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WO2025128594A1 - Méthodes de traitement d'un trouble de l'anxiété généralisée - Google Patents

Méthodes de traitement d'un trouble de l'anxiété généralisée Download PDF

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Publication number
WO2025128594A1
WO2025128594A1 PCT/US2024/059413 US2024059413W WO2025128594A1 WO 2025128594 A1 WO2025128594 A1 WO 2025128594A1 US 2024059413 W US2024059413 W US 2024059413W WO 2025128594 A1 WO2025128594 A1 WO 2025128594A1
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WO
WIPO (PCT)
Prior art keywords
lsd
orally disintegrating
disintegrating tablet
tartrate
subject
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Pending
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PCT/US2024/059413
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English (en)
Inventor
Robert Barrow
Daniel R. Karlin
Peter Mack
Nithya SRINIVAS
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Mind Medicine Inc
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Mind Medicine Inc
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Publication date
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Publication of WO2025128594A1 publication Critical patent/WO2025128594A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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

Definitions

  • the present invention relates to methods of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering lysergic acid diethylamide (LSD), or a salt thereof.
  • LSD lysergic acid diethylamide
  • LSD Lysergic acid diethylamide
  • Effects of LSD can include altered thoughts, feelings, awareness of surroundings, dilated pupils, increased blood pressure, and increased body temperature.
  • Therapeutic use of LSD is showing promising results for treating various neurological and behavioral disorders.
  • LSD is not associated with compulsive drug seeking (addiction), and there are relatively few medical emergencies and adverse effect.
  • Use of LSD is not associated with mental health problems and may even be protective. In a safe setting, no drug -related severe adverse effects have been observed after administration of LSD in healthy participants.
  • LSD has a relatively safe physiologically profile and a single administration may have both rapid-acting and long-lasting clinical effect.
  • Solid oral formulations as tablets or capsules are used in clinical development and commercially due to advantages in production, supply chain, and patient convenience.
  • Solid oral formulations can be immediate release, dissolving instantaneously in the mouth or stomach, or extended release in which the drug release is prolonged over time.
  • Orally disintegrating tablets (ODTs) are another solid dosage form which can increase the dissolution rate of a pharmaceutical product and promote pre-gastric absorption.
  • a method for preparing ODTs is freeze drying with, for example, the Zydis® ODT fastdissolve formulation (e.g., a freeze-dried oral solid dosage form that disperses almost instantly in the mouth with no water required).
  • the method may comprise administering to the subject LSD, or a salt thereof.
  • the methods may be for treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering lysergic acid diethylamide (LSD), or a salt thereof.
  • LSD salt may be d-LSD D-tartrate.
  • the generalized anxiety disorder is severe generalized anxiety disorder.
  • the generalized anxiety disorder is moderate generalized anxiety disorder.
  • the treatment described herein comprises administering LSD as an orally disintegrating tablet.
  • the orally disintegrating tablet may comprise: LSD, or a salt thereof; a nongelling matrix; a binder; a filler; and solvent.
  • the non-gelling matrix is maltodextrin.
  • the binder is hydroxypropyl methylcellulose.
  • the filler is mannitol.
  • the solvent is water.
  • the treatments described herein may results in the symptom of generalized anxiety disorder being reduced or eliminated between about 6 hours to about 12 hours after administration of LSD, or a salt thereof (e.g., administration of an orally disintegrating table comprising LSD, or a salt thereof).
  • the reduction or elimination of a symptom of generalized anxiety disorder is for about 12 weeks or greater after administration of LSD, or a salt thereof (e.g., administration of an orally disintegrating table comprising LSD, or a salt thereof).
  • a fast and long -lasting reduction or elimination of a symptom is desired.
  • HAM-A Hamilton Anxiety Scale
  • the subject has an about 20-point HAM-A improved score within about 12 weeks after administration of LSD, or a salt thereof (e.g., administration of an orally disintegrating tablet comprising LSD, or a salt thereof).
  • An improvement in HAM-A score indicates that generalized anxiety disorder, or a symptom thereof, is being treated or prevented in a subject.
  • an improvement in HAM-A score is a decrease in score.
  • FIG. 1 is a diagram of a design schema for a clinical study.
  • FIG. 3 depicts HAM-A response rate at Week 12 in a subject with GAD after treatment with d-LSD D-tartrate.
  • FIG. 5 depicts MADRS change from baseline in a subject with GAD after treatment with d- LSD D-tartrate.
  • FIG. 7 is a photograph of Zydis ODT containing LSD.
  • FIG. 8 is a diagram of a study design for comparing a capsule and ODT formulation of d-LSD D-tartrate.
  • FIG. 9 is a graph of mean +/- SE concentration versus time for d-LSD D-tartrate in an ODT formulation.
  • FIG. 10 is a graph of mean +/- SE concentration versus time for d-LSD D-tartrate in capsule and ODT formulations.
  • FIG. 11 is a graph of mean concentration versus time for absorption phase for d-LSD D-tartrate in capsule and ODT formulations.
  • FIG. 12 is a close up view of the graph of FIG. 11 from 0 through 15 minutes.
  • FIG. 13 is a chart showing a summary of concentration by time point for d-LSD D-tartrate capsule and ODT formulations.
  • FIG. 14 is a graph of mean concentration versus time for d-LSD D-tartrate in capsule and ODT formulations showing a threshold of 0.5 ng/mL.
  • FIG. 16 is a graph of PK versus any subjective effects for d-LSD D-tartrate in capsule and ODT formulations showing a threshold of 1 ng/mL.
  • FIG. 17 is a graph of mean +/- SE concentration versus time for OH metabolite PK in d-LSD D-tartrate in capsule and ODT formulations.
  • FIG. 18 is a chart showing comparison of crossover results for PK of the ODT formulation relative to the capsule formulation.
  • FIGs. 20A-20C are graphs showing VAS profile for ODT and capsule formulation of mean +/- SE versus, FIG. 20A shows any drug effect for period 1, FIG. 20B shows good drug effect for period 1, and FIG. 20C shows bad drug effect for period 1.
  • FIG. 21 is a graph of DSRC times for the ODT and capsule formulation for period 1.
  • the LSD is formulated as a capsule or tablet.
  • the tablet is an orally disintegrating tablet.
  • the administration of an orally disintegrating tablet comprising LSD, or a salt thereof has favorable pharmacokinetic properties as compared to the administration of a capsule comprising LSD, or a salt thereof. While all LSD salts are contemplated, the LSD salt may be d-LSD D-tartrate. Also described herein are doses and schedules of administration of LSD. In some embodiments, the dose of LSD is the dose of the LSD freebase.
  • the dose recited is the amount of the LSD freebase equivalent of d-LSD D-tartrate and not the amount of d-LSD D-tartrate.
  • HAM-A Hamilton Anxiety Scale
  • CGI-S Clinical Global Impressions - Severity
  • MADRS Montgomery- Asberg Depression Rating Scale
  • the methods described herein may be for the treatment of a subject with generalized anxiety disorder, or a symptom thereof.
  • the methods described herein may be for the treatment of a symptom or prevention of a symptom of generalized anxiety disorder in a subject.
  • the treatment is a treatment of the symptoms associated with generalized anxiety disorder.
  • the generalized anxiety disorder may be severe generalized anxiety disorder of moderate generalized anxiety disorder.
  • the symptom is symptom of severe generalized anxiety disorder.
  • the symptom is a symptom of moderate generalized anxiety disorder.
  • the treatment or prevention is directed toward a symptom of generalized anxiety disorder
  • the symptom is feeling nervous, having a sense of impending danger, panic, increased heart rate, rapid breathing, sweating, trembling, gastrointestinal problems, restlessness, fatigue, difficulty concentrating, loss of interest, lack of pleasure, grinding of teeth, constriction in chest, tinnitus, blurring of vision, increased frequency of micturition, irritability, muscle tension, a sleep disturbance, or sexual dysfunction.
  • the symptom of generalized anxiety disorder is feeling nervous. In some embodiments, the symptom of generalized anxiety disorder is having a sense of impending danger. In some embodiments, the symptom of generalized anxiety disorder is panic. In some embodiments, the symptom of generalized anxiety disorder is increased heart rate. In some embodiments, the symptom of generalized anxiety disorder is rapid breathing. In some embodiments, the symptom of generalized anxiety disorder is sweating. In some embodiments, the symptom of generalized anxiety disorder is trembling. In some embodiments, the symptom of generalized anxiety disorder is gastrointestinal problems. In some embodiments, the symptom of generalized anxiety disorder is restlessness. In some embodiments, the symptom of generalized anxiety disorder is fatigue.
  • the symptom of generalized anxiety disorder is difficulty concentrating. In some embodiments, the symptom of generalized anxiety disorder is irritability. In some embodiments, the symptom of generalized anxiety disorder is muscle tension. In some embodiments, the symptom of generalized anxiety disorder is a sleep disturbance. In some embodiments, the symptom of generalized anxiety disorder is sexual dysfunction. In some embodiments, the symptom of generalized anxiety disorder is loss of interest. In some embodiments, the symptom of generalized anxiety disorder is lack of pleasure. In some embodiments, the symptom of generalized anxiety disorder is grinding of teeth. In some embodiments, the symptom of generalized anxiety disorder is constriction in chest. In some embodiments, the symptom of generalized anxiety disorder is tinnitus. In some embodiments, the symptom of generalized anxiety disorder is blurring of vision. In some embodiments, the symptom of generalized anxiety disorder is increased frequency of micturition.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering lysergic acid diethylamide (LSD), or a salt thereof.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a composition comprising lysergic acid diethylamide (LSD), or a salt thereof.
  • the present disclosure provides use of lysergic acid diethylamide (LSD), or a salt thereof, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides use of a composition comprising lysergic acid diethylamide (LSD), or a salt thereof, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides lysergic acid diethylamide (LSD), or a salt thereof, for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a composition comprising lysergic acid diethylamide (LSD), or a salt thereof, for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of lysergic acid diethylamide (LSD), or a salt thereof, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the exposure level of LSD freebase is tested in the subject’s blood to determine completion of the treatment session.
  • an LSD salt it may be any pharmaceutically acceptable salt of LSD.
  • the LSD salt is d-LSD D-tartrate.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering d-LSD D-tartrate. In one aspect, the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a composition comprising d-LSD D-tartrate. In one aspect, the present disclosure provides use of d-LSD D-tartrate for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides use of a composition comprising d-LSD D-tartrate for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides d-LSD D-tartrate for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a composition comprising d-LSD D-tartrate for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of d-LSD D-tartrate in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the methods described herein may be effective in reducing gastrointestinal side effects associated with the administration of LSD.
  • the reduced gastrointestinal side effects are due to administration of an orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has reduced gastrointestinal side effects after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject may also have depression.
  • the subject is not undergoing a treatment for anxiety or depression prior to the administration of LSD, or a salt thereof.
  • LSD, or a salt thereof is administered as a monotherapy.
  • the subject is not administered a second agent for the treatment of generalized anxiety disorder or depression.
  • the subject is not administered a second agent for the treatment of generalized anxiety disorder.
  • the subject is not administered a second agent for the treatment of depression.
  • the LSD, or a salt thereof, described herein may be formulated for oral administration.
  • the LSD, or a salt thereof is administered as a composition.
  • the composition comprising LSD, or a salt thereof is formulated in a capsule or tablet.
  • the LSD, or a salt thereof is administered as a capsule.
  • International Application No. PCT/US2022/040653 further discloses the preparation of the capsule.
  • the LSD, or a salt thereof is administered as a tablet.
  • the tablet may be an orally disintegrating tablet.
  • International Application No. PCT/US2022/040636 further discloses the preparation of the orally disintegrating tablet.
  • the orally disintegrating tablet is a lyophilized orally disintegrating tablet.
  • the d-LSD D-tartrate is administered as an orally disintegrating tablet.
  • An orally disintegrating tablet is capable of disintegrating or dispersing within an interval of less than 60 seconds after being placed in contact with a physiological fluid such as saliva.
