WO2024074850A1 - Traitement de troubles mentaux - Google Patents

Traitement de troubles mentaux Download PDF

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Publication number
WO2024074850A1
WO2024074850A1 PCT/GB2023/052606 GB2023052606W WO2024074850A1 WO 2024074850 A1 WO2024074850 A1 WO 2024074850A1 GB 2023052606 W GB2023052606 W GB 2023052606W WO 2024074850 A1 WO2024074850 A1 WO 2024074850A1
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WO
WIPO (PCT)
Prior art keywords
indolealkylamine
acting
rapid
effective dose
mood
Prior art date
Application number
PCT/GB2023/052606
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English (en)
Inventor
Alexander William BLYTH
Original Assignee
ReWire Therapeutics Limited
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Publication date
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Publication of WO2024074850A1 publication Critical patent/WO2024074850A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to treating mental disorders, such as depression and/or an anxiety disorder and/or a trauma disorder (e.g. post-traumatic stress disorder (PTSD)) and/or a substance use disorder (e.g. drug dependency withdrawal disorder), including corresponding pharmaceutical compositions and/or dosage forms.
  • a trauma disorder e.g. post-traumatic stress disorder (PTSD)
  • a substance use disorder e.g. drug dependency withdrawal disorder
  • depression The most common mental disorders are depression and anxiety disorder. Depression is the leading cause of disability globally and it has a major impact on overall quality of life in those that suffer from it. In 2015, the number of people with depression globally was estimated to exceed 300 million. A similar number of people suffer from a range of anxiety disorders, with many people experiencing both conditions simultaneously (World Health Organization (2017) Depression and Other Common Mental Disorders: Global Health Estimates).
  • Depression and anxiety disorder are treated with psychotherapies such as cognitive behavioural therapy, or drugs such as antidepressants, or a combination of both.
  • psychotherapies such as cognitive behavioural therapy, or drugs such as antidepressants, or a combination of both.
  • antidepressants such as monoamine oxidase inhibitors, tricyclic and tetracyclic compounds, and selective monoamine reuptake inhibitors, is debatable — they require weeks to months of continuous treatment and have numerous undesirable side-effects (Jackobson et al. (2017) BMC Psychiatry 17:58).
  • There remains a need to provide an effective, long-term, and safe treatment for depression and/or anxiety disorder particularly in patients with treatment-refractory or treatment-resistant depression and/or anxiety disorder.
  • 5-MeO-DMT The indolealkylamine 5-methoxy-N,N-dimethyltryptamine
  • 5- MeO-DMT is a promising drug candidate that is thought to have rapid, beneficial effects on mental health and well-being.
  • 5- MeO-DMT is in clinical development and has recently been proven safe in a phase 1 dose escalation study (Reckweg et al. (2021) Front. Pharmacol. 12:760671).
  • Real world evidence suggests that 5-MeO-DMT improves anxiety, mood and well-being, including in patients with depression and/or anxiety disorder (Davis et al. (2019) Am. J. Drug Alcohol Abuse. 45(2):161- 169).
  • the present invention overcomes one or more of the above-mentioned problems, e.g. such as those associated with rapid acting indolealkylamines (for example, mitigating a “bad trip” experience).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a pharmaceutical composition or dosage form e.g., a combination or single agent product
  • this may reduce or inhibit one or more adverse effects associated with administration of a rapid-acting indolealkylamine alone, e.g., when treating a mental disorder.
  • the invention may provide an improved treatment for mental disorders.
  • an effective dose of a mood preparation agent such as ketamine
  • an adverse effect e.g. an anxiety and/or stress-related side-effect
  • a dosage form that is adapted to provide an effective dose of a mood preparation agent (e.g., ketamine) to a subject prior to an effective dose of a rapidacting indolealkylamine (e.g., 5-MeO-DMT) may alleviate an adverse effect (e.g.
  • an anxiety and/or stress-related side-effect associated with treatment with the rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • racemic ketamine has been suggested to protect against inflammation-induced vulnerability to stress behaviours in mouse models of depression (Mastrodonato et al. (2020) Behav. Brain Res. 378:112238). It is believed that that ketamine functions through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)- dependent rapid increases in BDNF release (Riggs and Gould (2021) Annual review of clinical psychology 17:207 -231). Ketamine has shown the capacity to produce a robust and sustained improvement in stress symptoms, in people with chronic suicidality (Dutton etal. (2022) Journal of affective disorders 300:401-417).
  • the invention provides a method for treating a mental disorder, the method comprising: (i) administering to a subject a mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of a rapidacting indolealkylamine; or (iii) providing an effective dose of a rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides a method for treating a mental disorder, the method comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • the invention provides a method for treating a mental disorder, the method comprising administering to a subject a mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for treating a mental disorder, the method comprising: (i) administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent; or (iii) providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for treating a mental disorder, the method comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for treating a mental disorder, the method comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for treating a mental disorder, the method comprising providing an effective dose of the rapidacting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides a mood preparation agent for use in a method for treating a mental disorder, the method comprising: (i) administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine; or (iii) providing an effective dose of a rapidacting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides a mood preparation agent for use in a method for treating a mental disorder, the method comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • the invention provides a mood preparation agent for use in a method for treating a mental disorder, the method comprising administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a mood preparation agent for use in a method for treating a mental disorder, the method comprising providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine.
  • the invention provides a combination of a mood preparation agent and a rapidacting indolealkylamine for use in a method for treating a mental disorder, the method comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a combination of a mood preparation agent and a rapidacting indolealkylamine for use in a method for treating a mental disorder, the method comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising: (i) administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent; or (iii) providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising: (i) administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine; or (iii) providing an effective dose of a rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention the use of a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine.
  • the invention provides the use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • the mental disorder may be treated by improving anxiety, mood and/or well-being in the subject.
  • the mood preparation agent and rapid-acting indolealkylamine may treat a mental disorder by improving (e.g. reducing) anxiety in the subject.
  • the mood preparation agent and rapid-acting indolealkylamine may treat a mental disorder by improving mood in the subject.
  • the mood preparation agent and rapid-acting indolealkylamine may treat a mental disorder by improving well-being in a subject.
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising: (i) administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of a mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine; or (iii) providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising providing an effective dose of a mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a mood preparation agent for use in a method for reducing or preventing an adverse effect (e.g.
  • the method comprising (i) administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine; or (iii) providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides a mood preparation agent for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of the rapidacting indolealkylamine.
  • the invention provides a mood preparation agent for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a mood preparation agent for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, the method comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, the method comprising: (i) administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of a mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine; or (iii) providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, the method comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapidacting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, the method comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, the method comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • the invention provides a combination of a mood preparation agent and a rapidacting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), the method comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine
  • the invention provides a combination of a mood preparation agent and a rapidacting indolealkylamine for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), the method comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising: (i) administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine; or (iii) providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • a rapid-acting indolealkylamine comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising: (i) administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine; (ii) providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine; or (iii) providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the invention provides the use of a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • the invention provides the use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine
  • the invention provides the use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mood preparation agent and a rapid-acting indolealkylamine.
  • the invention provides a dosage form for treating a mental disorder, comprising a mood preparation agent and a rapid-acting indolealkylamine (e.g. a combination dosage form), wherein the dosage form is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • a mood preparation agent e.g. a combination dosage form
  • a rapid-acting indolealkylamine e.g. a combination dosage form
  • the invention provides a pharmaceutical composition disclosed herein for use in medicine. In one aspect, the invention provides a method for treating disease the method comprising administering a pharmaceutical composition disclosed herein to a subject. In one aspect, the invention provides the use of a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating disease. In one aspect, the invention provides a pharmaceutical composition disclosed herein for use in treating a mental disorder. In one aspect, the invention provides a method for treating a mental disorder, the method comprising administering a pharmaceutical composition disclosed herein to a subject. In one aspect, the invention provides the use of a pharmaceutical composition disclosed herein in the manufacture of a medicament for treating a mental disorder.
  • the invention provides a pharmaceutical composition disclosed herein for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine).
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), the method comprising administering a pharmaceutical composition disclosed herein to a subject.
  • the invention provides the use of a pharmaceutical composition disclosed herein in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapidacting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine).
  • a dosage form e.g., a combination or single agent dosage form
  • the invention provides a method for treating disease the method comprising administering a dosage form disclosed herein to a subject.
  • the invention provides the use of a dosage form disclosed herein in the manufacture of a medicament for treating disease.
  • the invention provides a dosage form (e.g., a combination or single agent dosage form) disclosed herein for use in treating a mental disorder.
  • the invention provides a method for treating a mental disorder, the method comprising administering a dosage form (e.g., a combination or single agent dosage form) disclosed herein to a subject.
  • the invention provides the use of a dosage form (e.g., a combination or single agent dosage form) disclosed herein in the manufacture of a medicament for treating a mental disorder.
  • the invention provides a dosage form disclosed herein for use in a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine).
  • an adverse effect e.g. in a subject
  • an effective dose of a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine.
  • a combination dosage form or combination product may be one wherein both a rapid-acting indolealkylamine and mood preparation agent are present.
  • a single agent dosage form or single agent product may be one wherein either a rapid-acting indolealkylamine or a mood preparation agent are present.
  • the invention provides a method for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), the method comprising administering a dosage form disclosed herein to the subject.
  • the invention provides the use of a dosage form disclosed herein, in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine).
  • the invention provides a method for manufacturing a pharmaceutical composition (e.g., as disclosed herein), wherein the method comprises combining a mood preparation agent and a rapid-acting indolealkylamine.
  • the invention provides a method for manufacturing a dosage form (e.g., as disclosed herein), wherein the method comprises combining a mood preparation agent and a rapid-acting indolealkylamine into a dosage form that is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • the invention provides a use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in a method for manufacturing a pharmaceutical composition (e.g., as disclosed herein), comprising combining the mood preparation agent and the rapidacting indolealkylamine into a pharmaceutical composition that is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • a pharmaceutical composition e.g., as disclosed herein
  • the invention provides a use of a combination of a mood preparation agent and a rapid-acting indolealkylamine in a method for manufacturing a dosage form (e.g., as disclosed herein), comprising combining the mood preparation agent and the rapid-acting indolealkylamine into a dosage form that is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • a dosage form e.g., as disclosed herein
  • the invention provides a kit for treating a mental disorder, wherein the kit comprises:
  • the mood preparation agent and/or rapid-acting indolealkylamine comprised in the kit may be part of a pharmaceutical composition or dosage form as described herein.
  • a mood preparation agent may be administered to a subject to provide an effective dose of the mood preparation agent to the subject that will be provided with an effective dose of a rapidacting indolealkylamine (e.g. via subsequent administration of the rapid-acting indolealkylamine).
  • a rapid-acting indolealkylamine may be administered to a subject to provide an effective dose of the rapid-acting indolealkylamine to the subject that has been provided with an effective dose of a mood preparation agent (e.g. via prior administration of the mood preparation agent).
  • the terms “treat”, “treating” or “treatment” encompass prophylactic treatment (e.g., to prevent onset of a disorder, such as anxiety disorder) as well as corrective treatment (treatment of a subject already suffering from a disorder, such as depression).
  • preferably “treat”, “treating” or “treatment” as used herein means corrective treatment.
  • the terms “treat” “treating” or “treatment” as used herein refers to the disorder (e.g., depression) and/or a symptom thereof (e.g., low mood).
  • the terms “prevent”, “preventing” or “prevention” when used in the context of an adverse effect preferably refers to suppressing and/or delaying the onset, development and/or worsening of the adverse effect. In some embodiments, the terms “prevent”, “preventing” or “prevention” when used in the context of an adverse effect may mean suppressing development of the adverse effect entirely.
  • the terms “reduce”, “reducing” or “reduction” when used in the context of an adverse effect refers to a reduction in severity of the adverse effect (e.g., a reduction of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%, preferably 100%).
