 3 )-1H-indol-3-y
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt15 of 5-MeO-DMT-d11, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)- 1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1-d 2 (I-32), 2-(5-(methoxy-d 3 )-1H-indol-3- yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2 (I-33), and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,2-d2 (I-38).
  • a pharmaceutically acceptable salt15 of 5-MeO-DMT-d11 i.e., a pharmaceutically acceptable salt of one or more of 2-(5-
  • the active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 13 , i.e., a20 pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan- 1-amine-1,1,2,2-d4 (I-34); and (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d12, i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N- bis(methyl-d 3 )ethan-1-amine-1,2,2-d 3 (I-36) and/or 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N- bis(methyl-d3)ethan-1-amine-1,1,2-d3 (I)
  • the pharmaceutical formulation comprises an active salt mixture comprising: (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine- 1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2 (I-29); (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 4 , i.e., a pharmaceutically acceptable salt 30 of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-d3)-1H
  • the active salt mixture comprises, in sum, from 60% to 99% by weight, from 60% to 98% by weight, from 65% to 97% by weight, from 70% to 96% by weight, from 75% to 95% by weight, from 80% to 94% by weight, from 85% to 93% by weight, from 90% to 92% by weight, from 90% 5 to 99% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (i) a pharmaceutically acceptable salt of 5-MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I- 28) and/or 2-(5-(methoxy-d3)-1H-
  • the active salt mixture comprises, in sum, from 1% to 40% by weight, from 2% to 10 40% by weight, from 3% to 35% by weight, from 4% to 30% by weight, from 5% to 25% by weight, from 6% to 20% by weight, from 7% to 15% by weight, from 8% to 10% by weight, from 1% to 10% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (ii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 4 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d (I-26) 15 and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d (I-27).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d 4
  • the active salt mixture comprises from 0% by weight to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, based on a total weight of the active salt mixture, of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 ,20 i.e., a pharmaceutically acceptable salt of 2-(5-(methoxy-d 3 )-1H-indol-3-yl)-N,N-dimethylethan- 1-amine (I-25).
  • the active salt mixture contains no detectable amount of, or is otherwise substantially free of (iii) a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 , i.e., a pharmaceutically acceptable salt of 2- (5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25).
  • a pharmaceutically acceptable salt of 5-MeO-DMT-d 3 i.e., a pharmaceutically acceptable salt of 2- (5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (I-25).
  • the25 active salt mixture consists of or consists essentially of (i) a pharmaceutically acceptable salt of 5- MeO-DMT-d 5 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H- indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (I-28) and/or 2-(5-(methoxy-d3)-1H-indol-3-yl)- N,N-dimethylethan-1-amine-2,2-d2 (I-29); and (ii) a pharmaceutically acceptable salt of 5-MeO- DMT-d 4 , i.e., a pharmaceutically acceptable salt of one or more of 2-(5-(methoxy-d 3 )-1H-indol-3-30 yl)-N,N-dimethylethan-1-amine-1-d (I-26) and/or 2-(5-(methoxy-
  • the pharmaceutical formulation comprises a therapeutically effective amount of the 5 psychopharmaceutical agent.
  • the pharmaceutical formulation comprising the psychopharmaceutical agent typically contains a free base dose (free base equivalence when a salt form is used) of about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 25 mg, about 10 30 mg, about 40 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, or any range therebetween.
  • a free base dose free base equivalence when a salt form is used
  • a pharmaceutical formulation prepared with 40.4 mg of DMT fumarate (molar mass of 304.34 g/mol) would have a free base equivalence of DMT (molar mass of 188.27 g/mol) of about 25 mg as the unit dose.
  • the pharmaceutical formulation can, if desired, also contain other compatible therapeutic agents.
  • the pharmaceutical formulations may have a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of pharmaceutical formulation of about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 20 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg
  • a pharmaceutical formulation prepared from 40.4 mg of DMT fumarate (molar mass of 304.34 g/mol) in 1 mL of total volume of pharmaceutical formulation would have a free base concentration of psychopharmaceutical agent (in this example DMT free base; molar mass of 188.27 g/mol), of about 25 mg/mL.
  • free base concentrations of psychopharmaceutical agent below about 70 mg/mL 30 provide advantageous controlled-release profiles across the broadest range of release modifier molecular weight and release modifier concentrations.
  • difficulties with the pharmaceutical formulation may be encountered at free base concentrations of about 70 mg/mL 135
  • the free base concentration of psychopharmaceutical agent e.g., tryptamine psychedelic such as a compound 15 of Formula (I) through (III)
  • the free base concentration of psychopharmaceutical agent is typically kept below about 70 mg/mL, below about 65 mg/mL, below about 60 mg/mL, below about 55 mg/mL, with 10 to 50 mg/mL being preferred.
  • tryptamine psychedelics with longer half-lives, such as deuterated tryptamine psychedelics may provide significant advantages over their non-deuterated counterparts, 20 especially in subcutaneous dosage forms.
  • a therapeutically relevant psychedelic dose of DMT may be in the range of about 70 mg or higher (free base),25 whereas for deuterated analogs of DMT such as 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1- amine-1,1,2,2-d 4 (DMT-d 10 ) less drug (e.g., 10 to 50 mg, 15 to 50 mg, 20 to 40 mg, 30 to 50 mg, free base) may be needed to maintain desired blood concentrations owing to its longer half-life in vivo.
  • the lower dosing requirements of deuterated analogs of DMT such as DMT-d10 allow for lower concentrations of release modifier to be used to achieve desirable controlled-release profiles, 30 and for lower injection volumes. Release
  • the pharmaceutical formulation comprises a release modifier.
  • the release modifier is the component primarily responsible for providing a controlled, tunable, and linear release of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) upon injection of the pharmaceutical formulation, 5 such as upon subcutaneous injection.
  • the psychopharmaceutical agent e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier acts by thickening and building viscosity of the pharmaceutical formulation, while potentially also providing electrostatic attraction with the psychopharmaceutical agent, such that upon injection the psychopharmaceutical agent can be slowly released from the injection site (e.g., in the case of subcutaneous injection, within the fat or the layer of skin directly below the dermis 10 and epidermis) and absorbed more slowly, generating a depot-like release effect.
  • the release modifier may be a polymeric material, such as a hyaluronate salt or a carboxymethyl cellulose salt, which may, or may not, be crosslinked.
  • the rate of release of the psychopharmaceutical agent can be controlled through cross-linking or the lack thereof, or the extent of cross-linking of the release modifier.
  • Release modifiers which are not cross-linked will typically provide a shorter release 15 profile than those which are crosslinked, with crosslinking capable of extending the release significantly, such as over the course of a day or multiple days.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier is generally not crosslinked so as not to overextend the release 20 period.
  • the release modifier is considered a separate component from the psychopharmaceutical agent.
  • the release modifier is also considered a separate component from the pharmaceutically acceptable additive(s) described hereinafter (such as a buffering agent, a tonicity agent, a pH adjusting agent, etc.) when such pharmaceutically acceptable additives are included in the pharmaceutical formulation of the present disclosure, even though the release 25 modifier may perform a similar function to a particular additive(s).
  • the release modifier is considered different from a tonicity agent even though the release modifier contributes to the overall osmolality of the pharmaceutical formulation.
  • the release modifier is considered different from a buffering agent or a pH adjusting agent, even though the release modifier may influence the pH of the pharmaceutical formulation.
  • the release modifier is a hyaluronate salt (anionic salt form of hyaluronic acid), which is non-sulfated glycosaminoglycan and long- 137
  • Hyaluronate salts are biocompatible and are distributed widely throughout human connective, epithelial, and neural tissues.
  • the hyaluronate salt may include, but is not limited to, a sodium salt of hyaluronate (sodium hyaluronate), a potassium salt of hyaluronate (potassium hyaluronate), a calcium salt of 5 hyaluronate (calcium hyaluronate), a zinc salt of hyaluronate (zinc hyaluronate), and a magnesium salt of hyaluronate (magnesium hyaluronate), or a combination thereof.
  • the release modifier is sodium hyaluronate.
  • the hyaluronate salt may be produced by a microbial fermentation and purification process and is preferably pharmacopoeia compliant.
  • hyaluronate salts are known to be heat sensitive, and so cannot 10 be typically sterilized by thermal sterilization methods such as steam sterilization, dry-heat sterilization/depyrogenation, etc., which can cause polymer degradation. Instead, hyaluronate salts are sterilized by sterile filtration such as sterile filtration through a 0.25 ⁇ m filter size or less.
  • hyaluronate salts may be optionally sterilized with a secondary sterilization process such as ethylene oxide (ETO) gas sterilization or gamma sterilization under less harsh 15 conditions.
  • ETO ethylene oxide
  • the hyaluronate salt is a native hyaluronate salt, meaning it is not substituted, modified with pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the native hyaluronate salt possesses unmodified disaccharide units of glucuronate-N-acetylglucosamine. Examples may include, but are not limited to, sodium 20 hyaluronate products available from Lifecore Biomedical, Inc.
  • the hyaluronate salt is a non-native hyaluronate salt, i.e., those that are substituted, modified with pendant groups, conjugated, crosslinked, deacetylated, or otherwise covalently modified.
  • the non-native hyaluronate salts may be, inter alia, acetylated, deacetylated, alkylated, esterified, amidated, hydrazidated, epoxy grafted, silylated, sulfated, and/or crosslinked 25 hyaluronate salts. These modifications such as crosslinking may enable the formation of hydrogels of hyaluronate salts.
  • the degree of modification or substitution in non-native hyaluronate salts is typically about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any range therebetween.
  • non-native hyaluronate salts include, but are not limited to, sodium hyaluronate salts modified with pendant tyramine groups (an amidated hyaluronate salt) whereby 30 tyramine is introduced onto glucuronate units using amide bond chemistry (EDC chemistry); and Corgel® BioHydrogel products available from Lifecore Biomedical, Inc., whereby the tyramine substituted sodium hyaluronate (TS-NaHy) from above is subsequently cross-linked by forming 138
  • hyaluronate salts While crosslinked or hydrogels of hyaluronate salts may be employed in some cases, for the delivery of tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) in which a controlled-release is sought that provides 5 a duration of peak effects of about 30 to 120 minutes, the hyaluronate salt is generally not crosslinked or in hydrogel form so as not to overextend the release period and the resulting duration of peak effects beyond about 120 minutes.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the weight average molecular weight (Mw) of the hyaluronate salt may be about 500 kDa, about 550 kDa, about 600 kDa, about 650 kDa, about 700 kDa, about 750 kDa, about 800 kDa, 10 about 850 kDa, about 900 kDa, about 950 kDa, about 1,000 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 kDa, about 1,800 kDa, about 1,900 kDa, about 2,000 kDa, or any range therebetween such as from about 500 kDa to about 2,000 kDa, from about 600 kDa to about 1,500 kDa, from about 750 kDa to about 1,000 kDa, from about 1,000 kDa to about 2,000 kDa, from about 1,000
  • a weight average molecular weight of the hyaluronate salt which is above the aforementioned upper limit may result in pharmaceutical formulations which are too viscous, thereby complicating the sterile filtration process and resulting in painful injections, especially in the case of subcutaneous injections.
  • hyaluronate salts with a weight average molecular weight above the aforementioned upper limit may provide a release profile which is too slow for achieving the desired peak effects time course of about 30 to 120 minutes in the case of some tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)).
  • hyaluronate salts with a weight average molecular weight below the aforementioned lower limit 25 may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier.
  • the hyaluronate salt has a molecular weight range in between about 500 kDa, about 600 kDa, about 700 kDa, about 800 kDa, about 900 kDa, about 1,000 kDa, about 1,100 kDa, about 1,200 kDa, about 1,300 kDa, about 1,400 kDa, about 1,500 kDa, about 1,600 kDa, about 1,700 30 kDa, about 1,800 kDa, about 1,900 kDa, and about 2,000 kDa, or any intermediate range between any of these values.
  • the hyaluronate salt has a molecular weight range of about 500 kDa to about 2,000 kD
  • the hyaluronate salt has a molecular weight range of about 500 kDa to about 750 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,000 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 750 kDa to about 1,500 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 1,000 kDa to about 1,800 5 kDa. In some embodiments, the hyaluronate salt has a molecular weight range of about 900 kDa to about 1,400 kDa.
  • hyaluronate salts include, but are not limited to, sodium hyaluronate products HA700K (molecular weight range of 500 – ⁇ 750 kDa), HA1M (molecular weight range 10 of 750 – 1,000 kDa), and HA15M (molecular weight range of >1,000 – 1,800 kDa), available from Lifecore Biomedical, Inc., and Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa) available from Bloomage Freda Biopharm Co. Ltd.
  • a concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.02%, about 0.03%, about 0.04%, 15 about 0.05%, about 0.06%, about 0.08%, about 0.09%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 20 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • a release is sought that provides a peak effects time course of about 30 to 120 minutes
  • too high a concentration of hyaluronate salt may overextend the release profile and the resulting duration of peak effects beyond about 120 minutes, which is not clinically favorable as it would necessitate prolonged 30 supervised clinical observation.
  • the concentration of hyaluronate salt preferably does not exceed about 1%, about 0.95%, about 0.9%, about 0.85%, about 0.8%, about 0.75%, about 0.7%, about 0.65%, about 0.6%, about 0.55%, about 0.5% w/v. 140
  • the concentration of hyaluronate salt is from about 0.1% to about 0.5% w/v. Attempts to lower the concentration of hyaluronate salt by dilution (increasing injection volume) may not be possible in subcutaneous dosage forms, for example, since higher injection volumes, especially those above 3 mL, are associated with pain at the injection site. Conversely, 5 hyaluronate salt concentrations which are below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier.
  • a ratio of free base concentration of psychopharmaceutical agent (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per 10 total volume of pharmaceutical formulation (mg/mL), to the concentration of hyaluronate salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, about 105:1, about 110:1, about 115:1, about 120:1, about 15 125:1, about 130:1, or any range therebetween, such as from about 10:1 to about 130:1, about 15:1 to about 120:1, about 20:1 to about 110:1, or about 25:1 to about 100:1.
  • ratios below the aforementioned lower limit may result in pharmaceutical formulations with a 20 release profile which is overextended (too slow) in terms of clinical practicality. Ratios above the aforementioned upper limit tend to provide a release that is not meaningfully different from formulations lacking release modifier (too fast).
  • a ratio of the weight average molecular weight (Mw) of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free 30 base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 17:1, about 18:1, about 19:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 141
  • Ratios below the aforementioned lower 5 limit may result in pharmaceutical formulations with a release profile similar to those which are formulated without any release modifier (too fast), whereas ratios above the aforementioned upper limit may overextend the release (too slow) and the resulting duration of peak effects, which is not favorable in the case of certain tryptamine psychedelics (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)).
  • a ratio of the weight average molecular weight of the hyaluronate salt (in kDa) to a free base concentration of psychopharmaceutical agent, in terms of weight per total volume of pharmaceutical formulation (mg/mL), is preferably about 30:1, about 31:1, about 32:1, about 33:1, about 34:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 15 65:1, about 70:1, about 75:1, about 80:1, about 85:1, about 90:1, about 95:1, about 100:1, or any range therebetween, such as from about 35:1 to about 100:1, about 40:1 to about 100:1, about 42:1 to about 80:1, about 44:1 to about 60:1, or about 45:1 to about 55:1.
  • the release modifier is a carboxymethyl cellulose salt, which is a 20 cellulose derivative with carboxymethyl groups (-CH 2 COO-) bound to some of the hydroxyl groups of the glucopyranose monomers that make up the cellulose backbone.
  • the carboxymethyl cellulose salt may include, but is not limited to, a sodium salt of carboxymethyl cellulose (sodium carboxymethyl cellulose).
  • the carboxymethyl cellulose salt may be produced by reacting alkali cellulose with sodium monochloroacetate, and this reaction may be 25 performed under rigidly controlled conditions to control the degree of substitution (DS), which is the average number of hydroxyl groups of the glucopyranose monomers that are carboxymethylated, with the theoretical limit being a DS of 3.0.
  • the resultant polymer is purified and dried for pharmacopoeia compliance.
  • the carboxymethyl cellulose salt is not substituted, modified with 30 pendant groups, conjugated, crosslinked, or otherwise covalently modified. Rather, the carboxymethyl cellulose salt possesses a cellulose backbone formed from glucopyranose monomers which are substituted only with carboxymethyl groups. For example, in some 142
  • the carboxymethyl cellulose salt is not crosslinked with glycolic acid to form a croscarmellose salt such as sodium croscarmellose.
  • the carboxymethyl cellulose salt may have a degree of substitution (DS) of 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.05, 1.1, 1.15, 1.2, or any range therebetween, such as from 0.45 to less than 5 0.9, from 0.9 to less than 1.2, or from 1.2 to 1.5.
  • the carboxymethyl cellulose salt has a DS of 0.85 to 1.15 or 0.9 to 1.0.
  • the weight average molecular weight (Mw) of the carboxymethyl cellulose salt is typically below about 500 kDa, for example, about 50 kDa, about 60 kDa, about 70 kDa, about 80 kDa, about 90 kDa, about 100 kDa, about 110 kDa, about 120 kDa, about 130 kDa, about 140 kDa, 10 about 150 kDa, about 160 kDa, about 170 kDa, about 180 kDa, about 190 kDa, about 200 kDa, about 210 kDa, about 220 kDa, about 230 kDa, about 240 kDa, about 250 kDa, about 300 kDa, about 350 kDa, about 400 kDa, about 450 kDa, or any range therebetween, such as from about 90 kDa to about 300 kDa, from about 100 kDa to about 300 kDa, from
  • a weight average molecular weight of the 15 carboxymethyl cellulose salt which is above the aforementioned upper limit generally results in pharmaceutical formulations that exceed viscosity specifications for being injectable and syringeable, and are not generally approved by the Food & Drug Administration (FDA) for use in injectables.
  • FDA Food & Drug Administration
  • suitable carboxymethyl cellulose salts are typically those with a Brookfield viscosity, measured as 2% aqueous solutions using spindle number 3 at 30 rpm, of 20 from about 400 cP, about 600 cP, about 800 cP, about 1,000 cP, about 1,200 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, about 2,500 cP, about 2,750 cP, about 3,000 cP, about 3,100 cP, or any range therebetween, such as from about 400 cP to about 3,100 cP or about 1,500 cP to about 3,100 cP.
  • the carboxymethyl cellulose salt may include, but are not limited to, 25 AqualonTM and BlanoseTM sodium carboxymethyl cellulose products available from Ashland, such as AqualonTM/BlanoseTM grades 9M8F PH, 9M8XF, 9M31F PH, 9M31XF PH, and 7MF PH.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 143
  • carboxymethyl cellulose salt which exceed the aforementioned upper limit provide pharmaceutical formulations which are too viscous for sterile filtration, injectability, and/or 5 syringeability, for example may cause increased pain at the injection site.
  • carboxymethyl cellulose salt concentrations which are below the aforementioned lower limit may not provide any meaningful controlled-release effects, and the pharmaceutical formulation may instead behave similarly to those which are formulated without any release modifier.
  • a ratio of free base concentration of psychopharmaceutical agent, 10 (e.g., a free base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), to the concentration of carboxymethyl cellulose salt by weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v) is about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 35:1, about 40:1, about 45:1, about 50:1, about 55:1, about 60:1, about 65:1, about 70:1, about 75:1, about 15 80:1, about 85:1, about 90:1, about 95:1, about 100:1, or any range therebetween, such as from about 10:1 to about 100:1, about 13:1 to about 90:1, about 15:1 to about 75:1, or about 20:1 to about 50:1.
  • a ratio of the weight average molecular weight of the carboxymethyl cellulose salt (in kDa) to a free base concentration of psychopharmaceutical agent, (e.g., a free 20 base concentration of a compound of Formula (I) through (III)), in terms of weight per total volume of pharmaceutical formulation (mg/mL), is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 8:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48:1, about 50:1, or any range 25 therebetween, such as from about 1:1 to about 50:1, about 5:1 to about 40:1, about 10:1 to about 30:1, about 15:1 to about 20:1, or about 1:1 to about 10:1.
  • Aqueous vehicle The pharmaceutical formulation comprises an aqueous vehicle.
  • vehicle herein 30 refers to a diluent, adjuvant, excipient, carrier, and/or any other auxiliary or supporting ingredient with which a psychopharmaceutical agent and release agent of present disclosure is formulated for administration to a mammal.
  • aqueous vehicles include, but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. 5
  • the aqueous vehicle, and thus the pharmaceutical formulation may optionally contain one or more pharmaceutically acceptable additives, as desired/needed.
  • “Pharmaceutically acceptable additives” may be diluents, adjuvants, excipients, carriers, or any other auxiliary or supporting ingredient approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for 10 use in mammals, such as humans.
  • Examples of pharmaceutically acceptable additives include, but are not limited to, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, 20 glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide, or a combination thereof.
  • Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain 25 triglycerides of coconut oil, and palm seed oil, or a combination thereof.
  • Antimicrobial agents or preservatives include, but are not limited to, phenols (e.g., phenol), cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl-, ethyl-, and propyl-parabens, benzoic acid, sodium benzoate, and sorbic acid, or a combination thereof.
  • phenols e.g., phenol
  • cresols cresols
  • mercurials e.g., benzyl alcohol
  • chlorobutanol methyl and propyl p-hydroxybenzates
  • thimerosal benzalkonium chloride
  • benzethonium chloride methyl-, ethyl-, and propyl-parabens
  • benzoic acid sodium benzoate
  • sorbic acid or a combination thereof.
  • Stabilizing agents include, but are not limited to, fatty acids, fatty alcohols, alcohols, long chain fatty acid esters, long chain ethers, hydrophilic derivatives of fatty acids, polyvinyl pyrrolidones, polyvinyl ethers, polyvinyl alcohols, glycerol, methionine, monothioglycerol, 145
  • fatty acids may act as lipid carriers.
  • the fatty acid may have from 4 to 30 carbon atoms, 6 to 28 carbon atoms, 8 to 24 carbon atoms, 10 to 20 carbon atoms, or 12 to 18 carbon atoms.
  • the fatty acid may be a fatty monoacid or a fatty diacid.
  • Exemplary fatty acids may include, but are 5 not limited to, adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, arachidic acid, behenic acid, lignoceric acid, palmitolic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and combinations thereof.
  • the pharmaceutical formulation is formulated without a fatty acid to prevent hydrogel formation and an overextended release (for an example of a hydrogel that generates a release over days, see Kang NW, et al. Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin. Pharmaceutics.2021 Jun 11;13(6):864).
  • a tonicity agent is a chemical that, on inclusion within a pharmaceutical formulation, modulates the osmolality of the pharmaceutical formulation.
  • the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation provides a desired osmolality, and so no tonicity agent is needed/included.
  • the concentration of psychopharmaceutical agent and the release modifier in the pharmaceutical formulation does 20 not provide the osmolality specifications for injection, and so one or more tonicity agents may be included to reach a desired osmolality.
  • the pharmaceutical formulation comprises a tonicity agent
  • the concentration of the tonicity agent will be adjusted considering the osmolality contributions from the concentrations of psychopharmaceutical agent and the release modifier to provide a pharmaceutical formulation with a desirable osmolality range (e.g., 150 to 600 25 mOsm/kg).
  • Tonicity agents include, but are not limited to, sodium chloride; potassium chloride; calcium chloride; magnesium chloride; dextrose; glucose; mannitol; lactose; sorbitol; sucrose; alanine; ethanol; benzyl alcohol; creatinine; glycine; glycerol; histidine; polyethylene glycol; propylene glycol; sodium bicarbonate; sodium hydroxide; hydrochloric acid; phosphoric acid; a phosphate salt such as sodium phosphate or potassium phosphate; acetic acid; an acetate salt such 30 as sodium acetate, potassium acetate, or ammonium acetate; citric acid; a citrate salt such as sodium citrate or potassium citrate; arginine; ascorbic acid; an ascorbate salt such as potassium ascorbate or sodium ascorbate; edetic acid; an edetate salt such as sodium edetate or calcium 146
  • the tonicity agent is at least one selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, magnesium chloride, 5 dextrose, glucose, mannitol, lactose, sorbitol, sucrose, and sodium lactate.
  • the tonicity agent is sodium chloride.
  • the pharmaceutical formulation comprises sodium chloride at a concentration, in terms of weight per total volume of the pharmaceutical formulation expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, or any range therebetween such as from 10 about 0.1% to about 0.6%, about 0.2% to about 0.55%, about 0.3% to about 0.5% w/v.
  • a buffering agent is a chemical that on inclusion into the pharmaceutical formulation comprises a weak acid and its conjugate base in equilibrium, which resist changes in pH on addition of acid or base to the pharmaceutical formulation.
  • the buffering agent is considered a separate component from the psychopharmaceutical agent (e.g., a pharmaceutically acceptable salt of a compound of the present disclosure such as a 20 pharmaceutically acceptable salt of a compound of Formula (I) through (III)). In this sense, the buffering agent is not merely a counterion to the protonated form of the compound of the present disclosure.
  • the buffering agent when included, provides a buffering effect to resist changes in pH above that which may be provided by the psychopharmaceutical agent.
  • the buffering agent is also considered a separate component from the release modifier, and again, provides a buffering 25 effect to resist changes in pH above that which may be provided by the release modifier.
  • a suitable buffer is optionally selected that comprises an acid with a pKa value (or an acid having 147
  • the pharmaceutical formulation is not formulated with a buffering agent.
  • Antioxidants include, but are not limited to, bisulfite and sodium metabisulfite, ascorbic 5 acid, citric acid, tartaric acid, thiol derivatives, or combinations thereof.
  • the pharmaceutical formulation has an oxygen content of less than 2 ppm, such as between 0.1 ppm and 2 ppm.
  • Local anesthetics include, but are not limited to, procaine hydrochloride.
  • Complexing agents include, but are not limited to, cyclodextrins, including ca- 10 cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether- ⁇ -cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.), or combinations thereof.
  • Sequestering or chelating agents include, but are not limited to EDTA.
  • pH adjusting agents include, but are not limited to, sodium hydroxide, potassium 15 hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid, or combinations thereof.
  • Absorption enhancers include, but are not limited to, a hyaluronidase enzyme. In pharmaceutical formulations containing a hyaluronate salt, the hyaluronidase enzyme may have the added effect of breaking down the hyaluronate salt to speed drug release in cases where 20 increased release rates are desired.
  • This additive may be added to the pharmaceutical formulation immediately prior to injection or may be injected separately as part of a multi-component injection, such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up.
  • the pharmaceutical formulation does not contain a hyaluronidase enzyme, nor is a hyaluronidase enzyme employed during or post injection of the pharmaceutical formulation.
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • a pharmaceutically acceptable salt of a compound of Formula (I) through (III) the release modifier
  • an aqueous vehicle made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the 30 pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of water for injection, optionally a 148
  • the psychopharmaceutical agent e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the release modifier e.g., a tryptamine psychedelic
  • an aqueous vehicle made up of water for injection, optionally a 148
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of water for 5 injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle does not contain a tonicity agent such as sodium chloride.
  • a pH adjusting agent e.g., sodium hydroxide
  • the pharmaceutical formulation comprises the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and an aqueous vehicle made up of water for injection or 10 saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the pharmaceutical formulation is formulated without a buffering agent.
  • a pharmaceutically acceptable salt of a compound of Formula (I) through (III) e.g., a tryptamine psychedelic
  • the release modifier e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • an aqueous vehicle made up of water for injection or 10 saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the pharmaceutical formulation is formulated without a buffering agent.
  • a pH adjusting agent e.g., sodium hydroxide
  • the pharmaceutical formulation consists of, or consists essentially of, the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)); the release modifier; and water and optional tonicity agent (e.g., sodium chloride) 15 as the aqueous vehicle.
  • the psychopharmaceutical agent e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • water and optional tonicity agent e.g., sodium chloride
  • consists essentially of it is meant that the presence of additional components within the pharmaceutical formulation is permitted, provided the amounts of such additional components do not materially affect the essential characteristics of the pharmaceutical formulation—namely that the pharmaceutical formulation is suitable for injection and provides time-restricted temporal controlled-release of a psychopharmaceutical agent.