  • the orally disintegrating tablet is capable of dispersing within an interval of about 1 to about 60 seconds, about 1 to about 30 seconds, about 1 to about 10 seconds, or about 1 to about 5 seconds after being placed in contact with a physiological fluid such as saliva.
  • a physiological fluid such as saliva.
  • an orally disintegrating tablet it may be prepared as a stock solution. The stock solution may be utilized to prepare the tablet for administration to a subject with generalized anxiety disorder.
  • the orally disintegrating tablet comprises: a. LSD, or a salt thereof; b. a non-gelling matrix; c. a binder; d. a filler; and e. solvent.
  • d-LSD D- tartrate may be present in the stock solution in an amount of less than about 1%.
  • the orally disintegrating tablet stock solution comprises less than about 1% d-LSD D-tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.9% d-LSD D- tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.8% d-LSD D-tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.7% d-LSD D-tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.6% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.5% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.4% d-LSD D- tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.3% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.2% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.1% d-LSD D-tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.09% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.08% d-LSD D- tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.07% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.06% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.05% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.04% d-LSD D-tartrate.
  • the orally disintegrating tablet stock solution comprises less than about 0.03% d-LSD D- tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.02% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet stock solution comprises less than about 0.01% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 1% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.9% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.8% d-LSD D-tartrate.
  • the orally disintegrating tablet comprises less than about 0.7% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.6% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.5% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.4% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.3% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.2% d-LSD D-tartrate.
  • the orally disintegrating tablet comprises less than about 0.1% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.09% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.08% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.07% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.06% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.05% d-LSD D-tartrate.
  • the orally disintegrating tablet comprises less than about 0.04% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.03% d-LSD D-tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.02% d-LSD D- tartrate. In some embodiments, the orally disintegrating tablet comprises less than about 0.01% d-LSD D-tartrate.
  • the formulation of LSD described herein may comprise a non-gelling matrix.
  • the non-gelling matrix is a non-gelling gelatin (including fish gelatin), maltodextrin, modified starches, starch ethers, low molecular weight dextrans, or low to intermediate molecular weight cellulose gums.
  • the non-gelling matrix is described in U.S. Pat. No. 10,548,839.
  • maltodextrin when used as the non-gelling matrix in the orally disintegrating tablet described herein, maltodextrin may be present in an amount of about 2% to about 10% of the total stock solution formulation.
  • the orally disintegrating tablet stock solution comprises about 2% maltodextrin.
  • the orally disintegrating tablet stock solution comprises about 3% maltodextrin.
  • the orally disintegrating tablet stock solution comprises about 4% maltodextrin.
  • the orally disintegrating tablet stock solution comprises about 5% maltodextrin.
  • the orally disintegrating tablet stock solution comprises about 6% maltodextrin.
  • the orally disintegrating tablet stock solution comprises about 7% maltodextrin. In some embodiments, the orally disintegrating tablet stock solution comprises about 8% maltodextrin. In some embodiments, the orally disintegrating tablet stock solution comprises about 9% maltodextrin. In some embodiments, the orally disintegrating tablet stock solution comprises about 10% maltodextrin.
  • maltodextrin when used as the non-gelling matrix in the orally disintegrating tablet described herein, maltodextrin may be present in an amount of about 15% to about 77% of the formulation.
  • the orally disintegrating tablet comprises about 15% maltodextrin.
  • the orally disintegrating tablet comprises about 20% maltodextrin.
  • the orally disintegrating tablet comprises about 25% maltodextrin.
  • the orally disintegrating tablet comprises about 30% maltodextrin.
  • the orally disintegrating tablet comprises about 35% maltodextrin.
  • the orally disintegrating tablet comprises about 40% maltodextrin.
  • the orally disintegrating tablet comprises about 41% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 42% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 43% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 44% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 45% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 46% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 47% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 48% maltodextrin.
  • the orally disintegrating tablet comprises about 49% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 50% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 55% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 60% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 65% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 70% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 75% maltodextrin. In some embodiments, the orally disintegrating tablet comprises about 77% maltodextrin.
  • the formulation of LSD described herein may comprise a binder.
  • the binder is acacia gum, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, tragacanth, polyvinyl pyrrolidone (PVP), or starch.
  • the hydroxypropyl methylcellulose may be present in an amount of about 8% to about 38% of the formulation.
  • the orally disintegrating tablet comprises about 8% hydroxypropyl methylcellulose.
  • the orally disintegrating tablet comprises about 9% hydroxypropyl methylcellulose.
  • the orally disintegrating tablet comprises about 10% hydroxypropyl methylcellulose.
  • the orally disintegrating tablet comprises about 15% hydroxypropyl methylcellulose.
  • the orally disintegrating tablet comprises about 20% hydroxypropyl methylcellulose.
  • the formulation of LSD described herein may comprise a fdler.
  • the fdler is lactose (including anhydrous), mannitol, dicalcium phosphate, calcium sulfate, starch (starch as used herein can include dry or pre-gelled), cellulose (including microcrystalline cellulose), kaolin, sodium chloride, sorbitol, trehalose, or sucrose.
  • the orally disintegrating tablet stock solution comprises about 8% mannitol. In some embodiments, the orally disintegrating tablet stock solution comprises about 9% mannitol. In some embodiments, the orally disintegrating tablet stock solution comprises about 10% mannitol.
  • the mannitol may be present in an amount of about 15% to about 77% of the formulation.
  • the orally disintegrating tablet comprises about 15% mannitol.
  • the orally disintegrating tablet comprises about 20% mannitol.
  • the orally disintegrating tablet comprises about 25% mannitol.
  • the orally disintegrating tablet comprises about 30% mannitol.
  • the orally disintegrating tablet comprises about 35% mannitol.
  • the orally disintegrating tablet comprises about 36% mannitol.
  • the orally disintegrating tablet comprises about 37% mannitol. In some embodiments, the orally disintegrating tablet comprises about 38% mannitol. In some embodiments, the orally disintegrating tablet comprises about 38.3% mannitol. In some embodiments, the orally disintegrating tablet comprises about 39% mannitol. In some embodiments, the orally disintegrating tablet comprises about 40% mannitol. In some embodiments, the orally disintegrating tablet comprises about 45% mannitol. In some embodiments, the orally disintegrating tablet comprises about 50% mannitol. In some embodiments, the orally disintegrating tablet comprises about 55% mannitol. In some embodiments, the orally disintegrating tablet comprises about 60% mannitol.
  • the orally disintegrating tablet comprises about 65% mannitol. In some embodiments, the orally disintegrating tablet comprises about 70% mannitol. In some embodiments, the orally disintegrating tablet comprises about 75% mannitol. In some embodiments, the orally disintegrating tablet comprises about 77% mannitol.
  • the orally disintegrating tablet stock solution comprises: a. less than about 1% d-LSD D-tartrate; b. about 2% to about 10% maltodextrin; c. about 1% to about 5% hydroxypropyl methylcellulose; d. about 2% to about 10% mannitol; and e. water.
  • the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water.
  • the formulation described herein may be used for the treatment of a subject with generalized anxiety disorder, or a symptom thereof.
  • the formulation described herein may be used for the treatment of a symptom or prevention of a symptom of generalized anxiety disorder in a subject.
  • the treatment is a treatment of the symptoms associated with generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • the present disclosure provides use of an orally disintegrating tablet, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides an orally disintegrating tablet, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water.
  • the present disclosure provides use of an orally disintegrating tablet, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides an orally disintegrating tablet, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • LSD, or a salt thereof, described herein may be further administered to a subject at a specified dose or administration schedule.
  • the dose corresponds to the freebase equivalent of the LSD salt.
  • the schedule of administration may also include frequency and length of administration.
  • the dose is between about 25 pg to about 200 pg, wherein the amount of LSD correlates to the amount of the freebase equivalent of LSD.
  • the LSD, or a salt thereof is administered at a dose of about 25 pg, about 50 pg, about 100 pg, about 150 pg, or about 200 pg of the freebase equivalent of LSD.
  • the LSD, or a salt thereof is administered at a dose of about 25 pg of the freebase equivalent of LSD.
  • the LSD, or a salt thereof is administered at a dose of about 50 pg of the freebase equivalent of LSD.
  • the LSD, or a salt thereof is administered at a dose of about 100 pg of the freebase equivalent of LSD. In some embodiments, the LSD, or a salt thereof, is administered at a dose of about 150 pg of the freebase equivalent of LSD. In some embodiments, the LSD, or a salt thereof, is administered at a dose of about 200 pg of the freebase equivalent of LSD.
  • d-LSD D-tartrate When d-LSD D-tartrate is administered to a subject, the dose is between about 25 pg to about 200 pg, wherein the amount of LSD correlates to the amount of the freebase equivalent of LSD. In some embodiments, d-LSD D-tartrate is administered at a dose of about 25 pg, about 50 pg, about 100 pg, about 150 pg, or about 200 pg of the freebase equivalent of LSD. In some embodiments, d-LSD D- tartrate is administered at a dose of about 25 pg of the freebase equivalent of LSD. In some embodiments, d-LSD D-tartrate is administered at a dose of about 50 pg of the freebase equivalent of LSD.
  • d-LSD D-tartrate is administered at a dose of about 100 pg of the freebase equivalent of LSD. In some embodiments, d-LSD D-tartrate is administered at a dose of about 150 pg of the freebase equivalent of LSD. In some embodiments, d-LSD D-tartrate is administered at a dose of about 200 pg of the freebase equivalent of LSD.
  • about 146 pg of the d-LSD D-tartrate is equivalent to about 100 pg of LSD freebase.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg LSD, or a salt thereof. In one aspect, the present disclosure provides use of a dose of about 100 pg LSD, or a salt thereof, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides a dose of about 100 pg LSD, or a salt thereof, for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides the use of a dose of about 100 pg LSD, or a salt thereof, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg d-LSD D-tartrate.
  • the present disclosure provides use of a dose of about 100 pg d-LSD D-tartrate for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides a dose of about 100 pg d-LSD D-tartrate for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides the use of a dose of about 100 pg d-LSD D- tartrate in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the symptom of generalized anxiety disorder may be reduced or eliminated between about 6 hours to about 24 hours after administration.
  • the symptom of generalized anxiety disorder may be reduced or eliminated between about 6 hours to about 12 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 6 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 7 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 8 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 9 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 10 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 11 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 12 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 24 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder may be reduced or eliminated between about 6 hours to about 12 hours after administration.
  • the symptom of generalized anxiety disorder may be reduced or eliminated between about 6 hours to about 12 hours after administration of the orally disintegrating tablet comprising d-LSD D- tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 6 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 7 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated about 8 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 9 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 10 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 11 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the symptom of generalized anxiety disorder is reduced or eliminated about 12 hours after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated for a period of time greater than 10 weeks.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 12 weeks or greater after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 16 weeks or greater after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 20 weeks or greater after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 24 weeks or greater after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the symptom of generalized anxiety disorder is reduced or eliminated for an period of time greater than 10 weeks.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 12 weeks or greater after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 16 weeks or greater after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 20 weeks or greater after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the symptom of generalized anxiety disorder is reduced or eliminated for about 24 weeks or greater after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • LSD, or a salt thereof is administered intermittently. In some embodiments, the LSD, or salt thereof is administered at a frequency of one to four times per year. In some embodiments, the LSD, or a salt thereof, is administered one time per year. In some embodiments, the LSD, or a salt thereof, is administered two times per year. In some embodiments, the LSD, or a salt thereof, is administered three times per year. In some embodiments, the LSD, or a salt thereof, is administered four times per year. In some embodiments, the LSD, or a salt thereof, is administered weekly. In some embodiments, the LSD, or a salt thereof, is administered monthly. In some embodiments, the LSD, or a salt thereof, is administered between once per week and once per year. In some embodiments, the LSD, or a salt thereof, is administered once to a subject.
  • the administration may be followed by a drug holiday.
  • the drug holiday is from about one week to about one year. In some embodiments, the drug holiday is from about one to about four months.
  • the frequency may be once every about 10 to about 20 weeks.