  • the reduction may be a reduction in severity of the adverse effect when compared to severity of the same adverse effect in the same subject or an equivalent subject that has been provided with an effective dose of a rapid-acting indolealkylamine without first being provided with an effective dose of a mood preparation agent and/or that has not been treated in accordance with the present invention - preferably said same subject or equivalent subject is one that does not receive an effective dose of the mood preparation agent.
  • the adverse effect is preferably one or more anxiety and/or stress-related side-effects (e.g., at least 1 , 2, 3, 4, 5 or 6 anxiety and/or stress- related side effects).
  • a rapid-acting indolealkylamine preferably is any amount of a rapid-acting indolealkylamine which when provided to a subject alone, or in combination with another agent, (preferably alone) to a subject: (i) for treating a disorder (e.g., a mental disorder) is sufficient to effect such treatment of the disorder, or symptom thereof (i.e. is “therapeutically effective”); and/or (ii) inhibits or delays the onset or reoccurrence of a disorder (e.g., anxiety disorder) or a symptom thereof (i.e. is “prophylactically effective”).
  • a disorder e.g., a mental disorder
  • a disorder e.g., anxiety disorder
  • a symptom thereof i.e. is “prophylactically effective”.
  • “Inhibiting” the onset may mean either lessening the likelihood of a disorder’s onset (or symptom thereof) or preventing the onset entirely.
  • the effective dose of a rapid-acting indolealkylamine prevents the onset or reoccurrence of a disorder entirely.
  • the term “effective dose” when used in the context of a rapid-acting indolealkylamine is a dose that, when provided to a subject, may result in an adverse effect (e.g., an anxiety and/or stress-related side effect) when the subject has not been provided with an effective dose of a mood preparation agent disclosed herein prior to receiving the effective dose of rapid-acting indolealkylamine.
  • an “effective dose” of an agent may be provided or administered by way of a plurality of doses.
  • the plurality of doses may all be identical doses or may comprise different doses.
  • an effective dose of 250 mg of an agent e.g. mood preparation agent or rapid-acting indolealkylamine
  • an effective dose of 15 mg of an agent e.g. mood preparation agent or rapid-acting indolealkylamine
  • a 5 mg dose and a 10 mg dose of the agent e.g. mood preparation agent or rapid-acting indolealkylamine.
  • an effective dose when used in the context of a mood preparation agent is preferably any amount of a mood preparation agent which when provided to a subject alone, or in combination with another agent (preferably alone), reduces or prevents an adverse effect (preferably an anxiety and/or stress-related side effect), e.g. in a subject, associated with treatment with an effective dose of a rapid-acting indolealkylamine disclosed herein (e.g. provision of an effective dose of a rapid-acting indolealkylamine disclosed herein).
  • an adverse effect preferably an anxiety and/or stress-related side effect
  • an “anxiety and/or stress-related side effect” may comprise one or more of anxious distress, heart palpitations, panic, suicidal ideation or suicidal behaviour, and/or an increase in stress markers such as cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) or noradrenaline.
  • DHEA dehydroepiandrosterone
  • Anxious distress may refer to feelings of tension, unusual restlessness, difficulty concentrating (e.g., due to worry), fear (e.g., that something out may happen), or feelings of loss of control.
  • Anxious distress may encompass end-of-life anxiety. Depression with anxious distress is a clinically defined DSM-5 specifier.
  • “Suicidal ideation”, as used herein, may refer to thoughts about or an unusual preoccupation with suicide, or notions of death or wishing to cease living but not necessarily taking any active efforts to do so. Suicidal ideation may or may not present with intent to act. “Suicidal behaviour”, as used herein, may refer to self-injury with the desire to end one’s life that does not result in death.
  • the present invention may prevent or reduce an adverse effect (e.g., one or more anxiety related side effects) e.g., in a subject, associated with treatment with an effective dose of a rapid-active indolealkylamine (e.g. associated with provision of an effective dose of a rapidacting indolealkylamine disclosed herein).
  • an adverse effect e.g., one or more anxiety related side effects
  • a rapid-active indolealkylamine e.g. associated with provision of an effective dose of a rapidacting indolealkylamine disclosed herein.
  • the present invention prevents or reduces at least 1 , 2, 3, 4, 5 or 6 adverse effects, e.g., selected from anxious distress, heart palpitations, panic, suicidal ideation, suicidal behaviour, and/or an increase in stress markers (such as cortisol, alphaamylase, dehydroepiandrosterone (DHEA) and/or noradrenaline).
  • stress markers such as cortisol, alphaamylase, dehydroepiandrosterone (DHEA) and/or noradrenaline.
  • DHEA dehydroepiandrosterone
  • the present invention prevents or reduces at least an increase in stress markers (such as cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) and/or noradrenaline).
  • treatment in accordance with the present invention reduces at least an increase in one or more stress markers (such as cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) or noradrenaline) by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%, e.g., when compared to an increase in the same one or more stress markers in the same subject or an equivalent subject that has been provided with an effective dose of a rapid-acting indolealkylamine without first being provided with an effective dose of a mood preparation agent and/or that has not been treated in accordance with the present invention - preferably said same subject or equivalent subject is one that does not receive an effective dose of the mood preparation agent.
  • treatment in accordance with the present invention prevents any increase in the one or more stress markers.
  • Measuring stress markers may be performed using any technique known in the art. For example, stress markers in blood (or a component thereof, such as plasma) and/or saliva may be measured. Suitable techniques may include ELISA and/or mass-spectrometry analysis (e.g. LC-MS). Suitable techniques may be those taught in llthaug et al. (2020) Psychopharmacology 237(3): 773-785.
  • a patient’s response may be assessed using any technique, test or questionnaire known to those skilled in the art.
  • MADRS Monitoring-Asberg Depression Rating Scale
  • Suitable techniques may include those taught in llthaug et al. (2020) Psychopharmacology 237(3):773- 785.
  • a “rapid-acting indolealkylamine” as used herein may refer to a type of indolealkylamine which can improve one or more symptoms of a mental disorder within minutes to hours (e.g. which can improve one or more symptoms of a mental disorder within minutes or which can improve one or more symptoms of a mental disorder within hours).
  • a “rapid-acting indolealkylamine” as used herein may refer to a type of indolealkylamine capable of improving one or more symptoms of a mental disorder when a subject is provided with an effective dose of the rapid-acting indolealkylamine within 15 hours, 10 hours, 5 hours, 2 hours, 1 hour, 30 minutes, or 20 minutes, (e.g.
  • Exemplary rapid-acting indolealkylamines may include a lysergic acid amide (e.g. d- lysergic acid diethylamide (LSD) or ergine (LSA)), a tryptamine (e.g., psilocybin, a- methyltryptamine (AMT), N,N-dimethyltryptamine (DMT), bufotenine, 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) or 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT)), a P-carboline (e.g., harman, harmaline or harmine), a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a lysergic acid amide e.g. d- lysergic acid diethylamide (LSD) or ergine (LS
  • the rapid-acting indolealkylamine may be synthesised and/or manufactured according to any method known in the art. Sherwood et al (2020), ACS Omega, 5, 32067-32075 teaches a method for synthesising 5-MeO-DMT. Additionally, said rapid-acting indolealkylamines may be purchased, for example, 5-MeO-DMT may be purchased from Scientific Laboratory Supplies (Product Code: M-168-1 ML).
  • a rapid-acting indolealkylamine in accordance with the invention may comprise one or more of a lysergic acid amide, a tryptamine, or a p-carboline, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a rapid-acting indolealkylamine is selected from the group consisting of a lysergic acid amine, a tryptamine, a p-carboline, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a rapid-acting indolealkylamine of the invention is a tryptamine.
  • a rapid-acting indolealkylamine in accordance with the invention is not a tryptamine, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof. Accordingly, a rapid-acting indolealkylamine in accordance with the invention may comprise one or more of a lysergic acid amide or a p-carboline, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a lysergic acid amide may be d-lysergic acid diethylamide (LSD) or ergine (LSA).
  • a rapid-acting indolealkylamine in accordance with the invention is not d- lysergic acid diethylamide (LSD). Accordingly, a lysergic acid amide may be ergine (LSA).
  • a tryptamine may be psilocybin, a-methyltryptamine (AMT), N,N-dimethyltryptamine (DMT), bufotenine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or 5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT), preferably 5-MeO-DMT, or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • AMT a-methyltryptamine
  • DMT N,N-dimethyltryptamine
  • bufotenine 5-methoxy-N,N-dimethyltryptamine
  • 5-MeO-DMT 5-methoxy-N,N- diisopropyltryptamine
  • 5-MeO-DMT 5-MeO-DMT
  • a tryptamine may be psilocybin, a-methyltryptamine (AMT), N,N-dimethyltryptamine (DMT), bufotenine, 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or 5-methoxy-N,N-diisopropyltryptamine (5- MeO-DIPT), preferably 5-MeO-DMT.
  • AMT a-methyltryptamine
  • DMT N,N-dimethyltryptamine
  • bufotenine 5- methoxy-N,N-dimethyltryptamine
  • 5-MeO-DMT 5-methoxy-N,N-diisopropyltryptamine
  • MeO-DIPT 5-MeO-DMT.
  • a rapid-acting indolealkylamine in accordance with the invention is not psilocybin or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a tryptamine may be a-methyltryptamine (AMT), N,N-dimethyltryptamine (DMT), bufotenine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or 5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT).
  • a rapid-acting indolealkylamine in accordance with the invention is not N,N-dimethyltryptamine (DMT) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a tryptamine may be psilocybin, a- methyltryptamine (AMT), bufotenine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or 5- methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT).
  • a rapid-acting indolealkylamine in accordance with the invention is not psilocybin or N,N-dimethyltryptamine (DMT) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a tryptamine may be a- methyltryptamine (AMT), bufotenine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or 5- methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT).
  • a p-carboline may be harman, harmaline or harmine, or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a p-carboline may be harman, harmaline or harmine.
  • a rapid-acting indolealkylamine in accordance with the invention preferably comprises 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (such as 5-MeO-DMT hydrochloride).
  • a rapid-acting indolealkylamine consists of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof (such as 5-MeO-DMT hydrochloride), preferably a rapid-acting indolealkylamine is 5-MeO-DMT.
  • a 5-MeO-DMT salt may be a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt.
  • an analogue thereof may encompass structural and/or functional chemical analogues.
  • a “pharmaceutically acceptable salt” is intended to mean a salt that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject.
  • pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for administration to patients without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable salts may include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzy1 phenethylamine, 1-para-chlorobenzy1-2-pyrrolidin-1'-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and di sodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydroch
  • a “mood-preparation agent” as used herein may refer to a drug that (a) increases dopamine and/or serotonin and/or oxytocin (e.g. dopamine, serotonin, and oxytocin) and/or (b) decreases cortisol release when provided to a subject (e.g. when an effective dose is provided to the subject).
  • a “mood-preparation agent” as used herein may refer to a drug that (a) increases dopamine or serotonin or oxytocin and (b) decreases cortisol release when a subject is provided with an effective dose thereof.
  • the increase in dopamine, serotonin or oxytocin and/or decrease in cortisol may be determined by comparing the levels of dopamine, serotonin or oxytocin and/or cortisol in the same subject (preferably in the blood thereof or a component thereof) prior to providing the subject with an effective dose of the mood-preparation agent.
  • the increase may be an increase of at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 250% or 500%.
  • the increase may be an increase of 1-500%, 10- 250% or 20-100%.
  • the decrease may be a decrease of at least %, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 250% or 500%.
  • the decrease may be a decrease of 1-500%, 10-250% or 20-100%.
  • Levels of dopamine, serotonin, oxytocin, and/or cortisol may be measured using any technique known in the art, including ELISA and/or mass-spectrometry analysis.