  • this time-restricted controlled-release would provide a duration of peak effects of about 30 to 120 minutes.
  • the pharmaceutical formulation may have a pH of about 2, about 2.25, about 2.5, about 2.75, about 3, about 3.25, about 3.5, about 3.75, about 4, about 4.25, about 4.5, about 4.75, about 5, about 5.25, about 5.5, about 5.75, about 6, about 6.25, about 6.5, about 6.75, about 7, about 7.25, about 7.5, about 7.75, about 8, about 8.25, about 8.5, about 8.75, about 9, about 9.25, about 9.5, about 9.75, about 10, about 10.25, about 10.5, about 10.75, about 11, or any range 30 therebetween.
  • pH values which are too high are associated with tissue necrosis
  • pH values which are too low are associated with pain and inflammation at the injection site.
  • the pharmaceutical formulation is suitable for intravenous injection (is an 149
  • intravenous pharmaceutical formulation or intramuscular injection (is an intramuscular pharmaceutical formulation), and has a pH ranging from about 2 to about 11, about 3 to about 9, about 4 to about 7, about 4.5 to about 6.
  • the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and has a pH 5 ranging from about 3 to about 9, about 3 to about 7, about 4 to about 9, about 4 to about 7.5, about 4 to about 7, about 4.5 to about 7.5, about 4.5 to about 7, about 4.5 to about 6.5, about 4.5 to about 6.
  • the pharmaceutical formulation may have an osmolality of about 150 mOsm/kg, about 155 mOsm/kg, about 160 mOsm/kg, about 165 mOsm/kg, about 170 mOsm/kg, about 175 10 mOsm/kg, about 180 mOsm/kg, about 185 mOsm/kg, about 190 mOsm/kg, about 195 mOsm/kg, about 200 mOsm/kg, about 225 mOsm/kg, about 250 mOsm/kg, about 275 mOsm/kg, about 300 mOsm/kg, about 325 mOsm/kg, about 350 mOsm/kg, about 375 mOsm/kg, about 400 mOsm/kg, about 425 mOsm/kg, about 450 mOsm/kg, about 475 mOsm/kg, about 500 mOsm
  • the pharmaceutical formulation is isotonic with human blood serum, i.e., has an 20 osmolality of about 275 to about 300 mOsm/kg.
  • the pharmaceutical formulation may have viscosity of less than about 10,000 cP, less than about 9,000 cP, less than about 8,000 cP, less than about 7,000 cP, less than about 6,000 cP, less than about 5,000 cP, less than about 4,000 cP, less than about 3,000 cP, less than about 2,000 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less than about 50 cP, less 25 than about 45 cP, less than about 40 cP, less than about 35 cP, less than about 30 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, about 25 cP, about 28
  • viscosity values allow the pharmaceutical formulation to be syringeable and injectable, for example without causing excessive pain at the injection site.
  • suitable viscosity values also enable the use of sterile filtration as the sterilization technique.
  • the pharmaceutical formulation is suitable for subcutaneous injection (is a subcutaneous pharmaceutical formulation), and preferably has a viscosity of less than about 3,000 cP, less than about 2,500 cP, less than about 2,000 cP, less than about 1,500 cP, less than about 1,000 cP, less than about 500 cP, less than about 100 cP, less 10 than about 50 cP, less than about 25 cP, less than about 20 cP, for example, about 1 cP, about 2 cP, about 3 cP, about 4 cP, about 5 cP, about 8 cP, about 10 cP, about 12 cP, about 15 cP, about 18 cP, about 20 cP, about 22 cP, or any range therebetween.
  • the pharmaceutical formulation has a shelf-life as an aqueous solution of at least 1 day, 2 days, 3 days, 4 days 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 15 5 weeks, 6 weeks, or longer, without significant product degradation or physical changes such as precipitation.
  • the pharmaceutical formulation can be maintained/stored as an aqueous solution in open or closed environments, such as in open or closed flasks/vials under sub-ambient, ambient, or stress conditions (elevated temperatures) without appreciable degradation or physical changes such as precipitation.
  • compositions with a 20 prolonged shelf-life of at least several days or at least several weeks are advantageous because they may be prepared well in advance of administration if desired, and optionally stored, without materially affecting efficacy or injectability.
  • pharmaceutical formulations formed from a pharmaceutically acceptable salt of a compound of the present disclosure e.g., a compound of Formula (I) through (III), as the psychopharmaceutical agent, are characterized by 25 increased stability compared to formulations prepared using the same compound as free base but are otherwise substantially the same.
  • the pharmaceutical formulation of the present disclosure formed from a pharmaceutically acceptable salt of a compound of the present disclosure may be at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 30 50%, at least 55%, at least 60%, at least 65%, at least 70% more stable upon storage for 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, or longer, in terms of degradation or physical changes such as precipitation, compared to formulations prepared from a free base 151
  • the pharmaceutical formulation enables time-restricted temporal controlled-release of the 5 psychopharmaceutical agent via bolus injection to humans, and via bolus subcutaneous injection in particular.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the pharmaceutical formulations enable controlled-release of the tryptamine psychedelic via bolus injection to humans, and via bolus subcutaneous injection in particular, that mimics the clinically advantageous peak effects 10 time course of about 30 to 120 minutes achievable by IV infusion of such psychopharmaceutical agents over about 90 minutes.
  • the duration of peak effects following bolus injection of the pharmaceutical formulation is about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 15 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween, such as from about 30 to about 120 minutes, from about 30 to about 45 minutes, from about 40 to about 100 minutes, from about 45 to about 90 minutes, from about 50 to about 75 minutes, from about 60 to about 70 minutes.
  • the controlled-release of a psychedelic places the patient into a psychedelic state (a correlate of positive clinical outcomes) for about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 25 minutes, about 115 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, or any range therebetween, such as a psychedelic state time course of from about 35 minutes to about 100 minutes, from about 40 minutes to about 80 minutes, from about 35 to about 45 minutes, from about 50 minutes to about 60 minutes, from about 40 minutes to about 50 minutes, from about 90 minutes to about 120 30 minutes.
  • a psychedelic state time course of from about 35 minutes to about 100 minutes, from about 40 minutes to about 80 minutes, from about 35 to about 45 minutes, from about 50 minutes to about 60 minutes, from about 40 minutes
  • the time course that the patient experiences peak effects may also be assessed by the time the patient has a drug concentration in the blood of ⁇ 40 ng/mL, for example, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, 15 about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 150 ng/mL, or any range therebetween.
  • the time course that the patient spends in the psychedelic state may also be assessed by the time the patient has a therapeutically relevant concentration of the drug in the blood, e.g., 20 the time that the patient has a drug concentration between about 20 ng/mL and about 150 ng/mL, for example, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 25 125 ng/mL
  • the Mystical Experiences Questionnaire was first developed during an online survey on psilocybin-containing mushrooms and validated using data from experimental studies with controlled doses of psilocybin.
  • the revised version contains 30 items (MEQ30) regarding 30 subjective drug effects and is completed retrospectively. Effects are scored in total and on four subdomains (mystical, positive mood, space/time, ineffability), based on a percentage of maximum possible score.
  • MEQ30 Mystical Experience Questionnaire
  • the methods herein provide the patient with a Mystical Experience Questionnaire (MEQ30) score of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.
  • MEQ30 Mystical Experience Questionnaire
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 90% of subjects treated with the methods described herein have a Mystical Experience Questionnaire (MEQ30) score of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.
  • the 5-Dimensional Altered States of Consciousness Rating Scale measures 10 altered states of consciousness and contains 94 items (visual analog scales).
  • the 5D-ASC scale measures alterations in mood, perception, experience of self in relation to environment, and thought disorder.
  • the instrument consists of five subscales/dimensions and 11 lower-order scales.
  • the 5D-ASC dimension “Oceanic Boundlessness” (27 items) measures derealization and depersonalization associated with positive emotional states, ranging from heightened mood to 15 euphoric exaltation.
  • the corresponding lower-order scales include “experience of unity,” “spiritual experience,” “blissful state,” and “insightfulness.”
  • the dimension “Anxious Ego Dissolution” (21 items) summarizes ego disintegration and loss of self-control phenomena associated with anxiety.
  • the corresponding lower-order scales include “disembodiment,” “impaired control of cognition,” and “anxiety.”
  • the dimension “Visionary Restructuralization”20 (18 items) consists of the lower-order scales “complex imagery,” “elementary imagery,” “audio- visual synesthesia,” and “changed meaning of percepts.”
  • Two additional dimensions describe “Auditory Alterations” (15 items) and “Reduction of Vigilance” (12 items). Scoring is based on a percentage of maximum possible score.
  • the scale is well-validated and widely used to characterize the subjective effects of various psychedelic drugs. In some embodiments, the 5D-ASC is used to 25 measure changes in the subjects’ subjective psychedelic experience.
  • the methods herein provide the patient with a 5D-ASC score (e.g., on the oceanic boundlessness subscale) of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.
  • a 5D-ASC score e.g., on the oceanic boundlessness subscale
  • at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 90% of subjects treated with the methods 30 described herein have a 5D-ASC score (e.g., on the oceanic boundlessness subscale) of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%.
  • the methods herein provide the patient with a Hallucinogen Rating Scale (HRS) score (e.g., on the intensity subscale) 10 of at least 1.8, at least 2.0, at least 2.2, at least 2.4, at least 2.6, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0.
  • HRS Hallucinogen Rating Scale
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 90% of subjects treated with the methods described herein have a score on the Intensity subscale of the HRS of greater than > 2.79, for example, a score of at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at 15 least 3.8, or 4.0.
  • the visual analogue scale is a psychometric response scale that can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured.
  • the Bowdle VAS and Drug Rating VAS provides the subject with items of the drug rating questionnaire: feel drug, like drug, and dislike drug.
  • the VAS any drug effect involves the subject indicating (with vertical marks) on horizontal 100-mm visual analogue scales with the any drug effects item (“I can feel any drug effect”).
  • the subject has a maximum VAS score (e.g., Bond and Lader VAS, Bowdle VAS and Drug Rating 30 VAS, and/or VAS any drug effect) of > 60 mm or ⁇ 70 mm after treatment.
  • the subject has a VAS score (e.g., Bond and Lader VAS, Bowdle VAS and Drug Rating VAS, and/or VAS any drug effect) of greater than or equal to 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 155
  • VAS score e.g., Bond and Lader VAS, Bowdle VAS and Drug Rating VAS, and/or VAS any drug effect
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% of subjects treated with the methods described herein report a maximum VAS score (e.g., Bond and Lader VAS, Bowdle VAS and Drug Rating VAS, and/or VAS any drug effect) of greater than or 5 equal to 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, or 95 mm following treatment.
  • a maximum VAS score e.g., Bond and Lader VAS, Bowdle VAS and Drug Rating VAS, and/or VAS any drug effect
  • the subject experiences a VAS any drug effect score of ⁇ 70 mm for a duration of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 10 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween, such as from about 30 to about 120 minutes, from about 30 to about 45 minutes, from about 40 to about 100 minutes, from about 45 to about 90 minutes, from about 50 to about 75 minutes, from about 60 to about 70 minutes.
  • the 5-item Persisting Effects Questionnaire is a 5-item questionnaire that assesses 15 the meaningfulness, spiritual significance, psychological insightfulness, and how psychologically challenging a participant experience was during the medicine session. Scores are assessed on a scale from 0 (not at all) to 5 (extremely). Higher scores (under consideration of reverse-scored items) indicate stronger persisting treatment effects.
  • the patient reports their experience as the most or among the top five most meaningful experiences of their life according 20 to the Persisting Effects Questionnaire (PEQ).
  • the patient reports their experience as the most or among the top five most psychologically insightful experiences of their life, according to the Persisting Effects Questionnaire (PEQ).
  • the Profile of Mood States measures six identifiable mood- or affective states: Tension-Anxiety, Depression-Rejection, Anger-Hostility, Vigor-Activity, and Fatigue-Inertia. In 25 the original POMS, these states are addressed through 65 five-point adjective rating scales, and a sixth dimension (confusion-bewilderment) is added that does not appear in the abbreviated POMS wherein 32 questions are used to assess different periods (usually past two hours, sometimes past week).
  • the scales use a five-point score system, ranging from 0 (not at all) to 4 (extremely).
  • the scores of the different states are calculated using a scoring algorithm.
  • the methods herein provide the patient with a Real- Time Intensity scale score (e.g., on the emotional/metacognitive subscale) of at least 1.8, at least 2.0, at least 2.2, at least 2.4, at least 2.6, at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 5 3.6, at least 3.8, or 4.0.
  • a Real- Time Intensity scale score e.g., on the emotional/metacognitive subscale
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 90% of subjects treated with the methods described herein have a score on the Real-Time Intensity scale of greater than > 2.79, for example, a score of at least 2.8, at least 3.0, at least 3.2, at least 3.4, at least 3.6, at least 3.8, or 4.0.
  • the pharmaceutical formulation provides a controlled-release of the 10 psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an onset of effects within about 30 minutes, about 25 minutes, about 20 minutes, about 15 minutes, about 10 minutes post administration, such as from about 1 minute to about 30 minutes, about 5 minutes to about 25 minutes, about 10 minutes to 15 about 20 minutes, about 15 minutes to about 30 minutes, about 5 minutes to about 10 minutes.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves an offset of effects of greater than about 35 minutes and 20 up to about 180 minutes post administration, such as about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, about 125 minutes, about 130 minutes, about 135 minutes, about 140 minutes, about 145 25 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, post administration, or any range therebetween.
  • the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus 30 subcutaneous injection, with a drug concentration in the blood of ⁇ 40 ng/mL, corresponding to peak psychedelic effects.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • the pharmaceutical formulation may provide a drug concentration in the blood of about 157
  • 40 ng/mL about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 5 150 ng/mL, or any range therebetween.
  • these drug concentrations are preferably provided for a duration of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 10 minutes, about 110 minutes, about 115 minutes, about 120 minutes, or any range therebetween.
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which places the subject into a psychedelic state with a therapeutically 15 relevant concentration of the drug in the blood of about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about
  • the psychedelic state and therapeutically relevant concentration of the drug may last for about 35 minutes, about 40 minutes, 25 about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, about 130 minutes, about 140 minutes, about 150 minutes, about 160 minutes, about 170 minutes, about 180 minutes, or any range therebetween.
  • desirable pharmaceutical formulations provide a controlled-release of the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, to achieve the 158
  • C max maximum plasma levels
  • 5 pharmaceutical formulations of the present disclosure and in particular subcutaneous pharmaceutical formulations of the present disclosure, provide a smoother, more controlled delivery of the psychopharmaceutical agent contained therein compared to bolus IV injections of the same agent formulated without release modifier, which are known to cause high levels of drug spiking immediately following IV injection.
  • the pharmaceutical 10 formulations provide a controlled-release of the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, to achieve the aforementioned duration of peak effects and/or psychedelic state time course, along with a maximum concentration of drug in the blood (C max ) of about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, 80 ng/mL, or any range 15 therebetween, such as a Cmax of about 60 ng/mL to about 80 ng/mL.
  • C max maximum concentration of drug in the blood
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a concentration of the drug in the blood corresponding to 20 peak effects of about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, or any range therebetween, such as from about 60 ng/mL to about 80 ng/mL, followed by a steady-state exposure of from about 20 ng/mL to about 60 ng/mL, or any range therebetween, such as from about 20 ng/mL to about 40 ng/mL, about 25 ng/mL to about 35 ng/m
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which 159 achieves a concentration of the drug in the blood corresponding to peak effects of about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL, about 80 ng/mL, or any range therebetween, followed by a steady-state exposure of from about 40 ng/mL to about 60 ng/mL, or any range therebetween, such as from about 40 ng/mL to about 50 ng/mL, the steady-state exposure lasting 5 for at least 30 minutes, e.g., about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes,
  • the pharmaceutical formulation provides a controlled-release of the 10 psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a plasma half-life (t 1/2 ) of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 30 minutes to about 60 minutes, or from 15 about 35 minutes to about 50 minutes, or from about 40 minutes to about 45 minutes.
  • tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • bolus subcutaneous injection which achieves a plasma half-life (t 1/2 ) of about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 30 minutes to about 60 minutes, or from
  • the pharmaceutical formulation provides a controlled-release of the psychopharmaceutical agent such as tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) following bolus injection, including bolus subcutaneous injection, which achieves a time to maximum drug concentration (T max ) of about 10 20 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, or any range therebetween, such as from about 20 minutes to about 60 minutes, or from about 25 minutes to about 50 minutes, or from about 30 minutes to about 45 minutes, or from about 10 minutes to about 30 minutes.
  • tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • T max time to maximum drug concentration
  • the pharmaceutical formulation may display first order release kinetics of the psychopharmaceutical agent, as determined by the Dialysis—Drug Release Test (see Example section for experimental protocol). Accordingly, the release kinetics may fit best to the first order m athematical equation (2): 30 where Q is the concentration of the drug, Q 0 is the initial concentration of the drug, k is the first order rate constant, and t is the time. 160
  • the pharmaceutical formulation may extend the release of the psychopharmaceutical agent compared to the release of the same psychopharmaceutical agent from a formulation without release modifier but is otherwise substantially the same.
  • tryptamine psychedelics e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • a longer release period may result in a more clinically advantageous peak effects time course and clinical efficacy.
  • the time required for release of 25% of a total psychopharmaceutical agent content (free base equivalence) in the pharmaceutical formulation is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, 10 at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t 25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test (see Example section for experimental protocol).
  • the time required for release of 50% of a total psychopharmaceutical agent 15 content (free base equivalence) in the pharmaceutical formulation (t50%) is at least about 35% longer, at least about 40% longer, at least about 45% longer, at least about 50% longer, at least about 55% longer, at least about 60% longer, at least about 65% longer, at least about 70% longer, at least about 75% longer, at least about 80% longer, at least about 85% longer, at least about 90% longer, at least about 95% longer, at least about 100% longer than the t 50% of a formulation prepared20 without release modifier but is otherwise substantially the same, as determined by the Dialysis— Drug Release Test.
  • the pharmaceutical formulation provides a time- restricted controlled-release of the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) so as not to overextend the release and the resulting duration of peak effects beyond about 120 minutes to 25 avoid the prolonged supervised clinical observation requirements imposed by longer-acting psychopharmaceutical agents such as LSD and psilocybin.
  • the psychopharmaceutical agent such as a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III))
  • the t 25% is no more than about 250% longer, no more than about 225% longer, no more than about 200% longer, no more than about 190% longer, no more than about 180% longer, no more than about 170% longer, no more than about 160% longer, no more than about 150% longer, no more than about 30 140% longer, no more than about 130% longer than the t 25% of a formulation prepared without release modifier but is otherwise substantially the same, as determined by the Dialysis—Drug Release Test.
  • the t50% is no more than about 250% longer, no more than 161
  • the time required for release of 50% of a total psychopharmaceutical agent content in the pharmaceutical formulation is no more than about 120 minutes, no more than about 110 minutes, no more than about 100 minutes, no more than about 90 minutes, no more than about 80 minutes, no more than about 70 minutes, no more than about 60 minutes, no more than about 50 minutes, no more 10 than about 40 minutes, no more than about 30 minutes, as determined by the Dialysis—Drug Release Test.
  • Kits Also disclosed herein is a kit suitable for preparing the injectable pharmaceutical 15 formulation of the present disclosure.
  • the kit comprises a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the kit comprises (a1) a first solution comprising a 20 psychopharmaceutical agent and an aqueous vehicle, and (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle.
  • the kit components (a1) and (b1) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure.
  • the first solution comprises (as psychopharmaceutical agent) a 25 tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III).
  • the (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle.
  • the first solution may be prepared by contacting the compound of the present disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the 162
  • the compound of the present disclosure e.g., a compound of Formula (I) through (III)
  • an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the 162
  • the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) through (III) (free base equivalence when a salt form is used), by weight per total volume of first 5 solution of about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 mg/mL, about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about
  • a free base concentration of psychopharmaceutical agent e.g., a free base concentration of a compound of Formula (
  • the second solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 20 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%,
  • the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a 30 concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, 163
  • kit components (a1) and (b1) may be combined, contacted, 5 or otherwise brought together to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable unit doses and psychopharmaceutical agent concentrations.
  • Kits may be provided with different concentrations of psychopharmaceutical agent in component (a1), different concentrations of release modifier in component (b1), and/or different volume ratios of kit components (a1) and (b1) may be combined, 10 contacted, or otherwise brought together to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or psychopharmaceutical agent concentrations.
  • the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by using different volume ratios of kit 15 components (a1) : (b1).
  • a suitable volume ratio of (a1) : (b1) used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1.
  • the combining, contacting, or otherwise bringing 20 together of kit components (a1) and (b1) to generate the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the kit may include instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. 25
  • the kit comprises (a2) a psychopharmaceutical agent in solid form and (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the kit components (a2) and (b2) are intended to be combined, contacted, or otherwise brought together to generate the injectable pharmaceutical formulation of the present disclosure.
  • the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form.
  • a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form.
  • kits component (a2) can be used in kit component (a2).
  • the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt 5 by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range 10 therebetween, such as from about 0.1% to about 2%, about 0.1% to about 1.5%, about 0.1% to about 1%, about 0.1% to about 0.75%, about 0.1% to about 0.5%, about 0.15% to about 1%, about 0.2% to about 0.75%, or about 0.25% to about 0.5%.
  • the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration 15 of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%.
  • Kits may be combined, contacted, or otherwise brought together with kit component (a2) to generate the pharmaceutical formulation with suitable physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations.
  • Kits may be provided with different concentrations of release modifier in component (b2) and/or different volumes of kit component (b2) may be combined, contacted, or 25 otherwise brought together with kit component (a2) to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations.
  • Kits may be provided with different amounts of psychopharmaceutical agent in solid form in component (a2) to generate different pharmaceutical formulations with differentiated unit doses and psychopharmaceutical agent concentrations.
  • kit component (b2) with the solid dosage form of the psychopharmaceutical agent in kit component (a2) can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine 165
  • kit may include instructions for what volume of kit component (b2) 5 can be combined, contacted, or otherwise brought together with kit component (a2) to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc.
  • kits component (a1), kit component (b1), kit component (b2)) 10 may optionally contain one or more pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • pharmaceutically acceptable additives such as water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • Suitable aqueous vehicles include, 15 but are not limited to, water, saline, physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the 20 aqueous vehicle is made up of water for injection, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent.
  • the aqueous vehicle is formulated without a tonicity agent such as sodium chloride.
  • the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another is water, such as water for injection (WFI).
  • the aqueous vehicle used in one or more of kit components (a1), (a2), and/or (b2), independent of one another comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, about 0.4%, 30 about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, 166
  • a pH adjustment may be performed with a pH adjusting agent on one or more of kit component (a1), kit component (b1), and/or kit component (b2).
  • kit component (a1), kit component (b1), and/or kit component (b2) after combining, contacting, or otherwise bringing together the respective kit components (kit components (a1) with (b1) or kit components (a2) with (b2)), a pH adjustment may be performed with a pH adjusting agent to generate the final pharmaceutical formulation. Therefore, the kit may optionally comprise (c) a pH adjusting agent.
  • the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, 10 potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • the pH adjustment involves increasing the pH, and so kit component (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the 15 pH is adjusted with sodium hydroxide or potassium hydroxide, for example to generate the final pharmaceutical formulation.
  • the pharmaceutical formulation does not contain a buffering agent.
  • Preparative methods 20 Also disclosed herein is a method for preparing the pharmaceutical formulation of the present disclosure, the pharmaceutical formulation being suitable for injection.
  • the method comprises contacting a psychopharmaceutical agent, a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the contacting of the method may be conducted in a variety of ways, including through the use of conventional techniques known to 25 those skilled in the art of pharmaceutical science (see, Remington: The Science and Practice of Pharmacy).
  • the method for preparing the pharmaceutical formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the psychopharmaceutical agent is a tryptamine psychedelic, such 30 as a pharmaceutically acceptable salt of a compound of Formula (I) through (III).
  • the method involves reconstituting a pre-formed, typically solid form and in some cases crystalline solid form of the pharmaceutically acceptable salt of a compound of Formula (I) 167
  • the method involves contacting a solution comprising a pharmaceutically acceptable salt of a compound of Formula (I) through (III) in an aqueous vehicle with a release modifier in solid form or as a solution in an aqueous vehicle.
  • the method may involve contacting the compound of the present disclosure (e.g., a 5 compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the compounds of the present disclosure, thereby forming the pharmaceutically acceptable salt of a compound of Formula (I) through (III) in-situ.
  • the method may comprise contacting a psychopharmaceutical agent, a release modifier 10 such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle from components of a kit intended to be combined, contacted, or otherwise brought together. Any of the embodiments disclosed herein for the kit may be optionally used in the preparative methods herein.
  • the method comprises contacting (a1) a first solution comprising a 15 psychopharmaceutical agent and an aqueous vehicle, with (b1) a second solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt and an aqueous vehicle.
  • the first solution comprises (as psychopharmaceutical agent) a tryptamine psychedelic, such as a pharmaceutically acceptable salt of a compound of Formula (I) 20 through (III).
  • the (a1) first solution may be prepared from a pre-formed, typically solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of the present disclosure (e.g., a compound of Formula (I) through (III)) by contacting the pre-formed pharmaceutically acceptable salt of a compound of the present disclosure with aqueous vehicle.
  • the first solution may be prepared by contacting the compound of the present 25 disclosure (e.g., a compound of Formula (I) through (III)) as a free base with an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ.
  • the compound of the present 25 disclosure e.g., a compound of Formula (I) through (III)
  • an aqueous vehicle comprising available H + (aq) ions capable of ionizing/protonating the free base to form the pharmaceutically acceptable salt of a compound of the present disclosure within (a1) the first solution in-situ.
  • the first solution comprises a free base concentration of psychopharmaceutical agent, e.g., a free base concentration of a compound of Formula (I) 30 through (III) (free base equivalence when a salt form is used), by weight per total volume of first solution of about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, about 12 mg/mL, about 15 mg/mL, about 18 mg/mL, about 20 mg/mL, about 22 mg/mL, about 25 168
  • mg/mL about 28 mg/mL, about 30 mg/mL, about 32 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL, about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL, about 95 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, 5 about 150 mg/mL, about 160 mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL, about 200 mg/mL, or any range therebetween, such as from about 10 mg/mL to about 140 mg/mL, from about 20 mg/mL to about 100 mg/mL, from about 30 mg/mL to about 80 mg/mL, from about 40 mg/
  • the second solution comprises as the release modifier a 10 hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt by weight per total volume of (b1) the second solution expressed as a percentage (% w/v) may be about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, 15 about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%,
  • the second solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b1) the second 25 solution expressed as a percentage (% w/v) may be about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.6% to about 2%, about 0.7% to about 1.8%, about 0.8% to about 1.7%, about 0.9% to about 1.6%, about 1% to about 1.5%.
  • a suitable volume of each of the first solution (a1) and the second solution (b1) may be contacted to generate the pharmaceutical formulation with suitable physiochemical and controlled- release characteristics, as well as suitable unit doses and psychopharmac
  • Different concentrations of psychopharmaceutical agent in (a1) the first solution, different concentrations of release modifier in (b1) the second solution, and/or different volume ratios of (a1) the first solution to (b1) the second solution may be contacted to generate different pharmaceutical formulations with differentiated release characteristics, unit doses, and/or 5 psychopharmaceutical agent concentrations.
  • the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, unit dose, psychopharmaceutical agent concentration, release modifier, and release characteristics, by combining different volume ratios of (a1) the first solution to (b1) the second solution.
  • a suitable volume ratio of (a1) the first solution to (b1) the second 10 solution used to generate the pharmaceutical formulation may be from about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range therebetween, such as from about 2:1 to about 1:2, about 1.5:1 to about 1:1.5, about 1:1.