  • the LSD, or a salt thereof is administered once every about 10 weeks.
  • the LSD, or a salt thereof is administered once every about 12 weeks.
  • the LSD, or a salt thereof is administered once every about 14 weeks.
  • the LSD, or a salt thereof is administered once every about 16 weeks.
  • the LSD, or a salt thereof is administered once every about 18 weeks.
  • the LSD, or a salt thereof is administered once every about 20 weeks.
  • d-LSD D-tartrate When d-LSD D-tartrate is administered to a subject, d-LSD D-tartrate is administered at a frequency of one to four times per year. In some embodiments, d-LSD D-tartrate is administered one time per year. In some embodiments, d-LSD D-tartrate is administered two times per year. In some embodiments, d-LSD D-tartrate is administered three times per year. In some embodiments, d-LSD D- tartrate is administered four times per year.
  • d-LSD D-tartrate When d-LSD D-tartrate is administered to a subject the frequency may be once every about 10 to about 20 weeks. In some embodiments, d-LSD D-tartrate is administered once every about 10 weeks. In some embodiments, d-LSD D-tartrate is administered once every about 12 weeks. In some embodiments, d-LSD D-tartrate is administered once every about 14 weeks. In some embodiments, d- LSD D-tartrate is administered once every about 16 weeks. In some embodiments, d-LSD D-tartrate is administered once every about 18 weeks. In some embodiments, d-LSD D-tartrate is administered once every about 20 weeks.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg LSD, or a salt thereof one to four times per year.
  • the present disclosure provides use of a dose of about 100 pg LSD, or a salt thereof, one to four times per year for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides a dose of about 100 pg LSD, or a salt thereof, one to four times per year for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of a dose of about 100 pg LSD, or a salt thereof, one to four times per year in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg d-LSD D- tartrate freebase equivalent one to four times per year.
  • the present disclosure provides use of a dose of about 100 pg d-LSD D-tartrate freebase equivalent one to four times per year for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides a dose of about 100 pg d-LSD D-tartrate freebase equivalent one to four times per year for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of a dose of about 100 pg d-LSD D-tartrate freebase equivalent one to four times per year in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg LSD, or a salt thereof once every about 12 weeks.
  • the present disclosure provides use of a dose of about 100 pg LSD, or a salt thereof, once every about 12 weeks for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides a dose of about 100 pg LSD, or a salt thereof, once every about 12 weeks for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides use of a dose of about 100 pg d-LSD D-tartrate freebase equivalent once every about 12 weeks for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder. In one aspect, the present disclosure provides a dose of about 100 pg d- LSD D-tartrate freebase equivalent once every about 12 weeks for use in treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of a dose of about 100 pg d-LSD D-tartrate freebase equivalent once every about 12 weeks in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the dose of about 147 pg d-LSD D-tartrate correlates to about 100 pg of the LSD freebase.
  • the dose of about 100 pg d-LSD D-tartrate freebase equivalent correlates to about 100 pg of the LSD freebase.
  • the dose and frequency may be as described herein.
  • the orally disintegrating tablet may be administered one to four times per year or once every about 10 to about 20 weeks at an LSD freebase equivalent dose of about 100 pg.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water.
  • the present disclosure provides use of an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water.
  • the present disclosure provides use of an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet stock solution comprises: a. less than 1%% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water.
  • the present disclosure provides use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • the present disclosure provides use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder
  • the present disclosure provides a method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water.
  • the present disclosure provides use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, for the treatment of a symptom of generalized anxiety disorder or prevention of a symptom of generalized anxiety disorder.
  • the present disclosure provides the use of an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water, in the manufacture of a medicament for treating a symptom of generalized anxiety disorder or preventing a symptom of generalized anxiety disorder.
  • the subject’s serum concentration may be analyzed for the present of LSD freebase.
  • the presence of LSD freebase at an increased concentration over a period of time less than five hours may indicate that the formulation is effective in treating a symptom or preventing a symptom of generalized anxiety disorder with LSD, or a salt thereof.
  • Blood sampling for LSD freebase analysis occurred at multiple time points during treatment with LSD, or a salt thereof (e.g., at pre-dose (about 15 minutes prior to dose ⁇ 5 minutes), and about 5 minutes, about 10 minutes, and about 15 minutes post-dose (with a sampling window of ⁇ 1 minute), as well as at about 30 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 12 hours, and about 24 hours post-dose (with a sampling window of ⁇ 5 minutes).
  • pre-dose about 15 minutes prior to dose ⁇ 5 minutes
  • 5 minutes, about 10 minutes, and about 15 minutes post-dose with a sampling window of ⁇ 1 minute
  • at about 30 minutes about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 12 hours, and about 24 hours post-dose (with a sampling window of ⁇
  • the effectiveness of a treatment described herein may also be determined through subject participation in post treatment questionnaires, symptom reporting, and subject monitoring.
  • a subject’s decrease in symptoms of generalized anxiety disorder is considered treatment of a symptom of generalized anxiety disorder.
  • the methods described herein can also include the subject wearing a smartwatch and using a smartphone with built-in sensors to passively record heart rate, audio data, accelerometric data, angular velocity, orientation, number of steps, and activity type.
  • the data recorded by the smartwatch may be utilized by a medical professional to monitor the individual throughout a treatment session.
  • a subject When a subject reports their own outcome measurements it may be according to the Patient Global Impression scale, Sheehan Disability Scale, EQ-5D-5L, Pittsburgh Sleep Quality Index, or Arizona sexual Experiences Questionnaire. A subject may self-report their outcome by reporting their symptoms, or treatment thereof, to a medical professional. a. Pharmacokinetics
  • the LSD When a subject is administered LSD, or a salt thereof, according to the instant disclosure, the LSD exhibits rapid absorption and systemic bioavailability.
  • the administration of LSD, or a salt thereof, in an orally disintegrating tablet provides increased absorption and systemic bioavailability as compared to administration of LSD in a capsule. Detectable levels of LSD freebase from an orally disintegrating tablet may be observed within 5 to 30 minutes, 5 to 15 minutes, or 5 to 10 minutes.
  • the C max of the LSD freebase from an orally disintegrating tablet is between about 0.9 to 5.4 ng/mL (e.g., 0.798 to 4.60 ng/mL, or 1.75 to 3.65 ng/mL).
  • the AUC0-24 of the LSD freebase from an orally disintegrating tablet is between about 5.6 to about 45 ng «hr/mL (e.g., 3.34 to 33.5 ng «hr/mL, or 10.9 to 25.9 ng «hr/mL).
  • the AUCinf of the LSD freebase from an orally disintegrating tablet is between about 5.9 to about 48.0 ng «hr/mL (e.g., 3.68 to 35.3 ng «hr/mL, or 11.59 to 27.49 ng «hr/mL).
  • the T max after administration of LSD, or a salt thereof, in an orally disintegrating tablet is between about 1.0 hours to about 4 hours (e.g., 0.47 to 3.67 hours or 1.27 to 2.87 hours).
  • the T1/2 of the LSD freebase in an orally disintegrating tablet is between about 2.5 hours to about 10.3 hours (e.g., 1.37 to 8.3 hours or 3.21 to 6.89 hours).
  • Administration of an orally disintegrating tablet comprising LSD, or a salt thereof provides a time to symptom resolution that is between a time about 6 to about 12 hours on average (e.g., 6 to 10 hours on average or 8 to 10 hours on average).
  • the administration of an orally disintegrating tablet comprising LSD, or a salt thereof provides a resolving of acute perceptual effects from about 50% of patients by about 8 hours, about 70% of patients by about 10 hours, and about 40% of patients by about 7 hours.
  • an orally disintegrating tablet comprising LSD, or a salt thereof When an orally disintegrating tablet comprising LSD, or a salt thereof, is administered as described in the instant disclosure, a greater peak concentration of LSD freebase as compared to administration of LSD, or a salt thereof, in a different formulation at a comparable dose.
  • the orally disintegrating tablet comprising LSD, or a salt thereof provides a greater peak concentration of LSD freebase as compared to a capsule comprising LSD, or a salt thereof.
  • the subject’s serum LSD freebase concentration is between about 2 ng/mL to about 2.5 ng/mL within about five hours after administration of the orally disintegrating tablet. In some embodiments, the subj ect’ s serum LSD freebase concentration is about 2 ng/mL within about five hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.1 ng/mL within about five hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.2 ng/mL within about five hours after administration of the orally disintegrating tablet.
  • the subject’s serum LSD freebase concentration is about 2.3 ng/mL within about five hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.4 ng/mL within about five hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.5 ng/mL within about five hours after administration of the orally disintegrating tablet. [000126] In some embodiments, the subject’s serum LSD freebase concentration is between about 2 ng/mL to about 2.5 ng/mL within about four hours after administration of the orally disintegrating tablet.
  • the subject’s serum LSD freebase concentration is about 2 ng/mL within about four hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.1 ng/mL within about four hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.2 ng/mL within about four hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.3 ng/mL within about four hours after administration of the orally disintegrating tablet.
  • the subject’s serum LSD freebase concentration is about 2.4 ng/mL within about four hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.5 ng/mL within about four hours after administration of the orally disintegrating tablet.
  • the subject’s serum LSD freebase concentration is between about 2 ng/mL to about 2.5 ng/mL within about three hours after administration of the orally disintegrating tablet.
  • the subj ect’ s serum LSD freebase concentration is about 2 ng/mL within about three hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.1 ng/mL within about three hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.2 ng/mL within about three hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.3 ng/mL within about three hours after administration of the orally disintegrating tablet.
  • the subject’s serum LSD freebase concentration is about 2.4 ng/mL within about three hours after administration of the orally disintegrating tablet. In some embodiments, the subject’s serum LSD freebase concentration is about 2.5 ng/mL within about three hours after administration of the orally disintegrating tablet. [000129] In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.2 ng/mL higher within five hours as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.2 ng/mL higher within four hours as compared to administration of a capsule comprising d-LSD D-tartrate. In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.2 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.3 ng/mL higher within five hours as compared to administration of a capsule comprising d-LSD D-tartrate. In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.3 ng/mL higher within four hours as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.3 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.4 ng/mL higher within five hours as compared to administration of a capsule comprising d-LSD D-tartrate. In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.4 ng/mL higher within four hours as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.4 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.5 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.6 ng/mL higher within five hours as compared to administration of a capsule comprising d-LSD D-tartrate. In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.6 ng/mL higher within four hours as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.6 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.7 ng/mL higher within five hours as compared to administration of a capsule comprising d-LSD D-tartrate. In some embodiments, the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.7 ng/mL higher within four hours as compared to administration of a capsule comprising d-LSD D-tartrate.
  • the subject’s serum LSD freebase concentration after administration of an orally disintegrating tablet comprising d-LSD D-tartrate is about 0.7 ng/mL higher within three hours as compared to administration of a capsule comprising d- LSD D-tartrate.
  • the bioavailability of LSD freebase (e.g., C max ) is increased after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate.
  • the bioavailability of LSD freebase (e.g., C max ) is increased about 15% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate. In some embodiments, the bioavailability of LSD freebase (e.g., C max ) is increased about 16% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate.
  • the bioavailability of LSD freebase (e.g., C max ) is increased about 17% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D- tartrate. In some embodiments, the bioavailability of LSD freebase (e.g., C max ) is increased about 18% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate.
  • the bioavailability of LSD freebase (e.g., C max ) is increased about 19% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate. In some embodiments, the bioavailability of LSD freebase (e.g., C max ) is increased about 20% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D- tartrate.
  • the bioavailability of LSD freebase (e.g., C max ) is increased from about 15% to about 20% after administration of an orally disintegrating tablet comprising d-LSD D-tartrate as compared to a capsule comprising d-LSD D-tartrate.