  • Exemplary mood preparation agents may include ketamine or a derivative thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6- dehydronorketamine, 2-metoxyketamine, N-ethyl-norketamine, 2-fluorodeschloroketamine, 3- fluorodeschloroketamine, deschloroketamine, 2-bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), an N-methyl-D-aspartate (NMDA) antagonist (e.g., memantine, lanicemine, rislenemdaz, kynurenic acid, 4- chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK-801), rapastinel, a mono-oxidase inhibitor (e.g., a
  • SDRA serotonin-dopamine releasing agent
  • SDRI serotonin-dopamine reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • citalopram fluoexetine
  • a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid AMPA
  • TAK-653 TAK-653
  • Glutamic Acid beta-caryophyllene
  • an anti- NMDA antibody [or antigen binding fragment] or an arylcyclidine
  • ethylcyclidine methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1- (3-methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine), a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • the mood preparation agent may comprise (preferably is): ketamine or a derivative or analogue thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5- hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl- norketamine, 2-fluorodeschloroketamine, 3-fluorodeschloroketamine, deschloroketamine, 2- bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), an N-methyl-D-aspartate (NMDA) antagonist (e.g., memantine, lanicemine, rislenemdaz, kynurenic acid, 4-chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK- 801), rapastinel, a mono-oxidas
  • SDRA serotonin-dopamine releasing agent
  • SDRI serotonin-dopamine reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • citalopram or fluoexetine a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), TAK-653, Glutamic Acid, beta-caryophyllene, an anti-NMDA antibody [or antigen binding fragment])
  • arylcyclidine e.g., ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3- methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine), an anxiolytic (e.g.
  • the mood preparation agent comprises (more preferably is) ketamine, a derivative thereof or a pharmaceutically acceptable salt thereof, more preferably the mood preparation agent comprises (preferably is) ketamine.
  • a mood preparation agent in accordance with the invention is not ketamine or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent may include an N-methyl-D-aspartate (NMDA) antagonist (e.g., memantine, lanicemine, rislenemdaz, kynurenic acid, 4-chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK-801), rapastinel, a mono-oxidase inhibitor (e.g., a dopamine reuptake inhibitor (DRI) (e.g.
  • NMDA N-methyl-D-aspartate
  • DRI dopamine reuptake inhibitor
  • SDRA serotonin-dopamine releasing agent
  • SDRI serotonin-dopamine reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • citalopram fluoexetine
  • a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA
  • TAK-653 TAK-653
  • Glutamic Acid beta-caryophyllene
  • an anti-NMDA antibody antigen binding fragment
  • an arylcyclidine e.g., ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3- methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine), a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • the mood preparation agent may comprise (preferably is): an N-methyl-D-aspartate (NMDA) antagonist (e.g., memantine, lanicemine, rislenemdaz, kynurenic acid, 4-chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK-801), rapastinel, a mono-oxidase inhibitor (e.g., a dopamine reuptake inhibitor (DRI) (e.g.
  • NMDA N-methyl-D-aspartate
  • DRI dopamine reuptake inhibitor
  • SDRA serotonindopamine releasing agent
  • SDRI serotonin-dopamine reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • citalopram or fluoexetine a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AM PA), TAK-653, Glutamic Acid, beta-caryophyllene, an anti-NMDA antibody [or antigen binding fragment])
  • an arylcyclidine e.g., ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4- methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine), an anxiolytic (e.g.
  • a fast-acting anxiolytic 3,4-Methylenedioxymethamphetamine (MDMA), a cannabinoid (e.g. cannabidiol (CBD) or tetrahydrocannabinol (THC)), a substituted cathinone (e.g. 3-Methylmethcathinone (3mmC)), Valerian, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • MDMA 3,4-Methylenedioxymethamphetamine
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • a substituted cathinone e.g. 3-Methylmethcathinone (3mmC)
  • Valerian a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • the mood preparation agent may be synthesised and/or manufactured according to any method known in the art. Zekri et al (2020), Journal of Chemical Sciences, 132, 134 teaches a method for synthesising ketamine. Additionally, said mood preparation agent may be purchased, for example, ketamine may be purchased from MilliporeSigma (Product Code: C912Y05).
  • a mood preparation agent in accordance with the invention may comprise one or more of ketamine or a derivative thereof, an NMDA antagonist, or an arylcyclidine a derivative thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent may be selected from the group consisting of ketamine or a derivative thereof, an NMDA antagonist, or an arylcyclidine, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent of the invention is ketamine.
  • a derivative or analogue of ketamine may be esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl- norketamine, 2-fluorodeschloroketamine, 3-fluorodeschloroketamine, deschloroketamine, 2- bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010, or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a derivative or analogue of ketamine may be esketamine, arketamine, 6- hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2- metoxyketamine, N-ethyl-norketamine, 2-fluorodeschloroketamine, 3- fluorodeschloroketamine, deschloroketamine, 2-bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010.
  • An NMDA antagonist may be memantine, lanicemine, rislenemdaz, kynurenic acid, 4- chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK-801), rapastinel, or a mono-oxidase inhibitor (e.g., a DRI (e.g. modafinil or BTCP), a SDRA (e.g., 5-chloro aMT), an SDRI (e.g., sertraline), an SRI (e.g.
  • a DRI e.g. modafinil or BTCP
  • SDRA e.g., 5-chloro aMT
  • an SDRI e.g., sertraline
  • SRI e.g.
  • an NMDA antagonist may be memantine, lanicemine, rislenemdaz, kynurenic acid, 4-chlorokynurenine, MIJ-821 , apimostinel, dextrametorphane, dizocilpine (MK- 801), rapastinel, or a mono-oxidase inhibitor (e.g., a DRI (e.g.
  • a SDRA e.g., 5-chloro aMT
  • an SDRI e.g., sertraline
  • an SRI e.g. citalopram or fluoexetine
  • AMPA e.g., AMPA, TAK-653, Glutamic Acid, beta-caryophyllene, or an anti-NMDA antibody [or an anti-NMDA antigen binding fragment]
  • An arylcyclidine may be ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4- methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine, or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • an arylcyclidine may be ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine, 1- [1-(4-methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine.
  • a mood preparation agent comprises ketamine or a derivative or analogue thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl-norketamine, deschloroketamine, 2- fluorodeschloroketamine, 3-fluorodeschloroketamine, 2-bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010) or a pharmaceutically acceptable salt thereof (e.g., ketamine hydrochloride).
  • ketamine or a derivative or analogue thereof e.g., esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl-norketamine, deschloroketamine, 2- fluorode
  • a mood preparation agent consists of ketamine, a derivative or analogue thereof (e.g., esketamine, arketamine, 6- hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2- metoxyketamine, N-ethyl-norketamine, deschloroketamine, 2-fluorodeschloroketamine, 3- fluorodeschloroketamine, 2-bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), or a pharmaceutically acceptable salt thereof (e.g., ketamine hydrochloride). More preferably, a mood preparation agent is ketamine.
  • a mood preparation agent is ketamine.
  • ketamine refers to the racemic mixture of S- and R-enantiomers, whereas “esketamine” refers to (S)-ketamine.
  • the invention comprises providing a subject with (a) ketamine, a derivative or analogue thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5- hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl- norketamine, deschloroketamine, 2-fluorodeschloroketamine, 3-fluorodeschloroketamine, 2- bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), or a pharmaceutically acceptable salt thereof (e.g., ketamine hydrochloride) and (b) 5-MeO- DMT, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (such as 5-MeO-DMT hydrochloride). More preferably, the invention comprises providing a subject with ketamine and 5-MeO-DMT.
  • ketamine hydrochloride e.g
  • the invention comprises administering (a) ketamine, a derivative or analogue thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl-norketamine, deschloroketamine, 2-fluorodeschloroketamine, 3-fluorodeschloroketamine, 2- bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), or a pharmaceutically acceptable salt thereof (e.g., ketamine hydrochloride) and (b) 5-MeO- DMT, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (such as 5-MeO-DMT hydrochloride).
  • ketamine e.g., arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronor
  • the invention comprises administering ketamine and 5-MeO-DMT.
  • a mood preparation agent may be fast-acting, e.g. achieving a therapeutic effect within 15 hours, 10 hours, 5 hours, 2 hours, 1 hour, 30 minutes, or 20 minutes, (e.g. 5 minutes to 15 hours, 10 minutes to 5 hours or 15 minutes to 2 hours).
  • a mood preparation agent is an anxiolytic, such as a fast-acting anxiolytic.
  • a mood preparation agent is 3,4-Methylenedioxymethamphetamine (MDMA) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (preferably MDMA).
  • MDMA 3,4-Methylenedioxymethamphetamine
  • a mood preparation agent is a cannabinoid (e.g. a synthetic or natural cannabinoid) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent may be cannabidiol (CBD) or tetrahydrocannabinol (THC) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (preferably CBD or THC).
  • a mood preparation in accordance with the invention is not cannabidiol (CBD) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • CBD cannabidiol
  • a cannabinoid may be tetrahydrocannabinol (THC) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent is a substituted cathinone or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof.
  • a mood preparation agent may be 3-Methylmethcathinone (3mmC) or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (preferably 3mmC).
  • a mood preparation agent is Valerian or a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof (preferably Valerian).
  • Valerian is commercially available, e.g. from Holland & Barrett (UK).
  • Valerian may refer to one or more compounds of Valeriana officinalis (e.g. a root thereof or oil thereof).
  • Said one or more compounds are preferably therapeutically and/or pharmacologically active.
  • the one or more compounds may comprise valerenic acids, such as monoterpenes and sesquiterpenes, and/or iridoid glycosides.
  • a mood preparation agent and rapid-acting indolealkylamine according to the invention are preferably different agents.
  • a mental disorder in accordance with the invention may comprise one or more of depression (such as major depressive disorder and/or persistent depressive disorder (dysthymia)), anxiety disorder (such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety), trauma disorder (such as post-traumatic stress disorder (PTSD) and/or sexual trauma) and substance use disorder (e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder).
  • depression such as major depressive disorder and/or persistent depressive disorder (dysthymia)
  • anxiety disorder such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety
  • trauma disorder such as post-traumatic stress disorder (PTSD) and/or sexual trauma
  • substance use disorder e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder.
  • a mental disorder in accordance with the invention may comprise at least 2, 3 or 4 of depression (such as major depressive disorder and/or persistent depressive disorder (dysthymia)), anxiety disorder (such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety), trauma disorder (such as PTSD and/or sexual trauma) and substance use disorder (e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder).
  • depression such as major depressive disorder and/or persistent depressive disorder (dysthymia)
  • anxiety disorder such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety
  • trauma disorder such as PTSD and/or sexual trauma
  • substance use disorder e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder.
  • the mental disorder is depression, anxiety disorder and/or PTSD. More preferably, the mental disorder is depression and/or anxiety disorder.
  • a mental disorder may be selected from the group comprising (or consisting of) depression (such as major depressive disorder, or persistent depressive disorder (dysthymia)), anxiety disorder (such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety), trauma disorder (such as PTSD and/or sexual trauma) and substance use disorder (e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder).
  • depression such as major depressive disorder, or persistent depressive disorder (dysthymia)
  • anxiety disorder such as generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety
  • trauma disorder such as PTSD and/or sexual trauma
  • substance use disorder e.g., drug dependency withdrawal disorder, alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder.
  • a mental disorder may be diagnosed in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition
  • a subject suffers from suicidal ideation (e.g., suicidal ideation with intent to act), suicidal behaviour, and/or anxious distress.
  • Depression may be major depressive disorder and/or persistent depressive disorder (dysthymia). Depression may be treatment-refractory or treatment-resistant depression (e.g., treatment-resistant major depressive disorder or persistent depressive disorder (dysthymia)).
  • the invention may treat depression (e.g., major depressive disorder or persistent depressive disorder (dysthymia)) in a subject that suffers from suicidal ideation, suicidal behaviour and/or anxious distress. For example, the invention may treat depression with anxious distress.
  • An anxiety disorder may be generalized anxiety disorder, panic disorder, social anxiety disorder and/or end-of-life anxiety.
  • Anxiety disorder may be treatment-refractory or treatment- resistant anxiety disorder (e.g., treatment-resistant generalized anxiety disorder, panic disorder, social anxiety disorder or end-of-life anxiety).
  • the invention may treat anxiety disorder (e.g., generalized anxiety disorder, panic disorder or social anxiety disorder) in a subject that suffers from suicidal ideation and/or suicidal behaviour.