  • the contacting of (a1) the first solution to (b1) the second solution to generate the pharmaceutical 15 formulation may be performed well in advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the method may involve following instructions for what volume ratios of (a1) : (b1) can be used to prepare suitable injectable pharmaceutical formulations, for example, based on physiochemical properties, indication to be treated, dosing schedule and requirements, etc. 20
  • the method involves contacting (a2) a psychopharmaceutical agent in solid form with (b2) a solution comprising a release modifier such as a hyaluronate salt or a carboxymethyl cellulose salt, and an aqueous vehicle.
  • the psychopharmaceutical agent is a tryptamine psychedelic in solid form, such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), 25 in solid form.
  • any pre-formed, solid form and in some cases crystalline solid form, of the pharmaceutically acceptable salt of a compound of Formula (I) through (III) of the present disclosure can be used as (a2).
  • the solution comprises as the release modifier a hyaluronate salt such as sodium hyaluronate, and the aqueous vehicle.
  • a concentration of the hyaluronate salt 30 by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, about 170
  • the solution comprises as the release modifier a carboxymethyl cellulose salt such as sodium carboxymethyl cellulose, and the aqueous vehicle.
  • a concentration of carboxymethyl cellulose salt by weight per total volume of (b2) the solution expressed as a percentage (% w/v) may be about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, 10 about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1%, or any range therebetween, such as from about 0.6% to about 1%, about 0.7% to about 1%, about 0.75% to about 1%, about 0.75% to about 0.9%, about 0.75% to about 0.8%.
  • a suitable volume of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate the pharmaceutical formulation with suitable 15 physiochemical and controlled-release characteristics, as well as suitable psychopharmaceutical agent concentrations.
  • Different concentrations of release modifier in (b2) the solution and/or different volumes of (b2) the solution may be contacted with (a2) the psychopharmaceutical agent in solid form to generate different pharmaceutical formulations with differentiated release characteristics and psychopharmaceutical agent concentrations.
  • the same kit may be used to generate a range of differentiated pharmaceutical formulations in terms of, inter alia, psychopharmaceutical agent concentration, etc., by contacting different volumes of (b2) the solution with (a2) the psychopharmaceutical agent in solid form.
  • different amounts of (a2) the psychopharmaceutical agent in solid form may be used to generate different pharmaceutical formulations with differentiated unit doses and 25 psychopharmaceutical agent concentrations.
  • the contacting of (b2) the solution with (a2) the solid dosage form of the psychopharmaceutical agent can be accurately described as an act of reconstituting the solid dosage form of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III), in solid form and in some case in crystalline solid form). Reconstitution may be performed well in 30 advance of administration with the pharmaceutical formulation being optionally stored, or immediately prior to use.
  • the method may involve following instructions for what volume of (b2) the solution can be contacted with (a2) the psychopharmaceutical agent in solid form to prepare 171
  • the aqueous vehicle used in any of (a1) the first solution, (b1) the second solution, and/or (b2) the solution may optionally contain one or more 5 pharmaceutically acceptable additives, as desired/needed, such as water-miscible vehicles, non- aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizing agents, tonicity agents, buffering agents, antioxidants, local anesthetics, complexing agents, sequestering or chelating agents, pH adjusting agents, absorption enhancers, including combinations thereof.
  • Suitable aqueous vehicles include, but are not limited to, water, saline, 10 physiological or isotonic saline, phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • the aqueous vehicle is made up of saline, optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent other than sodium chloride.
  • the aqueous vehicle is made up of water, 15 optionally a buffering agent, optionally a pH adjusting agent (e.g., sodium hydroxide), and optionally a tonicity agent.
  • the aqueous vehicle is made up of water or saline, and optionally a pH adjusting agent (e.g., sodium hydroxide), wherein the aqueous vehicle is formulated without a buffering agent.
  • the aqueous vehicle is formulated without a tonicity agent such as sodium chloride.
  • the aqueous vehicle used 20 in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another is water, such as water for injection (WFI).
  • the aqueous vehicle used in one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution, independent of one another comprises sodium chloride at a concentration, in terms of weight per volume expressed as a percentage (% w/v), of about 0.1%, about 0.2%, about 0.3%, 25 about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, or any range therebetween, such as from about 0.1% to about 1.5%, about 0.2% to about 1%, about 0.3% to about 0.5% w/v.
  • a pH adjustment may be performed with a pH adjusting agent on 30 one or more of (a1) the first solution, (b1) the second solution, and/or (b2) the solution.
  • the method may comprise 172
  • the kit may optionally comprise (c) a pH adjusting agent.
  • the pH adjusting agent is at least one selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium 5 hydroxide, calcium hydroxide, magnesium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • the adjusting of the pH involves increasing the pH, and so (c) comprises a suitable base as pH adjusting agent, for example one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, ammonium hydroxide, calcium hydroxide and magnesium hydroxide.
  • the pH is adjusted with sodium hydroxide or 10 potassium hydroxide, for example to generate the final pharmaceutical formulation.
  • the pharmaceutical formulation does not contain a buffering agent.
  • the pharmaceutical formulations of the present disclosure must be sterile, as known and practiced in the art.
  • the method of the present disclosure may optionally comprise sterilizing the pharmaceutical formulation, for example as a final preparative step.
  • the method 15 may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the psychopharmaceutical agent in solid form, and/or (b2) the solution.
  • the method may optionally comprise sterilizing any one or more (including all) components used to prepare the pharmaceutical formulation, such as (a1) the first solution, (b1) the second solution, (a2) the 20 psychopharmaceutical agent in solid form, and/or (b2) the solution, and optionally sterilizing the pharmaceutical formulation, for example as a final preparative step.
  • sterilization may be carried out by steam sterilization, dry-heat sterilization/depyrogenation, gas sterilization, sterilization by ionizing radiation, sterilization by filtration, or unidirectional aseptic processing, for example according to the requirements set forth 25 in USP Sterilization and Sterility Assurance of Compendial Articles ⁇ 1211> and/or USP Sterility Tests ⁇ 71>.
  • sterile filtration is used. While not limited thereto, sterile filtration is usually carried out with assemblies having membranes of nominal pore size rating of 0.2 ⁇ m or less or 0.1 ⁇ m or less, according to the requirements set forth in USP Sterilization and Sterility Assurance of Compendial 30 Articles ⁇ 1211>. Sterile filtration may be carried out by passing the pharmaceutical formulation (or various components making up the pharmaceutical formulation, separately) through a membrane, a syringe filter, a vacuum device, a capsule assembly, a high pressure cartridge or filter 173
  • a suitable membrane typically a membrane which is capable of passing a bacterial challenge to retain a minimum of 10 7 CFU/cm 2 of B.dimunita.
  • membranes include, but are not limited to, those made from polyethersulfone (PES), polyvinylidene fluoride (PVDF), cellulose, cellulose acetate, mixed cellulose esters (MCE), nylon, 5 and hydrophilic polytetrafluoroethylene (PTFE).
  • PES polyethersulfone
  • PVDF polyvinylidene fluoride
  • MCE mixed cellulose esters
  • nylon polypropylene
  • PTFE hydrophilic polytetrafluoroethylene
  • the preparative method for producing the pharmaceutical formulation may not involve any sterilization processing, and instead the method involves assembly of already sterilized components.
  • the various kit components to be assembled e.g., (a1) the first solution with (b1) the second solution, 10 or (a2) the psychopharmaceutical agent in solid form with (b2) the solution
  • the end user such as a treating clinician, patient, or caregiver, would simply assemble the already sterilized kit components thereby forming the pharmaceutical formulation ready-to-use, with no additional sterilization processing needed.
  • the pharmaceutical formulations disclosed herein may be formulated for single or multiple 15 dosage administration.
  • the pharmaceutical formulation may be optionally stored and/or packaged in any suitable container, examples of which include, but are not limited to, an ampule, a vial, a syringe such as a pre-filled syringe, a cartridge, a reservoir or cartridge for an injection device such as an on-body drug delivery device or an auto-injector, etc.
  • the pharmaceutical 20 formulation is stored and/or packaged in a container adapted to prevent penetration of ultraviolet light, such as amber glass vial.
  • the container within which the pharmaceutical formulation is stored and/or packaged is not so adapted (and may be, for example, made of clear glass) with protection against ultraviolet light, if desired, provided by secondary packaging (for example packaging within which the receptacle containing the pharmaceutical 25 formulation may be placed).
  • secondary packaging for example packaging within which the receptacle containing the pharmaceutical 25 formulation may be placed.
  • the container is airtight and the pharmaceutical formulation is stored under an inert atmosphere, such as under nitrogen or argon, typically nitrogen.
  • the formulation may be stored at room temperature, e.g., at about 20 to about 30°C, or at cooler temperatures, for example at about 2 to about 8°C.
  • the pharmaceutical formulation may be stored in a freezer.
  • tamper resistant dosage forms/packaging of any of the 30 disclosed pharmaceutical formulations are contemplated.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a pharmaceutical formulation of the present disclosure.
  • the disease or disorder may be a neuropsychiatric disease or disorder or an inflammatory disease or disorder, such as a central nervous system (CNS) disorder and/or 5 psychological disorder, including those associated with a 5-HT2 receptor.
  • the pharmaceutical formulation is suitable for injection, thus its administration in therapy typically comprises parenteral administration via injection to affect a beneficial therapeutic response. Injection may involve administration through a needle (hypodermic needle), microneedles including hollow microneedles, or using a needle-free injection system whereby a 10 fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue.
  • the method comprises administering the pharmaceutical formulation intravenously to the subject (directly into the vein). In some embodiments, the method comprises administering the pharmaceutical formulation intramuscularly to the subject (within the muscle). In some embodiments, the method comprises 15 administering the pharmaceutical formulation intradermally to the subject (beneath the skin). In some embodiments, the method comprises administering the pharmaceutical formulation subcutaneously to the subject (within the fat or the layer of skin directly below the dermis and epidermis). Subcutaneous administration is a minimally invasive mode of administration. Subcutaneous tissue has few blood vessels and so drugs injected into it are intended for slow, 20 sustained rates of absorption, often with some amount of depot effect.
  • Subcutaneous administration can be performed by injection or by implantation of a sustained or timed-release device beneath 25 the surface of the skin. The site of the injection or device can be rotated when multiple injections or devices are needed.
  • the method may involve subcutaneously injecting several unit dose pharmaceutical formulations at multiple sites of the body surface.
  • a particular advantage of the subcutaneous delivery route in the therapeutic methods of the present disclosure is that it allows the medical practitioner to perform the administration in 30 a rather short intervention with the patient, compared to intravenous infusion protocols associated with DMT-based therapy. Moreover, the patient can be trained to perform self-administration. 175
  • the injection volume of the pharmaceutical formulation administered per injection is 5 usually about 3 mL or less, such as about 0.1 mL, about 0.2 mL, about 0.4 mL, about 0.6 mL, about 0.8 mL, about 1 mL, about 1.2 mL, about 1.4 mL, about 1.6 mL, about 1.8 mL, about 2 mL, about 2.2 mL, about 2.4 mL, about 2.6 mL, about 2.8 mL, about 3 mL, or any range therebetween such as from about 0.5 to about 3 mL, from about 1.5 to about 2.5 mL, from about 0.5 to about 1.5 mL, or from about 2 to about 2.5 mL.
  • single injection volumes of up to about 3 mL are 10 tolerated via the subcutaneous route without undue pain, especially those given in the patient’s abdomen, with injection volumes of about 2.5 mL or less, about 2 mL or less, or about 1.5 mL or less being well tolerated across various injection sites.
  • the injection volume of the pharmaceutical formulation administered is about 0.5 mL to about 1.5 mL.
  • administration may be carried out by dividing the total volume to be administered in multiple injections, e.g., two injections of 2 mL each, administered at different sites (e.g., two different injection sites) on the patient’s body.
  • the methods may involve administration of 1 injection at a single injection site, or 2, 3, 4, or more injections across multiple 20 injection sites, whereby the multiple injections add up to the total dose and volume administered.
  • the method comprises administering the pharmaceutical formulation as a bolus injection, in which a discrete amount of psychopharmaceutical agent (e.g., tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection within 30 minutes or less, 25 minutes or less, 20 minutes 25 or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, 1 minute or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, or 5 seconds or less, or any range therebetween.
  • the bolus injection may involve a single injection or multiple injections performed within the above-described time range.
  • the bolus injection involves a single injection within the above time range.
  • the method comprises 176
  • the method comprises administering the pharmaceutical formulation as a bolus subcutaneous injection, such as a single bolus subcutaneous injection.
  • the method comprises administering the pharmaceutical formulation as a bolus intramuscular injection, such as a single bolus intramuscular injection.
  • the method comprises administering the pharmaceutical 5 formulation as a bolus intradermal injection, such as a single bolus intradermal injection.
  • the method comprises administering the pharmaceutical formulation as a bolus intravenous injection, such as a single bolus intravenous injection.
  • the method comprises administering the pharmaceutical formulation as an infusion injection, in which a discrete amount of psychopharmaceutical agent 10 (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) is administered by injection over a prolonged period of greater than 30 minutes, greater than 40 minutes, greater than 50 minutes, greater than 60 minutes, greater than 70 minutes, greater than 80 minutes, greater than 90 minutes, greater than 100 minutes, greater than 110 minutes, greater than 120 minutes, etc.
  • the infusion injection may involve a single 15 prolonged injection, or multiple injections (short or prolonged) within the above-described time range.
  • the infusion injection involves a single injection within the above time range.
  • the method comprises administering the pharmaceutical formulation as an infusion subcutaneous 20 injection.
  • the method comprises administering the pharmaceutical formulation as infusion intramuscular injection.
  • the method comprises administering the pharmaceutical formulation as infusion intravenous injection. Any injection device that enables administration of the pharmaceutical formulation through the skin or other external boundary tissue of the subject may be used in the disclosed25 methods.
  • injection devices include, but are not limited to, needle and syringe, pre- filled syringe, canula, catheter, pen, auto-injector (e.g., ACTpen®, ArQ ® - Bios from Oval Medical Technologies), semi-auto injector (such as those from UnionMedico®) on-body drug delivery devices (e.g., patches, pumps, those with automatic needle insertion/retraction, belt worn devices, such as those available from Gerresheimer AG, etc.), implants, embedded needle tip 30 devices, a needle-free injection system (e.g., a jet injector), automatic injection devices, or other suitable injection device.
  • the injection device may be resuable or disposable (e.g., disposable hypodermic needle and syringe, disposable pen, disposable pump, disposable on-body drug 177
  • the injection device may be actuated manually or automatically.
  • Some automatic injection devices may be configured with automatic needle insertion/retraction, auto-pumps, or one or more microneedles, which in some embodiments may be coated with a pharmaceutical formulation disclosed herein. 5
  • hollow microneedles may be used to provide a fluid channel for delivery of the disclosed pharmaceutical formulations below the outer layer of the skin to improve delivery.
  • needle-free injection systems e.g., a jet injector
  • a fine, high velocity jet is generated by driving liquid through an orifice at high pressure to pierce the skin and underlying tissue.
  • needle-free injection systems may include those adapted with spring systems, lasers, or energy propelled 10 systems such as Lorentz force, gas propelled/air forced, or shove wave driven devices.
  • needle-free injection devices include, but are not limited to, Bioject® jet injectors such as Biojector® 2000, Viajet 3, DoseProTM, ZetaJetTM, Stratis® IM/SC, and Jupiter JetTM.
  • Multi- component injections such as using a dual chamber syringe or a multi-syringe (e.g., two syringe) set up, may also be performed.
  • the injection device can be optionally manufactured with smart 15 technology enabling remote activation and/or control of delivery. The remote activation can be performed via computer or mobile app.
  • the remote activation device can be password encoded.
  • This technology enables a healthcare provider to perform telehealth sessions with a patient, during which the healthcare provider can remotely activate and administer the pharmaceutical formulation via the desired delivery device while supervising the patient on the 20 televisit.
  • Subcutaneous injections may be performed by cleaning the area to be injected followed by an injection, usually at about a 45-degree angle to the skin when using a syringe and needle, or at about a 90-degree angle (perpendicular) if using an injector pen or other suitable injector device.
  • the appropriate injection angle is based on the length of needle 25 or injection device used, and the depth of the subcutaneous fat in the skin of the subject receiving the treatment.
  • the skin and underlying tissue may be pinched upwards prior to injection (the “pinch-up” technique).
  • Subcutaneous injection may be administered in the subject’s arm such as the outer area of the upper arm, thigh such as the front of the thigh (e.g., between 4 inches from the top of the thigh 30 and 4 inches above the knee), abdomen such as the anterior abdomen usually avoiding the 2-inch circle around the navel, the upper back, the upper area of the buttock, just behind the hip bone, and the like. Any of which may be performed using the “pinch-up” technique.
  • the choice of injection 178 is the choice of injection 178
  • injection site is based on the pharmaceutical formulation being administered, for example taking into account the volume of injection needed, as well as preference. Injections administered frequently or repeatedly should be administered in a different location each time, either within the same general site or a different site, but at least one inch away from recent injections as known and 5 practiced in the art. In most cases, subcutaneous injections can be easily performed by people with minor skill and training required.
  • the injection sites for self-injection procedures are the same as for injection by a healthcare professional, and the skill can be taught to patients using pictures, videos, or models of the subcutaneous tissue for practice, and in some cases facilitated by use of semi- or auto-injector devices or on-body drug delivery devices for facile self-administration. 10 Administration may follow a continuous administration schedule, or an intermittent administration schedule.
  • the administration schedule may be varied depending on the psychopharmaceutical agent employed, the condition being treated, etc. For example, administration may be performed once a day (QD), or in divided dosages throughout the day, such as 2-times a day (BID), 3-times a day (TID), 4-times a day (QID), or more. In some embodiments 15 administration may be performed nightly (QHS). In some embodiments, the pharmaceutical formulation may be administered as needed (PRN).
  • Administration may also be performed on a weekly or monthly basis, e.g., once a week, twice a week, three times a week, four times a week, every other week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven 20 weeks, every twelve weeks, etc., or less, or any range therebetween.
  • the pharmaceutical formulation may be administered monthly, for example, once monthly dosing or dosing every two months.
  • the administration schedule may also designate a defined number of treatments per treatment course, for example, administration may be performed 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, or 8 times per treatment course.
  • 25 one dose is administered to the subject in a treatment course.
  • multiple doses are administered to the subject in a treatment course.
  • two doses are administered to the subject one week apart, two weeks apart, three weeks apart, or four weeks apart, in a treatment course.
  • the treatment herein may involve two doses of the pharmaceutical formulation administered three weeks apart (e.g., day 1 and day 22).
  • three doses are administered to the subject one week apart, two weeks apart, three weeks apart, or four weeks apart, in a treatment course.
  • Other administration schedules may also be deemed appropriate using sound medical judgement. 179
  • the dosing can be continuous (7 days of administration in a week) or intermittent, for example, depending on the pharmacokinetics and a particular subject’s clearance/accumulation of the psychopharmaceutical agent. If intermittently, the schedule may be, for example, 4 days of administration and 3 days off (rest days) in a week or any other intermittent dosing schedule 5 deemed appropriate using sound medical judgement. For example, intermittent dosing may involve administration of a single dose within a treatment course. The dosing whether continuous or intermittent is continued for a particular treatment course, typically at least a 28-day cycle (1 month), which can be repeated with or without a drug holiday.
  • Longer or shorter courses can also be used such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 days, or longer, or any 10 range therebetween.
  • the course may be repeated without a drug holiday or with a drug holiday depending upon the subject.
  • Other schedules are possible depending upon the presence or absence of adverse events, response to the treatment, patient convenience, and the like.
  • the dosage and frequency (single or multiple doses) of administration can vary depending upon a variety of factors, including, but not limited to, the psychopharmaceutical agent to be 15 administered; the disease/condition being treated; route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.
  • the pharmaceutical formulation comprises a therapeutically effective amount of the psychopharmaceutical agent (e.g., a tryptamine psychedelic such as a pharmaceutically acceptable salt of a compound of Formula (I) through (III)), i.e., an amount that is sufficient to reduce or halt the rate of progression of the disease or disorder, to ameliorate or cure the disease or disorder and thus produce the desired therapeutic or 25 inhibitory effect, or to alleviate one or more symptoms of the disease or disorder.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring response to the treatment and adjusting the dosage upwards or downwards. 30 Dosages may be varied depending upon the requirements of the subject and the psychopharmaceutical agent being employed. The dose administered to a subject, in the context of the pharmaceutical formulations presented herein, should be sufficient to effect a beneficial 180
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage 5 amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual’s disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity or adverse side effects (e.g., caused 10 by sedative or psychotomimetic toxic spikes in plasma concentration of any of the psychopharmaceutical agents), and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of psychopharmaceutical agent by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode 15 of administration, and the toxicity profile of the selected agent.
  • a therapeutically effective amount of the psychopharmaceutical agent (free base equivalence) provided by the pharmaceutical formulation is about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 20 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.2 mg/kg, about 1.4 mg/kg, about 1.6 mg/kg, about 1.8 mg/kg, about 2.0 mg/kg, about 2.2 mg/kg, about 2.4 mg/kg, about 2.6 mg/kg, about 2.8 mg/kg, about 3.0 mg/kg, about 3.2 mg/kg, about 3.4 mg/kg, about 3.6 mg/kg, about 3.8 mg/kg, about 4.0 mg/kg, about 4.2 mg/kg, about 4.4 mg/kg,
  • the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the psychopharmaceutical agent, and a therapeutically effective amount may be a psychedelic dose.
  • a psychedelic dose (therapeutically effective amount) in terms of weight-based dosing (free base equivalence) may in some embodiments be about 0.1 mg/kg, about 0.15 mg/kg, about 0.2 mg/kg, about 0.25 mg/kg, about 0.3 mg/kg, about 0.35 mg/kg, about 0.4 mg/kg, about 0.45 mg/kg, 181
  • a psychedelic dose 10 (therapeutically effective amount) of a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) (in terms of free base equivalence) may in some embodiments be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, 15 about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 300 mg, or any range therebetween, such as from about 15
  • psychedelic doses are administered once, with the possibility of repeat doses at least 20 one week apart. In some instances, no more than 5 doses are given in any one course of treatment. Courses can be repeated as necessary, with or without a drug holiday.
  • Such acute treatment regimens may be accompanied by psychotherapy, before, during, and/or after the psychedelic dose.
  • These treatments are appropriate for a variety of mental health disorders disclosed herein, examples of which include, but are not limited to, major depressive disorder (MDD), therapy 25 resistant depression (TRD), anxiety disorders, and substance use disorders (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder), and combinations thereof such as an anxiety disorder with depression.
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III) 30 as the psychopharmaceutical agent in sub-psychedelic (yet still potentially serotonergic concentrations) doses
  • a tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • sub-psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)
  • doses may be performed in some embodiments to achieve durable therapeutic benefits, with decreased toxicity, and may thus be suitable for microdosing.
  • Sub-psychedelic 182 e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III) 30 as the psychopharmaceutical agent in sub-psychedelic (yet still potentially serotonergic concentrations) doses
  • dosing may in some embodiments provide the tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) (in terms of free base equivalence) in an amount of about 0.00001 mg/kg, about 0.00005 mg/kg, about 0.0001 mg/kg, about 0.0005 mg/kg, about 0.001 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.008 mg/kg, about 5 0.009 mg/kg, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.075 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about less than 0.1 mg/kg, or any range therebetween.
  • the tryptamine psychedelic e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (
  • sub-psychedelic doses are administered up to every day, for a treatment course (e.g., 1 month). However, there is no limitation on the number of doses at sub-psychedelic doses—dosing can be less frequent or 10 more frequent as deemed appropriate. Courses can be repeated as necessary, with or without a drug holiday.
  • Sub-psychedelic doses can be used, e.g., for the chronic treatment or maintenance of a variety of diseases or disorders disclosed herein, examples of which include, but are not limited to, depression (e.g., MDD), inflammation, pain, and neuroinflammation.
  • the pharmaceutical formulations of present disclosure may be administered via injection 15 for a maintenance regimen.
  • a “maintenance regimen” generally refers to the administration of a psychopharmaceutical agent following achievement of a target dose, e.g., following completion of an up-titration regimen, and/or following a positive clinical response, e.g., improvement of the patient's condition, either to the same agent or to a different agent.
  • the patient is administered a first psychopharmaceutical agent for a therapeutic 20 regimen and a second psychopharmaceutical agent for a maintenance regimen, wherein the first and second psychopharmaceutical agents are different.
  • the patient may be administered a therapeutic regimen of a first psychopharmaceutical agent which is not a tryptamine psychedelic (e.g., the first psychopharmaceutical agent is LSD, MDMA, etc.), followed by a tryptamine psychedelic (as the second psychopharmaceutical agent) in a maintenance regimen.
  • a different tryptamine psychedelic is used for the therapeutic regimen (first psychopharmaceutical agent) than is used for the maintenance regimen (second psychopharmaceutical agent).
  • the patient is administered the psychopharmaceutical agent for both a therapeutic regimen and a maintenance regimen.
  • the maintenance dose may be used to ‘maintain’ the therapeutic response and/or to prevent 30 occurrences of relapse.
  • the maintenance dose may be at or below the therapeutic dose.
  • the maintenance dose is a psychedelic dose. In some 183
  • the maintenance dose is a sub-psychedelic dose. Generally, dosing is carried out daily or intermittently for the maintenance regimen, however, maintenance regimens can also be carried out continuously, for example, over several days, weeks, months, or years. Moreover, the maintenance dose may be given to a patient over a long period of time, even chronically. 5
  • the methods provided herein may be used to treat a disease or disorder associated with a serotonin 5-HT 2 receptor.
  • the disease or disorder is a neuropsychiatric disease or disorder or an inflammatory disease or disorder.
  • the disease or disorder is a central nervous system (CNS) disorder and/or psychological disorder, including, but not limited to, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), 10 treatment-resistant depression (TRD), suicidal ideation, suicidal behavior, major depressive disorder with suicidal ideation or suicidal behavior, melancholic depression, atypical depression, dysthymia, non-suicidal self-injury disorder (NSSID), bipolar and related disorders (including, but not limited to, bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute psychedelic crisis, social anxiety 15 disorder, substance use disorders (including, but not limited to, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder), Alzheimer’s disease, cluster headache and migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain,
  • PTSD
  • the methods provided herein are used to treat a subject with a depressive disorder.
  • a depressive disorder or “depression” refers to a group of disorders characterized by low mood that can affect a person’s thoughts, behavior, feelings, and sense of well-being lasting for a period of time.
  • the depressive 30 disorder disrupts the physical and psychological functions of a person.
  • the depressive disorder causes a physical symptom such as weight loss, aches or pains, headaches, cramps, or digestive problems.
  • the depressive disorder causes a 184
  • the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, 5 catatonic depression, depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD).
  • the disease or disorder is major depressive disorder (MDD).
  • major depressive disorder refers to a condition characterized by a time 10 period of low mood that is present across most situations.
  • Major depressive disorder is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy, and pain without a clear cause.
  • major depressive order is characterized by symptoms of depression lasting at least two weeks.
  • Major depressive disorder can negatively affect a person’s personal, work, or school life, as well as sleeping, eating habits, and general health.
  • Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of people who commit suicide had major depressive disorder or another related mood disorder.
  • Dysthymia is a subtype of major depressive disorder consisting of the same cognitive and physical 20 problems as major depressive disorder with less severe but longer-lasting symptoms.
  • Exemplary symptoms of a major depressive disorder include, but are not limited to, feelings of sadness, tearfulness, emptiness or hopelessness, angry outbursts, irritability or frustration, even over small matters, loss of interest or pleasure in most or all normal activities, sleep disturbances, including insomnia or sleeping too much, tiredness and lack of energy, reduced appetite, weight loss or gain, 25 anxiety, agitation or restlessness, slowed thinking, speaking, or body movements, feelings of worthlessness or guilt, fixating on past failures or self-blame, trouble thinking, concentrating, making decisions, and remembering things, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems, such as back pain or headaches.