  • an orally disintegrating tablet comprising d-LSD D-tartrate has an onset of action of about 0.5 hour. In some embodiments, an orally disintegrating tablet comprising d- LSD D-tartrate has an onset of action of about 1 hour. In some embodiments, an orally disintegrating tablet comprising d-LSD D-tartrate has an onset of action of about 1.5 hours. In some embodiments, an orally disintegrating tablet comprising d-LSD D-tartrate has an onset of action of about 2 hours. In some embodiments, an orally disintegrating tablet comprising d-LSD D-tartrate has an onset of action of about 2.5 hours.
  • an orally disintegrating tablet comprising d-LSD D-tartrate has an onset of action that is 50% faster than the onset of action of a capsule comprising d-LSD D-tartrate.
  • the onset of action may be related to measuring LSD freebase concentration in the blood or measuring a subjective effect of the drug.
  • administration of an orally disintegrating tablet comprising d-LSD D- tartrate provides a decrease in concentration of LSD freebase in subject serum to below 1 ng/mL within 12 hours of administration of the orally disintegrating tablet.
  • administration of a capsule comprising d-LSD D-tartrate provides a decrease in concentration of LSD freebase in subject serum to below 1 ng/mL within 24 hours of administration of the orally disintegrating tablet.
  • administration of an orally disintegrating tablet comprising d-LSD D- tartrate provides a decrease in concentration of LSD freebase in subject serum to below 1 ng/mL in half the time as compared to administration of a capsule comprising d-LSD D-tartrate, wherein the faster decrease in serum concentration of the orally disintegrating tablet comprising d-LSD D-tartrate results in a shorter duration of adverse events requiring monitoring by a healthcare practitioner.
  • administration of an orally disintegrating tablet comprising d-LSD D- tartrate provides a decrease in concentration of LSD freebase in subject serum to below 1 ng/mL in half the time as compared to administration of a capsule comprising d-LSD D-tartrate, wherein the faster decrease in serum concentration of the orally disintegrating tablet comprising d-LSD D-tartrate results in a shorter duration of perceptual effects.
  • the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 7.5 ng «hr/mL and about 30 ng «hr/mL.
  • the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 7.73 ng «hr/mL and about 29.13 ng «hr/mL. In some embodiments, the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8.0 ng «hr/mL and about 27.0 ng «hr/mL.
  • the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8.28 ng «hr/mL and about 25.27 ng «hr/m L. In some embodiments, the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 11.0 ng «hr/mL and about 20.0 ng «hr/mL.
  • the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 11.71 ng «hr/mL and about 17.42 ng «hr/mL.
  • the AUC0-24 for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is higher than the AUC0-24 for d-LSD D-tartrate after administration of a capsule comprising the equivalent dose of LSD freebase.
  • the AUC m f for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8.0 ng «hr/mL and about 35.0 ng «hr/mL. In some embodiments, the AUC m f for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8.35 ng «hr/mL and about 31.85 ng «hr/mL.
  • the AUCmf for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8.87 ng «hr/mL and about 27.56 ng’hr/mL. In some embodiments, the AUC m f for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 10.0 ng «hr/mL and about 20.0 ng «hr/mL.
  • the AUCmf for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 12.87 ng «hr/mL and about 18.30 ng «hr/mL.
  • the AUCmf for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is higher than the AUCmf for LSD freebase after administration of a capsule comprising the equivalent dose of LSD freebase.
  • the AUCo-cmax for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 0.5 ng «hr/mL and about 10.0 ng «hr/mL. In some embodiments, the AUCo-cmax for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 0.76 ng «hr/mL and about 6.41 ng «hr/mL.
  • the AUCo-cmax for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 1.01 ng «hr/mL and about 5.45 ng «hr/mL. In some embodiments, the AUCo-cmax for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 1.44 ng «hr/mL and about 3.72 ng «hr/mL.
  • the AUCo-cmax for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is higher than the AUCo-cmax for LSD freebase after administration of a capsule comprising the equivalent dose of LSD freebase.
  • the T ma x for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 1 to about 3.5 hours. In some embodiments, the T ma x for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 1.38 hours to 3 hours.
  • the T max for the LSD freebase after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is lower than the T max for LSD freebase after administration of a capsule comprising the equivalent dose of LSD freebase.
  • the subject experience symptom resolution after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 6 hours to 12 hours.
  • the subject experience symptom resolution after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 6 hours to 10 hours.
  • the subject experience symptom resolution after administration of an orally disintegrating tablet comprising 100 pg of the LSD freebase equivalent of d-LSD D-tartrate is between about 8 hours to 10 hours.
  • HAM-A Hamilton Anxiety Scale
  • HAM-A Hamilton Anxiety Scale
  • Severe generalized anxiety disorder is classified by a Hamilton Anxiety Scale (HAM-A) score greater than 25, while moderate generalized anxiety disorder is classified by a HAM-A score of 16-24.
  • HAM-A score may have a HAM-A score below 16.
  • treatment results in a HAM-A score below 8.
  • the subject is measured at screening and baseline prior to administration of LSD, or a salt thereof.
  • a subject to be treated with LSD, or a salt thereof, as described herein has an initial HAM-A score higher than about 17 (e.g., 20).
  • a HAM-A score When a HAM-A score is measured, the medical professional assess the following items in a subject: anxious mood, tension, fears, insomnia, intellect, depressed mood, somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and general behavior at the interview. Each of the criterion are assess on a scale of 0 to 4, wherein 4 is the most severe symptoms. After administration of a GAM-A assessment, the medical professional may provide an assessment of the Montgomery-Asberg Depression Rating Scale (MADRS).
  • MADRS Montgomery-Asberg Depression Rating Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM-A Hamilton Anxiety Scale
  • the subject has between an about 15-point and about 25-point HAM- A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 15-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 16-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 17-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 18-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 19-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 20-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 21 -point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 22 -point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 23-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 24-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 25-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has a Hamilton Anxiety Scale (HAM-A) improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D- tartrate.
  • HAM-A Hamilton Anxiety Scale
  • the subject has between an about 15-point and about 25-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 15-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 16-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 17-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 18-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 19- point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 20-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 21 -point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D- tartrate. In some embodiments, the subject has an about 22-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 23-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 24-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 25 -point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of less than 10 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 10 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 9 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 8 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 7 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 6 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 5 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 4 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 3 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 2 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 1 about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of less than 10 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 10 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 9 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 8 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 7 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 6 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 5 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 4 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 3 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • HAM-A Hamilton Anxiety Scale
  • the subject has a Hamilton Anxiety Scale (HAM-A) score of 2 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has a Hamilton Anxiety Scale (HAM-A) score of 1 about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • HAM-A Hamilton Anxiety Scale
  • CGI-S Clinical Global Impressions - Severity
  • a subject may have a reduction in CGI-S between about 1.5-points and 2.0-points.
  • CGI-S is measured at least one week after administration of LSD, or a salt thereof.
  • the subject shows a CGI-S score change from 7 to 6, 6 to 5, 7 to 5, 6 to 4, or any CGI-S score lower than the CGI-S score prior to treatment.
  • the reduction in CGI-S may be measured about two days, one week, two weeks, four weeks, eight weeks, or 12 weeks after treatment.
  • CGI-S scale When the CGI-S scale is assessed in a subject the severity of the illness is determined as compared to the medical professionals understanding and prior assessments of subjects with generalized anxiety disorder.
  • a CGI-S scale is from 0-7, with 7 being a more severe illness.
  • the subject has a reduction in Clinical Global Impressions - Severity (CGI-S) within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • CGI-S Clinical Global Impressions - Severity
  • the subject has between an about 1.5-point and 2.0-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 1.5-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 1.6-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 1.7-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 1.8 -point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 1.9-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 2.0-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has a reduction in Clinical Global Impressions - Severity (CGI-S) within about 12 weeks after administration of the orally disintegrating tablet comprising d- LSD D-tartrate.
  • CGI-S Clinical Global Impressions - Severity
  • the subject has between an about 1.5-point and 2.0-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 1.5-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 1.6-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 1.7-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 1.8-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 1.9-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 2.0-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • MADRS Montgomery- -Asbe rg Depression Rating Scale
  • the treatment is measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS).
  • MADRS Montgomery-Asberg Depression Rating Scale
  • a subject may have a reduction in MADRS between about 15 -points and 20-points.
  • MADRS is measured at least one week after administration of LSD, or a salt thereof.
  • a medical profession determines the depression severity.
  • the MADRS assessment includes a questionnaire including 10 questions that are ranked from 0-6, wherein 6 indicates severe or continuous present of depression symptoms. When a subject is determined to have a high MADRS score, than the subject has a severe condition. The maximum MADRS score is 60.
  • a decrease in score by about 50% indicates a successful response.
  • the subject has an about 50% decrease in MADRS score after treatment with LSD, or a salt thereof.
  • a subject has been treated when the subject is determined to have a score of less than or equal to about 10.
  • the subject has a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • the subject has between an about 15 -point and 20-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 15-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 16-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 17-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 18-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has an about 19-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof. In some embodiments, the subject has an about 20-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • the subject has a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • the subject has between an about 15-point and 20-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d- LSD D-tartrate.
  • the subject has an about 15-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 16-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 17-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 18-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate.
  • the subject has an about 19- point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d-LSD D-tartrate. In some embodiments, the subject has an about 20-point reduction in MADRS within about 12 weeks after administration of the orally disintegrating tablet comprising d- LSD D-tartrate.
  • the dose is a the dose of the freebase equivalent of d-LSD D-tartrate.
  • the term "subject” refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog).
  • a mammal e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog.
  • “approximately” and “about” are synonymous. In some embodiments, “approximately” and “about” refer to the recited amount, value, or duration ⁇ 5%, ⁇ 4.5%, ⁇ 4%, ⁇ 3.5%, ⁇ 3%, ⁇ 2.5%, ⁇ 2%, ⁇ 1.75%, ⁇ 1.5%, ⁇ 1.25%, ⁇ 1%, ⁇ 0.9%, ⁇ 0.8%, ⁇ 0.7%, ⁇ 0.6%, ⁇ 0.5% ⁇ 0.4%, ⁇ 0.3%, ⁇ 0.2%, ⁇ 0.1%, ⁇ 0.09%, ⁇ 0.08%, ⁇ 0.07%, ⁇ 0.06%, ⁇ 0.05%, ⁇ 0.04%, ⁇ 0.03%, ⁇ 0.02%, or ⁇ 0.01%.
  • an effective amount means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.
  • a therapeutically effective amount can be given in unit dosage form .
  • administer refers to methods that may be used to enable delivery of compositions to the desired site of biological action.
  • treating describes the management and care of a patient for the purpose of combating a disease, a symptom of a disease, condition, symptom of a condition, disorder, or symptom of a disorder and includes the administration of LSD, or a salt thereof.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non- health-care professionals. [000192] ‘ ‘Generalized anxiety disorder” as used herein refers to a condition that is characterized by persistent and excessive worry.
  • Generalized anxiety disorder is present when an individual has difficulty controlling worry on more days than not for at least six months and has at least three defined symptoms (such as feeling nervous, irritable, on edge, having a sense of impending danger, panic, or doom, having an increased heart rate, breathing rapidly (hyperventilation), sweating, and/or trembling, feeling weak or tired, difficulty concentrating, having trouble sleeping, and experiencing gastrointestinal (GI) problems).
  • Generalized anxiety disorder is different from anxiety brought on by a specific stressor, such as illness.
  • Exemplary Embodiment 1A A method of treating Generalized Anxiety Disorder (GAD), including the step of: administering a serotonin-2A receptor agonist to an individual suffering from GAD.
  • GAD Generalized Anxiety Disorder
  • Exemplary Embodiment 2A A method of treating moderate GAD, including the step of: administering a serotonin-2A receptor agonist to an individual suffering from moderate GAD.
  • Exemplary Embodiment 4A A method of improving Hamilton Anxiety scale scores, including the steps of: administering a Hamilton Anxiety scale to an individual suffering from GAD; administering a serotonin-2A receptor agonist to the individual; and producing improved Hamilton Anxiety scale scores.
  • Exemplary Embodiment 5A A method of treating an anxiety disorder, including the step of: administering a serotonin-2A receptor agonist to an individual suffering from an anxiety disorder without concomitant therapy.