  • a trauma disorder may be post-traumatic stress disorder (PTSD) and/or sexual trauma.
  • Trauma disorder may be treatment-refractory or treatment-resistant trauma disorder (e.g., treatment-resistant PTSD or sexual trauma).
  • the invention may treat trauma disorder (e.g., PTSD or sexual trauma) in a subject that suffers from suicide ideation and/or suicidal behaviour.
  • a substance use disorder may be a substance-related and addictive disorder, such as alcohol use disorder, cannabis use disorder, opioid use disorder and/or tobacco use disorder.
  • the substance use disorder may be a disorder associated with withdrawal (e.g. a withdrawal disorder, such as a drug dependency withdrawal disorder).
  • a substance use disorder may be treatment- refractory or treatment-resistant substance use disorder (e.g., treatment-resistant alcohol use disorder, cannabis use disorder, opioid use disorder or tobacco use disorder).
  • the invention may treat a substance use disorder (e.g., alcohol use disorder, cannabis use disorder, opioid use disorder or tobacco use disorder) in a subject that suffers from suicide ideation, suicidal behaviour and/or anxious distress.
  • the invention may treat one or more symptoms of depression, anxiety disorder and/or PTSD, such as low mood, cognitive impairment, suicidal ideation, or diminished well-being.
  • PTSD depression, anxiety disorder and/or PTSD
  • improvements in suicidal ideation, cognitive impairment, symptoms of PTSD, depression and anxiety following 5-MeO-DMT use (Davis et al. (2020) Chronic Stress (Thousand Oaks) 4:2470547020939564 [DOI: 10.1177/2470547020939564]).
  • a “subject” as used herein may be a mammal, such as a human or other mammal.
  • a human subject Preferably “subject” means a human subject.
  • a “subject” is preferably an adult subject i.e., a human subject at least 18 years old.
  • the terms “subject” and “patient” are used synonymously herein.
  • a subject is preferably a subject having a mental disorder as defined herein.
  • disorder as used herein also encompasses a “disease”.
  • provision of an effective dose of a mood preparation agent to a subject prior to an effective dose of a rapid-acting indolealkylamine may be via any means known to a person skilled in the art.
  • an effective dose of a mood preparation agent may be administered prior to an effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent and a rapid-acting indolealkylamine may be administered simultaneously, or a rapid-acting indolealkylamine may be administered prior to a mood preparation agent, while still providing an effective dose of the mood preparation agent to a subject prior to an effective dose of the rapid-acting indolealkylamine.
  • the subject may be provided with an effective dose of the mood preparation agent before an effective dose of the rapid-acting indolealkylamine by delaying the availability (e.g. bioavailability) and/or uptake of the rapid-acting indolealkylamine by the subject (e.g. uptake into the bloodstream of the subject).
  • the subject may be provided with an effective dose of the mood preparation agent before an effective dose of the rapid-acting indolealkylamine by promoting the availability (e.g. bioavailability) and/or uptake of the mood preparation agent by the subject (e.g. uptake into the bloodstream of the subject).
  • an effective dose of the mood preparation agent before an effective dose of the rapid-acting indolealkylamine by promoting the availability (e.g. bioavailability) and/or uptake of the mood preparation agent by the subject (e.g. uptake into the bloodstream of the subject).
  • the aforementioned may be achieved by utilising a dosage form described herein.
  • provision of an effective dose to a subject in accordance with the invention preferably means providing an agent (e.g. rapid-acting indolealkylamine and/or mood preparation agent) in a form wherein the effective dose is available (e.g. bioavailable) for uptake by a subject.
  • agent e.g. rapid-acting indolealkylamine and/or mood preparation agent
  • the agent may be part of a dosage form or pharmaceutical composition as described herein.
  • the subject may only be provided with the effective dose once said effective dose has been released and is available (e.g. bioavailable) for uptake by the subject.
  • administer and “administering” as used herein preferably encompass contacting a subject with an agent (e.g. rapid-acting indolealkylamine and/or mood preparation agent).
  • agent e.g. rapid-acting indolealkylamine and/or mood preparation agent.
  • the agent may be part of a dosage form or pharmaceutical composition as described herein.
  • the agent (e.g. rapid-acting indolealkylamine and/or mood preparation agent) administered to the subject may not be in a form that is immediately available (e.g. bioavailable) for uptake by the subject.
  • a subject may be provided with an effective dose of the agent (e.g. rapid-acting indolealkylamine and/or mood preparation agent) only after administration has occurred.
  • the subject may be provided with an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • “simultaneously” refers to administration at substantially the same time (e.g., via the same or different routes of administration [preferably the same], or in the same or different pharmaceutical composition or dosage form [preferably the same]), preferably at the same time and preferably via the same route of administration.
  • “sequentially” refers to administration of an agent (e.g., a mood preparation agent) before or after administration of another agent (e.g., a rapid-acting indolealkylamine). In one embodiment, a mood preparation agent is administered before a rapid-acting indolealkylamine.
  • a mood preparation agent and a rapid-acting indolealkylamine are administered simultaneously, preferably wherein the mood preparation agent and the rapidacting indolealkylamine are comprised in a pharmaceutical composition or dosage form.
  • a mood preparation agent and a rapid-acting indolealkylamine are comprised in a pharmaceutical composition (e.g., a pharmaceutical composition of the present invention).
  • a mood preparation agent and a rapid-acting indolealkylamine are comprised in a dosage form adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject (e.g. a dosage form of the present invention).
  • a rapid-acting indolealkylamine may be comprised in a dosage form (e.g. a single agent dosage form) adapted to slow the release of the rapid-acting indolealkylamine to provide an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent (e.g., a single agent delayed-release dosage form).
  • a mood preparation agent e.g., a single agent delayed-release dosage form
  • the rapid-acting indolealkylamine may be administered to a subject prior to a mood preparation agent.
  • a rapid-acting indolealkylamine comprised in such a dosage form may provide an improved treatment with a more favourable benefit-risk profile as compared to an immediate release dosage form that does not delay the indolealkylamine action until after the mood preparation effects have been initiated.
  • an effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a rapid-acting indolealkylamine may encompass situations where the subject has been provided with a portion of an effective dose of a rapid-acting indolealkylamine, e.g. in a form wherein the portion of the effective dose is available (e.g. bioavailable) for uptake by the subject.
  • the subject is not provided with (or has not been provided with) 100% of an effective dose of a rapid-acting indolealkylamine (e.g.
  • the subject may have been provided with ⁇ 90%, ⁇ 80%, ⁇ 70%, ⁇ 60%, ⁇ 50%, ⁇ 40%, ⁇ 30%, ⁇ 20%, ⁇ 10%, ⁇ 5%, or ⁇ 1 % of an effective dose of the rapid-acting indolealkylamine (e.g.
  • an effective dose of a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a mood preparation agent e.g., ketamine
  • provision of an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to a subject after an effective dose of a mood preparation agent may encompass situations where the subject has been provided with a portion of an effective dose of a rapidacting indolealkylamine, e.g. in a form wherein the portion of the effective dose is available (e.g. bioavailable) for uptake by the subject, prior to receiving (at least) the effective dose (100% of the effective dose) of the mood preparation agent (e.g. in a form wherein 100% of the effective dose is available (e.g. bioavailable) for uptake by the subject).
  • the effective dose (100% of the effective dose) of the mood preparation agent e.g. in a form wherein 100% of the effective dose is available (
  • the present invention may encompass administering and/or providing more than an effective dose of the mood preparation agent, so long as at least the effective dose has been provided to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • the pharmacokinetics of a mood preparation agent suggests that the effect of the mood preparation agent (e.g., ketamine) would be rapid and prepare the subject for an effective dose of rapid-acting indolealkylamine (e.g., 5-MeO-DMT) within 1 hour of the mood preparation agent (e.g., ketamine).
  • the timing between the subject being provided with an effective dose of a mood preparation agent and an effective dose of a rapid-acting indolealkylamine is preferably controlled.
  • An effective dose of a mood preparation agent may be provided to the subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes before an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • An effective dose of a mood preparation agent may be provided to the subject ⁇ 90 minutes, preferably ⁇ 60 minutes, ⁇ 45 minutes, ⁇ 40 minutes, ⁇ 35 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes or ⁇ 10 minutes before an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • An effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a mood preparation agent e.g., ketamine
  • a mood preparation agent e.g., ketamine
  • an effective dose of a rapid-acting indolealkylamine e.g., 5-MeO-DMT.
  • an effective dose of a rapid-acting indolealkylamine may be provided to the subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes after an effective dose of a mood preparation agent (e.g. ketamine).
  • An effective dose of a rapid-acting indolealkylamine e.g.
  • 5-MeO-DMT may be provided to the subject ⁇ 90 minutes, preferably ⁇ 60 minutes, ⁇ 45 minutes, ⁇ 40 minutes, ⁇ 35 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes or ⁇ 10 minutes after an effective dose of a mood preparation agent (e.g. ketamine).
  • An effective dose of a rapid-acting indolealkylamine e.g. 5-MeO-DMT
  • an effective dose of a rapid-acting indolealkylamine is provided to the subject 20-40 minutes, more preferably 20-25 minutes after an effective dose of a mood preparation agent (e.g. ketamine).
  • Numeric ranges presented herein are inclusive of the numerical values explicitly recited as the limits of the range as well as all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, “20-40 minutes” encompasses 20 minutes as well as 40 minutes, the numerical values within the range, such as 25 minutes, and the sub-ranges, such as 21-25 minutes.
  • a dosage form of the invention may be adapted to provide an effective dose of a mood preparation agent at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes before an effective dose of a rapid-acting indolealkylamine when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a mood preparation agent ⁇ 90 minutes, preferably ⁇ 60 minutes, ⁇ 45 minutes, ⁇ 40 minutes, ⁇ 35 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes or ⁇ 10 minutes before an effective dose of a rapid-acting indolealkylamine when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a mood preparation agent 1-90 minutes, preferably 1-60 minutes, 5-60 minutes, 10-45 minutes or 15-45 minutes before an effective dose of a rapid-acting indolealkylamine when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a mood preparation agent 20-40 minutes, more preferably 20- 25 minutes before an effective dose of a rapid-acting indolealkylamine when administered to a subject.
  • a dosage form of the invention may be adapted to provide an effective dose of a rapid-acting indolealkylamine at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes after an effective dose of a mood preparation agent when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a rapid-acting indolealkylamine ⁇ 90 minutes, preferably ⁇ 60 minutes, ⁇ 45 minutes, ⁇ 40 minutes, ⁇ 35 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes or ⁇ 10 minutes after an effective dose of a mood preparation agent when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a rapid-acting indolealkylamine 1-90 minutes, preferably 1-60 minutes, 5- 60 minutes, 10-45 minutes or 15-45 minutes after an effective dose of a mood preparation agent when administered to a subject.
  • a dosage form may be adapted to provide an effective dose of a rapid-acting indolealkylamine 20-40 minutes, more preferably 20-25 minutes after an effective dose of a mood preparation agent when administered to a subject.
  • a rapid-acting indolealkylamine is comprised in a dosage form (e.g. a single agent dosage form) which is adapted to slow the release of the rapid-acting indolealkylamine to provide an effective dose of the rapid-acting indolealkylamine (e.g., 5- MeO-DMT) to a subject that has been provided with an effective dose of a mood preparation agent
  • the dosage form may be adapted to provide an effective dose of the rapid-acting indolealkylamine to the subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes after an effective dose of a mood preparation agent when administered to a subject, or 1-90 minutes, preferably 1-60 minutes, 5-60 minutes, 10-45 minutes or 15-45 minutes after an effective dose of a mood preparation agent when administered to a subject
  • a rapidacting indolealkylamine is comprised in a dosage form adapted to provide an effective dose of the rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to a subject 20-40 minutes, preferably 20-25 minutes, after an effective dose of a mood preparation agent when administered to a subject.