  • the term “atypical depression” refers to a condition wherein an individual 30 shows signs of mood reactivity (i.e., mood brightens in response to actual or potential positive events), significant weight gain, increase in appetite, hypersomnia, heavy, leaden feelings in arms or legs, and/or long-standing pattern of interpersonal rejection sensitivity that results in significant 185
  • exemplary symptoms of atypical depression include, but are not limited to, daily sadness or depressed mood, loss of enjoyment in things that were once pleasurable, major changes in weight (gain or loss) or appetite, insomnia or excessive sleep almost every day, a state of physical restlessness or being rundown that is noticeable by others, daily 5 fatigue or loss of energy, feelings of hopelessness, worthlessness, or excessive guilt almost every day, problems with concentration or making decisions almost every day, recurring thoughts of death or suicide, suicide plan, or suicide attempt.
  • the term “bipolar disorder” refers to a condition that causes an individual to experience unusual shifts in mood, energy, activity levels, and the ability to carry out day-to 10 day tasks.
  • Mood episodes are drastically different from the moods and behaviors that are typical for the person.
  • Exemplary symptoms of mania, excessive behavior include, but are not limited to, abnormally upbeat, jumpy, or wired behavior; increased activity, energy, or 15 agitation, exaggerated sense of well-being and self-confidence, decreased need for sleep, unusual talkativeness, racing thoughts, distractibility, and poor decision-making-for example, going on buying sprees, taking sexual risks, or making sheep investments.
  • Exemplary symptoms of depressive episodes or low mood include, but are not limited to, depressed mood, such as feelings of sadness, emptiness, hopelessness, or tearfulness; marked loss of interest or feeling no pleasure 20 in all-or almost all-activities, significant weight loss, weight gain, or decrease or increase in appetite, insomnia or hypersomnia (excessive sleeping or excessive sleepiness), restlessness or slowed behavior, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, decreased ability to think or concentrate, or indecisiveness, and thinking about, planning or attempting suicide.
  • Bipolar disorder includes bipolar I disorder, bipolar II disorder, and 25 cyclothymic disorder. Bipolar I disorder is defined by manic episodes that last at least 7 days or by severe manic symptoms that require hospitalization.
  • bipolar I disorder may also experience depressive episodes typically lasting at least 2 weeks. Episodes of depression with mixed features, i.e., depressive and manic symptoms at the same time, are also possible.
  • Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not severe 30 manic episodes typical of bipolar I disorder.
  • Cyclothymic disorder also referred to as cyclothymia is characterized by periods of hypomanic symptoms (elevated mood and euphoria) and depressive symptoms lasting over a period of at least 2 years. The mood fluctuations are not 186
  • catatonic depression refers to a condition causing an individual to remain speechless and motionless for an extended period.
  • Exemplary symptoms of catatonic 5 depression include, but are not limited to, feelings of sadness, which can occur daily, a loss of interest in most activities, sudden weight gain or loss, a change in appetite, trouble falling asleep, trouble getting out of bed, feelings of restlessness, irritability, feelings of worthlessness, feelings of guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and/or a suicide attempt.
  • the term “depressive disorder due to a medical condition” refers to a condition wherein an individual experiences depressive symptoms caused by another illness.
  • medical conditions known to cause a depressive disorder include, but are not limited to, HIV/AIDS, diabetes, arthritis, strokes, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease, metabolic conditions (e.g., vitamin B12 15 deficiency), autoimmune conditions (e.g., lupus and rheumatoid arthritis), viral or other infections (hepatitis, mononucleosis, herpes), back pain, and cancer (e.g., pancreatic cancer).
  • postpartum depression refers to a condition as the result of childbirth and hormonal changes, psychological adjustment to parenthood, and/or fatigue. Postpartum depression is often associated with women, but men can also suffer from postpartum 20 depression as well.
  • Exemplary symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopeless, emptiness, or overwhelmed; crying more often than usual or for no apparent reason; worrying or feeling overly anxious; feeling moody, irritable, or restless; oversleeping, or being unable to sleep even when the baby is asleep; having trouble concentrating, remembering details, and making decisions; experiencing anger or rage; losing interest in activities 25 that are usually enjoyable; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle pain; eating too little or too much; withdrawing from or avoiding friends and family; having trouble bonding or forming an emotional attachment with the baby; persistently doubting his or ability to care for the baby; and thinking about harming themselves or the baby.
  • premenstrual dysphoric disorder refers to a condition wherein an individual expresses mood lability, irritability, dysphoria, and anxiety symptoms that occur repeatedly during the premenstrual phase of the cycle and remit around the onset of menses or 187
  • exemplary symptoms of premenstrual dysphoric disorder includes, but are not limited to, lability (e.g., mood swings), irritability or anger, depressed mood, anxiety and tension, decreased interest in usual activities, difficulty in concentration, lethargy and lack of energy, change in appetite (e.g., overeating or specific food cravings), hypersomnia or insomnia, feeling 5 overwhelmed or out of control, physical symptoms (e.g., breast tenderness or swelling, joint or muscle pain, a sensation of 'bloating' and weight gain), self-deprecating thoughts, feelings of being keyed up or on edge, decreased interest in usual activities (e.g., work, school, friends, hobbies), subjective difficulty in concentration, and easy fatigability.
  • lability e.g., mood swings
  • irritability or anger irritability or anger
  • depressed mood anxiety and tension
  • decreased interest in usual activities e.g., difficulty in concentration, lethargy and lack of energy
  • change in appetite e.g.,
  • seasonal affective disorder refers to a condition wherein an 10 individual experiences mood changes based on the time of the year. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the fall and/or winter season. In some instances, an individual experiences low mood, low energy, or other depressive symptoms during the spring and/or summer season. Exemplary symptoms of seasonal affective disorder include, but are not limited to, feeling depressed most of the day or nearly every 15 day, losing interest in activities once found enjoyable, having low energy, having problems with sleeping, experiencing changes in appetite or weight, feeling sluggish or agitated, having difficulty concentrating, feeling hopeless, worthless, or guilty, and having frequent thoughts of death or suicide.
  • a depressive disorder comprises a medical diagnosis based on the 20 criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. In some embodiments, a depressive disorder comprises a medical diagnosis based on an independent medical evaluation.
  • the methods described herein are provided to a subject with depression that is resistant to treatment. In some embodiments, the subject has been diagnosed 25 with treatment-resistant depression (TRD).
  • treatment-resistant depression refers to a kind of depression that does not respond or is resistant to at least one or more treatment attempts of adequate dose and duration. In some embodiments, the subject with treatment-resistant depression has failed to respond to 1 treatment attempt, 2 treatment attempts, 3 treatment attempts, 4 treatment attempts, 5 treatment attempts, or more. In some embodiments, the subject with 30 treatment-resistant depression has been diagnosed with major depressive disorder and has failed to respond to 3 or more treatment attempts. In some embodiments, the subject with treatment 188
  • the methods provided herein reduce at least one sign or symptom of a depressive disorder. In some embodiments, the methods provided herein reduce at least one 5 sign or symptom of a depressive disorder by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the methods provided herein reduce at least one sign or symptom 10 of MDD. In some embodiments, the methods provided herein reduce at least one sign or symptom of MDD by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression is measured in a subject before, during, and/or after treatment with the methods described herein. In some embodiments, the sign or symptom of depression is measured according to a diary assessment, an assessment by clinician or caregiver, a clinical rating scale, an imaging test, or a blood of CSF test. In some embodiments, the sign or symptom of depression in a subject is measured using a neuropsychological assessment 20 or clinical rating scale.
  • the neuropsychological assessment or clinical rating scale is the Hamilton Depression Rating Scale, the Clinical Global Impression (CGI) Scale, the Montgomery-Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology (IDS), the Quick Inventory of Depressive Symptomatology (QIDS), 25 Young Mania Rating Scale (YMRS), the Columbia-Suicide Severity Rating Scale (C-SSRS), the Suicidal Ideation Attributes Scale (SIDAS), and/or Mini International Neuropsychiatric Interview (MINI).
  • CGI Clinical Global Impression
  • MADRS Montgomery-Asberg Depression Rating Scale
  • BDI Beck Depression Inventory
  • Zung Self-Rating Depression Scale the Raskin Depression Rating Scale
  • the Inventory of Depressive Symptomatology IDS
  • QIDS Quick Inventory of Depressive Symptomatology
  • YMRS the Columbia-Suicide Severity Rating
  • the sign or symptom of depression in a subject is measured using the Hamilton Depression Rating (HAM-D) scale.
  • the subject's HAM-D score decreases by between about 5% and about 100%, for example, about 5%, 5 about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Clinical Global Impression (CGI) scale.
  • CGI scale is a 3-item scale that measures illness 10 severity, global improvement or change, and therapeutic response.
  • the CGI is rated on a 7-point scale, with the severity of illness measured using a range of responses from 1 (normal) through 7 (amongst the most severely ill subjects).
  • the subject's CGI score decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 15 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Montgomery-Asberg Depression Rating Scale (MADRS).
  • the MADRS scale is a 10-item scale that measures the core symptoms of depression.
  • the subject to be treated has scored at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, and up to 19, up to 18, up to 17, up to 16, up to 15 on the MADRS prior to treatment with the methods herein.
  • the subject to be treated has, prior to beginning treatment with the methods herein, received a moderate to severe 30 diagnosis of depression according to the MADRS.
  • the subject to be treated has, prior to beginning treatment with the methods herein, received a moderate to severe diagnosis of MDD as defined by the DSM, 5th edition (DSM-5).
  • the subject to be 190 is defined by the DSM, 5th edition (DSM-5).
  • treated has scored at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, and up to 60, up to 55, up to 50, up to 45, up to 40, up to 35 on the MADRS prior to treatment with the methods herein, for example a MADRS score of 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, 5 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, or any range therebetween.
  • a clinically meaningful “within-group” change from baseline (“CFB”) on the MADRS has been reported to range between a 6- to 9-point reduction in total score (i.e., a MADRS CFB of -6 to -9).
  • a MADRS CFB of -6 to -9.
  • the change needed to be considered meaningful moves towards the higher end of the range.
  • the patient has a lower MADRS score compared with the subject’s MADRS score prior to treatment (baseline), i.e., the methods result in a negative MADRS Change From Baseline (“CFB”) score.
  • the methods described herein result in a MADRS CFB score, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 points, -14 15 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points, -28 points, -29 points, -30 points, or more, or any range therebetween.
  • a MADRS CFB score e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 points, -14 15 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -
  • the methods described herein result in a MADRS CFB score, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of - 10 to -20 points, -11 to -19 points, -12 to -18 points, or -13 to -17 points.
  • a 2-point difference in MDRS CFB between groups has been found to be clinically meaningful.
  • the methods described herein result in a MADRS CFB score reduction over placebo (also referred to as a placebo subtracted difference in MADRS CFB), e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -8 points, -9 points, 10 points, -11 points, 25 -12 points, -13 points, -14 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points, -28 points, -29 points, -30 points, -32 points, or more, or any range therebetween.
  • placebo also referred to as a placebo subtracted difference in MADRS CFB
  • the methods described herein result in a MADRS CFB score reduction over placebo, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 to -20 points, -12 to -18 points, 30 -13 to 16 points, or -14 to -15 points.
  • the MADRS CFB score reduction over placebo described above may be accompanied by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, 0.001 or less, 0.0005 or less, or 0.0001 or less.
  • CFB score described above can be converted into an effect size (Cohen’s d score) in order to inform about the magnitude of treatment effects.
  • the methods described herein provide an effect size of about 0.9, about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, 5 about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, or any range therebetween, such as from 1 to 3, 1.5 to 2.5, 1.8 to 2.4, or 2 to 2.2.
  • the methods described herein provide an effect size of 1.7 to 2.5, or 1.8 to 2.3, or 2 to 2.2. Such effect sizes are considered to be surprisingly large, especially in MDD treatment, where effect sizes typically range from 0.2 to 0.6. 10
  • the subject's MADRS score decreases from prior to treatment (baseline) by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, or any range therebetween, e.g., 15 at two-weeks post-dose, three-weeks post-dose, etc.
  • the subject's MADRS score decreases from prior to treatment (baseline) by at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%, or any range therebetween, e.g., at three-weeks post-dose.
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% of subjects treated with the methods described herein have a MADRS score decrease from baseline by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 25 85%, about 90%, about 95%, or about 100%, e.g., at two-weeks post-dose, three-weeks post-dose, etc.
  • the methods described herein provide a response rate (i.e., number of responders versus total number of subjects treated within a group) of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60% measured two- 30 weeks post-dose, three-weeks post dose, etc., with responders being defined as subjects who had a reduction of MADRS score from baseline of at least 50%.
  • the methods described herein provide a remission rate (i.e., number of remitters versus total number of subjects treated within a group) of at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 28%, at least 30% measured two-weeks post-dose, three-weeks post dose, etc., with remitters 5 being defined as subjects who had a total MADRS score of 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, 1 or less.
  • the subjects have a sustained response to treatment with the methods of the present disclosure, whereby the reduction from baseline in the MADRS at two-weeks post- dose, three-weeks post dose, etc. (e.g., a MADRS score decreases from baseline of at least about 10 50%) is maintained at least four-weeks post-dose, at least five-weeks post-dose, at least six-weeks post-dose, at least seven-weeks post-dose, at least eight-weeks post-dose, at least nine-weeks post- dose, at least ten-weeks post-dose, at least eleven-weeks post-dose, at least twelve-weeks post- dose, at least 4 months post-dose, at least 5 months post-dose, at least 6 months post-dose.
  • a MADRS score decreases from baseline of at least about 10 50%
  • the sign or symptom of depression in a subject is measured using 15 the Beck Depression Inventory (BDI).
  • BDI Beck Depression Inventory
  • the patient has a lower BDI score compared with the subject’s BDI score prior to treatment (baseline), i.e., the methods result in a negative BDI Change From Baseline (“CFB”) score.
  • baseline BDI Change From Baseline
  • the methods described herein result in a BDI CFB score, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 points, -14 points, -15 points, -16 points, -17 points, -18 points, 25 -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points, -28 points, -29 points, -30 points, or more, or any range therebetween.
  • a BDI CFB score e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 points, -14 points, -15 points, -16 points, -17 points, -18 points, 25 -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -
  • the methods described herein result in a BDI CFB score, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 to -20 points, -11 to -19 points, -12 to -18 points, or -13 to -17 points.
  • the methods described herein result in a BDI CFB 30 score reduction over placebo, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -8 points, -9 points, 10 points, -11 points, -12 points, -13 points, -14 points, -15 points, -16 points, - 17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 193
  • the methods described herein result in a BDI CFB score reduction over placebo, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 to -20 points, -12 to -18 points, -13 to 16 points, or -14 to -15 points.
  • 5 the BDI CFB score reduction over placebo described above may be accompanied by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, 0.001 or less, 0.0005 or less, or 0.0001 or less.
  • the subject's BDI score decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, 10 about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Zung Self-Rating Depression Scale.
  • the Zung Self-Rating Depression Scale is a 20-item self- report questionnaire that measures the psychological and somatic symptoms associated with 15 depression.
  • the questionnaire takes about 10 minutes to complete, and items are framed in terms of positive and negative statements. Each item is scored on a Likert scale ranging from 1 to 4. A total score is derived by summing the individual item scores, and ranges from 20 to 80. Most people with depression score between 50 and 69, while a score of 70 and above indicates severe depression.
  • the subject's 20 Zung Self-Rating Depression score decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using 25 the Raskin Depression Rating Scale.
  • a total score is derived by summing the individual item scores, and scores of 9 or greater represents moderate depression.
  • the subject's Raskin Depression Rating Scale score 30 decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, 194
  • the sign or symptom of depression in a subject is measured using the Inventory of Depressive Symptomatology (IDS).
  • IDS Inventory of Depressive Symptomatology
  • the subject's IDS score decreases by between about 10 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using 15 the Quick Inventory of Depressive Symptomatology (QIDS).
  • the QIDS is a 16-item inventory that measures depressive signs and symptoms.
  • a total score is derived by summing the individual item scores; scores between 11-15 indicate moderate depression, scores between 16-20 indicate severe depression, and scores 21 or greater indicate very severe depression.
  • the subject's QIDS score decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Young Mania Rating Scale (YMRS).
  • a total score is derived by summing the individual item scores; scores between 9-15 indicate mild 30 mania, scores between 16-25 indicate moderate mania, and scores 26 or greater indicate severe mania.
  • the subject's YMRS score decreases by between about 5% and about 100%, for example, about 5%, about 10%, 195
  • the sign or symptom of depression in a subject is measured using 5 the Columbia-Suicide Severity Rating Scale (C-SSRS).
  • C-SSRS measures the severity of suicidal ideation and behavior.
  • a subject is considered to have suicidal ideation and/or behavior if they answer “yes” to any of the 10 questions.
  • the subject's C-SSRS score decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using 15 the Suicidal Ideation Attributes Scale (SIDAS).
  • the SIDAS measures the presence and severity of suicidal thoughts.
  • the subject's SIDAS score decreases by between about 5% and about 20 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the Mini International Neuropsychiatric Interview (for example, version 7.0.2) is 25 a diagnostic interview instrument for psychiatric disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases-10.
  • treating according to the methods of the disclosure results in an improvement in a psychiatric disorder (e.g., depression, etc.) compared to pre-treatment of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, 30 about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to a Mini International Neuropsychiatric Interview 196
  • the subject has a lower MINI 7.0.2 score compared with the subject’s MINI 7.0.2 score prior to treatment.
  • the sign or symptom in subjects with depression is measured using a Spielberger's Trait and Anxiety Inventory, a Generalized Anxiety Disorder 7-Item Scale, a 5 Warwick-Edinburgh Mental Wellbeing Scale, a Flourishing Scale, a Snaith Hamilton Anhedonia Pleasure Scale, a Life Orientation Test, a Meaning in Life Questionnaire, a Brief Resilience Scale, a Dysfunctional Attitudes Scale, a 44-item Big Five Inventory, a Peters 21-item Delusional Inventory, an Examination of Anomalous Self-Experience, a Ruminative Responses Scale, a White Bear Suppression Inventory, a Barrett Impulsivity Scale, a Brief Experiential Avoidance 10 Questionnaire, a Modified Tellegen Absorption Questionnaire, a Scale to Assess Therapeutic Relationship, Credibility
  • the sign or symptom of depression measured using any of the assessments listed above decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using an imaging test before, during, or after treatment with the methods described herein.
  • the imaging test is a CT scan.
  • the imaging test is a functional 197
  • the functional MRI scan measures the blood oxygen level-dependent (BOLD) response as an indicator of brain activity and/or functional connectivity.
  • BOLD response is measured in the subject at resting state, in response to emotional faces, or in response to music.
  • the BOLD response in a region of the brain increases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, or more, compared to prior to treatment.
  • the 10 BOLD response in the amygdala increases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, or more, compared to prior to treatment.
  • the BOLD response in a 15 region of the brain decreases by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the BOLD response in the amygdala decreases by 20 between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to treatment.
  • the sign or symptom of depression is measured using a marker for 25 depression in the blood or cerebral spinal fluid.
  • the marker for depression is measured in the subject before, during, or after treatment with the methods or compositions described herein.
  • the marker for depression is red blood cell folate, serum folate, vitamin B12, plasma homocysteine, serum methylfolate, and/or testing for one or more of brain-derived neurotrophic factor (BDNF) Val66Met, bone morphogenetic protein rs41271330, 30 and/or 5-HTTLPR polymorphisms.
  • BDNF brain-derived neurotrophic factor
  • the marker for depression decreases by between about 5% and about 300%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, 198
  • the marker for depression increases by between about 5% and about 300%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 10 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, or about 300%, or more, compared to prior to treatment.
  • the disease or disorder is an anxiety disorder.
  • anxiety disorder refers to a state of apprehension, uncertainty, and/or fear resulting from the anticipation of an event and/or situation.
  • Anxiety disorders cause physiological and 15 psychological signs or symptoms.
  • physiological symptoms include muscle tension, heart palpitations, sweating, dizziness, shortness of breath, tachycardia, tremor, fatigue, worry, irritability, and disturbed sleep.
  • Non-limiting examples of psychological symptoms include fear of dying, fear of embarrassment or humiliation, fear of an event occurring, etc.
  • Anxiety disorders also impair a subject’s cognition, information processing, stress levels, and 20 immune response.
  • the methods disclosed herein treat chronic anxiety disorders.
  • a “chronic” anxiety disorder is recurring.
  • anxiety disorders include, but are not limited to, generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, panic attack, a phobia-related disorder (e.g., phobias related to flying, heights, specific animals such as spiders/dogs/snakes, receiving injections, blood, etc., agoraphobia), separation 25 anxiety disorder, selective mutism, anxiety due to a medical condition, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), substance-induced anxiety disorder, etc.
  • the subject in need thereof develops an anxiety disorder after experiencing the effects of a disease.
  • the effects of a disease include diagnosis of an individual with said disease, diagnosis of an individual’s loved ones with said disease, social isolation due to 30 said disease, quarantine from said disease, or social distancing as a result of said disease.
  • an individual is quarantined to prevent the spread of the disease.
  • the disease is COVID-19, SARS, or MERS.
  • a subject develops an anxiety disorder after job loss, loss of housing, or fear of not finding employment.
  • the disease or disorder is generalized anxiety disorder (GAD).
  • GAD generalized anxiety disorder
  • Generalized anxiety disorder is characterized by excessive anxiety and worry, fatigue, restlessness, 5 increased muscle aches or soreness, impaired concentration, irritability, and/or difficulty sleeping.
  • a subject with generalized anxiety disorder does not have associated panic attacks.
  • the methods herein are provided to a subject with generalized anxiety disorder also having symptoms of depression.
  • the disease or disorder is social anxiety disorder.
  • social anxiety disorder is a marked fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others.
  • Non-limiting examples of situations which 15 induce social anxiety include social interactions (e.g., having a conversation, meeting unfamiliar people), being observed (e.g., eating or drinking), and performing in front of others (e.g., giving a speech).
  • the social anxiety disorder is restricted to speaking or performing in public.
  • treating according to the methods of the disclosure reduces or ameliorates a symptom of social anxiety disorder.
  • after treating the 20 symptom is reduced compared to prior to treating by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the disease or disorder is a compulsive disorder, such as obsessive- compulsive disorder (OCD), body-focused repetitive behavior, hoarding disorder, gambling 25 disorder, compulsive buying, compulsive internet use, compulsive video gaming, compulsive sexual behavior, compulsive eating, compulsive exercise, body dysmorphic disorder, hoarding disorder, dermatillomania, trichotillomania, excoriation, substance-induced obsessive compulsive and related disorder, or an obsessive-compulsive disorder due to another medical condition, etc., or a combination thereof.
  • the disease or disorder is obsessive-compulsive 30 disorder (OCD).
  • at least one sign or symptom of an anxiety disorder is improved following treatment disclosed herein.
  • treatment causes a demonstrated improvement in one or more of the following: State-Trait Anxiety Inventory (STAI), The Dutch Temperament and Character Inventory (TCI), Dutch Personality Questionnaire-2-Revised (NPV-2-R), Beck Anxiety 5 Inventory (BAI), Hospital Anxiety and Depression Scale (HADS), Generalized Anxiety Disorder questionnaire-IV (GADQ­ IV), Hamilton Anxiety Rating Scale (HARS), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire 4 (PHQ- 4), Social Phobia Inventory (SPIN), Brief Trauma Questionnaire (BTQ), combat Exposure Scale (CES), Mississippi 10 Scale for combat-Related PTSD (M-PTSD), Posttraumatic Maladaptive Beliefs Scale (PMBS), Perceived Threat Scale (DRAI)
  • TAI The Dutch Temperament and Character Inventory
  • NDV-2-R Dutch Personality Questionnaire-2-Re
  • treating according to the methods of the disclosure results in an improvement in an anxiety disorder 30 compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the 201
  • the Spielberger State-Trait Anxiety Inventory is utilized to evaluate the safety and efficacy of the methods of the present disclosure for the treatment of 5 anxiety disorders (e.g., GAD).
  • the STAI is a widely used instrument that contains separate self- report scales for measuring “state” and “trait” anxiety. “State” anxiety is transient anxiety due to a stressful stimulus, whereas “trait” anxiety is the predisposition of a subject to react with anxiety to stressful situations.
  • the STAI is self-reported and contains 40 items scored by a 4 point Likert scale with semantic guides taking approximately 10 minutes.
  • the STAI contains 20 questions 10 related to state anxiety and 20 questions related to trait anxiety. Each section is scored between 20 and 80, with higher scores correlating with greater anxiety. Low scores indicate a mild form of anxiety and high scores indicate a severe form of anxiety. Both scales have anxiety absent and anxiety present questions. Anxiety absent questions represent the absence of anxiety in a statement like, “I feel secure.” Anxiety present questions represent the presence of anxiety in a statement 15 like “I feel concerned.”
  • the patient after treatment with the methods of the present disclosure the patient has a lower STAI score compared with the subject’s STAI score prior to treatment (baseline), i.e., the methods result in a negative STAI Change From Baseline (“CFB”) score.
  • baseline i.e., the methods result in a negative STAI Change From Baseline (“CFB”) score.
  • the methods described herein result in a STAI CFB score, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 20 points, -14 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points, -28 points, -29 points, -30 points, or more, or any range therebetween.
  • a STAI CFB score e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 points, -11 points, -12 points, -13 20 points, -14 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points
  • the methods described herein result in a STAI CFB score, e.g., at two-weeks post-dose, at three-weeks post- dose, etc., of -10 to -20 points, -11 to -19 points, -12 to -18 points, or -13 to -17 points.
  • the methods described herein result in a STAI CFB score reduction over placebo, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -8 points, -9 points, 10 points, -11 points, -12 points, -13 points, -14 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points, -26 points, -27 points, -28 points, -29 points, -30 points, or more, or any range therebetween.
  • placebo e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -8 points, -9 points, 10 points, -11 points, -12 points, -13 points, -14 points, -15 points, -16 points, -17 points, -18 points, -19 points, -20 points, -21 points, -22 points, -23 points, -24 points, -25 points,
  • the methods described herein result in a STAI CFB score reduction over placebo, e.g., at two-weeks post-dose, at three-weeks post-dose, etc., of -10 to -20 points, -12 to -18 points, -13 to 16 points, or -14 to -15 points.
  • placebo described above may be accompanied by a p-value of 0.05 or less, 0.01 or less, 0.005 or less, 0.001 or less, 0.0005 or less, or 0.0001 or less.
  • the subject's STAI score decreases from prior to treatment (baseline) by between about 5% and about 100%, for example, about 5%, about 10%, about 15%, about 20%, 5 about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • At least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% of subjects treated with the methods described herein have a STAI score decrease from baseline by between about 5% and about 100%, for example, 10 about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • the Dutch Temperament and Character Inventory is utilized to evaluate the safety and efficacy of the methods of the present disclosure for the treatment of 15 anxiety disorders (e.g., GAD).
  • the TCI involves 240 bi-directional true-false alternatives, allowing a detailed assessment of personality traits, with a good internal consistency.
  • Temperament is characterized on four dimensions: novelty seeking, harm avoidance, reward dependence, and persistence; character on three dimensions: self-directedness, cooperativeness, and self-transcendence.
  • the four temperament dimensions are assumed to be underlined by 20 specific neurotransmission systems.
  • the Dutch Personality Questionnaire-2-Revised (NPV-2-R) is utilized to evaluate the safety and efficacy of the methods of the present disclosure for the treatment of anxiety disorders (e.g., GAD).
  • the NPV-2-R is the most frequently used (clinical) personality questionnaire in The Netherlands.
  • the NPV-2-R has satisfactory reliability, validity25 and internal consistencies, and includes 140 items. All items are answered on a bi-directional three- point scale (true - ?
  • the NPV-2-R also has subscales; neuroticism has the subscales: depression and anxiety (depressive en 30 angst), social anxiety has the subscales shyness and social avoidance (verlegenheid en paragraph vermijding), rigidity has subscales for neatness and inflexibility (ordelijkheid en inflexibiliteit) and dominance has subscales for leadership and independence (leidinggeven en unless 203
  • the Mini International Neuropsychiatric Interview (MINI) (for example, version 7.0.2) is a diagnostic interview instrument for psychiatric disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the International Classification of Diseases-10.