  • Exemplary Embodiment 6A A method of treating anxiety and depression, including the steps of: administering a serotonin-2A receptor agonist to an individual suffering from anxiety and depression; and treating anxiety and depression at the same time.
  • Exemplary Embodiment 7A A method of rapidly treating GAD, including the steps of: administering a serotonin-2A receptor agonist to an individual suffering from GAD; and producing an improvement in GAD symptoms within 48 hours of administration.
  • Exemplary Embodiment 8A A method of treating GAD and reducing risk of suicide in an individual, including the steps of: administering a serotonin-2A receptor agonist to an individual suffering from GAD; and preventing suicidality or suicidal ideation in the individual during and after treatment.
  • Exemplary Embodiment 9A A method of reducing or treating adverse effects of serotonin- 2A receptor agonists, including the steps of: administering a serotonin-2A receptor agonist to an individual; administering an adverse effect reducing agent to the individual; and reducing or treating adverse effects caused by the serotonin-2A receptor agonist.
  • Exemplary Embodiment IB A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a serotonin-2A receptor agonist, wherein said pharmaceutical composition is in a form of an oral solid molded fast-dispersing and fastdisintegrating dosage form.
  • Exemplary Embodiment 2B The pharmaceutical composition of Exemplary Embodiment IB, wherein said serotonin-2A receptor agonist is chosen from the group consisting of lysergic acid diethylamide (LSD), psilocybin, psilocin, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), R-MDMA, S-MDMA, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamie (DOB), salts thereof, tartrates thereof, solvates thereof, isomers thereof, analogs thereof, homologues thereof, and deuterated forms thereof.
  • LSD lysergic acid diethylamide
  • psilocybin psilocin
  • mescaline 3,4-
  • Exemplary Embodiment 3B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition is capable of disintegrating or dispersing within an interval selected from 1 to 60 seconds, 1 to 30 seconds, 1 to 10 seconds, and 2 to 8 seconds, after being placed in contact with a physiological fluid.
  • Exemplary Embodiment 4B The pharmaceutical composition of Exemplary Embodiment IB, wherein said fluid is saliva.
  • Exemplary Embodiment 5B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides detectable levels of said serotonin-2A receptor agonist within to 30 minutes, 5 to 15 minutes, and 5 to 10 minutes.
  • Exemplary Embodiment 6B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides a greater peak concentration per unit of drug dosed compared to other solid oral formulations of said serotonin-2A receptor agonist.
  • Exemplary Embodiment 7B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides a Cmax or AUC that is within ⁇ 20% of the values for other solid oral formulations of said serotonin-2A receptor agonist.
  • Exemplary Embodiment 8B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides a Tmax that is between a time selected from 1 to 3.5 hours, and 1.38 to 3 hours.
  • Exemplary Embodiment 9B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides a time to symptom resolution that is between a time selected from 6 to 12 hours on average, 6 to 10 hours on average, and 8 to 10 hours on average.
  • Exemplary Embodiment 10B The pharmaceutical composition of Exemplary Embodiment IB, wherein said pharmaceutical composition provides a resolving of acute perceptual effects selected from 50% of patients by 8 hours, 70% of patients by 10 hours, and 40% of patients by 7 hours .
  • Exemplary Embodiment 1 IB A method of treating an individual, including the steps of: administering to the individual a serotonin-2A receptor agonist in a fastdisintegrating orally disintegrating tablet (ODT); and treating the individual.
  • ODT fastdisintegrating orally disintegrating tablet
  • Exemplary Embodiment 12B The method of Exemplary Embodiment 11B, wherein the serotonin-2A receptor agonist is chosen from the group consisting of lysergic acid diethylamide (LSD), psilocybin, psilocin, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), R-MDMA, S- MDMA, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyltryptamine (DMT), 2,5- dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamie (DOB), salts thereof, tartrates thereof, solvates thereof, isomers thereof, analogs thereof, homologues thereof, and deuterated forms thereof.
  • LSD lysergic acid diethylamide
  • psilocybin psilocin
  • mescaline 3,4-methyl
  • Exemplary Embodiment 13B The method of Exemplary Embodiment 11B, wherein said administering step provides faster absorption, faster bioavailability, and faster time to maximum concentration which provides faster time to desired clinical effects of the serotonin-2A receptor agonist than other solid oral formulations of the serotonin-2A receptor agonist.
  • Exemplary Embodiment 15B The method of Exemplary Embodiment 14B, wherein said administering step provides less variability in duration of perceptual effects than other solid oral formulations of LSD.
  • Exemplary Embodiment 16B The method of Exemplary Embodiment 14B, further including, after said treating step, the step of taking a blood sample of the individual, determining an exposure level of LSD, and releasing the individual from a treatment session based on the exposure level.
  • Exemplary Embodiment 17B The method of Exemplary Embodiment 14B, further including, after said treating step, the step of conducting a clinical evaluation of the individual, determining whether the side effects of the serotonin-2A receptor agonist have concluded, and releasing the individual from a treatment session based on the clinical evaluation.
  • Exemplary Embodiment 18B The method ofExemplary Embodiment 14B, further including, after said treating step, the step of the individual conducting a functional test, determining whether the side effects of the serotonin-2A receptor agonist have concluded, and releasing the individual from a treatment session based on the functional test.
  • Exemplary Embodiment 19B The method ofExemplary Embodiment 14B, further including, after said treating step, the step of the individual completing a questionnaire, determining whether the side effects of the serotonin-2A receptor agonist have concluded, and releasing the individual from a treatment session based on the questionnaire.
  • Exemplary Embodiment 20B The method of Exemplary Embodiment 14B, wherein said administering step provides faster systemic bioavailability of OH-LSD than other solid oral formulations of serotonin-2A receptor agonists.
  • Exemplary Embodiment 2 IB The method of Exemplary Embodiment 11B, wherein said administering step is further defined as administering a lower dose of the serotonin-2A receptor agonist than with other solid oral formulations of the serotonin-2A receptor agonist to obtain the same concentration in the individual.
  • Exemplary Embodiment 22B The method ofExemplary Embodiment 1 IB, further including the step of modifying administration of the solid oral immediate release formulation and affecting a second peak concentration of the serotonin-2A receptor agonist in plasma of the individual.
  • Exemplary Embodiment 23B The method ofExemplary Embodiment 1 IB, further including the step of the individual wearing a smartwatch and using a smartphone and utilizing built-in sensors of the smartwatch and smartphone to passively record heart rate, audio data, accelerometric data, angular velocity, orientation, number of steps, and activity type.
  • Exemplary Embodiment 24B The method ofExemplary Embodiment 23B, further including the step of sending data recorded with the smartwatch and smartphone to a mobile device of a medical professional and the medical professional monitoring the individual throughout a treatment session.
  • Exemplary Embodiment 25B The method of Exemplary Embodiment 11B, wherein the individual has trouble swallowing, is elderly, or has dementia.
  • Exemplary Embodiment 26B The method of Exemplary Embodiment 11B, wherein said treating step is further defined as treating a condition or disease chosen from the group consisting of anxiety disorders, depression, headache disorder, obsessive compulsive disorder (OCD), personality disorders, stress disorders, drug disorders, gambling disorder, eating disorder, body dysmorphic disorder, pain, neurodegenerative disorders, autism spectrum disorder, eating disorders, and neurological disorders.
  • a condition or disease chosen from the group consisting of anxiety disorders, depression, headache disorder, obsessive compulsive disorder (OCD), personality disorders, stress disorders, drug disorders, gambling disorder, eating disorder, body dysmorphic disorder, pain, neurodegenerative disorders, autism spectrum disorder, eating disorders, and neurological disorders.
  • Exemplary Embodiment 27B The method of Exemplary Embodiment 11B, wherein the serotonin-2A receptor agonist is LSD and is in a form chosen from free base and salt.
  • Exemplary Embodiment 28B The method of Exemplary Embodiment 27B, wherein the LSD is in a salt form and the salt is chosen from the group consisting of hydrochloride, hydrobromide, maleate, tartrate, citrate, phosphate, fumarate, sulfate, mesylate, acetate, and oxalate.
  • Exemplary Embodiment 29B The method of Exemplary Embodiment 27B, wherein said administering step is further defined as administering 0.01-1 mg of LSD.
  • Exemplary Embodiment 30B A method of providing rapid absorption and/or bioavailability of a serotonin-2A receptor agonist, including the steps of: administering to the individual a serotonin-2A receptor agonist in a fastdisintegrating orally disintegrating tablet (ODT); and providing systemic bioavailability of the serotonin-2A receptor agonist in the individual within 5 minutes.
  • ODT fastdisintegrating orally disintegrating tablet
  • Exemplary Embodiment 3 IB The method of Exemplary Embodiment 30B, wherein the serotonin-2A receptor agonist is chosen from the group consisting of lysergic acid diethylamide (LSD), psilocybin, psilocin, mescaline, 3,4-methylenedioxymethamphetamine (MDMA), R-MDMA, S- MDMA, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), dimethyltryptamine (DMT), 2,5- dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-bromoamphetamie (DOB), salts thereof, tartrates thereof, solvates thereof, isomers thereof, analogs thereof, homologues thereof, and deuterated forms thereof.
  • LSD lysergic acid diethylamide
  • psilocybin psilocin
  • mescaline 3,4-
  • Exemplary Embodiment 32B The method of Exemplary Embodiment 3 IB, wherein the serotonin-2A receptor agonist is LSD and is in a form chosen from free base and salt.
  • Exemplary Embodiment 33B The method of Exemplary Embodiment 32B, wherein the LSD is in a salt form and the salt is chosen from the group consisting of hydrochloride, hydrobromide, maleate, tartrate, citrate, phosphate, fumarate, sulfate, mesylate, acetate, and oxalate.
  • Exemplary Embodiment 37B The method of Exemplary Embodiment 35B, further including after said determining step, an evaluation step chosen from the group consisting of conducting a clinical evaluation of the individual, the individual conducting a functional test, the individual completing a questionnaire, and combinations thereof, determining whether the side effects of the serotonin-2A receptor agonist have concluded, and releasing the individual from a treatment session based on results of the evaluation step.
  • an evaluation step chosen from the group consisting of conducting a clinical evaluation of the individual, the individual conducting a functional test, the individual completing a questionnaire, and combinations thereof, determining whether the side effects of the serotonin-2A receptor agonist have concluded, and releasing the individual from a treatment session based on results of the evaluation step.
  • Exemplary Embodiment 38B The method of Exemplary Embodiment 35B, wherein said determining step allows the individual to be released from the treatment session earlier than with other solid oral formulations of the serotonin-2A receptor agonist.
  • Exemplary Embodiment 1C A method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering lysergic acid diethylamide (LSD), or a salt thereof.
  • LSD lysergic acid diethylamide
  • Exemplary Embodiment 2C The method of Exemplary Embodiment 1C, wherein the LSD salt is d-LSD D-tartrate.
  • Exemplary Embodiment 4C The method of Exemplary Embodiment 3C, wherein the orally disintegrating tablet comprises: a. LSD, or a salt thereof; b. a non-gelling matrix; c. a binder; d. a filler; and e. solvent.
  • Exemplary Embodiment 5C The method of Exemplary Embodiment 4C, wherein the LSD salt is d-LSD D-tartrate.
  • Exemplary Embodiment 6C The method of Exemplary Embodiment 4C, wherein the nongelling matrix is maltodextrin.
  • Exemplary Embodiment 7C The method of Exemplary Embodiment 4C, wherein the binder is hydroxypropyl methylcellulose.
  • Exemplary Embodiment 8C The method of Exemplary Embodiment 4C, wherein the fdler is mannitol.
  • Exemplary Embodiment 9C The method of Exemplary Embodiment 4C, wherein the solvent is water.
  • Exemplary Embodiment 10C The method of any one of Exemplary Embodiments 4C-9C, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water.