  • an effective dose of the rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a rapid-acting indolealkylamine is comprised in a dosage form (e.g. a single agent dosage form) which is adapted to slow the release of the rapid-acting indolealkylamine to provide an effective dose of the rapid-acting indolealkylamine (e.g., 5- MeO-DMT) to a subject that has been provided with an effective dose of a mood preparation agent
  • the dosage form may be adapted to provide an effective dose of the rapid-acting indolealkylamine to the subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes or at least 60 minutes after administration to the subject, or 1-90 minutes, preferably 1-60 minutes, 5-60 minutes, 10-45 minutes or 15-45 minutes after administration to the subject.
  • a rapidacting indolealkylamine is comprised in a dosage form adapted to provide an effective dose of the rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to a subject 20-40 minutes, preferably 20-25 minutes, after administration to the subject.
  • an effective dose of the rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • At least one mood preparation agent when carrying out the invention at least one mood preparation agent is administered to a subject.
  • at least 2, 3, 4, 5, 6, 7, or 8 mood preparation agents may be administered.
  • each of said mood preparation agents are administered simultaneously.
  • At least one rapid-acting indolealkylamine is administered to a subject.
  • at least 2, 3, 4, 5, 6, 7, or 8 rapid-acting indolealkylamines e.g. different rapid-acting indolealkylamines
  • each of said rapid-acting indolealkylamine are administered simultaneously.
  • composition or dosage form of the invention may comprise at least one mood preparation agent.
  • at least 2, 3, 4, 5, 6, 7, or 8 mood preparation agents e.g. different mood preparation agents.
  • a pharmaceutical composition or dosage form of the invention may comprise at least one rapid-acting indolealkylamine.
  • at least 2, 3, 4, 5, 6, 7, or 8 rapid-acting indolealkylamines e.g. different rapid-acting indolealkylamines.
  • a mood preparation agent and a rapid-acting indolealkylamine may be administered via the same or different (preferably the same) routes of administration.
  • suitable methods of administration of a mood preparation agent (e.g., ketamine) and/or a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) include, but are not limited to, oral (e.g., via sublingual and/or buccal routes), intranasal, inhalation (e.g., smoking and/or vaporizing) or parenteral routes.
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • uccal or “buccally” refers to administration via the inner lining or tissue of the cheek and may encompass the front of the mouth, the roof of the mouth, and/or one or both sides of the mouth.
  • sublingual or “sublingually” refers to administration via tissue under the tongue in the mouth.
  • a mood preparation agent, a rapid-acting indolealkylamine, a combination thereof, a dosage form thereof (e.g., a dosage form of the present invention), or a pharmaceutical composition may be formulated in any suitable manner for administration to a subject.
  • a mood preparation agent, a rapid-acting indolealkylamine, a combination thereof, a dosage form thereof (e.g., a dosage form of the present invention), or a pharmaceutical composition may be formulated for oral (e.g., buccal and/or sublingual), intranasal, inhalation (e.g., smoking and/or vaporizing) or parenteral administration.
  • a rapid-acting indolealkylamine, a mood preparation agent, a combination thereof, a dosage form thereof (e.g., a dosage form of the present invention), or a pharmaceutical composition is formulated for oral administration (e.g., buccal and/or sublingual administration).
  • a rapid-acting indolealkylamine, a mood preparation agent, a combination thereof, a dosage form thereof (e.g., a dosage form of the present invention) or a pharmaceutical composition is formulated for buccal administration.
  • a mood preparation agent, a rapid-acting indolealkylamine, a combination thereof, or a dosage form thereof may be formulated with a pharmaceutically acceptable carrier, excipient, adjuvant, propellant and/or salt.
  • Suitable pharmaceutically acceptable carriers are well known in the art and may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • Pharmaceutically acceptable carriers and excipients include, but are not limited to, glidants, diluents, lubricants, colorants, disintegrants, granulating agents, binding agents, polymers, emulsifiers, stabilizers, plasticizers and/or coating agents.
  • a mood preparation agent, a rapid-acting indolealkylamine, or a combination thereof is formulated in a pharmaceutical composition comprising at least an effective dose of a rapid-acting indolealkylamine and/or at least an effective dose of a mood preparation agent, and preferably a pharmaceutically acceptable excipient.
  • a rapid-acting indolealkylamine, or a combination of a mood preparation agent and a rapid-acting indolealkylamine is formulated in a dosage form disclosed herein, preferably a dosage form of the present invention.
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine is formulated in a kit of the present invention.
  • a pharmaceutical composition or dosage form or kit of the invention may comprise at least one effective dose of a mood preparation agent and at least one effective dose of a rapid-acting indolealkylamine.
  • a method for manufacturing the same may comprise combining at least one effective dose of a mood preparation agent and at least one effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent and/or rapid-acting indolealkylamine is present in a pharmaceutical composition and/or dosage form herein (preferably dosage form), it is preferred that it is present at more than an effective dose.
  • a kit of the invention For example, in some instances 100% of the amount of mood preparation agent and/or rapid-acting indolealkylamine present may not be in a form that is capable of being available (e.g. bioavailable) for uptake by a subject (e.g. due to a portion remaining associated with a substrate present in a dosage form). Thus, more than the effective dose may be present, e.g. in order to mitigate any losses based thereon.
  • the pharmaceutical composition and/or dosage form may comprise at least 101%, 105%, 110%, 115%, 120%, or 125% of the effective dose of a mood preparation agent and/or rapid-acting indolealkylamine.
  • the amount of a mood preparation agent and/or rapid-acting indolealkylamine (preferably mood preparation agent and rapid-acting indolealkylamine) present in a pharmaceutical composition and/or dosage form may be at least 1 %, 5%, 10%, 20%, or 25% higher than the stated effective dose.
  • provision of an effective dose to a subject in accordance with the invention preferably means providing an agent (e.g. rapid-acting indolealkylamine and/or mood preparation agent) in a form wherein the effective dose is available (e.g. bioavailable) for uptake by a subject.
  • agent e.g. rapid-acting indolealkylamine and/or mood preparation agent
  • the agent may be part of a dosage form or pharmaceutical composition as described herein.
  • the agent may be part of a kit as described herein.
  • the subject may only be provided with the effective dose once said effective dose has been released and is available (e.g. bioavailable) for uptake by the subject.
  • a dosage form e.g., a combination or single agent dosage form
  • a dosage form is a tablet, a capsule, a film, a laminate or a lypohilisate.
  • a “lypohilisate” as used herein refers to a freeze-dried dosage form.
  • a dosage form e.g., a combination or single agent dosage form
  • a dosage form is orally dissolvable or dispersible, optionally wherein the dosage form (e.g., a combination or single agent dosage form) is an orally dissolvable tablet, an orally dissolvable film or laminate, or an oral lypohilisate.
  • An “oral lypohilisate” refers to a lypohilisate which is dissolvable or dispersible orally (preferably buccally and/or sublingually), e.g. on or under the tongue (e.g. an oral melt).
  • a dosage form of the present invention is an orally dissolvable film or laminate.
  • an orally dissolvable film or laminate preferably provides buccal adhesion to the subject’s mouth (e.g., to the inner lining or tissue of the cheek). Said films or laminates may facilitate the provision of active ingredients when administered buccally. Adaptation of a dosage form (e.g.
  • combination dosage form comprising both a rapid-acting indolealkylamine and a mood preparation agent
  • a mood preparation agent to provide an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine when administered to a subject
  • the dosage form may be so adapted by employing one or more additional constituents, such as a substrate as described herein.
  • adaptation of a dosage form e.g.
  • a single agent dosage form to slow the release of a rapid-acting indolealkylamine to provide an effective dose of rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent
  • a dosage form disclosed herein may be a controlled- release dosage form or a delayed-release dosage form.
  • delayed-release may refer to the delayed dissolution and/or disintegration of a dosage form so as to delay release of one or more active ingredients (e.g., a rapid-acting indolealkylamine), for example in the mouth or gastrointestinal environment of the subject. Delayed dissolution and/or disintegration of a dosage form (e.g. a substrate layer thereof) may be achieved by providing a physical barrier preventing such dissolution and/or disintegration. A delayed-release dosage form may adhere to the tissue of the mouth and release the active agents slowly overtime as the oral saliva gradually dissolves the dosage form.
  • active ingredients e.g., a rapid-acting indolealkylamine
  • the active ingredient Prior to dissolution and/or disintegration the active ingredient (e.g., a rapid-acting indolealkylamine) may be in a form that is substantially unavailable (e.g. is substantially not bioavailable) for uptake by the subject. After dissolution and/or disintegration the active ingredient (e.g. , a rapidacting indolealkylamine) may be in a form that is available (e.g. is bioavailable) for uptake by the subject. During dissolution and/or disintegration, a portion of the active ingredient (e.g., a rapid-acting indolealkylamine) may be in a form that is available (e.g. is bioavailable) for uptake by the subject.
  • controlled-release may refer to the release of one or more active ingredients (e.g., a rapid-acting indolealkylamine) to an environment in a controlled manner, for example in the mouth or gastrointestinal environment of the subject.
  • a controlled release may begin within a few minutes after administration or after expiration of a delay period (lag time) after administration.
  • Adaptation of a dosage form to provide an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine when administered to a subject may be achieved by the use of two or more different substrates.
  • the dosage form may comprise a first substrate with which a mood preparation agent is associated and a second substrate with which a rapid-acting indolealkylamine is associated.
  • the thickness of the substrate may alter the rate at which the mood preparation agent and/or rapid-acting indolealkylamine is provided to a subject. Additionally or alternatively, the nature of the substrate (e.g. the nature of a chemical [e.g. polymer] forming the substrate) may alter the rate at which the mood preparation agent and/or rapid-acting indolealkylamine is provided to a subject.
  • a dosage form of the present invention comprises a first substrate with which a mood preparation agent is associated and a second substrate with which a rapidacting indolealkylamine is associated, wherein the first substrate has a faster dissolution and/or disintegration rate in the body of a subject (e.g., in the mouth of the subject or in the gastrointestinal tract of the subject, preferably in the mouth) than the second substrate.
  • a first substrate has a faster dissolution and/or disintegration rate in the buccal and/or sublingual cavity of a subject, preferably in the buccal cavity, than the second substrate.
  • the rapid-acting indolealkylamine or mood preparation agent Prior to dissolution and/or disintegration of a substrate with which the rapid-acting indolealkylamine or mood preparation agent (as applicable) is associated, the rapid-acting indolealkylamine or mood preparation agent (as applicable) may be in a form that is substantially unavailable (e.g. is substantially not bioavailable) for uptake by the subject.
  • the rapid-acting indolealkylamine or mood preparation agent (as applicable) may be in a form that is available (e.g. is bioavailable) for uptake by the subject.
  • a portion of the rapid-acting indolealkylamine or mood preparation agent (as applicable) may be in a form that is available (e.g. is bioavailable) for uptake by the subject.
  • a first substrate with which a mood preparation agent is associated comprises a first polymer layer and the second substrate with which a rapid-acting indolealkylamine is associated comprises a second polymer layer.
  • the first polymer layer and/or second polymer layer may comprise a polymer matrix.
  • a first substrate with which a mood preparation agent is associated comprises a polymer matrix
  • a second substrate with which a rapid-acting indolealkylamine is associated comprises entericrelease beads, optionally wherein the enteric-release beads are dispersed within the polymer matrix.
  • the enteric-release beads may comprise an enteric polymer coating.
  • a polymer for use in a dosage form of the invention may comprise one or more of cellulose and/or derivatives thereof, synthetic or natural gums (such as xanthan gum and/or derivatives thereof), acrylic polymer and/or copolymer thereof (e.g., methacrylic acid polymers), polyalkylene oxide, polyalkylene glycol, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, carrageenan, alginic acid and/or salts thereof, carboxyvinyl polymers, pectin and/or derivatives thereof, and starch and/or derivatives thereof, methacrylic acid copolymers (e.g., ethyl acrylate-methacrylic acid copolymers, methyl acrylate-methacrylic acid copolymers or methyl methacrylate-methacrylic acid copolymers), hydroxypropyl methylcellulose, hydroxyprop
  • a polymer layer or polymer matrix may comprise a mixture of sodium carboxymethylcellulose and hydroxypropylmethyl cellulose (this mixture is known to have advantageous film forming characteristics and rapid oral dissolution).