  • treating according to the methods of the disclosure results in an improvement in a 5 psychiatric disorder (e.g., anxiety, etc.) compared to pre-treatment of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to a Mini International Neuropsychiatric Interview assessment.
  • a 5 psychiatric disorder e.g., anxiety, etc.
  • the subject has a lower MINI 7.0.2 score compared with the subject’s MINI 10 7.0.2 score prior to treatment.
  • the disease or disorder is attention deficit disorder (ADD).
  • ADD is most commonly diagnosed in children under the age of 16 who have 6 or more symptoms of inattention (5 or more for older teenagers) for at least 6 consecutive months, but no signs of hyperactivity/impulsivity.
  • the symptoms of inattention include, but are not limited to, trouble 15 paying attention, avoids long mental tasks such as homework, trouble staying on task, disorganized or forgetful, doesn’t appear to listen when spoken to, doesn’t pay close attention to details. Loses things often, makes careless mistakes, and struggles to follow through with instructions.
  • the disease or disorder is attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • ADHD is marked by an ongoing pattern of inattention and/or hyperactivity-impulsivity.
  • Hyperactivity- 20 impulsivity symptoms may often include, but are not limited to, fidgeting or squirming while seated, leaving their seats in situations where staying seated is expected, running, dashing, or climbing around at inappropriate times, being unable to engage in hobbies quietly, being constantly in motion, talking excessively, answering questions before they are fully asked, having difficulty waiting for one’s turn, and interrupting or intruding on others during conversations or 25 activities.
  • the disease or disorder is a headache disorder.
  • the term “headache disorder” refers to a disorder characterized by recurrent headaches. Headache disorders include migraine, tension-type headache, cluster headache, and chronic daily headache syndrome. 30
  • a method of treating cluster headaches in a subject in need thereof is disclosed herein.
  • at least one sign or symptom of cluster headache is improved following treatment.
  • the sign or symptom of cluster headache is 204
  • Cluster headache is a primary headache disorder and belongs to the trigeminal autonomic cephalalgias.
  • the definition of cluster headaches is a unilateral headache with at least one autonomic symptom ipsilateral to the headache.
  • Attacks are 5 characterized by severe unilateral pain predominantly in the first division of the trigeminal nerve- the fifth cranial nerve whose primary function is to provide sensory and motor innervation to the face.
  • Attacks are also associated with prominent unilateral cranial autonomic symptoms and subjects often experience agitation and restlessness during attacks.
  • a subject with cluster headaches also experiences nausea and/or vomiting.
  • a subject 10 with cluster headaches experiences unilateral pain, excessive tearing, facial flushing, a droopy eyelid, a constricted pupil, eye redness, swelling under or around one or both eyes, sensitivity to light, nausea, agitation, and restlessness.
  • a method of treating migraines in a subject in need thereof is disclosed herein.
  • a migraine is a moderate to severe headache that affects one half or both sides 15 of the head, is pulsating in nature, and last from 2 to 72 hours.
  • Symptoms of migraine include headache, nausea, sensitivity to light, sensitivity to sound, sensitivity to smell, dizziness, difficulty speaking, vertigo, vomiting, seizure, distorted vision, fatigue, or loss of appetite.
  • the migraine is a migraine without aura, a migraine with aura, a chronic migraine, an abdominal migraine, a basilar migraine, a menstrual migraine, an ophthalmoplegic migraine, an ocular migraine, an ophthalmic migraine, or a hemiplegic migraine.
  • the migraine is a migraine without aura.
  • a migraine 25 without aura involves a migraine headache that is not accompanied by a headache.
  • the migraine is a migraine with aura.
  • a migraine with aura is primarily characterized by the transient focal neurological symptoms that usually precede or sometimes accompany the headache. Less commonly, an aura can occur without a headache, or with a non-migraine headache.
  • the migraine is a hemiplegic migraine.
  • a hemiplegic migraine 30 is a migraine with aura and accompanying motor weakness.
  • the hemiplegic migraine is a familial hemiplegic migraine or a sporadic hemiplegic migraine.
  • the migraine is a basilar migraine.
  • a subject with a basilar migraine has a migraine 205
  • the migraine is a menstrual migraine.
  • a menstrual migraine occurs just before and during menstruation.
  • the subject has an abdominal migraine.
  • Abdominal 5 migraines are often experienced by children.
  • Abdominal migraines are not headaches, but instead stomach aches.
  • a subject with abdominal migraines develops migraine headaches.
  • the subject has an ophthalmic migraine also called an “ocular migraine.” Subjects with ocular migraines experience vision or blindness in one eye for a short time with or after a migraine headache.
  • a subject has an ophthalmoplegic 10 migraine.
  • Ophthalmoplegic migraines are recurrent attacks of migraine headaches associated with paresis of one or more ocular cranial nerves.
  • the subject in need of treatment experiences chronic migraines.
  • a subject with chronic migraines has more than fifteen headache days per month.
  • the subject in need of treatment experiences episodic migraines.
  • a subject with episodic migraines has less than 15 fifteen headache days per month.
  • a method of treating chronic daily headache syndrome (CDHS) in a subject in need thereof is disclosed herein.
  • a subject with CDHS has a headache for more than four hours on more than 15 days per month.
  • CHDS affects 4% of the general population.
  • Chronic migraine, chronic 20 tension-type headaches, new daily persistent headache, and medication overuse headaches account for the vast majority of chronic daily headaches.
  • the frequency of headaches and/or related symptoms decreases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, 25 about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to said treating.
  • the length of a headache attack decreases by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 30 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, compared to prior to said treating.
  • At least one sign or symptom of headache disorder is improved following administration of a compound disclosed herein.
  • a sign or symptom of a headache disorder is measured according to a diary assessment, an assessment by a clinician or caregiver, or a clinical scale.
  • treatment of the present disclosure 5 causes a demonstrated improvement in one or more of the following: the Visual Analog Scale, Numeric Rating Scale, the Short Form Health Survey, Profile of Mood States, the Pittsburgh Sleep Quality Index, the Major Depression Inventory, the Perceived Stress Scale, the 5-Level EuroQoL- 5D, the Headache Impact Test; the ID-migraine; the 3-item screener; the Minnesota Multiphasic Personality Inventory; the Hospital Anxiety and Depression Scale (HADS), the 50 Beck10 Depression Inventory (BDI; both the original BD151 and the second edition, BDI-1152), the 9- item Patient Health Questionnaire (PHQ- 9), the Migraine Disability Assessment Questionnaire (MI- DAS), the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1), the European Quality of Life-5 Dimensions (EQ-5D), the Short-form 36 (SF-36), or a combination thereof.
  • the Visual Analog Scale Numeric Rating Scale, the Short Form Health Survey, Profile of Mood States, the Pittsburgh
  • treating according to the methods of the disclosure results in an 15 improvement in a headache disorder compared to pre-treatment of about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the diary assessments, assessments by a clinical or caregiver, or clinical scales, described herein or known in the art.
  • the sign or symptom 20 of the headache disorder is measured according to a diary assessment, a physical or psychological assessment by clinician, an imaging test, an electroencephalogram, a blood test, a neurological examination, or combination thereof.
  • the blood test evaluates blood chemistry and/or vitamins.
  • the disease or disorder is a substance use disorder.
  • Substance 25 addictions which can be treated using the methods herein include addictions to addictive substances/agents such as recreational drugs and addictive medications.
  • addictive substances/agents include, but are not limited to, alcohol, e.g., ethyl alcohol, gamma hydroxybutyrate (GHB), caffeine, nicotine, cannabis (marijuana) and cannabis derivatives, opiates and other morphine-like opioid agonists such as heroin, phencyclidine and phencyclidine-like 30 compounds, sedative hypnotics such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates and psychostimulants such as cocaine, amphetamines and amphetamine-related drugs such as dextroamphetamine and methylamphetamine. Examples of 207
  • addictive medications include, e.g., benzodiazepines, barbiturates, and pain medications including alfentanil, allylprodine, alphaprodine, anileridine benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, 5 dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphano
  • the disease or disorder is alcohol use disorder (AUD).
  • the disease or disorder is nicotine use (e.g., smoking) 15 disorder, and the therapy is used for e.g., smoking cessation.
  • a diary assessment, an assessment by a clinician or caregiver, or a clinical scale is used for measuring the substance use disorder and/or the response to treatment herein.
  • Non-limiting examples of clinical scales, diary assessments, and assessments by a clinician or caregiver include: The Fagerstöm Test for Nicotine Dependence and the Questionnaire on Smoking Urges.
  • the disclosure provides for the management of sexual dysfunction, which may include, but is not limited to, sexual desire disorders, for example, decreased libido; sexual arousal disorders, for example, those causing lack of desire, lack of arousal, pain during intercourse, and orgasm disorders such as anorgasmia; and erectile dysfunction; particularly sexual dysfunction disorders stemming from psychological factors.
  • the disease or disorder is an eating disorder.
  • eating disorder refers to any of a range of psychological disorders characterized by abnormal or disturbed eating habits.
  • Non-limiting examples of eating disorders include pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant/restrictive food intake disorder, binge-eating disorder, other specified feeding or eating disorder, unspecified feeding or eating 30 disorder, or combinations thereof.
  • the eating disorder is pica, anorexia nervosa, bulimia nervosa, rumination disorder, avoidant/restrictive food intake disorder, binge- eating disorder, or combinations thereof.
  • the methods disclosed herein treat 208
  • a “chronic” eating disorder is recurring.
  • at least one sign or symptom of an eating disorder is improved following administration of a compound disclosed herein.
  • a sign or symptom of an eating disorder is measured according to a diary assessment, an assessment by a clinician or 5 caregiver, or a clinical scale.
  • Non-limiting examples of clinical scales, diary assessments, and assessments by a clinician or caregiver include: the Mini International Neuropsychiatric Interview (MINI), the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD), the Eating Disorder Examination (EDE), the Eating Disorder Questionnaire (EDE-Q), the Eating Disorder Examination Questionnaire Short Form (EDE-QS), the Physical Appearance State and 10 Trait Anxiety Scale-State and Trait version (PASTAS), Spielberger State-Trait Anxiety Inventory (STAI), Eating Disorder Readiness Ruler (ED-RR), Visual Analogue Rating Scales (VAS), the Montgomery-Asberg Depression Rating Scale (MADRS), Yale-Brown Georgia Eating Disorder Scale (YBC-EDS), Yale-Brown Georgia Eating Disorder Scale Self Report (YBC-EDS-SRQ), the Body Image State Scale (BISS), Clinical impairment assessment (CIA) questionnaire, the Eating 15 Disorder Inventory (EDI) (e.g.
  • treating according to the methods of the disclosure results in an improvement in an eating disorder compared to pre-treatment of about 5%, about 10%, about 15%, about 20%, about 25%, about 20 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of the diary assessments, assessments by a clinical or caregiver, or clinical scales, described herein or known in the art.
  • the disease or disorder is multiple sclerosis (MS).
  • MS is a chronic, 25 inflammatory disease of unknown etiology that involves an immune-mediated attack on the central nervous system. Myelin and the oligodendrocytes that form myelin appear to be the primary targets of the inflammatory attack, although the axons themselves are also damaged.
  • MS disease activity can be monitored by cranial scans, including magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses.
  • MRI magnetic resonance imaging
  • the diagnosis of clinically 30 definite MS as determined by the Poser criteria requires at least two neurological events suggesting demyelination in the CNS separated in time and in location.
  • Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsing- 209
  • RRMS remitting multiple sclerosis
  • SPMS secondary progressive MS
  • Relapses result from inflammation and demyelination, whereas restoration of nerve conduction and remission is 5 accompanied by resolution of inflammation, redistribution of sodium channels on demyelinated axons and remyelination.
  • the multiple sclerosis is relapsing multiple sclerosis.
  • the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis.
  • the methods herein reduce a symptom of multiple sclerosis in the subject.
  • the symptom is a MRI-monitored multiple sclerosis disease 10 activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased tune to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in 15 whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.
  • the methods herein decrease or inhibit reduction of brain volume.
  • brain volume is measured by percent brain volume change (PBVC).
  • PBVC percent brain volume change
  • the methods herein increase time to confirmed disease progression. In some embodiments, time to confirmed disease progression is 20 increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, for example at least 20-60%.
  • the methods herein decrease abnormalities observed in whole Brain MTR histogram.
  • the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score.
  • the accumulation of physical disability is assessed by the time to confirmed disease progression as 25 measured by Kurtzke Expanded Disability Status Scale (EDSS) score.
  • the disease or disorder is a disease or disorder characterized by, or otherwise associated with, neuroinflammation.
  • Treatment herein may provide cognitive benefits to subject’s suffering from neurological and neurodegenerative diseases such as Alzheimer’s disease and other dementia subtypes, Parkinson’s disease, amyotrophc lateral sclerosis (ALS), and 30 others where neuroinflammation is a hallmark of disease pathophysiology and progression.
  • neurological and neurodegenerative diseases such as Alzheimer’s disease and other dementia subtypes, Parkinson’s disease, amyotrophc lateral sclerosis (ALS), and 30 others where neuroinflammation is a hallmark of disease pathophysiology and progression.
  • ALS amyotrophc lateral sclerosis
  • the methods of the present disclosure 10 are used for the treatment of neurological and neurodegenerative disorders such as Alzheimer’s disease, dementia subtypes, Parkinson’s disease, and amyotrophc lateral sclerosis (ALS), where neuroinflammation is associated with disease pathogenesis.
  • the methods of the present disclosure are used for the treatment of Alzheimer’s disease.
  • the methods of the present disclosure are used for the treatment of dementia.
  • the methods of the present disclosure are used for the treatment of Parkinson’s disease.
  • the methods of the present disclosure are used for the treatment of amyotrophc lateral sclerosis (ALS).
  • ALS amyotrophc lateral sclerosis
  • such treatment may stimulate neurogenesis, provoke neuroplastic changes, and/or provide neuroinflammatory benefits (e.g., reduced neuroinflammation compared to prior to the beginning of treatment), and as a result, may 20 slow or prevent disease progression, slow or reverse brain atrophy, and reduce symptoms associated therewith (e.g., memory loss in the case of Alzheimer’s and related dementia disorders).
  • treating according to the methods of the disclosure 25 results in an improvement in cognition in subject’s suffering from a neurological or neurodegenerative disease compared to pre-treatment of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, according to any one of a diary assessments, assessments by a clinical or caregiver, or 30 clinical scales, described herein or known in the art. Further, many of the behavioral issues associated with chronic and/or life-threatening illnesses, including neurodegenerative disorders such as Alzheimer’s disease, may benefit from 211
  • depression, anxiety, or stress can be common among patients who have chronic and/or life-threatening illnesses such as Alzheimer's disease, autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis), cancer, coronary heart disease, diabetes, epilepsy, HIV/AIDS, 5 hypothyroidism, multiple sclerosis, Parkinson’s disease, and stroke.
  • autoimmune diseases e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis
  • cancer e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis
  • coronary heart disease e.g., systemic lupus erythematosus, rheumatoid arthritis, and psoriasis
  • cancer e.g., systemic lupus erythemat
  • Patients that have depression, anxiety, or stress concurrent with another medical disease or illness can have more severe symptoms of both illnesses and symptoms of depression, 10 anxiety, or stress can continue even as a patient’s physical health improves.
  • the methods described herein can be used to treat depression, anxiety, and/or stress associated with a chronic or life- threatening disease or illness. Accordingly, in some embodiments, the methods herein are used to treat symptoms, e.g., depression, anxiety, and/or stress, associated with a chronic and/or life-threatening disease or 15 disorder, including neurological and neurodegenerative diseases. In some embodiments, the methods provided herein reduce at least one sign or symptom of a neurological and/or neurodegenerative disease.
  • the methods provided herein reduce at least one sign or symptom of a neurological and/or neurodegenerative disease (e.g., depression, anxiety, and/or stress) by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 20 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment, e.g., according to any one of the diary assessments, assessments by a clinical or caregiver, or clinical scales, described herein or known in the art.
  • a neurological and/or neurodegenerative disease e.g., depression, anxiety, and/or stress
  • the disease or disorder is Alzheimer’s disease. In some embodiments, the methods herein are used for the treatment of depression, anxiety, and/or stress associated with Alzheimer’s disease. In some embodiments, the disease or disorder is Parkinson’s disease. In some embodiments, the methods herein are used for the treatment of depression, anxiety, and/or stress associated with Parkinson’s disease. In some embodiments, the disease or 30 disorder is amyotrophc lateral sclerosis (ALS). In some embodiments, the methods herein are used for the treatment of depression, anxiety, and/or stress associated with amyotrophc lateral sclerosis (ALS). In some embodiments, the disease or disorder is cancer related depression and anxiety. 212
  • the methods disclosed herein are used for treatment of brain injury, including traumatic brain injury (TBI).
  • TBI is an injury to the brain caused by an external force, and can be classified based on severity, ranging from mild traumatic brain injury (mTBI/concussion) to severe traumatic brain injury.
  • mTBI/concussion mild traumatic brain injury
  • TBI can also be categorized by mechanism, 5 as either a closed or penetrating head injury, or other features such as whether it is occurring in a specific location or over a widespread area.
  • TBI can result in physical, cognitive, social, emotional and behavioral symptoms, which may be treated herein.
  • Some of the imaging techniques used for diagnosis and recovery markers include computed tomography (CT) and magnetic resonance imaging (MRIs).
  • the disease or disorder is a neurological and developmental disorder such as autism spectrum disorder, including Asperger’s syndrome.
  • Asperger’s syndrome is a subtype of autism spectrum disorder that is treatable with anxiety drugs.
  • Subjects with autism spectrum disorder may present with various signs and symptoms, including, but not limited to, a preference for non-social stimuli, aberrant non-verbal social behaviors, decreased 15 attention to social stimuli, irritability, anxiety (e.g., generalized anxiety and social anxiety in particular), and depression.
  • the autism spectrum disorder comprises a medical diagnosis based on the criteria and classification from Diagnostic and Statistical Manual of Mental Disorders, 5th Ed (DSM-5).
  • autism spectrum disorder including reduced social 20 behavior, anxiety, and depression (see Markopoulos A, Inserra A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder. Front Pharmacol.2022;12:749068).
  • the signs and symptoms of autism spectrum disorder may be treated with the methods herein.
  • the disease or disorder is a genetic condition that causes learning 25 disabilities and cognitive impairment.
  • Fragile X syndrome caused by changes in the gene Fragile X Messenger Ribonucleoprotein 1 (FMR1), which can cause mild to moderate intellectual disabilities in most males and about one-third of affected females.
  • FMR1 Fragile X Messenger Ribonucleoprotein 1
  • Fragile X syndrome and autism spectrum disorder are closely associated because the FMR1 gene is a leading genetic cause of autism spectrum disorder (see Markopoulos A, Inserra 30 A, De Gregorio D, Gobbi G. Evaluating the Potential Use of Serotonergic Psychedelics in Autism Spectrum Disorder. Front Pharmacol. 2022;12:749068).
  • Subjects with fragile X syndrome may display anxiety, hyperactive behavior (e.g., fidgeting and impulsive actions), attention deficit 213
  • the disease or disorder is mental distress, e.g., mental distress in frontline healthcare workers.
  • the compounds and compositions disclosed herein are used for treatment of tic disorders, including Tourette’s Syndrome, which is also variously referred to as Tourette Syndrome, Tourette’s Disorder, Gilles de la Tourette syndrome (GTS), or simply 10 Tourette’s or TS.
  • the tic disorder may also be a pediatric autoimmune disorder associated with streptococcal infection (PANDAS), a transient tic disorder, a chronic tic disorder, or a tic disorder not otherwise specified (NOS).
  • Tic disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM) based on type (motor or phonic) and duration of tics (sudden, rapid, nonrhythmic movements), or similarly by the World Health Organization (ICD-10 codes).
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • ICD-10 codes World Health Organization
  • Transient tic disorders are generally characterized by multiple motor and/or phonic tics that occur for at least four weeks but less than 12 months.
  • Chronic tic disorders are generally characterized by either single or multiple motor or phonic tics, but not both, which are present for more than a year. Tourette's Syndrome is diagnosed when both motor and phonic tics are present (although not necessarily concurrently) for more than one year.
  • Tourette’s syndrome is a chronic 25 neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics.
  • the typical age of onset is between five and seven years. Affected children may become the target of teasing by peers, which in turn can result in low self-esteem, social isolation, poor school performance, depression and anxiety.
  • sudden, forceful tics can be painful, and violent head and neck tics have been reported to cause secondary 30 neurologic deficits, such as compressive cervical myelopathy.
  • Tourette's Syndrome patients are also at increased risk for obsessive-compulsive disorder (OCD), depression, and attention-deficit- hyperactivity disorder (ADHD).
  • OCD obsessive-compulsive disorder
  • ADHD attention-deficit- hyperactivity disorder
  • the methods of the present disclosure can also be used for the treatment of tics induced as a side effect of a medication; tics associated with autism; and Tourettism (the presence of Tourette-like symptoms in the absence of Tourette's Syndrome (e.g., as a result of another disease or condition, such as a sporadic, genetic, or neurodegenerative 5 disorder)).
  • the disease or disorder is a fluency disorder.
  • a “fluency disorder” is an interruption in the flow of speaking characterized by atypical rate, rhythm, and disfluencies (e.g., repetitions of sounds, syllables, words, and phrases; sound prolongations; and blocks), which may also be accompanied by excessive tension, speaking avoidance, struggle 10 behaviors, and secondary mannerisms. People with fluency disorders also frequently experience psychological, emotional, social, and functional impacts as a result of their communication disorder.
  • Childhood-onset fluency disorder is an interruption in the flow of speaking characterized by specific types of disfluencies, including (i) repetitions of sounds, syllables, and monosyllabic words; (ii) prolongations of consonants when it 15 isn’t for emphasis; and (iii) blocks (i.e., inaudible or silent fixation or inability to initiate sounds).
  • These disfluencies can affect the rate and rhythm of speech and may be accompanied by negative reactions to speaking; avoidance behaviors (i.e., avoidance of sounds, words, people, or situations that involve speaking); escape behaviors, such as secondary mannerisms (e.g., eye blinking and head nodding or other movements of the extremities, body, or face); and physical tension.
  • avoidance behaviors i.e., avoidance of sounds, words, people, or situations that involve speaking
  • escape behaviors such as secondary mannerisms (e.g., eye blinking and head nodding or other movements of the extremities, body, or face); and physical tension.
  • Children 20 and adults who stutter also frequently experience psychological, emotional, social, and functional consequences from their stuttering, including anxiety (e.g., social anxiety), a sense of loss of control, and negative thoughts or feelings about themselves or about communication.
  • Childhood- onset fluency disorder can co-occur with other disorders, such as attention- deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, language or 25 learning disability, seizure disorders, anxiety disorders (e.g., social anxiety disorder), speech sound disorders, and other developmental disorders.
  • the disease or disorder may include conditions of the autonomic nervous system (ANS).
  • the disease or disorder may include pulmonary disorders (e.g., 30 asthma and chronic obstructive pulmonary disorder (COPD).
  • the disease or disorder may include cardiovascular disorders (e.g., atherosclerosis). 215
  • the disclosure provides for the management of different kinds of pain, including but not limited to cancer pain, e.g., refractory cancer pain; neuropathic pain; postoperative pain; opioid-induced hyperalgesia and opioid-related tolerance; neurologic pain; postoperative/post-surgical pain; complex regional pain syndrome (CRPS); shock; limb 5 amputation; severe chemical or thermal burn injury; sprains, ligament tears, fractures, wounds and other tissue injuries; dental surgery, procedures and maladies; labor and delivery; during physical therapy; radiation poisoning; acquired immunodeficiency syndrome (AIDS); epidural (or peridural) fibrosis; orthopedic pain; back pain; failed back surgery and failed laminectomy; sciatica; painful sickle cell crisis; arthritis; autoimmune disease; intractable bladder pain; pain 10 associated with certain viruses, e.g., shingles pain or herpes pain; acute nausea, e.g., pain that may be causing the nausea or the abdominal pain that frequently accompanies sever nausea; migraine
  • cancer pain
  • the pain may be persistent or chronic pain that lasts for weeks to years, in some cases even though the injury or illness that caused the pain has healed or gone away, and in some cases despite previous medication and/or treatment.
  • the disclosure includes the treatment/management of any combination of these types of pain or conditions.
  • the pain treated/managed is acute breakthrough pain or pain related to wind-up that can occur in a chronic pain condition.
  • the pain treated/managed is cancer pain, e.g., refractory cancer pain.
  • the pain treated/managed is post-surgical pain.
  • the pain treated/managed is orthopedic pain.
  • the pain 25 treated/managed is back pain.
  • the pain treated/managed is neuropathic pain. In some embodiments of the disclosure, the pain treated/managed is dental pain. In some embodiments of the disclosure, the condition treated/managed is depression. In some embodiments of the disclosure, the pain treated/managed is chronic pain in opioid-tolerant patients. 30 In some embodiments, the disease or disorder is arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, childhood arthritis, fibromyalgia, gout, and lupus. In some embodiments, the disease or disorder is osteoarthritis. In some embodiments, the disease or 216
  • Fibromyalgia is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, 5 memory and mood issues. Fibromyalgia is believed to amplify painful sensations by affecting brain and spinal cord processes involving painful and nonpainful signaling. Symptoms often begin after an event, such as physical trauma, surgery, infection or significant psychological stress. In other cases, symptoms gradually accumulate over time with no single triggering event.
  • the disease or disorder is inflammatory bowel disease (IBD).
  • IBD is a term for two conditions, Crohn’s disease and ulcerative colitis, that are characterized by chronic inflammation of the gastrointestinal (GI) tract, with such prolonged inflammation resulting 15 in damage to the GI tract.
  • Subjects suffering from IBD may experience persistent diarrhea, abdominal pain, rectal bleeding/bloody stools, weight loss, and fatigue.
  • the disease or disorder is a sleep disorder such as narcolepsy, insomnia, nightmare disorder, sleep apnea, central sleep apnea, obstructive sleep apnea, hypopnea, sleep-related hypoventilation, restless legs syndrome, and jet lag.
  • the disease or disorder is narcolepsy.
  • the method is used to treat a disease or condition by modulating N- 25 methyl-D-aspartic acid (NMDA) activity.
  • the disease or condition is selected from: levodopa-induced dyskinesia; dementia (e.g., Alzheimer's dementia), tinnitus, treatment resistant depression (TRD), major depressive disorder, melancholic depression, atypical depression, dysthymia, neuropathic pain, agitation resulting from or associated with Alzheimer's disease, pseudobulbar effect, autism, Bulbar function, generalized anxiety disorder, Alzheimer's 30 disease, schizophrenia, diabetic neuropathy, acute pain, depression, bipolar depression, suicidality, neuropathic pain, or post-traumatic stress disorder (PTSD).
  • the disease or condition is a psychiatric or mental disorder (e.g., schizophrenia, mood disorder, substance 217
  • the disease or condition is a neurological disorder (e.g., Huntington's disease (HD), Alzheimer's disease (AD), 5 or systemic lupus erythematosus (SLE)).
  • a neurological disorder e.g., Huntington's disease (HD), Alzheimer's disease (AD), 5 or systemic lupus erythematosus (SLE)).
  • the disclosure relates to a method of treating an ocular disease, such as uveitis, corneal disease, ulceris, iridocyclitis, glaucoma, and cataracts, by administering ophthalmically the pharmaceutical formulation, for example, in the form of an eye drop formulation.
  • the administering physician can provide a method of treatment that is prophylactic or therapeutic by adjusting the amount and timing of any of the salt forms of the compounds described herein on the basis of observations of one or more symptoms of the disorder or condition being treated.
  • the subject is a mammal.
  • the mammal is a 15 human.
  • the pharmaceutical formulations of the present disclosure may be used as a standalone therapy.
  • the pharmaceutical formulations of the present disclosure are administered without psychological support. 20 Adjuvant/Combination Therapy
  • the pharmaceutical formulations of the present disclosure may be used as an adjuvant/combination therapy.