  • Exemplary Embodiment 11C The method of any one of Exemplary Embodiments 4C-10C, wherein the orally disintegrating tablet stock solution comprises: a. less than about 1% d-LSD D-tartrate; b. about 2% to about 10% maltodextrin; c. about 1% to about 5% hydroxypropyl methylcellulose; d. about 2% to about 10% mannitol; and e. water.
  • Exemplary Embodiment 12C The method of any one of Exemplary Embodiments 4C-10C, wherein the orally disintegrating tablet comprises: a. less than 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • Exemplary Embodiment 13C The method of any one of Exemplary Embodiments 4C-10C or 12C, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. about 87% water.
  • Exemplary Embodiment 14C The method of any one of Exemplary Embodiments 1C-13C, wherein the LSD, or the freebase equivalent of a salt thereof, is administered at a dose of about 25 pg to about 200 pg.
  • Exemplary Embodiment 15C The method of any one of Exemplary Embodiments 1C-14C, wherein the LSD, or the freebase equivalent of a salt thereof, is administered at a dose of about 25 pg. about 50 pg, about 100 pg, about 150 pg, or about 200 pg.
  • Exemplary Embodiment 16C The method of any one of Exemplary Embodiments 1C-15C, wherein the LSD, or the freebase equivalent of a salt thereof, is administered at a dose of about 100 pg.
  • Exemplary Embodiment 17C The method of any one of Exemplary Embodiments 3C-16C, wherein the subject’s serum LSD freebase concentration is between about 2 ng/mL to about 2.5 ng/mL within about four hours after administration of the orally disintegrating tablet.
  • Exemplary Embodiment 18C The method of any one of Exemplary Embodiments 1C-17C, wherein the generalized anxiety disorder is severe generalized anxiety disorder.
  • Exemplary Embodiment 19C The method of any one of Exemplary Embodiments 1C-18C, wherein the generalized anxiety disorder is moderate generalized anxiety disorder.
  • Exemplary Embodiment 20C The method of any one of Exemplary Embodiments 1C-19C, wherein the symptom of generalized anxiety disorder is feeling nervous, having a sense of impending danger, panic, increased heart rate, rapid breathing, sweating, trembling, gastrointestinal problems, restlessness, fatigue, difficulty concentrating, irritability, muscle tension, a sleep disturbance, or sexual dysfunction.
  • Exemplary Embodiment 21C The method of any one of Exemplary Embodiments 3C-20C, wherein the symptom of generalized anxiety disorder is reduced or eliminated between about 6 hours to about 12 hours after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • Exemplary Embodiment 22C The method of any one of Exemplary Embodiments 3C-21C, wherein the symptom of generalized anxiety disorder is reduced or eliminated for about 12 weeks or greater after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • Exemplary Embodiment 23C The method of any one of Exemplary Embodiments 3C-22C, wherein the subject has a Hamilton Anxiety Scale (HAM- A) improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • HAM- A Hamilton Anxiety Scale
  • Exemplary Embodiment 24C The method of any one of Exemplary Embodiments 3C-23C, wherein the subject has an about 20-point HAM-A improved score within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • Exemplary Embodiment 25C The method of any one of Exemplary Embodiments 1C-24C, wherein the subject is not administered a second agent for the treatment of generalized anxiety disorder or depression.
  • Exemplary Embodiment 27C The method of any one of Exemplary Embodiments 3C-26C, wherein the subject has an about 1.8-point reduction in CGI-S within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • Exemplary Embodiment 28C The method of any one of Exemplary Embodiments 1C-27C, wherein the subject has depression.
  • Exemplary Embodiment 29C The method of any one of Exemplary Embodiments 3C-28C, wherein the subject has a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) within about 12 weeks after administration of the orally disintegrating tablet comprising LSD, or a salt thereof.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • Exemplary Embodiment 32C The method of any one of Exemplary Embodiments 1C-31C, wherein the LSD, or salt thereof, is administered once every about 12 weeks.
  • Exemplary Embodiment 33C A method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet one to four times per year, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water.
  • Exemplary Embodiment 34C A method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering an orally disintegrating tablet once every about 12 weeks, wherein the orally disintegrating tablet comprises: a. d-LSD D-tartrate; b. maltodextrin; c. hydroxypropyl methylcellulose; d. mannitol; and e. water.
  • Exemplary Embodiment 35C A method of treating a symptom or preventing a symptom of generalized anxiety disorder in a subject, comprising administering a dose of about 100 pg lysergic acid diethylamide (LSD), or the freebase equivalent of a salt thereof.
  • LSD lysergic acid diethylamide
  • Exemplary Embodiment 36C The method of Exemplary Embodiment 35C, wherein the LSD, or a salt thereof, is administered as an orally disintegrating tablet.
  • Exemplary Embodiment 37C The method of Exemplary Embodiment 35C or Exemplary Embodiment 36C, wherein the LSD, or a salt thereof, is administered one to four times per year.
  • Exemplary Embodiment 38C The method of Exemplary Embodiment 35C or Exemplary Embodiment 36C, wherein the LSD, or a salt thereof, is administered once every about 12 weeks.
  • Exemplary Embodiment 39C The method of any one of Exemplary Embodiments 33C-38C, wherein the orally disintegrating tablet stock solution comprises: a. less than about 1% d-LSD D-tartrate; b. about 2% to about 10% maltodextrin; c. about 1% to about 5% hydroxypropyl methylcellulose; d. about 2% to about 10% mannitol; and e. water.
  • Exemplary Embodiment 40C The method of any one of Exemplary Embodiments 33C-38C, wherein the orally disintegrating tablet comprises: a. less than about 1% d-LSD D-tartrate; b. about 15% to about 77% maltodextrin; c. about 8% to about 38% hydroxypropyl methylcellulose; d. about 15% to about 77% mannitol; and e. less than 10% water.
  • Exemplary Embodiment 41C The method of any one of Exemplary Embodiments 33C-38C or 40C, wherein the orally disintegrating tablet stock solution comprises: a. less than 1% d-LSD D-tartrate; b. about 6% maltodextrin; c. about 2% hydroxypropyl methylcellulose; d. about 5% mannitol; and e. 87% water.
  • Example 1 A Phase 2, Multi-center, Randomized, Double-Blind, Parallel-Group, Dose-Finding Study to Assess the Effect of Four Doses of D-LSD D-tartrate (also referred to as MM-120) for the Treatment of Anxiety Symptoms.
  • Body mass index [BMI] 18 to ⁇ 38 mg/kg 2 .
  • W OCBP Women of childbearing potential
  • WOCBP mens physiologically capable of becoming pregnant
  • barrier contraception e.g., condom with or without spermicidal cream or jelly
  • Prior history or known first-degree relative (i.e., mother/father/full siblings) with a lifetime diagnosis of schizophrenia spectrum, or other psychotic disorders or bipolar disorder (bipolar I, bipolar II or cyclothymic disorder).
  • ketamine use including: ketamine therapy within the past 3 months before screening (including as part of a clinical trial); illicit use of ketamine >10 uses in the past 10 years; or use of ketamine for treatment of an excluded condition (see exclusion criteria #4, #5, #6)
  • Any form of medicinal therapy should be stable 3 months prior to screening with no plan to start, stop or alter the use of any prescribed medications, supplements or other therapeutics from Baseline (Visit 2) until End of Study. Note: Exclusion does not apply to medications that need to be tapered for inclusion in the study and reference is to achieving and maintaining a steady state.
  • Any form of non-medicinal therapy should be stable 3 months prior to screening with no plan to start, stop or alter the use of psychotherapy, acupuncture, hypnosis, or other similar therapy from the time of providing informed consent until End of Study.
  • DBS deep brain stimulation
  • VNS vagus nerve stimulation
  • ECT electroconvulsive therapy
  • TMS transcranial magnetic stimulation
  • Any chronic infection including human immunodeficiency virus (HIV), hepatitis B, or hepatitis C, unless the subject is asymptomatic and is expected to remain asymptomatic during the study and, in the opinion of the Investigator, the infection is unlikely to confound the results of the study.
  • HIV human immunodeficiency virus
  • hepatitis B hepatitis B
  • hepatitis C hepatitis C
  • cardiovascular disease including but not limited to coronary artery disease, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction (within 1 year prior to Screening [Visit 1]), angina pectoris (within 1 year prior to Screening [Visit 1]), coronary artery bypass graft or artificial heart valve (within 1 year prior to Screening [Visit 1]), stroke, transient ischemic attack (TIA) or any other clinically significant arrhythmia.
  • Uncontrolled hypertension g. Blood pressure (BP) outside the range of 90-140 mmHg systolic BP or 50-90 mmHg diastolic BP after an approximately 5 minutes of rest.
  • BP Blood pressure
  • ECG electrocardiogram
  • k Resting QT interval corrected using Fridericia’s formula (QTcF) > 450 msec (male) or > 460 msec (female) at Baseline (Visit 2) or inability to determine QTcF. l.
  • Moderate-to-severe renal impairment indicated by an estimated glomerular filtration rate (eGFR) of ⁇ 50 mL/min/1.73 m 2 at Screening (Visit 1), based on the Cockroft-Gault formula.
  • eGFR estimated glomerular filtration rate
  • CYP2D6 cytochrome P450
  • genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of oral LSD in healthy volunteers.
  • Subjects with no functional CYP2D6 i.e., poor metabolizers
  • dosing session lengths are expected to vary from a minimum of 8 hours to up to 12 hours or longer in some cases.
  • PSQI Pittsburgh Sleep Quality Index
  • a total sample of 180 subjects (36 per dose arm and 36 for the placebo arm) was required to ensure a mean power > 87% for an MCP-Mod analysis rejecting the hypothesis of a constant doseresponse curve using the multiple comparisons procedure (MCP), assuming a null placebo response, a maximum standardized effect of 0.6 within the doses range, and a common standard deviation within the dose arms, if a study-wise one-sided type-1 error rate ⁇ 0.05 is required.
  • MCP multiple comparisons procedure
  • the analysis assumes 4 doses of active medication (25, 50, 100, and 200 pg freebase-equivalent) and placebo.
  • HAM-A Hamilton Anxiety Rating Scale
  • the HAM-A scale is fit- for-purpose to assess anxiety symptoms in subjects with GAD.
  • Eligibility for this study was based in part on a minimum HAM-A Total Score of 20. This was to target enrollment to a population of subjects who had significant anxiety that were sensitive to measurement by the HAM-A. A HAM-A Total Score of 17 and above has been used as a cut-off for inclusion in clinical trials for GAD medications. Additionally, to ensure that only subjects with relatively stable anxiety severity were enrolled, the HAM-A was completed at Screening (Visit 1) and Baseline (Visit 2) and the Total Score from both assessments must have been at least 20 points; this exclusion criterion helped prevent enrolling subjects with transient anxiety related to daily stressors. These measures together ensured that the study population consisted of subjects with clinically significant anxiety that is sensitive to measurement by the HAM-A.
  • the minimal recognizable (“threshold”) dose of LSD in humans is reported to be approximately 10-25 pg and doses above 50-75 pg typically produce an altered state of consciousness (including enhanced capacity for introspection, altered psychological functioning and perceptual changes such as illusions, pseudo-hallucinations, synesthesia and alterations of thinking and time experience).
  • Threshold the dose at which psychoactive effects are perceivable by patients on average
  • doses above 50-75 pg typically produce an altered state of consciousness (including enhanced capacity for introspection, altered psychological functioning and perceptual changes such as illusions, pseudo-hallucinations, synesthesia and alterations of thinking and time experience).
  • supportive supervised conditions i.e., appropriate set and setting
  • adverse drug reactions were typically mild and resolved within a day.
  • Transient anxiety, short-lived headaches, nausea and mild increases in heart rate and blood pressure were the most commonly reported adverse events (AEs).