  • a first polymer layer and second polymer layer comprise at least one polymer in common.
  • a polymer may be an enteric polymer.
  • An "enteric polymer” as used herein may refer to a gastric resistant polymer that is relatively (e.g. substantially) insoluble at the acidic pH of the stomach (e.g., about pH 1 to about pH 4), but soluble (or more soluble) at a higher pH (e.g., about pH 4.5 to about pH 8), which corresponds to the pH in the small intestine or thereafter, particularly in the duodenum or ileum.
  • An enteric polymer may comprise any water-insoluble polymer indicated to as acceptable within the U.S. Pharmacopeia/National Formulary as a coating for the gastric and/or enteric delivery of active ingredients.
  • an enteric polymer may comprise methacrylic acid copolymers (e.g., ethyl acrylate-methacrylic acid copolymers; methyl acrylate-methacrylic acid copolymers or methyl methacrylate-methacrylic acid copolymers), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, a derivative thereof, or a combination thereof.
  • methacrylic acid copolymers e.g., ethyl acrylate-methacrylic acid copolymers; methyl acrylate-methacrylic acid copolymers or methyl methacrylate-methacrylic acid copolymers
  • hydroxypropyl methylcellulose hydroxypropyl methylcellulose acetate succinate
  • hydroxypropyl methylcellulose phthalate
  • a first substrate (e.g., a first polymer layer) with which a mood preparation agent may be associated may be formed from a polymer that (i) is hydrophilic or more hydrophilic than a polymer of the second layer e.g., it is water soluble such as poly(vinyl alcohol); (ii) has a low molecular weight or a lower molecular weight than a polymer of the second layer (e.g., 10,000- 50,000 Mw); (iii) comprises at least one disintegrant, optionally wherein the disintegrant comprises a cellulose derivative, starch derivative or crosslinked polyvinylpyrrolidone; and/or (iv) is non-inert, e.g., is soluble and/or swellable, or is less inert, e.g., is more soluble and/or more swellable, than a polymer of the second layer.
  • a first substrate (e.g., a first polymer layer) with which a mood preparation agent may be associated may be formed from a polymer that has a molecular weight of ⁇ 50,000 Mw, ⁇ 40,000 Mw, ⁇ 30,000 Mw, ⁇ 20,000 Mw or ⁇ 10,000 Mw.
  • a first substrate (e.g., a first polymer layer) with which a mood preparation agent may be associated may be formed from a polymer that has a molecular weight of 10,000-50,000 Mw, e.g. 20-000-40,000 Mw, 10,000-30,000 Mw, or 30,000-50,00 Mw.
  • a “disintegrant” as used herein may refer to a swellable carrier, excipient, or adjuvant that exhibits low water solubility (e.g., is substantially insoluble or is insoluble in water) but swells when wetted to cause a substrate to disintegrate.
  • a disintegrant may comprise, for example, cellulose derivatives (e.g., cellulose esters), starch derivatives or crosslinked polyvinylpyrrolidone.
  • a second substrate with which a rapid-acting indolealkylamine may be associated may be formed from a polymer that: (i) is hydrophobic or more hydrophobic than a polymer of the first layer e.g., it is not water soluble such as polyacrylic acid; (ii) has a high molecular weight e.g., >50,000 Mw or a higher molecular weight than a polymer of the first layer; (iii) is inert, e.g., is non-soluble and/or non-swellable, or is more inert, e.g., less soluble and/or less swellable, than a polymer of the first layer.
  • a second substrate e.g., a second polymer layer
  • a second substrate with which a rapid-acting indolealkylamine may be associated may be formed from a polymer that has a molecular weight of >50,000 Mw, >60,000 Mw, >70,000 Mw, >80,000 Mw, >90,000 Mw or >100,000 Mw.
  • a second substrate with which a rapid-acting indolealkylamine may be associated may comprise a polymer comprising methacrylic acid copolymers (e.g., ethyl acrylate-methacrylic acid copolymers; methyl acrylate- methacrylic acid copolymers or methyl methacrylate-methacrylic acid copolymers), hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, a derivative thereof, or a combination thereof.
  • the polymer may be an enteric polymer.
  • compositions and dosage forms may be for use in, but not limited to, preventing, treating, managing, or ameliorating a disorder (e.g., a mental disorder), or one or more symptoms thereof, and/or in research.
  • a disorder e.g., a mental disorder
  • the pharmaceutical compositions and dosage forms (e.g., combination and single agent dosage forms) disclosed herein may be suitable for veterinary uses or pharmaceutical uses in humans.
  • the pharmaceutical compositions and dosage forms (e.g., a combination and single agent dosage form) disclosed herein may be used in any therapeutic use or method disclosed herein.
  • a mood preparation agent or a rapid-acting indolealkylamine depend on the precise nature of the mood preparation agent and/or a rapidacting indolealkylamine, the route of administration, the nature of the pharmaceutical formulation or dosage form, the age of the patient, the nature, extent or severity of the patient’s condition, contraindications, if any, and the judgement of the attending physician. Variations in these dosage levels can be adjusted using standard empirical routines for optimisation.
  • an effective dose of a mood preparation agent may be at least 10 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg or at least 300 mg.
  • An effective dose of a mood preparation agent e.g., ketamine
  • An effective dose of a mood preparation agent may be 10-500 mg, 25-400 mg, 50-350 mg, or 50-300 mg.
  • an effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a mood preparation agent is 50-250 mg or 150-250 mg, e.g., 50- 100mg, 100-150mg, 150-200 mg, or preferably 200-250 mg.
  • an effective dose of a mood preparation agent (e.g., ketamine) is about 50 mg.
  • an effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a mood preparation agent is about 150 mg.
  • an effective dose of a mood preparation agent e.g., ketamine
  • an effective dose of a mood preparation agent is about 250 mg.
  • the dose corresponds to the amount of free base delivered when the mood preparation agent salt is taken. In one embodiment, where a mood preparation agent is present as a salt, the dose corresponds to the total amount of the mood preparation agent salt.
  • An effective dose of a rapid-acting indolealkylamine may be at least 1 mg, at least 2 mg, at least 5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, or at least 50 mg.
  • An effective dose of a rapid-acting indolealkylamine may be ⁇ 100 mg, ⁇ 75 mg, ⁇ 60 mg ⁇ 50 mg, ⁇ 40 mg, ⁇ 30 mg, ⁇ 20 mg, ⁇ 10 mg, or ⁇ 5 mg.
  • An effective dose of a rapid-acting indolealkylamine may be 1-100 mg, 2-75 mg, or 5-60 mg.
  • an effective dose of a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • an effective dose of a rapid-acting indolealkylamine is 5-50 mg, e.g., 5-10 mg, 10-20 mg, 20-30 mg, 20-60 mg, 30-40 mg, or 40-50 mg.
  • an effective dose of a rapid-acting indolealkylamine is 5-40 mg (e.g. 5-20 mg or 20-40 mg).
  • an effective dose of a rapidacting indolealkylamine is about 40 mg. In some embodiments, an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) is about 5 mg. In some embodiments, an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) is about 10 mg. In some embodiments, an effective dose of a rapid-acting indolealkylamine (e.g., 5- MeO-DMT) is about 15 mg. In preferred embodiments, an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) is about 20 mg.
  • the dose corresponds to the amount of free base delivered when the rapid-acting indolealkylamine salt is taken. In one embodiment, where a rapid-acting indolealkylamine is present as a salt, the dose corresponds to the total amount of the rapid-acting indolealkylamine salt.
  • the invention comprises administering to a subject a mood preparation agent (e.g., ketamine) to provide a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg, or about 250 mg, preferably about 250 mg, of a mood preparation agent (e.g., ketamine) to the subject prior to a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • the invention comprises administering a mood preparation agent (e.g., ketamine) to provide a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg , or about 250 mg, preferably about 250 mg, of a mood preparation agent (e.g., ketamine) to a subject that will be provided with a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • the invention comprises administering to a subject a mood preparation agent (e.g., ketamine) and a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to provide a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg , or about 250 mg, preferably about 250 mg, of a mood preparation agent (e.g., ketamine) to the subject prior to a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • 5-MeO-DMT rapid-acting indolealkylamine
  • the invention comprises administering to a subject a rapidacting indolealkylamine (e.g., 5-MeO-DMT) to provide a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to the subject after a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or preferably about 150 mg, or about 250 mg, of a mood preparation agent (e.g., ketamine).
  • a rapidacting indolealkylamine e.g., 5-MeO-DMT
  • a mood preparation agent e.g., ketamine
  • the invention comprises administering a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to provide a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to a subject that has been provided with a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg, or about 250 mg, preferably about 250 mg, of a mood preparation agent (e.g., ketamine).
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a mood preparation agent e.g., ketamine
  • the invention comprises administering to a subject a mood preparation agent (e.g., ketamine) and a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to provide a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) to the subject after a dose of 50-350 mg, 50- 250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg, or about 250 mg, preferably about 250 mg, of a mood preparation agent (e.g., ketamine).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a dosage form of the invention preferably comprises an effective dose of a mood preparation agent (e.g., ketamine) and an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO- DMT).
  • a dosage form may comprise (i) a dose of 50-350 mg, 50-250 mg, 150- 250 mg, 200-250 mg, or about 50 mg, about 150 mg, or about 250 mg, preferably about 250 mg of a mood preparation agent (e.g., ketamine) and (ii) a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a dosage form of the invention preferably comprises more than an effective dose of a mood preparation agent (e.g., ketamine) and more than an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • a dosage form may comprise (i) more than a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or more than about 50 mg, more than about 150 mg, or more than about 250 mg, preferably more than about 250 mg of a mood preparation agent (e.g., ketamine) and (ii) more than a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or more than about 5 mg, more than about 10 mg, more than about 15 mg, or more than about 20 mg, preferably more than about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • the dosage form may comprise an amount of a rapid-acting indolealkylamine and/or mood preparation agent (preferably rapid-acting indolealkylamine and mood preparation agent) that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • a rapid-acting indolealkylamine and/or mood preparation agent preferably rapid-acting indolealkylamine and mood preparation agent
  • a dosage form of the invention may comprise at least 10 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg or at least 300 mg of a mood preparation agent.
  • a dosage form of the invention may comprise ⁇ 500 mg, ⁇ 400 mg, ⁇ 350 mg, ⁇ 300 mg, ⁇ 275 mg, ⁇ 250 mg, ⁇ 225 mg, ⁇ 200 mg, ⁇ 175 mg, ⁇ 150 mg, ⁇ 125 mg, ⁇ 100 mg, ⁇ 75 mg, or ⁇ 50 mg of a mood preparation agent.
  • a dosage form of the invention may comprise 10-500 mg, 25-400 mg, 50-350 mg, or 50-300 mg of a mood preparation agent.
  • a dosage form comprises 50-250 mg or 150-250 mg, e.g., 50-1 OOmg, 100-150mg, 150-200 mg, or preferably 200-250 mg of a mood preparation agent.
  • a dosage form comprises about 50 mg of a mood preparation agent, a dosage form comprises about 150 mg of a mood preparation agent Most preferably, a dosage form comprises about 250 mg of a mood preparation agent.
  • the dosage form may comprise an amount of a mood preparation agent that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • a dosage form of the invention may comprise at least 1 mg, at least 2 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 30 mg, at least 40 mg, or at least 50 mg of a rapid-acting indolealkylamine.
  • a dosage form of the invention may comprise ⁇ 100 mg, ⁇ 75 mg, ⁇ 60 mg ⁇ 50 mg, ⁇ 40 mg, ⁇ 30 mg, ⁇ 20 mg, ⁇ 15 mg, ⁇ 10 mg, or ⁇ 5 mg of a rapid-acting indolealkylamine.
  • a dosage form of the invention may comprise 1-100 mg, 2-75 mg, or 5-60 mg of a rapid-acting indolealkylamine.
  • a dosage form comprises 5-50 mg, e.g., 5- 10 mg, 10-20 mg, 20-60 mg, 20-30 mg, 30-40 mg, or 40-50 mg of a rapid-acting indolealkylamine.