  • the subject with a disorder is administered a pharmaceutical formulation of the present disclosure and at least one additional therapy and/or therapeutic.
  • administration of an additional therapy and/or 25 therapeutic is prior to administration of the pharmaceutical formulation of the present disclosure.
  • administration of an additional therapy and/or therapeutic is after administration of the pharmaceutical formulation of the present disclosure.
  • administration of an additional therapy and/or therapeutic is concurrent with administration of the pharmaceutical formulation of the present disclosure.
  • administration of an 30 additional therapy and/or therapeutic is prior to, during, and/or after administration of the pharmaceutical formulation of the present disclosure.
  • the pharmaceutical formulation of the present disclosure may be accompanied by psychotherapy before, during, and/or after each dose.
  • the pharmaceutical formulation of the present disclosure may be administered using a different dosing schedule than the additional 5 therapy and/or therapeutic.
  • the subject may be taking an antidepressant medication on a daily schedule (e.g., daily oral dosing), while the pharmaceutical formulation of the present disclosure may be administered using an intermittent dosing schedule as described herein, e.g., one dose in a treatment course or two doses administered three weeks apart ( ⁇ 3 days) in a treatment course.
  • adjunctive therapy or combination therapy provides 10 detectable plasma levels of the psychopharmaceutical agent and the at least one additional therapeutic (e.g., antidepressant medication) at the same time.
  • a subject taking an antidepressant medication on a daily schedule e.g., daily oral dosing
  • adjunctive therapy or combination therapy does not lead to detectable plasma levels of the psychopharmaceutical agent and the at least one additional therapeutic (e.g., antidepressant medication) at the same time.
  • the pharmaceutical formulation comprises a tryptamine psychedelic (e.g., a pharmaceutically acceptable salt of a compound of Formula (I) through (III)) as the 20 psychopharmaceutical agent
  • the additional therapeutic is an antidepressant medication, an anticonvulsant, lisdexamfetamine dimesylate, an antipsychotic, an anxiolytic, an anti- inflammatory drug, a benzodiazepine, an N-methyl-D-aspartate (NMDA) receptor antagonist, an analgesic drug, a cardiovascular drug, an opioid antagonist, or combinations thereof.
  • the additional therapeutic is an antidepressant medication.
  • the pharmaceutical formulation of the present disclosure is used in adjuvant therapy for patients already taking an antidepressant medication (e.g., SSRIs, SNRIs, etc.).
  • an antidepressant medication e.g., SSRIs, SNRIs, etc.
  • the psychopharmaceutical agent contained within the pharmaceutical formulation of the present disclosure is considered herein to be separate and distinct from the 30 antidepressant medication, despite both potentially having antidepressant properties.
  • “antidepressant medication” refers to non-psychedelic agents, with most regulator-approved antidepressant medications being monoamine antidepressant agents 219
  • the antidepressant medication is an approved pharmacological treatment for a depressive disorder in at least one jurisdiction, such as the United States of America, the European Union, the United 5 Kingdom, Australia, New Zealand, and Japan.
  • an antidepressant medication indirectly affects a neurotransmitter receptor, e.g., via interactions affecting the reactivity of other molecules at a neurotransmitter receptor.
  • the antidepressant medication is an agonist.
  • the antidepressant medication is an antagonist.
  • the antidepressant medication is a tricyclic antidepressant 10 (“TCA”), selective serotonin reuptake inhibitor (“SSRI”), serotonin reuptake inhibitor (“SRI”), serotonin and noradrenaline reuptake inhibitor (“SNRI”), dopamine reuptake inhibitor (“DRI”), noradrenaline reuptake inhibitor (“NRU”), dopamine, serotonin, and noradrenaline reuptake inhibitor (“DSNRI”), a monoamine oxidase inhibitor (“MAOI”), including a reversible inhibitor of monoamine oxidase type A (RIMA), or combinations thereof.
  • TCA tricyclic antidepressant 10
  • SSRI selective serotonin reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • SNRI serotonin and noradrenaline reuptake inhibitor
  • DRI dopamine reuptake inhibitor
  • NRU noradrenaline reuptake inhibitor
  • the TCA is imipramine or clomipramine.
  • the antidepressant medication is a serotonin reuptake inhibitor (“SRI”).
  • the antidepressant medication is a selective serotonin reuptake inhibitor (SSRI).
  • the SSRI is citalopram, escitalopram, paroxetine, sertraline, fluvoxamine, fluoxetine, or combinations thereof.
  • the 20 antidepressant medication is a serotonin and noradrenaline reuptake inhibitor (SNRI).
  • the SNRI is venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, or combinations thereof.
  • the antidepressant effects are augmented with the use of pregabalin as an additional therapeutic.
  • the antidepressant medication acts (either directly or indirectly) at more than one type of neurotransmitter receptor. 25
  • the antidepressant medication is chosen from buproprion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, dextromethorphan, cariprazine, vortioxetine, vilazodone, and levomilnacipram.
  • Antidepressant medications such as SSRIs are usually taken orally, typically in tablet form, and usually need to be taken daily.
  • the pharmaceutical 30 formulation of the present disclosure is used as adjuvant therapy for patients taking a stable dose of antidepressant medication, such as patients on background antidepressant medication(s) including SSRIs and SNRIs.
  • the pharmaceutical formulation of the present 220 is used as adjuvant therapy for patients taking a stable dose of antidepressant medication, such as patients on background antidepressant medication(s) including SSRIs and SNRIs.
  • the subject is taking an antidepressant medication monotherapy.
  • the subject is taking a combination of antidepressant medications.
  • the subject is taking an 5 antidepressant medication such as citalopram, escitalopram, paroxetine, sertraline, fluoxetine, venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, buproprion, vortioxetine, vilazodone, or combinations thereof.
  • the additional therapeutic is an anticonvulsant.
  • the anticonvulsant is gabapentin, carbamazepine, ethosuximide, lamotrigin, 10 felbamate, topiramate, zonisamide, tiagabine, oxcarbazepine, levetiracetam, divalproex sodium, phenytoin, fosphenytoin.
  • the anticonvulsant is topiramate.
  • the additional therapeutic is an antipsychotic.
  • the antipsychotic is a phenothiazine, butryophenone, thioxanthene, clozapine, risperidone, olanzapine, or sertindole, quetiapine, aripiprazole, zotepine, perospirone, a 15 neurokinin-3 antagonist, such as osanetant and talnetant, rimonabant, or a combination thereof.
  • the additional therapeutic is an anxiolytic.
  • an anxiolytic is chosen from alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.
  • the additional therapeutic is an anti-inflammatory drug.
  • the anti-inflammatory drug is a nonsteroidal anti-inflammatory drugs (NSAIDS), steroid, acetaminophen (COX-3 inhibitors), 5-lipoxygenase inhibitor, leukotriene receptor antagonist, leukotriene A4 hydrolase inhibitor, angiotensin converting enzyme antagonist, beta blocker, antihistaminic, histamine 2 receptor antagonist, phosphodiesterase-4 antagonist, cytokine 25 antagonist, CD44 antagonist, antineoplastic agent, 3-hydroxy-3-methylglutaryl coenzyme A inhibitor (statins), estrogen, androgen, antiplatelet agent, antidepressant, Helicobacter pylori inhibitors, proton pump inhibitor, thiazolidinedione, dual-action compounds, or combination thereof.
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • COX-3 inhibitors COX-3 inhibitors
  • 5-lipoxygenase inhibitor 5-lipoxygenase inhibitor
  • leukotriene receptor antagonist leukotriene A4 hydrolase inhibitor
  • the additional therapeutic is a benzodiazepine. In some 30 embodiments, the benzodiazepine is diazepam or alprazolam. In some embodiments, the additional therapeutic is a N-methyl-D-aspartate (NMDA) receptor antagonist. In some embodiments, the NMDA receptor antagonist is ketamine. In some 221
  • the NMDA receptor antagonist is nitrous oxide.
  • the additional therapeutic is an analgesic.
  • the analgesic is acetaminophen.
  • the analgesic is a nonsteroidal anti- inflammatory drug (NSAID), such as aspirin, ibuprofen and naproxen.
  • the 5 analgesic is a COX-2 inhibitor, such as rofecoxib, celecoxib, parecoxib, and etoricoxib.
  • the analgesic is an opioid.
  • the additional therapeutic is a cardiovascular drug.
  • Non-limiting examples of cardiovascular drugs include digoxin or (3 ⁇ ,5 ⁇ ,12 ⁇ )-3-[(O-2,6-dideoxy- ⁇ -D-ribo- hexopyranosyl-(1 ⁇ 4)-O-2,6-dideoxy- ⁇ -D-ribo-hexopyranosyl-(1 ⁇ 4)-2,6-dideoxy- ⁇ -D- 10 ribohexopyranosyl) oxy]-12,14-dihydroxy-card-20(22)-enolide, lisinopril, captopril, ramipril, trandolapril, benazepril, cilazapril, enalapril, moexipril, perindopril, quinapril, fludrocortisone, enalaprilate, quinapril, perindopril, apixaban, dabigatran, edoxaban, heparin, rivaroxaban, war
  • the additional therapeutic is an opioid antagonist.
  • opioid antagonists include naloxone, naltrexone, nalmefene, nalorphine, nalrphine20 dinicotinate, levallrphan, samidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol, 6- naltrexol, axelopran, bevenopran, methylsamidorphan, naldemedine, buprenorphine, decozine, butorphanol, levorphanol, nalbuphine, pentazocine, and phenazocine.
  • the additional therapeutic is a serotonin receptor modulator.
  • serotonin receptor modulators include glemanserin (MDL-11,939), 25 eplivanserin (SR-46,349), ketanserin, ritanserin, altanserin, acepromazine, mianserin, mirtazapine, quetiapine, SB204741, SB206553, SB242084, LY272015, SB243213, blonanserin, SB200646, RS102221, nefazodone, volinanserin (MDL-100,907), pimavanserin (ACO-103), nelotanserin, lorcaserin, flibanserin, and roluperiodone.
  • the subject is administered at least one therapy in addition to 30 administration of the pharmaceutical formulation of the present disclosure.
  • therapies include transcranial magnetic stimulation, cognitive behavioral therapy, interpersonal psychotherapy or psychedelic-assisted psychotherapy (PAP), dialectical behavior therapy, 222
  • a method of treating a subject in need thereof comprises 5 administering to the subject a therapeutically effective amount of the pharmaceutical formulation in a controlled environment, wherein the subject is provided with psychological support.
  • a method of treating a subject in need thereof comprises at least one of the following: (i) administering to the subject a therapeutically effective amount of the pharmaceutical 10 formulation in a controlled environment, wherein the subject is provided with psychological support; (ii) having the subject participate in one or more pre-administration psychological support session(s); and/or (iii) having the subject participate in one or more post-administration psychological 15 support session(s).
  • the subject may not feel the effects of the drug for about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, or any range therebetween. This period after administration and before the onset of effects will be referred to herein as the initial stage of the treatment session.
  • the time marked by the onset of the drug’s effects will be referred to herein as the early stage of the treatment session.
  • the subject will experience peak effects at about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 1.75 hours, about 2 hours after administration, or any range therebetween.
  • the time period marked by the peak drug 25 experience will be referred to herein as the peak stage of the treatment session.
  • the effects may substantially wear off from about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 2 hours after administration, or any range therebetween. This time period will be referred to as the late stage of the treatment session.
  • the subject s ability to reach a non-dual state (e.g., a mystical experience), or a sense of unity, boundlessness, ego-dissolution or transcendence correlates with positive clinical outcome.
  • a non-dual state e.g., a mystical experience
  • a sense of unity, boundlessness, ego-dissolution or transcendence correlates with positive clinical outcome.
  • Pre-administration psychological support session the subject participates in at least one psychological support session before administration begins (“pre-administration psychological support session” or “preparation session”).
  • a pre-administration psychological support session may be held 15 about 1 month prior to the administration.
  • a pre-administration psychological support session may be held about 2 weeks prior to the administration.
  • a pre-administration psychological support session may be held about 1 week prior to the administration.
  • a pre-administration psychological support session may be held about 3 days prior to the administration.
  • a pre-administration 20 psychological support session may be held about 1 day prior to the administration.
  • a pre-administration psychological support session may be held on the same day as and prior to administration. In some embodiments, a pre-administration psychological support session may be held in any range in between about 1 month prior to the administration to the same day as administration. 25
  • the subject may participate in one, two, three, four, five, six, seven, or eight pre-administration psychological support sessions. In some embodiments, the subject may participate in at least two pre-administration psychological support sessions. In some embodiments, the subject may participate in at least three pre-administration psychological support sessions. In some embodiments, the subject may participate in pre-administration 30 psychological support sessions at least once per week, for at least two or three weeks prior to the administration session. In some embodiments, the subject may additionally participate in a pre- administration psychological support session the day before the administration session. 224
  • the pre-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a therapist.
  • the psychological support sessions may be group sessions, wherein more than one subject meets with a single therapist, or more than one therapist.
  • one or more of the subject’s family members or 5 friends may be present at the pre-administration psychological support session(s).
  • the goals of the pre-administration session may include (i) establishing therapeutic alliance between subject and therapist; (ii) answering the subject’s questions and addressing any concerns; and/or (iii) demonstrating and practicing the skills of self- directed inquiry and experiential processing.
  • the pre-administration 10 psychological support sessions focus on discussion of possible psychedelic effects, and/or preparing subjects for the dosing session by practicing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting relevant therapeutic goals, building rapport, and/or establishing therapeutic alliance.
  • skills of self-directed inquiry and experiential processing may be demonstrated and/or practiced.
  • breathing 15 exercises meant to promote calm and/or ease anxiety may be demonstrated and/or practiced.
  • the breathing exercise comprise instructing the subject to focus on their breath and/or sensations associated with the breath throughout the body. For example, the subject may be instructed to breathe in for a count of four, to hold their breath for a moment, and then to breathe out for a count of eight.
  • the therapist and subject may discuss the most 20 helpful ways to support in case of emotional distress during the treatment session.
  • the subject is given access (e.g., online access) to materials concerning the safety and mechanism of action of the drug.
  • the pre-administration psychological support sessions will serve to establish a therapeutic goal for the treatment session.
  • the subject suggests 25 the therapeutic goal for herself or himself.
  • the therapist suggests the therapeutic goal to the subject.
  • the subject is reminded of the therapeutic goal during the pre-administration psychological support session.
  • the therapists are trained to counsel the subject before, during, and/or after the treatment sessions.
  • the therapist will have mental health 30 training.
  • the therapist will be a clinical psychologist, a psychiatrist, a social worker, a doctor or a nurse.
  • the therapist will meet the following criteria: (i) demonstrate independent clinical experience with direct subject care in areas that require 225
  • Treatment Sessions 5
  • the subject may be supervised by one or more trained therapists.
  • the therapist supervising the subject during the treatment session may be the same therapist from the subject’s pre-administration psychological support session(s), or may be a different therapist.
  • the therapist(s) may provide psychological support to the subject as necessary.
  • the term “psychological support” refers to any measure(s) taken by the therapist 10 during the subject’s treatment session to ensure the safety of the subject and maximize the clinical effectiveness of the treatment session.
  • the psychological support may be anything done by the therapist to (1) to ensure psychological safety of the subject; (2) to allow the subject’s subjective experience to unfold naturally within the boundaries of the therapeutic intention set at the preparation; (3) to maintain participant’s attention and awareness on the experience of the 15 present moment thus allowing exposure and processing of the challenging emotional states and personal memories; and/or (4) to generate insights and solutions for the resolution of challenging personal situations, conflicts and traumatic experiences.
  • support can be in the form of therapeutic touch, verbal reassurance, guided imagery and/or relaxation or breathing exercises.
  • the support may comprise reminders, encouragement, or active 20 guiding. Typically, only one technique is applied at a time to allow for minimal intervention and interference with the subject’s unique process.
  • the main therapeutic goals of the therapist during the treatment session are to (i) minimize extreme anxiety, and (ii) provide appropriate support that enables the skills and processes of self-directed inquiry and experiential processing.
  • 25 the therapist demonstrates genuine presence, patience, curiosity, and/or openness during the treatment session.
  • Presence refers to being totally available and present with the subject during all stages of the treatment session, and exuding calmness at all times.
  • “Curiosity” refers to interest and willingness to understand the subject’s experience, without making assumptions.
  • “Patience” means that the therapist facilitates the participant taking as much time as needed to explore their 30 experiences without controlling the natural urge to help or direct the experience. “Openness” is the ability of the therapist to remain cognitively and experientially open, including a capacity to 226
  • the psychological support may comprise curious questioning.
  • questioning of subjects is used to help the subjects shift and 5 sustain their attention towards different levels of cognition and emotions (“How does that make you feel?”). Due to the applicability across a range of mental states and within various settings, the technique of curious questioning can typically be used safely and consistently during the treatment session, regardless of the quality or intensity of the experience of each subject.
  • the level of psychological support will vary during the various 10 stages of the subject’s treatment experience (e.g., the initial stage, the early stage, the peak stage, and the late stage).
  • the type of psychological support will vary during the various stages of the subject’s treatment experience (e.g., the initial stage, the early stage, the peak stage, and the late stage). Because non-dual, ego-dissolution or “unitive” experiences have been shown to positively correlate with the magnitude and durability of the clinical response, the 15 therapist will, in some embodiments, attend to such states with particular care. In some embodiments, a subject may experience of a compromised sense of self during the subject’s treatment experience.
  • non-dual, ego-dissolution or “unitive” experiences refer to an altered state of consciousness in which there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a compromised sense of “self’ and instead only a undivided background awareness, often characterized by a sense of unity or “oneness” that exceeds sensory or cognitive apprehension.
  • a non-dual 25 experience is state of consciousness in which the subject-object dichotomy in normal waking consciousness is substituted for a unified background awareness that is centerless and undivided.
  • an ego dissolution experience is a spontaneously occurring state of consciousness where there is a reduction in the self-referential awareness that defines normal waking consciousness, resulting in a compromised sense of “self’.
  • a unitive 30 experience is an experience characterized by a sense of unity or “oneness” that exceeds sensory or cognitive apprehension. 227
  • psychological support may be used to reduce severe and/or prolonged anxiety.
  • Anxiety prior to or during the onset of effects may not be uncommon, and the therapists may be specially trained to recognize and actively manage subjects through such periods of anxiety until the subject is comfortable enough to continue on 5 their own.
  • therapists validate the subject’s feelings of anxiety without providing interpretations of perceptual disturbances or guiding subjects towards a particular image or memory, other than encouraging them to stay relaxed and open to the emergent experiences.
  • the therapist may help alleviate anxiety using a grounding exercise. In such an exercise, the subject may be encouraged to pay attention to the sounds around 10 them or to sensations on their skin when touching the bed/couch, ground, or other objects.
  • the therapist may encourage the subject to lie down, practice relaxation and breathing exercises, and/or listen to calming music.
  • the therapist may remind the subject of the intention for the treatment session. For example, the therapist may ask the subject “What does feeling better or recovery feel like?” 15 or any number of similar questions. Such reminders prior to the onset of or at the onset of effects provide an implicit direction for the subjective experience during the treatment session.
  • the therapist may remind the subject that their primary task during this session is to simply collect new and interesting experiences which can then be discussed with the therapist after the session.
  • the therapist may remind the participant of the purpose of the therapy and the role of 20 experiential processing, namely allowing the participant to be open and curious to whatever arises and encountering thoughts and feelings previously unknown to them.
  • the therapist emphasizes that this process inherently requires letting go and a willing passivity to the psychedelic experience.
  • the subject might experience perceptual changes in visual, 25 auditory or olfactory modes, and a range of unusual physical sensations. These experiences could be anxiety-provoking.
  • the therapist may practice reassuring “arm holding”.
  • the therapist may encourage the subject to put on an eye mask, such as a Mindfold eyeshade. In some embodiments, the therapist encourages the subject to put on the eye mask before, during, or after the onset of the effects. In some embodiments, the therapist may encourage the subject to put on headphones and 5 listen to music. In some embodiments, the headphones reduce outside noise (e.g., “noise- cancelling” headphones). In some embodiments, the music is calming music such as instrumental (e.g., classical) music. In some embodiments, the music comprises nature sounds and/or the sound of moving water (e.g., ocean sounds). In some embodiments, the music comprises isochronic tones. In some embodiments, the music comprises moments of silence.
  • an eye mask such as a Mindfold eyeshade. In some embodiments, the therapist encourages the subject to put on the eye mask before, during, or after the onset of the effects. In some embodiments, the therapist may encourage the subject to put on headphones and 5 listen to music. In some embodiments,
  • the 10 music is emotionally evocative.
  • the music comprises a playlist which mirrors the pharmacodynamics of a typical high-dose treatment session: the initial stage, the early stage, the peak stage, and the late stage.
  • listening to music helps the subject to focus on their internal experience.
  • therapists may, in some embodiments, actively 15 guide participants through such experiences without interpreting or judging the experiences or giving advice. Once participants are comfortable, the therapist may encourage them to again engage in introspection. During the peak and late stages of the treatment session, the therapist may encourage subjects to face and explore their experience, including the challenging ones.
  • self-directed inquiry refers to directing attention to internal 25 states. Subjects are encouraged to be curious about experiences in the present moment, including foreground and background thoughts, emotions, and physical sensations. During the preparation and integration stages, this inquiry might mean asking specific and detailed questions to help direct attention to internal states. However, during the period of drug action, inquiry might simply mean an attitude of openness to inner experiences. 30 As used herein, “experiential processing” refers to a participant’s ability to maintain full attention on the experiences that come into awareness through self-directed enquiry. This includes 229
  • the therapist will employ a transdiagnostic therapy.
  • the transdiagnostic therapy is a Method of Levels (MOL) therapy.
  • the MOL therapy comprises Self­Directed Enquiry and Experiential Processing.
  • MOL uses brief, but detailed, curious questioning to help subjects shift and sustain their attention towards different levels of cognition and emotions. The emphasis within MOL is on identifying and working with a subject’s underlying distress as opposed to just their symptoms.
  • MOL related methods and techniques can include: (1) Self-directed enquiry-directing 10 attention to internal states.
  • the psychological support comprises mindfulness-based therapy or cognitive behavioral therapy (CBT).
  • the psychological support is informed by a functional theory of human behavior called Perceptual Control Theory.
  • Perceptual Control Theory a functional theory of human behavior
  • the subject will try to avoid emerging experiences or distract him/herself while trying to regain cognitive control over the unusual state of their mind.
  • Such distractions may 25 take different forms.
  • the subject might want to engage in a conversation or prematurely describe in detail their experience, visions or insights.
  • the therapist may aim to remain as silent as possible, thereby enabling the subject and his/her inner experience to direct the course of the treatment session.
  • the therapist may use active listening skills paired with prompts to encourage the subject to continue focusing attention on 30 present experiences, particularly if the participant engages the therapist in conversation.
  • a subject might ask to go to the bathroom or have a drink of water. The sudden and urgent character of such requests might suggest that they are really trying to avoid emerging material.
  • 230 a functional theory of human behavior
  • the therapist may encourage the subject to stay with the experience by simply redirecting their attention. For example, the therapist may say something like, “We will take a bathroom break at the end of this piece of music” or “I will get you water in a little while. Why don’t you put the eye shades back on and relax for a few minutes?” If the subject is trying to avoid 5 a difficult experience, they might listen to the suggestion and relax. In some embodiments, spontaneous movement such as shaking, stretching or dancing while engaging with the experience is accepted and often encouraged, unless the movement seems to be a way to distract oneself from the experience. In some embodiments, if the subject continues to move around a lot, reminders to periodically return to a lying down position and to actively 10 focus inwards may be provided.
  • the therapist is not required to understand, support or even have an opinion about the nature or content of the subject’s experiences, but the therapist may validate them and convey openness toward the subject’s own view of them without dismissing or pathologizing any experience based on its unusual content. These experiences may provide the subject with a 15 perspective that goes beyond identification with their personal narrative. In some embodiments, the therapist will validate one or more of the subject’s experiences. In some embodiments, validation of the experiences simply means acknowledging the courage of opening up to the experience and the possibility that any experience will serve the intention of the session.
  • a therapist provides psychological support for about 0.15 hours, 20 about 0.25 hours, about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 2 hours, about 3 hours, or any range therebetween, or longer, immediately after administration.
  • the therapist uses guided imagery and/or breathing exercises to calm the subject and/or focus the subject’s attention.
  • the therapist holds the hand, arm, or shoulder of the subject.
  • the therapist 25 counsels the subject 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 subject’s own mental space.
  • the therapist avoids initiating conversation with the subject, but responds if the subject initiates conversation.
  • active intervention is kept to a minimum 30 during the treatment experience.
  • the subject is encouraged to explore their own mental space, and simple guided imagery may be used to assist relaxation. “Guided imagery” 231
  • Integration session refers to an exercise wherein the subject is asked to imagine a scene (e.g., “Invite a scene, perhaps a landscape, and tell me where you find yourself’; “Imagine a place that feels safe to you.”).
  • Post-Administration Psychological Support Session (“integration session”)
  • subjects may be encouraged to engage in post-administration 5 integration sessions with their therapist.
  • Integration is a process that involves processing, or embodying, a psychedelic experience within a therapeutic context. The process initially begins by the subject verbalizing and reflecting upon any experience from the treatment session, and discussing it openly with their therapist.
  • Successful integration of a therapy experience accommodates for emotional changes and comprises of translating experiences into new insights, 10 perspectives, and subsequently new behaviors that can be used to benefit the subject’s quality of life. New perspectives might in turn influence the participant’s current knowledge or values and lead to new ways of relating to cognitions, emotions, behaviors and physical experiences.
  • the goals and supportive methods used by the therapist throughout integration sessions should remain consistent, regardless of the intensity or content of the 15 subjective experience explored by the subject. That said, the methods of support used by the therapist should accommodate for the full range of experiences a subject might have faced.
  • the integration process is not one that should be limited to the sessions with the therapist, and is a process that will likely continue to unfold beyond the visits in clinic.
  • the subject participates in at least one psychological support session after administration (“post-administration psychological support session” or “integration session”).
  • post-administration psychological support session may be held on the same day as the treatment session, after the effects of the drug (e.g., a compound of Formula (I) through (III)) have substantially worn off.
  • a post-administration 30 psychological support session may be held the day after the treatment session.
  • a post-administration psychological support session may be held two days after the treatment session.
  • a post-administration psychological support session may 232
  • a post-administration psychological support session may be held three days after the treatment session.
  • a post-administration psychological support session may be held about one week after the treatment session.
  • a post-administration psychological support session may be held about two weeks after the treatment session.
  • a post-administration psychological support 5 session may be held about one month after the treatment session.
  • a post- administration psychological support session may be held about three months after the treatment session.
  • a post-administration psychological support session may be held about six months after the treatment session.
  • a post-administration psychological support session may be held about twelve months after the treatment session.
  • post-administration psychological support session may be held in a time range in between any of the preceding times.
  • the subject may participate in one, two, three, four, five, six, seven, or eight post-administration psychological support sessions. In some embodiments, the subject may participate in at least two, or at least three post-administration psychological support sessions. 15
  • the post-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a therapist. In some embodiments, the psychological support sessions may be group sessions, wherein more than one subject meets with a single therapist, or more than one therapist. In some embodiments, one or more of the subject’s family members or friends may be present at the post-administration psychological support session(s). 20 In some embodiments, the post-administration psychological support session may focus on integration of the treatment experience.
  • Integration may involve processing a psychedelic experience in a therapeutic context. Integration may comprise psychological and somatic processing of the experience and a successful assimilation of insights into the subject’s life for the purpose of growth, healing and/or well-being.
  • a subject may be 25 encouraged to talk about and reflect upon their experiences during the treatment session.
  • integration may comprise an external expression of the treatment experience, such as choice of words, tone of voice, gestures, and/or particular physical activities (yoga, exercise, bodywork, etc.).
  • integration comprises creatively expressing any insights or experiences gained during a treatment experience, for example through poetry, art, 30 music/singing, dance, writing or drawing.