  • Study drug (d-LSD D-tartrate at 25, 50, 100 or 200 pg freebase equivalent or placebo) was administered under blinded conditions. To maintain the blind, all subjects received a total of 8 capsules, which were a combination of active capsules each containing 25 pg d-LSD D-tartrate freebase equivalent and/or placebo capsules, depending on the subject’s randomized dose (see Table 2). All 8 capsules were taken together as the subject’s single dose of study drug. Administration of study drug occurred only during Day 1/Dosing Session (Visit 3B). [000320] Subjects took the 8 study drug capsules orally with ad libitum water. Subjects had 15 minutes to swallow all 8 capsules. Administration of study drug was witnessed by the Investigator and/or Dosing Session Monitor(s), and the subject subsequently was monitored at all times until released from the clinic by the study site designated physician.
  • the MINI was administered at Screening (Visit 1) to help determine subject eligibility.
  • the psychiatric interview using the MINI was conducted by a certified site rater. DSMs may administer the MINI if qualified.
  • the MINI was a short structured diagnostic interview for the major psychiatric disorders in DSM-III-R, DSM-IV and DSM-5 and ICD-10.
  • the standard MINI assesses the 17 most common disorders in mental health. It takes approximately 15 minutes to administer.
  • C-SSRS Columhia-Suicide Severity Rating Scale
  • the HAM-A was used as the primary outcome measure for this study for the evaluation of anxiety symptoms. It was administered to determine eligibility at Screening (Visit 1) and Baseline (Visit 2) and was administered at additional visits. The HAM-A took approximately 20 minutes to administer.
  • the HAM-A was completed by a central rater (see further details below).
  • the HAM-A consists of the following 14 items that encompass both psychological and somatic symptoms of anxiety:
  • the MADRS was administered during the study at the visits. The MADRS takes approximately 15-20 minutes to administer.
  • the MADRS is used to assess depression severity and to detect changes due to antidepressant treatment.
  • This questionnaire includes 10 clinician-completed items. Each of the 10 questions is scored with a range of 0-6 points. An item score of 0 indicates item not present or normal, while an item score of 6 indicates severe or continuous presence of the symptoms. The total possible score is 60, and higher scores represent a more severe condition. A decrease in score by > 50% indicates a response to treatment, and an actual score of ⁇ 10 indicates a remission of symptoms.
  • CGI-S Clinical Global Impression - Severity
  • CGI-I Clinical Global Impression - Improvement
  • CGI-S The CGI-S scale is used to assess the subject’s current severity of illness at the time of the assessment relative to the clinician's past experience with patients who have the same diagnosis.
  • the CGI-S comprises 1 Investigator-completed (or trained rater-completed) item with 7 possible ratings (1-7 points), where a higher score indicates more severe illness.
  • CGI-I The CGI-I scale is used to measure the clinician’s assessment of how much the subject’s illness has improved or worsened relative to Baseline (Visit 2).
  • the CGI-I comprises 1 Investigator-completed (or trained rater-completed) item with 7 possible ratings (1-7 points), where a lower score indicates improvement, and a higher score indicates worsening.
  • CGI-I values were similar across all timepoints in the placebo group.
  • participants from all MM 120 dose groups experienced statistically significant changes in CGI-I compared with placebo.
  • the 50 pg, 100 pg, and 200 pg dose groups had statistically significant changes in CGI-I compared with placebo.
  • PGI-S Patient Global Impression - Severity
  • PGI-C Patient Global Impression - Change
  • the PGI scale is the patient-reported outcome counterpart to the CGI scale.
  • the PGI is adapted to the patient population and can be used to measure disease severity (PGI-S) or change in clinical status (PGI-C).
  • the PGI-S and PGI-C each comprise 1 subject-completed item with 5 possible ratings (1-5).
  • a higher score indicates more severe illness.
  • a lower score indicates change for the better (improvement in symptoms) and a higher score change for the worse (worsening symptoms).
  • PGI-C PGI-C.
  • the 50 pg, 100 pg, and 200 pg dose groups had statistically significant changes in PGI-C compared with placebo.
  • the 100 pg dose group had statistically significant changes in PGI-C compared with placebo at all other timepoints post-treatment through Week 12.
  • the SDS was administered during the study at the visits.
  • the SDS was a patient reported outcome measure.
  • the SDS is a composite of 3 self-rated items designed to measure the extent to which 3 major domains in the patient’s life (work, social life/leisure activities and family life/home responsibilities) are functionally impaired by psychiatric or medical symptoms.
  • the SDS is used to assess the extent to which these 3 major domains in the subject’s life are functionally impaired.
  • EQ-5D-5L [000351] The EQ-5D-5L was administered during the study at the visits. The EQ-5D was a patient reported outcome measure.
  • the EQ-5D has been developed by the EuroQol Group and can be used to evaluate health outcomes over a wide range of health conditions and treatments.
  • the EQ-5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS).
  • the EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. In the EQ-5D-5L version, each dimension has 5 levels of responses: no problems, slight problems, moderate problems, severe problems, and extreme problems. [000354]
  • the EQ VAS records the subject’s self-rated health on a 20-cm vertical VAS, with endpoints labeled as “the best health you can imagine” and “the worst health you can imagine.”
  • the PSQI was administered during the study at the visits.
  • the PSQI was a patient reported outcome measure.
  • the PSQI assesses sleep quality and disturbances over the preceding month. This questionnaire includes 19 self-rated questions and 5 questions rated by the bed partner or roommate (if available).
  • the ASEX was administered during the study at the visits.
  • the ASEX is a patient reported outcome measure.
  • the MEQ30 is a psychometrically validated instrument that includes 30 self-rated questions.
  • the 30 items are combined into the following 4 subscales:
  • Each of the 4 subscales contributes to the MEQ30 total score, which has a range of 0-150 points.
  • the MEQ30 total score is computed by taking the average response to all items and reported as a percentage. Subject is considered to have had a “complete mystical experience” when > 60% of the maximum possible score is achieved on all 4 factor subscales.
  • 5D-ASC 5-Dimensional Altered States of Consciousness Rating Scale
  • the 5D-ASC was administered the day after dosing, at Day 2 (Visit 4), to retrospectively assess the subject’s peak alteration of consciousness during Day 1/Dosing Session (Visit 3B) as compared with their normal waking consciousness.
  • 5D-ASC is a patient-reported outcome measure.
  • the 5D-ASC includes 94 self-rated items (visual analog scales). It is well-validated and has been used to characterize the acute subjective effects of LSD in experimental studies.
  • the 94 items are combined into the following 5 subscales/dimensions with 11 lower-order scales defined for the first 3 subscales/dimension:
  • Anxious ego dissolution (ego disintegration and loss of self-control phenomena associated with anxiety); subscales within this dimension include: o Disembodiment o Impaired control of cognition o Anxiety
  • Visionary restructuralization subscales within this dimension include: o Complex imagery o Elementary imagery o Audio-visual synesthesia o Changed meaning of percepts o Auditory alterations o Vigilance reduction.
  • Treatment Assignment/Blinding Question On Day 2 (Visit 4), a 5-point Likert scale was used to evaluate each subject’s assessment of whether they received active study drug or placebo during Day 1/Dosing Session (Visit 3B).
  • the treatment assignment question is a patient-reported outcome measure. Subjects are asked to indicate which of the following statements they agree with the most:
  • the Dosing Release Checklist was performed by the site-designated licensed physician (MD/DO) to evaluate the subject’s psychological and physiological status. This included an evaluation to ascertain that the subject no longer meets DSM- 5 criteria for Hallucinogen Intoxication. Subjects were assessed for release criteria starting at 8 hours ( ⁇ 10 minutes) post-administration and subsequently assessed at approximately 9, 10, 11 and 12 hours ( ⁇ 10 minutes) post-dose. The Dosing Session Release Checklist was administered hourly ( ⁇ 10 minutes) until all release criteria were met. At a minimum, the Dosing Release Checklist was completed at 8- and 12-hours post-dose.
  • the Dosing Session Release Checklist would be repeated approximately every hour ( ⁇ 10 minutes) until all criteria were met and the subject is deemed eligible for release. Subjects were kept under continuous observation until their release was deemed safe by the site-designated licensed physician.
  • subjects In order to be eligible for release, subjects MUST: Self-report readiness for release (i.e., physical and mental readiness, and understanding of restrictions), be deemed eligible for safe release in the medical judgment of the study site-designated licensed physician, and have no active suicidal ideation or behavior as determined by the C-SSRS. And must NOT: Meet DSM-5 criteria for Hallucinogen Intoxication, display clinically significant psychomotor depression, activation or other signs or symptoms, or display clinically significant abnormal mental status.
  • BMI body mass index
  • SD standard deviation
  • the Full Analysis Set is defined as all randomized participants with a valid baseline HAM-A assessment and at least one post-baseline HAM-A assessment.
  • Percentages are based on the number of participants in the Full Analysis Set in each dose-level (N).
  • Example 1A Two Solid Oral Formulations of D-LSD D-tartrate, a Fast-Dispersing Orally Disintegrating Tablet and an Immediate Release Powder in Capsule
  • Example 2A Phase 1, Open-label Study to Compare the Pharmacokinetics of Two Formulations of d-LSD D-tartrate in Healthy Volunteers
  • PK pharmacokinetics
  • C-SSRS Columbia Suicide Severity Rating Scale
  • Blood sampling for PK analysis occurred at pre-dose (15 minutes prior to dose ⁇ 5 minutes), and 5 minutes, 10 minutes, and 15 minutes post-dose (with a sampling window of ⁇ 1 minute), and at 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, and 24 hours post-dose (with a sampling window of ⁇ 5 minutes).
  • Blood samples were collected using an indwelling peripheral venous cannula which subjects have implanted the morning of each dosing day (i.e., Visit 2a for Evaluation Period 1 and Visit 4a for Evaluation Period 2). Prior to dosing, all subjects ate a light snack of approximately 500 calories, standardized and provided by the sites, and did not consume any food after dosing until at least 6 hours post dose.
  • the Dosing Session Monitor Manual (DSMM) must be reviewed and understood by all Dosing Session Monitors prior to their participation in monitoring any subjects during their dosing in this study.
  • the DSMM provided detailed information regarding credentials, training requirements, and instructions on the proper management of each dosing session day.
  • Both PESM and DSMM provide information regarding details and criteria for release from in-patient hospitalization at the CRU at Visit 3 and Visit 5.
  • Eligible subjects returned to the CRU for Visit 2a following an overnight fast (at least 10 hours). They were admitted as inpatients and underwent pre-dose safety assessments and urine drug screen (UDS) and pregnancy testing. The results of the UDS and pregnancy test (where applicable) must be negative for the subj ect to have proceed to study drug dosing .
  • site personnel assisted the subjects in putting on an Apple Watch and setting up an iPhone equipped with the MSMSTM application for monitoring during the dosing session. Subjects wore this device during the entirety of the dosing session.
  • a venous cannula was implanted, and a pre-dose blood sample was collected. All subjects ate a light snack of approximately 500 calories, standardized and provided by the sites prior to dosing, and did not consume any food until at least 6 hours post dose. This standardized meal was designed to mimic the conditions in a prior clinical trial in order to make accurate assumptions regarding the PK profile observed in this trial, relative to the efficacy and safety observed. Subjects were dosed with study drug within 30 minutes of eating the snack. [000402] Subjects randomized to receive capsules took study drug capsules of d-LSD D-tartrate orally with 250 mL of water.
  • Subjects randomized to receive ODT took the ODT formulation of d-LSD D-tartrate by placing the study drug on top of the tongue allowing the tablet to disintegrate. Subjects were NOT permitted to drink water with the ODT dosing; however, at least 15 minutes after ODT dosing subjects should drink up to 250 mL of water.
  • subjects were monitored by two site personnel as follows: Via a direct video monitoring link, a site medical staff member monitored the dosing session at all times through post-dose hour 16 if deemed necessary, to ensure patient safety. Subjects were also physically monitored by a trained DSM, who remained in the dosing room with the subject for the first 6 hours post-dose. Between 6- and 8-hours post- dose, they were monitored at least every half-hour by the DSM. From 8-hours post-dose through 16-hours post-dose they were monitored by the DSM at least every hour or until release criteria are achieved.