  • a dosage form comprises 5-20 mg, or 20-40 mg of a rapidacting indolealkylamine.
  • the dosage form comprises about 40 mg of a rapid-acting indolealkylamine.
  • the dosage form comprises about 5 mg of a rapid-acting indolealkylamine.
  • the dosage form comprises about 10 mg of a rapid-acting indolealkylamine.
  • the dosage form comprises about 15 mg of a rapid-acting indolealkylamine. In preferred embodiments, the dosage form comprises about 20 mg of a rapid-acting indolealkylamine.
  • the dosage form may comprise an amount of a rapid-acting indolealkylamine that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • a pharmaceutical composition of the invention preferably comprises an effective dose of a mood preparation agent (e.g., ketamine) and an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • the pharmaceutical composition may comprise (i) a dose of 50-350 mg, 50-250 mg, 150-250 mg, 200-250 mg, or about 50 mg, about 150 mg, or about 250 mg, preferably about 250 mg of a mood preparation agent (e.g., ketamine) and (ii) a dose of 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or about 5 mg, about 10 mg, about 15 mg, or about 20 mg, preferably about 20 mg of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g
  • a pharmaceutical composition of the invention preferably comprises more than an effective dose of a mood preparation agent (e.g., ketamine) and more than an effective dose of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • a rapid-acting indolealkylamine e.g., 5-MeO-DMT
  • the pharmaceutical composition may comprise (i) a dose of more than 50-350 mg, 50-250 mg, 150-250 mg, 200- 250 mg, or more than about 50 mg, more than about 150 mg, or more than about 250 mg, preferably more than about 250 mg of a mood preparation agent (e.g., ketamine) and (ii) a dose of more than 5-50 mg, 20-60 mg, 20-40 mg, 5-20 mg, or more than about 5 mg, more than about 10 mg, more than about 15 mg, or more than about 20 mg, preferably more than about 20 mg of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • the pharmaceutical composition may comprise an amount of a rapid-acting indolealkylamine and/or mood preparation agent (preferably rapid-acting indolealkylamine and mood preparation agent) that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • a pharmaceutical composition of the invention may comprise at least 10 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 125 mg, at least 150 mg, at least 175 mg, at least 200 mg, at least 225 mg, at least 250 mg, at least 275 mg or at least 300 mg of a mood preparation agent.
  • a pharmaceutical composition of the invention may comprise ⁇ 500 mg, ⁇ 400 mg, ⁇ 350 mg, ⁇ 300 mg, ⁇ 275 mg, ⁇ 250 mg, ⁇ 225 mg, ⁇ 200 mg, ⁇ 175 mg, ⁇ 150 mg, ⁇ 125 mg, ⁇ 100 mg, ⁇ 75 mg, or ⁇ 50 mg of a mood preparation agent.
  • a pharmaceutical composition of the invention may comprise 10-500 mg, 25-400 mg, 50-350 mg, or 50-300 mg of a mood preparation agent.
  • a pharmaceutic composition comprises 50-250 mg, e.g., 50-1 OOmg, 100-150mg, 150-200 mg, or preferably 200-250 mg of a mood preparation agent.
  • a pharmaceutical composition comprises about 50 mg of a mood preparation agent. In some embodiments, a pharmaceutical composition comprises about 150 mg of a mood preparation agent. Most preferably, a pharmaceutical composition comprises about 250 mg of a mood preparation agent.
  • the pharmaceutical composition may comprise an amount of a mood preparation agent that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • a pharmaceutical composition of the invention may comprise at least 1 mg, at least 2 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 30 mg, at least 40 mg, or at least 50 mg of a rapid-acting indolealkylamine.
  • a pharmaceutical composition of the invention may comprise ⁇ 100 mg, ⁇ 75 mg, ⁇ 60 mg ⁇ 50 mg, ⁇ 40 mg, ⁇ 30 mg, ⁇ 20 mg, ⁇ 15 mg, ⁇ 10 mg, or ⁇ 5 mg of a rapid-acting indolealkylamine.
  • a pharmaceutical composition of the invention may comprise 1-100 mg, 2-75 mg, or 5-60 mg of a rapid-acting indolealkylamine.
  • a pharmaceutical composition comprises 5-50 mg, e.g., 5-10 mg, 10-20 mg, 20-30 mg, 20-60 mg, 30-40 mg, or 40-50 mg of a rapid-acting indolealkylamine.
  • a pharmaceutical composition comprises 5-20 mg or 20-40 mg of a rapid-acting indolealkylamine.
  • the pharmaceutical composition comprises about 40 mg of a rapid-acting indolealkylamine.
  • the pharmaceutical composition comprises about 5 mg of a rapid-acting indolealkylamine.
  • the pharmaceutical composition comprises about 10 mg of a rapid-acting indolealkylamine.
  • the pharmaceutical composition comprises about 15 mg of a rapid-acting indolealkylamine. In preferred embodiments, the pharmaceutical composition comprises about 20 mg of a rapid-acting indolealkylamine.
  • the pharmaceutical composition may comprise an amount of a rapid-acting indolealkylamine that is at least 1%, 5%, 10%, 20%, or 25% higher than the amounts stated above.
  • the invention further comprises providing the subject with a third agent (e.g. a third therapeutic agent). At least one dose of the third agent (e.g. effective dose) may be provided to the subject after an effective dose of the mood preparation agent, either before or after (preferably after) providing the subject with an effective dose of the rapid-acting indolealkylamine.
  • the mood preparation agent, rapid-acting indolealkylamine, and third agent may be administered simultaneously or sequentially (preferably simultaneously).
  • a dose of the third agent may be any dose known in the art to be therapeutically effective.
  • a dosage form of the invention may further comprise at least one dose (e.g. effective dose) of the third agent.
  • a pharmaceutical composition of the invention may further comprise at least a dose (e.g. effective dose) of the third agent.
  • the dose in this context may be one effective dose of the third agent, more than one effective dose of the third agent, a fraction of an effective dose of the third agent, or a multiple of an effective dose of the third agent.
  • the dose may be at least 0.5x, 1x, 1.2x, 1.5x, 2x, 2.5x or 3x the effective dose of the third agent.
  • the dose may be 0.5x to 3x, 1x to 2.5x, 1.5x to 2x, 1.2x to 1.5x, or 2x to 2.5x (preferably 2x) the effective dose of the third agent.
  • the dose is more than one effective dose of the third agent.
  • the dose may be at least one, two, three or four dose(s).
  • Each of the dose(s) may be one effective dose of the third agent, more than one effective dose of the third agent, a fraction of an effective dose of the third agent, or a multiple of an effective dose of the third agent, as detailed above.
  • the dose of the third active agent may be provided to a subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 25 minutes or at least 30 minutes after the effective dose of rapid-acting indolealkylamine.
  • the dose of the third active agent may be provided to a subject ⁇ 45 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes, ⁇ 10 minutes, or ⁇ 5 minutes after the effective dose of rapid-acting indolealkylamine.
  • the dose of the third agent may be provided to a subject 1-30 minutes, preferably 5-30 minutes, e.g., 5-10 minutes, or 10-20 minutes, or more preferably 20-30 minutes after the effective dose of rapid-acting indolealkylamine.
  • a dosage form of the invention may be further adapted to provide a dose of the third agent after the effective dose of the mood preparation agent and the effective dose of the rapid-acting indolealkylamine when administered to the subject.
  • a dosage form of the invention may be further adapted to provide a dose of the third agent at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 25 minutes or at least 30 minutes after the effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • a dosage form is adapted to provide a dose of the third agent less than 45 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes after the effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • a dosage form is adapted to provide a dose of the third agent 1-30 minutes, preferably 5-30 minutes, e.g., 5-10 minutes, or 10-20 minutes, or more preferably 20-30 minutes after the effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • the third agent may be a mood preparation agent, such as a different mood preparation agent.
  • the third agent is MDMA.
  • the third agent is a rapid-acting indolealkylamine. Effective doses are described for mood preparation agents and rapid-acting indolealkylamines herein.
  • the invention further comprises providing at least a further dose of the same or different rapid-acting indolealkylamine to the subject, preferably the same rapidacting indolealkylamine (e.g., 5-MeO-DMT).
  • the same rapid-acting indolealkylamine e.g., 5-MeO-DMT.
  • the invention may comprise administering to a subject a mood preparation agent and one or more rapid-acting indolealkylamine (preferably one e.g., 5-MeO-DMT) to provide an effective dose of the mood preparation agent to a subject prior to an effective dose of a rapid-acting indolealkylamine and at least a further dose of the same or different rapid-acting indolealkylamine, preferably the same rapid-acting indolealkylamine (e.g., 5-MeO-DMT).
  • the at least a further dose may be provided to the subject after the effective dose of the rapid-acting indolealkylamine.
  • Said at least a further dose may be administered simultaneously or sequentially with the mood preparation agent and/or rapid-acting indolealkylamine for providing the first effective dose.
  • the dosage form of the invention may further comprise at least a further dose of the same or different rapid-acting indolealkylamine (preferably the same rapid-acting indolealkylamine).
  • a pharmaceutical composition of the invention may further comprise at least a further dose of the same or different rapid-acting indolealkylamine (preferably the same rapid-acting indolealkylamine).
  • the at least a further dose in this context may be one effective dose of a rapid-acting indolealkylamine, more than one effective dose of a rapid-acting indolealkylamine, a fraction of an effective dose of a rapid-acting indolealkylamine, or a multiple of an effective dose of a rapid-acting indolealkylamine.
  • the at least further dose may be at least 0.5x, 1x, 1 ,2x, 1 ,5x, 2x, 2.5x or 3x the effective dose of the rapid-acting indolealkylamine.
  • the at least further dose may be 0.5x to 3x, 1x to 2.5x, 1 ,5x to 2x, 1 ,2x to 1 ,5x, or 2x to 2.5x (preferably 2x) the effective dose of the rapid-acting indolealkylamine.
  • the at least further dose is more than one effective dose of a rapid-acting indolealkylamine.
  • the at least a further dose may be at least one, two, three or four (preferably one e.g., 5-MeO- DMT) further dose(s).
  • Each of the further dose(s) may be one effective dose of a rapid-acting indolealkylamine, more than one effective dose of a rapid-acting indolealkylamine, a fraction of an effective dose of a rapid-acting indolealkylamine, or a multiple of an effective dose of a rapid-acting indolealkylamine, as detailed above.
  • At least a further dose may comprise, or preferably consist of, a dose of 5-50 mg, 20-40 mg, about 20 mg, or preferably about 40 mg of the same or different rapid-acting indolealkylamine (preferably the same, e.g., 5-MeO-DMT).
  • a dose of 5-50 mg, 20-40 mg, about 20 mg, or preferably about 40 mg of the same or different rapid-acting indolealkylamine preferably the same, e.g., 5-MeO-DMT.
  • the invention may comprise administering to a subject a mood preparation agent (e.g., ketamine) and one or more rapidacting indolealkylamine (preferably one e.g., 5-MeO-DMT) to provide a dose of 50-350 mg, 50-250 mg, 200-250 mg, or preferably about 250 mg, of a mood preparation agent (e.g., ketamine) to the subject prior to an effective dose of 5-50 mg, 20-40 mg, or preferably about 20 mg, of a rapid-acting indolealkylamine (e.g., 5-MeO-DMT) and at least a further dose of 5- 50 mg, 20-40 mg, 20 mg, or preferably 40 mg, of the same or different rapid-acting indolealkylamine (preferably the same e.g., 5-MeO-DMT).
  • a mood preparation agent e.g., ketamine
  • rapidacting indolealkylamine preferably one e.g., 5-M
  • the at least a further dose of the same or different rapid-acting indolealkylamine may be provided to a subject at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 25 minutes or at least 30 minutes after the effective dose of rapid-acting indolealkylamine (e.g., 20 mg of 5-MeO-DMT).
  • the at least a further dose of a rapid-acting indolealkylamine may be provided to a subject ⁇ 45 minutes, ⁇ 30 minutes, ⁇ 25 minutes, ⁇ 20 minutes, ⁇ 15 minutes, ⁇ 10 minutes, or ⁇ 5 minutes after the effective dose of rapid-acting indolealkylamine (e.g., 20 mg of 5-MeO-DMT).