  • the subject may be encouraged to reflect on both the thoughts and the feelings that he or she underwent during the treatment session, as well as to express those ideas and emotions into a concrete form that can serve as a tool 233
  • the subject may be encouraged to acknowledge and connect with the range of the emotional cognitive and physical experiences of the treatment session and relate them to current experiences in their life situation. This may be accomplished, for example, by discussing them initially with their 5 therapist, and perhaps later with their family, friends, and support circle. Integration helps accommodate changes in emotional states as new insights are generated and integrated. When further explored through oscillating attention between foreground and background thoughts and emotions, such insights may lead to natural and effortless changes in perspectives or behaviors.
  • the integration process is not limited to initial integration meetings with the 10 therapist, but continues to unfold spontaneously through a participant’s own processing and actions in every day life.
  • EMBARK In some embodiments, the psychological support administered to the subject is a six- domain framework for psychedelic-assisted psychotherapy (PAP) referred to as EMBARK, which is a transdiagnostic, trans-drug model.
  • PAP psychedelic-assisted psychotherapy
  • the six clinical domains of EMBARK are: (1) Existential- 20 Spiritual, (2) Mindfulness, (3) Body Aware, (4) Affective-Cognitive, (5) Relational, and (6) Keeping Momentum. (1) Existential-Spiritual.
  • Psychedelic medicines are well known to catalyze profound encounters with mystical or spiritual content and existential concerns, such as mortality, alienation, or questions of life meaning.
  • Several PAP clinical trials have found that participants often report 25 profound experiences of an existential or spiritual nature that may hold enduring significance for them.
  • the potency of participants’ mystical experiences has been found to correlate with a range of treatment benefits, including reductions in symptoms of depression and treatment-resistant depression, increased motivation to stop problematic cocaine use, decreases in cancer-related depression and anxiety, greater success in nicotine cessation, and other positive changes in 30 psychological functioning.
  • existential and spiritual elements of PAP warrant recognition as potential sources of treatment benefit.
  • the current state of knowledge suggests that anti-depressive outcomes may 234
  • therapists 10 prepare the physical treatment space in a way that demonstrates respect for the subjective sense of sacredness that may arise for the participant and open the session with a brief, collaboratively designed ritual. If phenomena in this domain arise during the medicine session, therapists are invited to use supportive psychotherapy or evidence-based interventions of their preference during the integration phase to explore the participant’s experience, support them in developing a sense15 of what actions it could motivate, and co-create plans for life changes and/or further spiritual self- development. Examples of approaches with evidentiary bases to use in this process include meaning-oriented psychotherapies, Logotherapy, or Spiritual Guidance, which is derived from the evidence-based approach of motivational interviewing (MI), despite not being an Evidence-Based Therapy (EBT) itself.
  • MI evidence-based approach of motivational interviewing
  • EBT Evidence-Based Therapy
  • M domain represents a place in EMBARK for preparing the participant to attend to their 30 thoughts and feelings with compassion during a medicine session and for working with increases in psychological flexibility and other metacognitive shifts during integration.
  • Mindfulness has been found helpful in disrupting ruminative thought patterns, enabling more cognitive flexibility, 235
  • EMBARK therapists begin a course of PAP treatment by teaching basic mindfulness skills to the participant. This teaching is only meant to ensure that the participant knows how to attend to their internal experience during the medicine session, which is when a more enduringly increased capacity for 5 mindfulness may arise.
  • therapists help to anchor whatever aspect of mindfulness arose for the participant through the use of indication-specific mindfulness practices.
  • Therapists may also help the participant integrate a new feeling of self-compassion or support them in using the momentary abatement of ruminative thoughts as an opportunity to develop mindfulness-based skills that may prevent a recurrence.
  • Therapists can use their own mindfulness- 10 based interventions within the bounds of the guidelines provided, or they can use suggested interventions drawn from Rumination-Focused Cognitive-Behavioral Therapy (RF-CBT) Mindfulness-Based Cognitive Therapy (MBCT) included in the treatment manual.
  • RF-CBT Rumination-Focused Cognitive-Behavioral Therapy
  • MBCT Mindfulness-Based Cognitive Therapy
  • therapists are taught to work with the participant in this domain within a trauma-informed approach to mindfulness and to avoid imposing one’s own beliefs or biases onto the participant’s experience.
  • Body Aware PAP participants have reported that embodied phenomena are a notable part of their experience of a medicine session. There are few EBTs that provide support in conceptualizing or responding to these phenomena, though innovative somatic psychotherapy approaches have offered suggestions.
  • EMBARK therapists are prepared to respond to embodied treatment events using the most widely accepted elements of these novel somatic approaches, such 20 as “pendulation,” or the process of helping a participant alternate between active, embodied engagement with trauma material and self-soothing.
  • EMBARK also encourages integration of somatic elements from more established EBTs, such as somatic awareness training exercises and self-regulation skills from Mindfulness-Based Relapse Prevention (MBRP) or Dialectical Behavioral Therapy (DBT) to support therapeutic outcomes in this domain.
  • MBRP Mindfulness-Based Relapse Prevention
  • DBT Dialectical Behavioral Therapy
  • the techniques used 25 by EMBARK therapists in this domain do not require them to work with the body in an intensive, hands-on way and are thus not prohibitively far beyond their standard psychotherapeutic training.
  • EMBARK therapists are instructed to prioritize non-touch interventions and limit their touch-based interventions to basic supportive touch that minimizes points of contact between parties, like handholding or placing a hand on a participant’s shoulder to convey support or offer grounding. More intensive forms of touch (e.g., 5 full-body embraces) are omitted until further research establishes them as safe, effective interventions.
  • Therapists also rigorously assess for the participant’s consent to touch-based interventions during preparation and proactively give participants a chance to reject any form of touch during preparation, immediately before the provision of touch in the medicine session, and at any time during the touch, so as not to move beyond the participant’s espoused level of comfort.
  • Body aware and Mindfulness domains The primary distinction between the Body aware and Mindfulness domains is found less in their associated interventions than in participants’ subjective experiences of how benefits arise and the integration goals that best support these benefits.
  • Body aware treatment goals follow from medicine session events that a participant locates in their body and involve integration practices that work with shifts in somatic awareness.
  • Treatment goals in the Mindfulness domain involve 15 benefits that adhere more closely to the core concepts of psychological flexibility and other metacognitive shifts and are sustained with practices that build upon a participant’s revised relationship with the contents of their mind.
  • somatic phenomena are hypothesized to contribute to therapeutic outcomes in two ways.
  • Depressive symptoms are notable for their disturbance of embodiment (e.g., fatigue or energy loss, disruptions 20 of sleep and appetite, weight gain or loss).
  • EMBARK approach to depression begins with the notion that many depressed individuals have developed a habitual response to challenging feelings that entails dimming their awareness of them through a kind of automatic, unconscious avoidance and characteristic depressive experience of feeling numb and withdrawn. Participants in PAP medicine 20 sessions have often experienced a greater facility in reconnecting with this avoided material and have implicated these experiences in their positive treatment outcomes. In the preparation phase, EMBARK therapists are tasked with helping participants understand the importance of adopting an approach orientation during the medicine session. They also help the participants develop one or more self-soothing techniques.
  • the therapists’ role is to remind the 25 participant to welcome challenging content if needed and to help them utilize the previously learned self-soothing techniques when necessary.
  • EMBARK therapists help participants use experiences of approaching challenging material as the basis for updating maladaptive core beliefs about oneself or the world and cultivating an enduring attitude of greater acceptance in their emotional life. All of these interventions are taught and employed in 30 a way that is respectful of participant autonomy, the principles of trauma-informed care, and cultural differences in relating to and expressing one’s emotions. 238
  • a core element of depression is social isolation, both actual and felt. This isolation may derive from patterns or beliefs learned in early life relationships, such as a sense that one is unacceptable, deserves to be alone, or may lose love if they express themselves freely in the presence of another person.
  • the altered relational dynamics of a PAP medicine session may provide opportunities for relational repatterning that 15 supplants these maladaptive beliefs.
  • EMBARK therapists are also prepared to support relational benefits that may arise for the participant outside of their interactions with the therapists, such as an internally felt sense of social connectedness or emotional empathy or an autobiographical review process that examines past and present relationships in the participant’s life.
  • EMBARK therapists are trained to apply a broad lens to what helpful post-treatment change might look like. For some participants, the most supportive change may be at the level of personal behaviors, such as problem drinking or procrastination. For 5 others, change may be warranted in their personal contexts, such as relationships or work environments. Some participants may find additional benefit in taking aim at collective concerns that have a bearing on their life, such as structural Vietnamese or exploitative work conditions, through participation in collective organizing.
  • the EMBARK approach recognizes the potential of both individual and collective forms of change in the service of enhancing a participant’s psychological, 10 spiritual, and social wellbeing.
  • the EMBARK model adheres to the three-phase PAP treatment design that has been used in all clinical trials published to date. It involves non-drug preparation sessions prior to administration (Pre-Administration Psychological Support Sessions), medicine sessions in which the psychedelic medicine is administered (Psychological Support During Treatment Sessions), and 15 non-drug integration sessions after the date of administration (Post-Administration Psychological Support Sessions).
  • therapists are given a set of general tasks, as well as domain-specific tasks for each of the six domains.
  • these two sets of tasks are woven together into suggested agendas for each session, which therapists can 20 apply with flexibility and responsiveness to the needs of a specific participant.
  • the therapists’ general aims for this phase have included building 30 rapport and trust, learning about the participant’s experience of their mental health challenges, explaining basic elements of PAP treatment and what to expect from the medicine session, providing preparatory instructions about diet and aftercare, and responding to participant questions 240
  • therapists tasked with teaching basic mindfulness skills to a participant may do so using mindfulness-based tools from ACT, DBT, other mindfulness-based EBTs, or a meditative spiritual tradition, provided that the tool meets the following criteria set forth in the EMBARK manual: (1) 25 it invites the participant to cultivate a receptive, attentive state, (2) does not contain elements that could potentially clash with a participant’s religious beliefs, (3) and abides by trauma-informed practices detailed in the manual.
  • the manual also provides example interventions for therapists who do not have relevant expertise to bring in for any given task. Ethical considerations based on the four care cornerstones are woven throughout the guidelines set forth for therapist interventions. 30 For example, the guidelines for the discussion of therapist-participant dynamics requires that it include an exploration of cultural dynamics, in line with the cornerstone of culturally competent care. 241
  • the pre-dosing therapist tasks thus serve a similar purpose to the tasks in the preparation phase in that they set the stage for phenomena in 5 any domain to arise and bring the potential for benefit.
  • These stage-setting tasks are woven together into a suggested pre-dosing agenda for the medicine phase that includes a collaborative ritual (E), a check-in about intentions (K), and a brief somatic awareness practice (B).
  • E collaborative ritual
  • K check-in about intentions
  • B brief somatic awareness practice
  • the six EMBARK domains thus continue to serve therapists as a conceptual frame for laying the groundwork for a broad variety of pro-therapeutic outcomes.
  • EMBARK s six- domain framework comes to serve therapists in a new way as a practical rubric for helping them 15 to characterize in-session events and determine what domain-specific interventions these events might call for. For example, if they observe the participant experiencing what they identify as a somatic trauma process, they can recall the training they received in the Body aware domain, and apply the interventions associated with it.
  • a set of suggested 5 integration goals are provided in each indication-specific manual, along with guidelines and suggestions for working toward each of these goals. These goals are organized by domain to provide continuity with events that arose in the medicine session. Together, therapists and participants choose a subset of these goals, or develop their own, as long as they are based on a clear clinical rationale. This selection process is guided primarily by what transpired in the 10 medicine session using a tool provided in each EMBARK manual.
  • a participant who had an experience that they identify as spiritual may benefit from support in advancing their spiritual self-development or spiritual practices (E), or a participant who had a strong emotional opening might be best served by continued processing and reflection that may lead to revised core beliefs or a sustained movement away from emotional avoidance (A).
  • the selection 15 process is also informed by the participant’s previously stated intentions for treatment and the functional meanings of their symptoms. For instance, if a depressed participant initially framed their suffering in terms of loneliness and set an intention of understanding their isolation, it might benefit them to consider goals in the Relational domain, even if nothing observable transpired in that domain during the medicine session. All integration goals are framed in terms of three possible 20 spheres of change: individual behavior, personal context, and broader context.
  • Individual behavior changes may include stopping a maladaptive behavior, changing an old behavior, or adopting a new practice.
  • Personal context changes may include updates to social, vocational, or physical contexts that support treatment benefit, such as moving away from a social circle that encourages problem drinking or moving into a vocational field more congruent with one’s revised personal 25 values.
  • the broader context refers to structural, cultural, or economic conditions that have real, mental health consequences for the individual. Participants who decide that change at this level would be supportive for them may benefit from taking collective action (e.g., community activism, labor organizing) that addresses broader conditions in a way that feels congruent with their revised values or sense of self and/or serve as a form of socialization or behavioral activation.
  • EMBARK was designed to support short-term PAP interventions in clinical trial settings, aftercare may also be considered or needed to properly support the patient 10 after their participation in the trial or other treatment settings.
  • psychological support may be provided remotely to a subject.
  • a therapist providing psychological support may not be in the same room, the same building, or in the same facility as a subject.
  • Remote psychological support may be provided, for 15 example by telephone (i.e., by voice call), by video call or video conference, by text, or by email.
  • a pre-administration therapy session is conducted remotely.
  • a post-administration therapy session e.g., an integration session
  • psychological support is provided remotely during the subject’s 20 treatment session.
  • the subject is administered the drug in his or her own home, and a therapist provides psychological support by voice call, video call, text, email, etc., for a time period (e.g., about 0.15 hours, about 0.25 hours, about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 2 hours, about 3 hours, or any range therebetween, or longer) after the subject has taken the drug.
  • a time period e.g., about 0.15 hours, about 0.25 hours, about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 2 hours, about 3 hours, or any range therebetween, or longer
  • the 25 subject is administered the drug in an administration facility as described herein, and the therapist provides psychological support to the subject a therapist provides psychological support by voice call, video call, text, email, etc., for a time period (e.g., about 0.15 hours, about 0.25 hours, about 0.5 hours, about 0.75 hours, about 1.0 hours, about 1.25 hours, about 1.5 hours, about 2 hours, about 3 hours, or any range therebetween, or longer) after the subject has taken the drug.
  • remote psychological support is provided to the subject using a digital or electronic system.
  • the digital or electronic system may comprise one or more of the following features: 1) The digital or electronic system securely connects 244
  • the digital or electronic system allows a subject to qualify, prequalify, or register for a clinical trial, or a psychological support session; 3)
  • the digital or electronic system is configured to help therapists and/or physicians manage and interact with patients, for example, 5 the electronic system may allow the therapist to share documents with subjects, keep notes about sessions, or schedule future sessions; 4)
  • the digital or electronic system is configured to provide alerts for crisis intervention, for example, the digital or electronic system may allow the subject to contact the therapist if they are feeling anxiety or otherwise urgently need to talk to the therapist; 5)
  • the digital or electronic system is configured to help prepare the subject for a visit with their 10 therapist and/or physician, for example, the digital or electronic system may contain information regarding drug (e.g., psilocybin or a deuterated form thereof), the therapeutic protocol, etc.; 6)
  • the digital or electronic system is configured to allow the therapist to provide psychological support during the subject’
  • the digital or electronic system is an “app” for use on a mobile phone or a computer.
  • the digital or electronic system is a website.
  • the digital or electronic system comprises a “chat” feature which allows communication between the subject and the therapist in real time.
  • the 25 website comprises a video calling feature, which allows for the therapist to communicate with the subject using video communication.
  • the digital or electronic system is configured to allow a single therapist to provide psychological support to one or more subjects at or around the same time.
  • psychological support sessions may be pre-recorded (e.g., audio or 30 video recording) and provided to the subject for use at the subject’s convenience via the digital or electronic system.
  • the term “set and setting” refers to the subject’s mindset (“set”) and the physical and social environment (“setting”) in which the user has the treatment session.
  • the pharmaceutical formulation may be administered in a particular set and setting.
  • the set and setting is controlled, to the extent possible, to maximize 5 therapeutic benefit of the treatment session.
  • administration is performed in a facility specifically designed for treatment. Administration to the subject in a facility where the subject feels safe and comfortable may help ease anxiety in the subject, and may facilitate maximum clinical benefit. Administration may be performed, for example, in the subject’s home or at a clinical facility.
  • administration is performed in a facility (e.g., a room) with a substantially non-clinical appearance, for example, in a room that comprises soft furniture (e.g., plush couches, chairs, or pillows) and/or plants.
  • the room may be decorated using muted colors (e.g., greyed, dulled, or desaturated colors).
  • the light in the room is dimmed and/or light levels are kept or adjusted to be relatively low.
  • the room lighting is adjusted for intensity and/or color.
  • a virtual reality or augmented reality system e.g., computer with visual/graphical and auditory outputs
  • the room comprises a sound system, for example a high- resolution sound system. In some embodiments, the sound system can allow for simultaneous ambient and earphone listening. In some embodiments, the subject may bring meaningful 20 photographs or objects into the administration room.
  • the room comprises a couch. In some embodiments, the room comprises a bed. In some embodiments the room comprises more than one couch or bed, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 couches or beds. In some embodiments, the subject sits on or lies in the couch or bed for approximately 1 hour, 2 hours, 3 hours, or any range therebetween, or a substantial 25 fraction thereof, immediately after administration.
  • the subject listens to music for approximately 1 hour, 2 hours, 3 hours, or any range therebetween, or a substantial fraction thereof, immediately after administration. In some embodiments, the subject wears an eye mask for approximately 1 hour, 2 hours, 3 hours, or any range therebetween, or a substantial fraction thereof, immediately after administration. In some embodiments, the subject is provided 30 with a weighted blanket. In some embodiments, each subject is supervised by one therapist during the treatment session. In some embodiments, each subject is supervised by more than one therapist during the 246
  • Embodiments of the disclosure include use of additional tools and/or technique(s) with dosage/administration, including various transcranial magnetic stimulation (TMS) methods and protocols, for example, prior or subsequent to one or more dosing(s), biofeedback devices, etc. Some embodiments can be used with a digital health product or digital solution.
  • TMS transcranial magnetic stimulation
  • Digital biomarkers can include, but are not limited to number of and/or time of phone calls/e-mails/texts; word length in text communication; gestures used (taps, swipes, or other); gyroscope derived information e.g. orientation of the phone; acceleration of the phone; keystroke patterns; location derived information from GPS; facial 15 expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep patterns; specific words or emojis used or not used; and/or the like.
  • a digital health product can be utilized to determine dosing amount and/or dosing frequency, indicator of a need for re-dosing, re-dosing amount, a warning or alert, as tracking of compliance, etc. 20
  • methods of treatment can include providing a clearance time for a subject or patient, such one or more medications is not present or substantially cleared from the system of the subject/patient.
  • methods of treatment can be configured such that, upon administration, the subject is not taking other serotonergic medications such as: selective-serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic anti­depressants, 25 monoamine oxidase inhibitors and/or antipsychotics.
  • the method of treatment includes treatment concurrently with one or more medications, including but not limited to selective-serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors.
  • the method includes treatment such that subjects or patients take concomitant compounds or medications, including but 30 not limited to benzodiazepines, cannabidiol (CBD) and/or other cannabinoids (e.g., THC (tetrahydrocannabinol); THCA (tetrahydrocannabinolic acid); CBD (cannabidiol); CBDA (cannabidiolic acid); CBN (cannabinol); CBG (cannabigerol); CBC (cannabichromene); CBL 247
  • the methods of the present disclosure allow the patient being treated to remain on any ongoing antidepressants (e.g., SSRIs) throughout the treatment course.
  • any ongoing antidepressants e.g., SSRIs
  • the method includes treatment such that a subject has not taken one or more medications, particularly has not taken one or more serotonergic medications for at least 10 2 days, at least, 3 days, at least 4 days, at least 5 days, at least six days, at least 1 week, at least 2, 3, or 4 weeks before administration of the pharmaceutical formulation.
  • the method includes treatment such that a subject has taken one or more medications, particularly has taken one or more serotonergic medications for at least 2 days, at least, 3 days, at least 4 days, at least 5 days, at least six days, at least 1 week, at least 2, 3, or 4 weeks before administration of the 15 pharmaceutical formulation.
  • Embodiments of the disclosure include methods utilizing a digital biomarker, for example, as a diagnostic and/or prognostic tool for patient management pre-, during and/or post treatment, wherein the digital biomarker is one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and/or emotional valence.
  • the digital biomarker is one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and/or emotional valence.
  • the digital biomarker is identified from patterns in smartphone use such as swipes, taps, and other touchscreen activities, and can be scientifically validated to provide measurements of subject status, such as cognition and mood, including, by way of non­limiting example, as disclosed in one or more of the following, each of which is herein expressly incorporated by reference for all purposes: US20170086727, US20170258382, US20170258383, 25 US20170287348, U.S. Ser. No. 10/148,534, U.S. Pat. No. 9,737,759, and/or U.S. Ser. No. 10/231,651.
  • Biomarkers which may serve as a diagnostic and/or prognostic tool for patient management pre, during and/or post treatment may be identified using one or more of: number of and/or time of phone calls/e-mails/texts; word length in text communication; gestures used (taps, swipes, or 30 other); gyroscope derived information e.g. orientation of the phone; acceleration of the phone; keystroke patterns; location derived information from GPS; facial expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep 248
  • health components and/or connected biomonitors and/or smart devices/wearables can be utilized to collect information to be used in diagnostic and/or prognostic outputs.
  • a heart rate monitor or similar device can collect a subject’s data and heart rate 5 variability (for example only, as disclosed in US10,058,253, the entirety of which is herein incorporated by reference) can be used to assess/determine a metric relating to the subject’s current emotional state, relative change in emotional state, etc., which can be used in determining a new or follow-on treatment plan, adjusting a treatment plan, etc.
  • a method of assessing 10 a subject pre, during and/or post treatment of a central nervous system disorder to determine whether to provide treatment or a further treatment comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining the treatment based on an outcome.
  • the method can further comprise the step of administering the pharmaceutical formulation of the present disclosure, for a 15 first or a subsequent time.
  • the biomarker is identified from patterns in smartphone use such as swipes, taps, and other touchscreen activities, and are scientifically validated to provide measurements of cognition and mood.
  • the pattern is identified using one or more of: number of and/or time of phone calls/e­mails/texts; word length in text 20 communication; gestures used (taps, swipes, or other); gyroscope derived information e.g. orientation of the phone; acceleration of the phone; keystroke patterns; location derived information from GPS; facial expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep patterns; specific words or emojis used or not used; and/or the like.
  • gyroscope derived information e.g. orientation of the phone; acceleration of the phone; keystroke patterns; location derived information from GPS; facial expressions and/or microexpressions; voice or vocal markers; natural language processing; social media use; sleep patterns; specific words or emojis used or not used; and/or the like.
  • Embodiments include a method of assessing a subject pre, during and/or post treatment of a central nervous system disorder to determine whether to provide treatment or a further treatment with the pharmaceutical formulation of the present disclosure, comprising monitoring one or more biomarkers associated with executive function, cognitive control, working memory, processing speed, and emotional valence, and determining the treatment based on an outcome; the method 30 can further comprise administering the pharmaceutical formulation of the present disclosure for a first or a subsequent time.
  • the disclosure provides for treating 2 or more subjects, the method comprising administering to each subject a therapeutically effective amount of the pharmaceutical formulation of the present disclosure, at the same time or substantially the same time (e.g., dosed within several minutes of each other, within 5, 10, 15, 20, 25, or 30 min of each other), wherein 5 each subject is aware of the other subject also receiving treatment.
  • the subjects are in the same room.
  • the subjects are in different rooms.
  • the disclosure provides a method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical formulation of the present disclosure, and providing a virtual reality/immersive reality digital tool.
  • the light in the room is dimmed and/or light levels are kept or adjusted to be relatively low.
  • darkened glasses or eye shades are provided.
  • the room lighting is adjusted for intensity and/or color.
  • a virtual reality or augmented reality system e.g., computer with visual/graphical and auditory outputs
  • the subject is a male.
  • the subject is a female.
  • the female subject is pregnant or post-partum.
  • the subject is attempting to reduce or eliminate their use of a pharmaceutical agent, such as an antidepressant or an anti-epileptic drug.
  • the subject is attempting to reduce 20 or eliminate their use of the pharmaceutical agent before becoming pregnant, having surgery or other medical procedure, or starting to use a different pharmaceutical agent.
  • the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle aged subject.
  • the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age.
  • the25 subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about 30-35, about 35- 40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age.
  • the subject may have a chronic disease or a terminal disease.
  • the subject may have a life-altering disease or condition (such as the loss of a limb or onset of 30 blindness).
  • the subject may have recently been diagnosed with a disease, disorder, or condition. For example, the subject may have been diagnosed within 1 month, within 3 months, within 6 months, 250
  • the subject may have been living with a disease, disorder, or condition for an extended period time, such as at least 6 months, at least 1 year, at least 3 years, at least 5 years, or at least 10 years.
  • the subject may be a cancer patient, such as a Stage 4 or terminal 5 cancer patient.
  • the subject may have been determined to have a limited time to live, such as less than 1 year, less than 6 months, or less than 3 months.
  • the subject may have previously taken a psychedelic drug, or may have never previously taken a psychedelic drug.
  • the subject may or may not have previously taken psilocybin, a psilocybin mushroom (“magic mushroom”), LSD (lysergic acid diethylamide or 10 acid), mescaline, or DMT (N,N-dimethyltryptamine).
  • the subject may have previously taken one or more serotonergic antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs)).
  • SSRIs selective serotonin reuptake inhibitors
  • the subject has never previously taken a serotonergic antidepressant.
  • the subject has not taken any serotonergic antidepressants for at least 2 weeks, at least 4 weeks, or at 15 least 6 weeks prior to receiving treatment with the pharmaceutical formulation.
  • the subject treated with the methods herein is taking an antidepressant such as a serotonergic antidepressant as part of ongoing treatment.
  • the subject to be treated herein may be taking a stable chronic dose of antidepressant medication(s).
  • the subject treated with the methods herein is taking a sedative or hypnotic as part of ongoing 20 treatment.
  • the subject may have previously received electroconvulsive therapy (ECT).
  • ECT electroconvulsive therapy
  • the subject has not received any ECT for at least 2 weeks, at least 4 weeks, or at least 6 weeks prior to receiving treatment with the pharmaceutical formulation.
  • the subject may have a medical condition that prevents the subject from receiving a 25 particular medical therapy (such as an SSRI or ECT).
  • the subject may have previously had an adverse reaction to a particular medical therapy (such as an SSRI or ECT).
  • a prior medical therapy such as an SSRI or ECT was not effective in treating a disease, disorder, or condition (e.g., GAD, MDD, etc.) in the subject.
  • any single term, single element, single phrase, group of terms, group of phrases, or group of elements described herein can each be specifically excluded from the claims.
  • a range is given in the specification, for example, a temperature range, a time range, a composition, or concentration range, all intermediate ranges and subranges, as well as all 15 individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the aspects herein. It will be understood that any elements or steps that are included in the description herein can be excluded from the claimed compositions or methods.
  • salt forms of were prepared by crystallization of I-1 (free base) with stoichiometric (1.0 molar equivalent) quantities, or with sub-stoichiometric (0.5 molar equivalents) quantities in 10 the case of hemi-salts, of the corresponding organic acid (fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, or glycolic acid), from ethanol.
  • the salt form identifier and salt type are provided in Table 5. Table 5.
  • LiAlD4 Lithium aluminum deuteride
  • I-8a A flask was charged with 15 ml of I-8 (free base) ethanol solution which was heated to reflux, and a single charge of fumaric acid (1.07g, 1.05 eq) added. After complete dissolution, this was allowed to cool to room temperature, then cooled further to 0°C and filtered, with additional ethanol (3 x 5ml, 3 x 2 vol) used to rinse out the flask and wash the cake.