  • Evaluation Period 1 Following Evaluation Period 1, during the Washout Period and between Visit 3 and Visit 4a, subjects received a phone call or teleconference from the site, to assess safety, by collecting AEs, concomitant medications, and C-SSRS, and to schedule Visit 4a within the allotted time window. All subjects dosed in Evaluation Period 1 returned to the CRU to undergo crossover treatment 12 ⁇ 2 days after their first dose in Evaluation Period 2.
  • Visit 4a Evaluation Period 2
  • Subjects repeated pre-dose procedures and evaluations a new venous cannula was implanted in the same fashion as in Evaluation Period 1, and safety labs, including serum HCG if visit date is >28 days from screening, UDS, and urine pregnancy screen was performed.
  • Site personnel again assisted the subjects in putting on an Apple Watch and setting up an iPhone equipped with the MSMS application.
  • Subjects again reviewed preparatory education about the planned study drug (MM-120) with the DSM.
  • Evaluation Period 2 For dosing in Evaluation Period 2, subjects ate a light snack of approximately 500 calories, standardized and provided by the sites prior to dosing, and then received the appropriate study drug within 30 minutes of eating and did not consume any food until at least 6 hours post dose. Subjects who received d-LSD D-tartrate capsules in Evaluation Period 1 (Visit 2b) received d-LSD D-tartrate ODT 100 pg, in Evaluation Period 2 provided as a single ODT containing 146.4 pg LSD-D-tartrate which is equivalent to 100 pg of LSD freebase and subjects who received d-LSD D-tartrate ODT in Evaluation Period 1 (Visit 2b) receive d- LSD D-tartrate 100 pg capsule in Evaluation Period 2, administered as 4 x 25 pg capsules. All capsules or ODT must have been consumed within 1 to 2 minutes of distribution to the subject. Following dosing, subjects remained in the study unit for 24 hours post-dose.
  • the participant undertakes the Dosing Release Checklist each hour ( ⁇ 10 minutes) until the criteria are met or a minimum of 16 hours have elapsed post dose. Participants were discharged after a 24-hour post-dose period once they meet the requirements for discharge from the Clinical Research Unit.
  • Discharge From Clinical Research Unit ⁇ s.EpjDischarge from the CRU may only occur if the following conditions are satisfied: Participants meet the criteria for release from continuous in-person monitoring as described in the DSMM, evidencing that the participant no longer meets DSM-5 criteria for Hallucinogen Intoxication and is not displaying physiological changes suggestive of serotonin syndrome. [000414] Participants were presenting a low risk of self-harm and suicide, evidenced by no clinically significant change between pre- and post-dose C-SSRS assessments. Participants who newly answer ‘Yes’ to suicidal ideation items 1-3 on post-dose C-SSRS required further assessment of suicide risk and safety planning by a site licensed physician prior to discharge. Participants answering ‘Yes’ to suicidal ideation items 4-5 or who displayed self-injurious behavior during admission to the CRU may be considered for referral to Accident and Emergency (A&E) or local National Health Service (NHS) mental health crisis services.
  • A&E Accident and Emergency
  • NHS National Health Service
  • Body mass index between 18.0 and 30.0 kg/m2 and weight of at least 50 kg and no more than 100 kg, inclusive at Screening.
  • WOCBP Women of childbearing potential
  • MINI Mini International Neuropsychiatric Interview
  • medical/psychiatric records e.g., Major Depressive Disorder, anxiety disorders, obsessive-compulsive disorder, dysthymic disorder, panic disorder, dissociative disorder, anorexia nervosa or bulimia nervosa.
  • History of alcohol or substance use disorder within 12 months prior to Screening (Visit 1) (includes diagnosis of alcohol or drug use disorder) OR any illicit use of psychedelics (LSD, psilocybin, MDMA, ketamine, etc.) within the past 3 months.
  • over-the-counter medications prescription drugs, vitamins, dietary supplements, vaccines, herbal supplements, including CBD, within 5 half-lives OR 14 days (whichever is longer) prior to first dose of study drug.
  • use of potent CYP3A4/5 inhibitors or inducers the use of moderate CYP3A4/5 inhibitors is allowed at Investigator discretion medications, in addition to those listed above, that may be expected to significantly interfere with the metabolism or excretion of study drug, which may be associated with a significant drug interaction with study drug, or that may pose a significant risk to the subject’s participation in the study.
  • Any chronic infection including human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
  • HIV human immunodeficiency virus
  • hepatitis B hepatitis B
  • hepatitis C hepatitis C
  • Moderate-to-severe renal impairment indicated by an estimated glomerular filtration rate (eGFR) of ⁇ 60 mL/min/1.73 m2 at Visit 1, based on the Cockcroft-Gault formula at Visit 1 Note: These laboratory evaluations may be repeated once at the discretion of the Investigator. If the repeat test is within the reference range, the subject may be included only if the Investigator considers that the previous finding will not introduce additional risk factors and will not interfere with interpretation of safety data.
  • eGFR estimated glomerular filtration rate
  • Safety and tolerability was assessed by the incidence and severity of AEs, vital sign assessments, C-SSRS, clinical laboratory assessments, and physical examinations.
  • Subjects were provided with a smartphone (Apple iPhone) and a smartwatch (Apple Watch) equipped with the application MSMSTM which utilized built-in sensors to passively record the following data: heart rate, audio data, accelerometric data, angular velocity (gyroscope), orientation (compass), number of steps (pedometer), and activity type.
  • MSMSTM built-in sensors to passively record the following data: heart rate, audio data, accelerometric data, angular velocity (gyroscope), orientation (compass), number of steps (pedometer), and activity type.
  • Smart phone The smart phone collects the following data from the subject: acceleration, orientation, motion, distance, steps, and activity.
  • the devices are connected to a cloud server located in UK and data is securely transmitted and stored.
  • FIG. 10 is a graph of mean +/- SE concentration versus time for d-LSD D-tartrate in capsule and ODT formulations (FIG. 9 depicting ODT only).
  • Table 3A shows a summary of PK parameters for d-LSD D-tartrate in capsule and ODT formulations. Parameters were summarized as mean ⁇ SD (geomean), except T max which was summarized as median (min, max). This shows that the average Cmax and AUC increased given the same unit of drug dosed, and increased absorption is equal to greater maximum concentration achieved, and greater overall concentration over time achieved per unit of drug dosed. Tmax also decreased in ODT formulation versus capsule formulation, and showed faster absorption, which can result in faster onset of clinical effects.
  • FIG. 10 is a graph of mean +/- SE concentration versus time for D-LSD D-tartrate in capsule and ODT formulations.
  • FIG. 11 is a graph of mean concentration versus time for absorption phase (up to 4 hours post-dose) for d-LSD D-tartrate in capsule and ODT formulations.
  • FIG. 12 is a close up view of the graph of FIG. 11 from 0 through 15 minutes. There was faster absorption (i.e., time to first detectability, time to maximum concentration) with the ODT formulation versus the capsule formulation. The drug was also absorbed to greater extent for the ODT formulation.
  • FIG. 13 is a chart showing a summary of concentration by time point for d-LSD D-tartrate capsule and ODT formulations.
  • the ODT formulation had lower variability in exposure at later time points, which was consistent with faster absorption. Reduced later-variability can shorten the duration of the exposure and shorten the duration of the perceptual effects (which are adverse events). Therefore, the ODT formulation provides reduced variability in exposure at later time points, that is any time after 5 hours post-dose.
  • FIG. 14 is a graph of mean concentration versus time for d-LSD D-tartrate in capsule and ODT formulations showing a threshold of 0.5 ng/mL with a dashed line (overlaid on the graph of FIG. 10), i.e., the time to get exposure back below a given ’’threshold” concentration. It took on average 12 hours for capsule and ODT formulations to fall below the threshold of 0.5 ng/mL. All subjects fell below threshold after 24 hours. This is true both on average and for the time to all patients. This is important, because if this time were variable, that could mean more variability in the duration of perceptual effects (i.e., longer AEs) which would require longer monitoring.
  • FIG. 15 is a graph of mean concentration versus time for d-LSD D-tartrate in capsule and ODT formulations showing a threshold of 1 ng/mL with a dashed line (overlaid on the graph of FIG. 10). It took on average 8 hours for capsule and ODT formulations to fall below the threshold of 1 ng/mL. All subjects fell below threshold after 12 hours for ODT formulation, while all subjects fell below threshold after 24 hours for capsule formulation. The time for all subjects to fall below threshold is lower for the ODT formulation compared to capsule formulation, because the ODT formulation PK is less variable.
  • FIG. 17 is a graph of mean +/- SE concentration versus time for OH metabolite PK in d-LSD D-tartrate in capsule and ODT formulations.
  • the ODT formulation shows increased C ma x and AUC of metabolite compared to the capsule formulation.
  • the ODT formulation shows faster absorption of metabolite compared to the capsule formulation.
  • FIG. 18 shows a comparison of crossover results for PK of the ODT formulation relative to the capsule formulation.
  • FIG. 19 is a graph showing crossover (incomplete block) results of PK of the ODT formulation relative to the capsule formulation.
  • FIGs. 20A-20C are graphs showing VAS profile for ODT and capsule formulation of mean +/- SE versus, FIG. 20A shows any drug effect for period 1 , FIG. 20B shows good drug effect for period 1, and FIG. 20C shows bad drug effect for period 1.
  • FIG. 21 is a graph of DSRC times for the ODT and capsule formulation for period 1.
  • the ODT formulation of d-LSD D-tartrate provides a faster time to absorption and bioavailability (within 5 minutes) than the capsule formulation which can take 15-20 minutes to reach the gut to start to be absorbed and become bioavailable.
  • the ODT formulation has a faster time to maximum concentration which provides a faster time to desired clinical effects. Since the average concentration in the body is higher after administration of the ODT formulation, a lower dose of 92.3 pg (or other doses such as 90 pg instead of 100 pg) with the ODT formulation than can be given than with the capsule formulation. There is also less variation in the elimination phase with the ODT formulation, which is important in determining when the acute perception- and consciousness-altering effects have concluded in a treatment session.
  • a blood test and/or a clinical assessment, patient-completed assessment, or combinations thereof can be performed on an individual to check their exposure level of LSD, and if they are below a certain amount (such as 1 ng/mL), they can be cleared to be released from the treatment session/clinic because any acute effects or side effects have concluded or sufficiently resolved to enable release of the patient. While the time it takes to be below a certain exposure level can vary based on the dose of LSD given and the individual’s physical characteristics, the fact that the ODT has reduced variability and faster absorption means that most patients will be clear of symptoms sooner and therefore monitoring time is reduced.

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Abstract

La présente divulgation concerne une méthode de traitement d'un symptôme ou de prévention d'un symptôme d'un trouble de l'anxiété généralisée, comprenant l'administration d'un comprimé orodispersible contenant du LSD, ou un sel de celui-ci, à un sujet dont l'état le nécessite.
PCT/US2024/059413 2023-12-11 2024-12-10 Méthodes de traitement d'un trouble de l'anxiété généralisée Pending WO2025128594A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023023182A1 (fr) * 2021-08-19 2023-02-23 Mind Medicine, Inc. Formulations de comprimés lyophilisés orodispersibles de diéthylamide d'acide d-lysergique pour des applications thérapeutiques
WO2023108277A1 (fr) * 2021-12-14 2023-06-22 Agile Pharmaceuticals Solutions Inc. Formulations de cannabinoïdes et de psychédéliques comprenant des agents hydrotropes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023023182A1 (fr) * 2021-08-19 2023-02-23 Mind Medicine, Inc. Formulations de comprimés lyophilisés orodispersibles de diéthylamide d'acide d-lysergique pour des applications thérapeutiques
WO2023108277A1 (fr) * 2021-12-14 2023-06-22 Agile Pharmaceuticals Solutions Inc. Formulations de cannabinoïdes et de psychédéliques comprenant des agents hydrotropes

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Title
ANONYMOUS: " A Dose-Finding Study of MM-120 (LSD D-Tartrate) for the Treatment of Anxiety Symptoms ", NCT05407064 || CLINICALTRIALS.GOV, 25 October 2023 (2023-10-25), XP093328309, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT05407064> *

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