  • I-8a was 15 isolated as a crystalline solid with a yield of 1.480g (4.71 mmol, 44.6%, 97.0% by LC, 1 H NMR confirmed identity as 1:1 fumarate salt).
  • I-8b A flask was charged with 18 ml of I-8 (free base) ethanol solution which was heated to reflux, and then benzoic acid (4.04g, 3.15 eq) was added in one charge. After ensuring all solid had dissolved, the solution was cooled in an ice bath and stirred for an additional 60 minutes at 20 this temperature then filtered and further ice cold ethanol (2 x 2 vol) used to rinse out the flask and wash the cake.2.272g (7.09 mmol) of I-8b was obtained.
  • I-8b was thus obtained as a white crystalline solid in a yield of 1.534g (4.79 mmol, 45.4%, 91.1% by LC, 1 H NMR confirmed identity as 1:1 benzoate salt).
  • I-8c A flask was charged with 18 ml of I-8 (free base) ethanol solution which was heated 256
  • I-8d is prepared analogously by crystallization of I-8 (free base) with a stoichiometric (1.0 molar equivalent) quantity of succinic acid from ethanol. II.
  • Tryptamines 15 Materials and Methods Fumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d 3 )ethan-1-amine-1,1,2,2-d 4 (DMT- d10 fumarate; 1:1)(I-8a) was prepared as described above.
  • the release modifier used is shown in Table 9 in terms of the molecular weight range (and in parentheses the weight average molecular weight, Mw), and the commercial supplier. 257 Table 9.
  • pH pH was measured by AccumetTM Research Model AR10 pH meter, available from Fisher Scientific. 5
  • Osmolality Osmolality was measured using Advanced® Micro-Osmometer, Model 3320, from Advanced Instruments. Filtration was performed using a Syringe filter unit, 0.22 ⁇ m, PVDF, 33 mm filter, available from Sigma-Aldrich. Dialysis—Drug Release Test.
  • a 200 mL Erlenmeyer flask containing 100 mL of release 10 medium (0.9% w/v NaCl) was equipped with a magnetic stir bar and placed into a water bath to maintain a release medium temperature of 37°C. The stirring rate was set to 400 rpm.
  • a 1-2 mL volume of test item (formulation or control) was introduced into a Pur-A-LyzerTM Maxi dialysis tube (pore size: 6-8 kDa molecular weight cutoff (MWCO), available from Sigma Aldrich). The dialysis tube was then immersed into the 100 mL of release medium inside the Erlenmeyer flask 15 and a timer was started.
  • MWCO molecular weight cutoff
  • Dissolution medium (0.5 mL) was withdrawn from the Erlenmeyer flask at 10, 20, 30, 45, 60, 90, and 120 minutes for assays, and an equal volume of fresh release medium was used to replace the withdrawn dissolution medium.
  • the time-sampled dissolution medium was assayed by ultra performance liquid chromatography (UPLC) to analyze the drug release of the test item.
  • the percent drug release was then plotted versus time (minutes), and also modelled 258 as a first order kinetic plot. From these plots, the time in minutes required for 25% of drug release (t 25% ) and 50% of drug release (t 50% ) were calculated.
  • Ultra Performance Liquid Chromatography UPLC
  • the ratio of C:A was calculated by dividing the Mw value in kDa by the parameter A in mg/mL (nominal). Both the ratio of A:B and C:A are written below without the consequent “1” and the ratio symbol (:), for example a ratio of 50:1 is simply represented as 50. 5 Table 11.
  • the release profiles of the formulations are also evaluated by the Dialysis—Drug Release Test, including the time in minutes required for 25% of drug release (t25%) and 50% of drug release 10 (t 50% ), and the respective percent changes in these values compared to the control (made without release modifier).
  • Formulations 1-6 To investigate the role of different concentrations of sodium hyaluronate (0.1, 0.2, 0.3, 0.4, 15 0.5, and 0.75% w/v, nominal) in the formulations, six different sodium hyaluronate solutions were made by dissolving a corresponding amount of sodium hyaluronate (750 – 1,000 kDa) (1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, and 7.5 mg, respectively), in water (0.7 mL), followed by incubation at 37°C and stirring. The sodium hyaluronate solutions were then filtered through a 0.22 ⁇ m PVDF filter.
  • sodium hyaluronate solutions were then filtered through a 0.22 ⁇ m PVDF filter.
  • Solutions of DMT-d 10 fumarate were prepared by dissolving 15.85 mg of 20 DMT-d 10 fumarate (10 mg free base equivalence of DMT-d 10 ) in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium hyaluronate solution was then mixed with the solution of DMT-d10 fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing.
  • a control formulation (10 mg/mL free base equivalence of DMT-d 10 , nominal) without release modifier was prepared by diluting the solution of DMT-d10 fumarate with water 25 (0.7 mL). Formulations are shown in Table 12. 260 Table 12. Each formulation was subjected to the Dialysis—Drug Release Test.
  • Fig.3 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, with 5 the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 6).
  • these formulations will also be remade with an appropriate saline vehicle instead of water without effecting the release profile. Nonetheless, these formulations support the notion 10 that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug.
  • Formulations 7-9 To investigate the effects of drug concentration, formulations were prepared using a fixed 15 sodium hyaluronate concentration (1% w/v, nominal) at 10 mg/mL, 25 mg/mL, and 50 mg/mL free base equivalence of DMT-d 10 (nominal).
  • Solutions of DMT-d 10 fumarate were prepared by dissolving 15.85 mg of DMT-d10 fumarate (10 mg free base equivalence of DMT-d10), 39.62 mg of DMT-d10 fumarate (25 mg free base equivalence of DMT-d10), or 79.25 mg of DMT-d10 fumarate (50 mg free base equivalence of DMT-d 10 ) in water (0.3 mL), followed by incubation at 20 37°C and stirring.
  • Sodium hyaluronate solutions were prepared using 10 mg of sodium hyaluronate (750 – 1,000 kDa) and water (0.7 mL), followed by incubation at 37°C and stirring.
  • Formulations 7, 8, and 9 show the drug release of Formulations 7, 8, and 9, respectively, and that each formulation provided a desirable controlled-release profile at the tested drug loading.
  • Formulations 10-15 10 To investigate the role of sodium hyaluronate molecular weight, different formulations were prepared with varying molecular weights of sodium hyaluronate using a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of DMT-d10 (25 mg/mL, nominal). Stock solutions were prepared as follows: - Stock (a).79.25 mg of DMT-d 10 fumarate (50 mg free base equivalence of DMT-d 10 ) 15 was dissolved in 0.5% (w/v) saline (0.75 mL).
  • a control formulation 25 mg/mL free base equivalence of DMT-d10, nominal
  • release modifier 25 mg/mL free base equivalence of DMT-d10, nominal
  • Formulations are shown in Table 14. 262
  • the osmolality of all formulations remained within an acceptable range for injection, and the pH adjustment of stock (a) (solution of DMT-d10 fumarate) was well tolerated with respect to 5 stability of the final formulations.
  • Each formulation was subjected to the Dialysis—Drug Release Test.
  • Formulations 13-15 made from higher molecular weight sodium hyaluronate, 500 – ⁇ 750 kDa, 750 – 1,000 kDa, and >1,000 – 1,800 kDa, respectively, provided a 5 desirable controlled-release profile, with the highest molecular weight (Formulation 15) providing a nearly 130% increase at each of T25% and T50% (Figs.8A and 8B, and Table 16). These data indicate that a sodium hyaluronate molecular weight cutoff of at least 500 kDa 10 seems to exist for establishing controlled-release characteristics.
  • Formulations 16-18 To investigate the role of sodium hyaluronate molecular weight at high drug loadings, different formulations were prepared with varying molecular weights of sodium hyaluronate using 15 a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of DMT-d10 (70 mg/mL, nominal) in 0.9% (w/v) saline with no pH adjustments.
  • Stock solutions were prepared as follows: - Stock (a).221.9 mg of DMT-d 10 fumarate (140 mg free base equivalence of DMT-d 10 ) was dissolved in 0.9% (w/v) saline (1.0 mL). The pH and osmolality were measured.
  • Formulations 16-18 made from high drug loading in high molecular weight sodium hyaluronate (500 – ⁇ 750 kDa, 750 – 1,000 kDa, and >1,000 – 1,800 kDa) provided a release that was marginally slower than control (no release modifier), with percent change of T50% values compared to control of +32%, + 28%, and +24%, respectively. This is indicative of not enough sodium hyaluronate being used to compensate for the high drug content.
  • Formulations 19-21 To investigate the release profile with 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl- 10 d 3 )ethan-1-amine-1,1,2,2-d 4 (5-MeO-DMT-d 10 ), different formulations were prepared with varying molecular weights of sodium hyaluronate using a fixed sodium hyaluronate concentration (0.5% w/v, nominal) and free base concentration of 5-MeO-DMT-d10 (25 mg/mL, nominal) in 0.3% (w/v) saline with no pH adjustments.
  • Formulation 21 made with sodium hyaluronate >1,000 – 1,800 kDa was much more effective in providing a controlled-release, with percent change of T25% and T50% values compared to control of +93% each.
  • Solutions of DMT-d10 fumarate were prepared by dissolving 15.85 mg of DMT-d10 fumarate (10 mg free base equivalence of DMT-d10) in water (0.3 mL), followed by incubation at 37°C and stirring. Each sodium carboxymethyl cellulose solution 10 was then mixed with the solution of DMT-d10 fumarate, and the resulting formulations were vigorously stirred to ensure complete mixing.
  • a control formulation (10 mg/mL free base equivalence of DMT-d 10 , nominal) without release modifier was prepared by diluting the solution of DMT-d 10 fumarate with water (0.7 mL). Formulations are shown in Table 21. 15 Each formulation was subjected to the Dialysis—Drug Release Test. Fig.
  • IPS 5007 diet was provided as a daily ration throughout the study. A 350 g ration of feed per dog was provided once daily, except during designated procedures. On the morning of dosing (pre-dose), the animals were deprived from their daily food allowance until 2 h post dose. Mains quality tap water was available ad libitum. Details of diet and water are maintained at the test 30 facility. Prior to acceptance for use on study, animals were subject to an examination and the results found to be satisfactory. All animals were weighed prior to each dose administration and the 269 bodyweights recorded. Animals were checked regularly throughout the duration of the study. Any clinical signs were closely monitored and recorded. Holding and study areas had automatic control of light cycles and temperature. Light hours were 07:00-19:00 h.
  • Ranges of temperature and humidity measured during the study were 15-24°C 5 and 40-70%, respectively.
  • DMT-d 10 fumarate (I-8a) Batch No. ABN-1177 was supplied by Quotient Sciences and was stored frozen and protected from light and moisture in a freezer set to maintain a temperature of ⁇ -20oC at the Test Facility.
  • DMT fumarate (I-1a) Batch No. 0000040525 was supplied by Biosynth. Table 22 shows the material characteristics.
  • 10 Sodium hyaluronate was Hyatrue® HA-EP1.8 (molecular weight range of 900-1,400 kDa), available from Bloomage Freda Biopharm Co. Ltd. Test Items.
  • DMT-d 10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 15 6 (control) or in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) (Formulation 28) at a free base concentration of 0.4 mg/mL (nominal) for SC injection.
  • WFI water for injection
  • Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • the solution was made to final volume of 15 mL, using the pre- calibrated line, with 0.9% w/v saline. The final pH was recorded as 5.53. The solution was then filtered using a 0.22 ⁇ M PVDF syringe filter in the laminar air flow cabinet (LAFC). The visual appearance of the solution was recorded as a clear, colorless, homogenous solution.
  • the final 5 control solution had a free base concentration of 0.41 mg/mL DMT-d10. The control solution was protected from light at all times.
  • Formulation 28 On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 11.02 mg of DMT-d 10 fumarate was 10 weighed into a 20 mL headspace vial containing a magnetic stir bar.3.5 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 2 mg/mL (nominal) DMT-d 10 .
  • Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, 4 and 8 hr post dose. Immediately following blood sample collection, the tubes were inverted to ensure mixing with the anticoagulant and immediately placed on wet ice. As soon as practically possible, but no later than 30 minutes 10 from collection, samples were centrifuged in a refrigerated (ca +4°C) centrifuge at approximately 1500 g for 10 minutes.
  • the resultant plasma was decanted into appropriately labelled polypropylene tubes in 96-well plate format and stored in a freezer set to maintain a temperature of ⁇ -65°C until analysis. The samples were protected from light. Bioanalysis. Plasma samples were analyzed for DMT-d 10 using an established LC-MS/MS 15 assay. Pharmacokinetic parameters were determined from the DMT-d10 plasma concentration-time profiles using commercially available software (Phoenix® WinNonlin®). Results. All dose administrations of DMT-d10 were performed without incident. No adverse reactions to the administration were observed in any of the animals dosed. Mild, transient clinical 20 signs were recorded post-dose.
  • DMT-d10 formulated in either 0.9% w/v saline (control) or 1% w/v (nominal) sodium hyaluronate (Formulation 28) are presented.
  • DMT-d10 was administered SC at a free base equivalent dose of 0.1 mg/kg.
  • Plasma DMT-d 10 concentrations were quantifiable up to 2 hours in all animals following SC administration of control (Fig.12A), 272 and up to 4 hours following SC administration of Formulation 28 (Fig.12B).
  • Fig.12A controls
  • Fig.12B up to 4 hours following SC administration of Formulation 28
  • Test Items DMT-d 10 fumarate was formulated in 1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 29) or 4 mg/mL (Formulation 30) for SC injection. Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing. 273
  • Formulation 29 On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 110.7 mg of DMT-d 10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.6.914 mL of WFI was added 5 to the vial and set to stir, making a stock solution with a free base concentration of 10.1 mg/mL (nominal) DMT-d 10 . The stock solution had a density of 1.002 g/cm 3 .
  • the formulation thus had a free base 20 concentration of 4.15 mg/mL (nominal) DMT-d 10 and a sodium hyaluronate concentration of 1% w/v (nominal). The visual appearance of the formulation was recorded as a clear, colorless, homogenous solution.
  • Subcutaneous injections The target dose was 0.5 mg/kg free base at a dose concentration of 2 mg/mL, or 1.0 mg/kg free base at a dose concentration of 4 mg/mL.
  • Appropriate volumes of 25 dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes. Animals were identified by microchip and tattoo.
  • the pharmacokinetic parameters for DMT-d10 formulated in Formulations 28-30 SC at 0.1, 0.5 and 1 mg/kg are presented.
  • the 0.1 mg/kg data (Formulation 28) were calculated in part A (see Table 24) and are repeated here to determine dose proportionality.
  • Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following 15 SC administration.
  • Median T max ranged from 0.5 to 0.75 hr suggesting similar absorption profiles after SC administration for the lower dose levels (Figs.13A-13B).
  • the interpretation of the absorption kinetics may be impacted by the sparse samples collected during the phase and the interindividual variability at the high dose (1 mg/kg; Table 26).
  • C Formulation Stability – Pharmacokinetics (PK) of DMT-d10 in Male Beagle Dogs Following Subcutaneous Administration at 1 mg/kg Formulated in Increasing Sodium Hyaluronate Concentrations The objective of this study was to determine how increasing concentrations of sodium 15 hyaluronate affect the release of DMT-d10 into systemic circulation after SC administration. This study was conducted using the same CRO, housing, and materials as described above in part A.
  • DMT-d10 fumarate was formulated in 0.1% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 2 mg/mL (Formulation 31), 20 0.25% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 32), or 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a nominal free base concentration of 4 mg/mL (Formulation 33) for SC injection.
  • Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • 25 Formulation 31 On the morning of dosing, DMT-d 10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 58.32 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.16.9 mL of WFI was added 276
  • Formulation 32 On the morning of dosing, DMT-d10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to 10 room temperature. Using a precision analytical balance, 120.4 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.14.9 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 5.10 mg/mL (nominal) DMT-d 10 . The stock solution had a density of 1.000 g/cm 3 .
  • Formulation 33 On the morning of dosing, DMT-d 10 fumarate was removed from storage 20 (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 130.92 mg of DMT-d10 fumarate was weighed into a 20 mL headspace vial containing a magnetic stir bar.12.4 mL of WFI was added to the vial and set to stir, making a stock solution with a free base concentration of 6.66 mg/mL (nominal) DMT-d10. The stock solution had a density of 1.001 g/cm 3 .
  • DMT-d 10 plasma concentration-time profiles formulated in 0.1% (Formulation 31), 0.25% (Formulation 32), 0.5% (Formulation 33), and 1% (Formulation 30) w/v (nominal) sodium 278 hyaluronate at a SC dose of 1 mg/kg are presented in Fig.15 (Formulation 31 dosed at 0.5 mg/kg free base was dose adjusted to 1 mg/kg). Corresponding pharmacokinetic parameters for DMT- d 10 are presented in Table 28.
  • the PK parameters for Formulation 30 and control were calculated in part B and A, respectively, and are shown here for ease of comparison.
  • Plasma DMT-d10 5 concentrations were quantifiable up to 4 hours in all animals following SC administration.
  • Median T max increased as sodium hyaluronate concentration increased 3-fold from 0.25 hr at 0.1% w/v (nominal) sodium hyaluronate (Formulation 31) to 0.75 hr at 1% w/v (nominal) sodium hyaluronate (Formulation 30) (Figs.16-19).
  • MRTinf a parameter describing the duration of DMT- d 10 systemic exposure
  • MRTinf a parameter describing the duration of DMT- d 10 systemic exposure
  • 10 i.e., 0.921 hr at 0.1% w/v (nominal) sodium hyaluronate (Formulation 31) to 1.50 hr at 1% w/v (nominal) sodium hyaluronate (Formulation 30).
  • the incremental increase in MRTinf can be seen graphically in Fig.16.
  • t 1/2 , C max and AUC inf values were not changed (Figs. 17-19, respectively).
  • DMT-d 10 fumarate was formulated as a solution in 0.9% (w/v) saline, pH 5.5- 10 6, at a free base concentration of 4 mg/mL (nominal) (control) or in 0.4% (w/v, nominal) sodium hyaluronate in 0.3% (w/v) saline at a free base concentration of 20 mg/mL (nominal) (Formulation 34) for SC injection.
  • Each test item was prepared on the morning of dose administration and stored at ambient temperature, protected from light, until dosing.
  • the pH was adjusted using 1M NaOH and 2M HCl to achieve a final pH of 5.51.
  • the control solution was then made to final volume using a pre-calibrated line on the glass vial with 0.9% (w/v) saline. Sterile filtration using a 0.22 ⁇ M filter was then carried out.
  • the control solution had a free base concentration of 4 mg/mL (nominal) DMT-d 10 .
  • Formulation 34 A 0.3% (w/v) saline solution was prepared by adding 3.35 mL of 0.9% 25 (w/v) to a sterile glass vial with 6.65 mL of WFI, followed by magnetically mixing. Once homogeneous, the density was measured to be 1.000 g/cm 3 .
  • DMT-d 10 fumarate was removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 311.1 mg of DMT-d 10 fumarate was weighed into a suitably sized sterile glass container.2.839 mL of 30 the previously prepared 0.3% (w/v) solution (equivalent to 60% of the final stock volume) was added to the container and set to stir at a temperature of 37°C at 300 rpm. The visual appearance was recorded as a clear/yellowish homogenous solution at this stage. The pH was measured using 280
  • a 0.8% (w/v, nominal) sodium hyaluronate solution was prepared by precisely mixing 3.193 mL of 1.25% (w/v, nominal) sodium hyaluronate and 1.799 mL of 0.8% (w/v) saline in a glass container until homogeneous.
  • the density of the resultant 0.8% (w/v, nominal) sodium hyaluronate solution was recorded to be 1.002 g/cm 3 .
  • 2.032 mL of the DMT-d10 fumarate stock solution and 1.988 mL of the 0.8% (w/v, nominal) sodium hyaluronate solution were added to a 10 new sterile vial and magnetically stirred until homogeneous.
  • the formulation thus had a free base concentration of 20 mg/mL (nominal) DMT-d10 and a sodium hyaluronate concentration of 0.40% w/v (nominal). The final visual appearance of the formulation was recorded as a clear, colorless, homogenous solution.
  • the target dose was 1 mg/kg free base at a dose concentration of 15 20 mg/mL (nominal), or 1.0 mg/kg free base at a dose concentration of 4 mg/mL (nominal).
  • Appropriate volumes of dose were calculated per each animal based on real animal bodyweights and a target dose volume of 0.05 mL/kg or 0.25 mL/kg. The volumes were pulled into plastic Troge 2.5 mL syringes.
  • DMT-d10 was formulated in 0.4% w/v (nominal) sodium hyaluronate containing 0.3% w/v NaCl at a SC dose solution concentration of 20 mg/mL (nominal) (Formulation 34) and delivered 15 as a dose volume of 0.05 mL/kg or in 0.9% w/v NaCl at a SC dose solution concentration of 4 mg/mL (nominal) (control) and delivered as a dose volume of 0.25 mL/kg, both at a free base dose of 1 mg/kg.
  • the DMT-d 10 plasma concentration-time concentrations are presented in Figs.20A and 20B.
  • Corresponding pharmacokinetic parameters for DMT-d10 are presented in Table 30.
  • Plasma DMT-d10 concentrations were quantifiable up to 4 hours in all animals following SC20 administration.
  • Median T max values were 0.25 hr for both Formulation 34 and control.
  • Cmax and AUCinf decreased by about 35% for Formulation 34 compared to control. 282
  • both formulations have solubility limits ⁇ 20 mg/mL.
  • the high dose solution concentration affords a lower SC injection volume (0.5 mL for a 10 kg dog) thereby diminishing possible discomfort and/or local tissue damage associated with the injection site.
  • Test Items DMT fumarate and DMT-d10 fumarate were formulated together as a solution in 0.5% (w/v, nominal) sodium hyaluronate in water for injection (WFI) at a free base concentration of 10 mg/mL/analyte (nominal); total free base concentration of 20 mg/mL (nominal) (Formulation 35) for SC injection. Each test item was prepared on the morning of dose 25 administration and stored at ambient temperature, protected from light, until dosing.
  • Formulation 35 On the morning of dosing, DMT-d 10 fumarate and DMT fumarate were removed from storage (frozen, in a freezer set to maintain ⁇ -20°C, protected from light) and allowed to equilibrate to room temperature. Using a precision analytical balance, 80.1 mg of DMT- d 10 fumarate and 82.3 mg of DMT fumarate were weighed into a suitably sized sterile glass 283 container. 2.853 mL of WFI was added to the container and magnetically stirred. Once homogeneous, the stock solution was sterile filtered using a 0.22 ⁇ M PVDF filter.
  • the stock solution had a free base concentration of 17.7 mg/mL (nominal) DMT-d 10 and a free base concentration 17.8 mg/mL DMT (combined free base concentration of DMT-d10 + DMT of 35.5 5 mg/mL).
  • 1.832 mL of the stock solution was added to a new sterile glass vial.1.203 mL of 1.25% (w/v, nominal) sodium hyaluronate solution was added to the vial and vortex mixed to homogenize.
  • the formulation thus had a free base concentration of 10.7 mg/mL (nominal) DMT- d10 and a free base concentration of 10.8 mg/mL (nominal) DMT (combined free base concentration of DMT-d 10 + DMT of 21.5 mg/mL) and a sodium hyaluronate concentration of 10 0.5% w/v (nominal). Subcutaneous injections.
  • DMT + DMT-d10 were co-dosed (via Formulation 35) at 0.5 mg/kg/analyte, total dose of 1.0 mg/kg (free base), each at a dose concentration of 10 mg/mL (nominal), total dose concentration of 20 mg/mL (nominal) and a dose volume of 0.05 mL/kg calculated per each animal based on real animal bodyweights.
  • the volumes were pulled into plastic 15 Troge 2.5 mL syringes. Animals were identified by microchip and tattoo. Animals were dosed via SC injection into the back of the neck over ca 30 seconds using a 21G (AGANI) needle. Animals were restrained appropriately throughout and returned to their pre-trial housing post dose.
  • the experimental design is shown in Table 31. Table 31.
  • Blood samples (ca 1 mL) were collected from the jugular vein by venipuncture into tubes containing K2EDTA anticoagulant at the following time-points: Predose, 0.033 (2 min), 0.083 (5 min), 0.25 (15 min), 0.5 (30 min), 0.75 (45min), 1, 2, and 4 hr post dose. 284
  • DMT and DMT-d10 were co-dosed via Formulation 35 in 0.5% w/v (nominal) sodium hyaluronate in water for injection (WFI) at a SC dose solution concentration of 10 mg/mL/analyte (total: 20 mg/mL) (nominal) and dose volume of 0.05 mL/kg (0.5 mL for a 10 kg dog).
  • WFI water for injection
  • DMT and DMT-d10 plasma concentration-time concentrations are presented in Figs 21A and 21B.
  • Corresponding pharmacokinetic parameters for DMT and DMT-d 10 are presented in Table 32.
  • Formulations were prepared using water for injection (WFI). Filtration was performed using a Syringe filter unit, 0.22 ⁇ m, PVDF, 33 mm filter, 5 available from Sigma-Aldrich. The Dialysis—Drug Release Test and UPLC were performed as previously described in section II. Formulations and release profiles 10 Formulations and their preparative methods are presented below. Formulations are presented in terms of the parameters A, B, and C as shown previously in Table 11.
  • Formulations 36-38 To investigate the role of different concentrations of sodium hyaluronate (0.5, 0.75, and 15 1% w/v, nominal) at fixed molecular weight on the release of ketamine (12.5 mg/mL free base equivalence, nominal), three different stock sodium hyaluronate solutions were made at 1, 1.5, and 2% w/v (nominal) concentrations by dissolving 10 mg, 15 mg, and 20 mg of sodium hyaluronate (>1,000 – 1,800 kDa), respectively, in a volume of WFI to reach 1 mL, followed by incubation at 37°C and stirring. The stock sodium hyaluronate solutions were then filtered through a 0.22 ⁇ m 20 PVDF filter.
  • a stock solution of ketamine HCl (25 mg/mL free base equivalence of ketamine, nominal) was prepared by dissolving 115 mg of ketamine HCl in 4 mL of WFI, followed by incubation at 37°C and stirring. The solutions were used as is and no pH adjustments were made. Each stock sodium hyaluronate solution was then mixed in a 1:1 volume ratio with the stock solution of ketamine HCl, and the resulting formulations were vigorously stirred to ensure 25 complete mixing.
  • a control formulation (12.5 mg/mL free base equivalence of ketamine, nominal) without release modifier was prepared by mixing stock solution of ketamine HCl with WFI in a 1:1 volume ratio. Formulations are shown in Table 34. 289 Table 34.
  • Fig. 22 shows the drug release is highly controlled by the concentration of sodium hyaluronate in the formulation, 5 with the control formulation providing the fastest release, and increasing sodium hyaluronate concentrations providing increasingly slower drug release, with the slowest release provided by the highest sodium hyaluronate content (Formulation 38).
  • These formulations support the notion that sodium hyaluronate serves as a robust polymer matrix for tunable and controlled-release of drug. 10
  • the preceding merely illustrates the principles of the methods and compositions. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the disclosure and are included within its spirit and scope.

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Abstract

L'invention concerne des formulations pharmaceutiques injectables, des procédés pour leur production, des kits et leurs utilisations dans le traitement de maladies ou de troubles. Les formulations pharmaceutiques injectables comprennent un agent psychopharmaceutique, un modificateur de libération et un véhicule aqueux. Les formulations pharmaceutiques permettent une libération contrôlée temporelle limitée dans le temps de l'agent psychopharmaceutique lors de l'administration par injection telle qu'une injection sous-cutanée. Les maladies ou troubles pouvant être traités avec les formulations pharmaceutiques comprennent, par exemple, des maladies ou troubles neuropsychiatriques ou des maladies ou troubles inflammatoires, tels qu'un trouble du système nerveux central (SNC) et/ou un trouble psychologique, y compris ceux associés à un récepteur 5-HT2.
PCT/EP2024/062406 2023-05-05 2024-05-06 Formulations pharmaceutiques injectables Pending WO2024231331A1 (fr)

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