  • the at least a further dose of a rapid-acting indolealkylamine may be provided to a subject 1-30 minutes, preferably 5-30 minutes, e.g., 5-10 minutes, or 10-20 minutes, or more preferably 20-30 minutes after the effective dose of rapidacting indolealkylamine (e.g., 20 mg of 5-MeO-DMT).
  • a dosage form of the invention may be further adapted to provide at least a further dose of the same or different rapid-acting indolealkylamine (preferably the same rapid-acting indolealkylamine) after the effective dose of the mood preparation agent and the effective dose of the rapid-acting indolealkylamine when administered to the subject.
  • the same or different rapid-acting indolealkylamine preferably the same rapid-acting indolealkylamine
  • a dosage form of the invention may be further adapted to provide at least a further dose of a rapid-acting indolealkylamine (e.g., 40 mg of 5-MeO-DMT) at least 1 minute, at least 2 minutes, at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 25 minutes or at least 30 minutes after the effective dose of the rapid-acting indolealkylamine (e.g., 20 mg of 5-MeO-DMT) when administered to a subject.
  • a rapid-acting indolealkylamine e.g. 40 mg of 5-MeO-DMT
  • a dosage form is adapted to provide at least a further dose of a rapid-acting indolealkylamine (e.g., 40 mg of 5-MeO-DMT) less than 45 minutes, less than 30 minutes, less than 25 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes after the effective dose of the rapidacting indolealkylamine (e.g., 20 mg of 5-MeO-DMT) when administered to a subject.
  • a rapid-acting indolealkylamine e.g. 40 mg of 5-MeO-DMT
  • a dosage form is adapted to provide at least a further dose of a rapid-acting indolealkylamine (e.g., 40 mg of 5-MeO-DMT) 1-30 minutes, preferably 5-30 minutes, e.g., 5- 10 minutes, or 10-20 minutes, or more preferably 20-30 minutes after the effective dose of the rapid-acting indolealkylamine (e.g., 20 mg of 5-MeO-DMT) when administered to a subject.
  • a rapid-acting indolealkylamine e.g. 40 mg of 5-MeO-DMT
  • a dosage form of the invention may further comprise at least a further substrate with which the dose of the third agent is associated, preferably wherein the at least a further substrate has a slower dissolution and/or disintegration rate in the body of a subject (preferably in the mouth of the subject e.g., in the buccal cavity of the subject) than the second substrate with which the effective dose of the rapid-acting indolealkylamine is associated.
  • a dosage form of the invention may further comprise at least a further substrate with which the at least a further dose of a rapid-acting indolealkylamine is associated, preferably wherein the at least a further substrate has a slower dissolution and/or disintegration rate in the body of a subject (preferably in the mouth of the subject e.g., in the buccal cavity of the subject) than the second substrate with which the effective dose of the rapid-acting indolealkylamine is associated.
  • the at least a further substrate comprises at least a further polymer layer e.g., a polymer matrix.
  • the at least a further substrate e.g., the at least a further polymer layer
  • a dosage form of the invention may be in the form of a laminate.
  • An exemplary laminate may be one shown in Figure 1.
  • a dosage form may comprise a plurality of substrate layers.
  • a dosage form may comprise a substrate layer associated with a mood preparation agent (e.g. a substrate layer comprising a mood preparation agent) and a substrate layer associated with a rapid-acting indolealkylamine (e.g. a substrate layer comprising a rapid-acting indolealkylamine).
  • said dosage form comprises a substrate layer associated with a rapid-acting indolealkylamine (e.g. a substrate layer comprising a rapid-acting indolealkylamine) sandwiched by (e.g. sandwiched between) a substrate layer associated with a mood preparation agent (e.g.
  • a substrate layer comprising a mood preparation agent and a further substrate layer associated with a mood preparation agent (e.g. a substrate layer comprising a mood preparation agent).
  • a substrate layer comprising a mood preparation agent e.g. a substrate layer comprising a mood preparation agent
  • the substrate layers associated with a mood preparation agent form an outermost surface of the dosage form for contact with a subject.
  • the substrate layers associated with a mood preparation agent may comprise the same substrate.
  • the substrate layer associated with a rapid-acting indolealkylamine is the same as the substate layer associated with a mood preparation agent.
  • the substrate comprises (e.g. is formed from) a water soluble chemical, most preferably PVA (polyvinyl alcohol).
  • PVA polyvinyl alcohol
  • a dosage form of the invention comprises one or more further substrate layers (referred to herein as “blank” substrate layers), wherein said substrate layers are not associated with (e.g. do not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent).
  • the dosage form may comprise at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 “blank” substrate layers (preferably at least 2). For example, 2-8 or 4-6 “blank” substrate layers may be present.
  • the one or more “blank” substrate layers may be positioned between a substrate layer associated with a mood preparation agent and a substrate layer associated with a rapid-acting indolealkylamine.
  • the one or more “blank” substrate layers may serve to separate the time between the provision of an effective dose of the mood preparation agent and rapid-acting indolealkylamine.
  • the number of “blank” substrate layers may be varied to fine-tune the timing of provision of the effective dose of the mood preparation agent and rapid-acting indolealkylamine.
  • additional “blank” substrate layers may increase the time between the provision of effective doses and fewer “blank” substrate layers may decrease the time between the provision of effective doses.
  • Varying the thickness and/or chemical nature (e.g. constituents comprised in the same) of the “blank” substrate layer(s) may also be employed to fine-tune the timing of provision of an effective dose described herein.
  • the dosage form as described may take advantage of the positioning (e.g. geometric positioning) of the substrate layers to provide a subject with an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • a substrate layer closest to the centre of the laminate may be the last layer to provide a dose of any associated agent (e.g. a rapid-acting indolealkylamine) to a subject administered the dosage form.
  • the substrate layers may all be fast-release substrate layers.
  • the dosage form of the invention is in the form of a laminate, wherein the dosage form comprises (or consists of):
  • a second substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); and
  • a fifth substrate layer that is associated with a mood preparation agent.
  • the numbering of the substrate layers may refer to the order of the substrate layers of the laminate in normal use, with the first substrate layer being at the top of the laminate in normal use, and the fifth substrate layer being at the bottom of the laminate in normal use.
  • the first and fifth substrate layers together may provide an effective dose of the mood preparation agent.
  • the third substrate layer provides an effective dose of the rapid-acting indolealkylamine.
  • the dosage form comprises a further substrate layer associated with a rapid-acting indolealkylamine.
  • the two substrate layers associated with a rapid-acting indolealkylamine may together provide an effective dose of the rapid-acting indolealkylamine.
  • the dosage form of the invention is in the form of a laminate, wherein the dosage form comprises (or consists of):
  • a second substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fifth substrate layer that is associated with a third agent (e.g. a rapid-acting indolealkylamine);
  • a third agent e.g. a rapid-acting indolealkylamine
  • a sixth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • an eighth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); and
  • the numbering of the substrate layers may refer to the order of the substrate layers of the laminate in normal use, with the first substrate layer being at the top of the laminate in normal use, and the ninth substrate layer being at the bottom of the laminate in normal use.
  • the fifth substrate layer may be associated with a different rapid-acting indolealkylamine (e.g. an effective dose thereof).
  • the fifth substrate layer is preferably associated with the same rapid-acting indolealkylamine as the third and seventh substrate layers.
  • the fifth substrate layer provides at least a further dose of a rapid-acting indolealkylamine, as described herein.
  • the third and seventh substrate layers together provide an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a dosage form in the form of a laminate, wherein the dosage form comprises:
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); and
  • a fifth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); wherein the second and third substrate layers sandwich the first, fourth and fifth substrate layers (e.g. the first, fourth and fifth substrate layers are sandwiched between the second and third substrate layers), wherein the fourth substrate layer is positioned between the second substrate layer and the first substrate layer, and wherein the fifth substrate layer is positioned between the third substrate layer and the first substrate layer.
  • the second and third substrate layers together may provide an effective dose of the mood preparation agent.
  • the first substrate layer provides an effective dose of the rapid-acting indolealkylamine.
  • the dosage form comprises a further substrate layer associated with a rapid-acting indolealkylamine.
  • the first and further substrate layers may together provide an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a dosage form in the form of a laminate, wherein the dosage form comprises:
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fifth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a seventh substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); wherein the second and third substrate layers sandwich the first, fourth, fifth, sixth, and seventh substrate layers (e.g. the first, fourth, fifth, sixth, and seventh substrate layers are sandwiched between the second and third substrate layers), wherein the fourth substrate layer is positioned between the second substrate layer and the first substrate layer, wherein the fifth substrate layer is positioned between the third and sixth substrate layers, and wherein the seventh substrate layer is positioned between the first and sixth substrate layers.
  • the first and sixth substrate layers may be associated with the same rapid-acting indolealkylamine. In such an embodiment, the first and sixth substrate layers preferably together provide an effective dose of the rapid-acting indolealkylamine.
  • the invention provides a dosage form in the form of a laminate, wherein the dosage form comprises:
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fifth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a seventh substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a ninth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); wherein the second and third substrate layers sandwich the first, fourth, fifth, sixth, seventh, eighth, and ninth substrate layers (e.g. the first, fourth, fifth, sixth, seventh, eighth, and ninth substrate layers are sandwiched between the second and third substrate layers), wherein the fourth substrate layer is positioned between the second substrate layer and the first substrate layer, wherein the fifth substrate layer is positioned between the third and sixth substrate layers, wherein the seventh substrate layer is positioned between the sixth and eighth substrate layers, and wherein the ninth substrate layer is positioned between the eighth and first substrate layers.
  • the fourth substrate layer is positioned between the second substrate layer and the first substrate layer
  • the fifth substrate layer is positioned between the third and sixth substrate layers
  • the seventh substrate layer is positioned between the sixth and eighth substrate layers
  • the ninth substrate layer is positioned between the eighth and first substrate layers
  • the eighth substrate layer may be associated with a third agent, preferably a different rapid-acting indolealkylamine (e.g. an effective dose thereof).
  • the eighth substrate layer is preferably associated with the same rapid-acting indolealkylamine as the first and sixth substrate layers.
  • the eighth substrate layer provides at least a further dose of a rapid-acting indolealkylamine, as described herein, and the first and sixth substrate layers together provide an effective dose of the rapid-acting indolealkylamine.
  • positioned between when used in the context of the laminate does not exclude the presence of further additional layers between those explicitly recited.
  • additional substrate layers there may be additional substrate layers present.
  • the substrate layer(s) is/are not associated with (e.g. does/do not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent) (e.g. are “blank” substrate layers).
  • Embodiments related to the various pharmaceutical compositions and dosage forms of the invention are intended to be applied equally to methods of treatment, uses, methods of manufacture, and kits of the invention, and vice versa.
  • a mood preparation agent includes a plurality of such candidate agents and reference to “a rapid-acting indolealkylamine” includes reference to one or more a rapidacting indolealkylamine and equivalents thereof known to those skilled in the art, and so forth.
  • Figure 1 shows an example dosage form (e.g. sublingual dosage form) of the invention having multiple substrate layers (indicated by numerals 1-9).
  • Substrate layers 1 and 9 e.g. which when sublingually administered make first contact with the subject’s oral mucosa
  • a mood preparation agent e.g. ketamine
  • Substrate layers 3 and 7 are associated with a rapid-acting indolealkylamine (e.g. 5-MeO-DMT).
  • Substrate layers 3 and 7 are preferably associated with the same rapid-acting indolealkylamine.
  • Substrate layer 5 may (in some embodiments) be associated with a third agent (e.g.
  • substrate layer 5 is associated with the same rapid-acting indolealkylamine, the amount of active agent associated with substrate layer 5 may, in one embodiment, be greater than that associated with substrate layers 3 and 7.
  • “Blank” substrate layers 2, 4, 6, and 8 are not associated with either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent).
  • the “blank” substrate layers 2, 4, 6, and 8 serve to separate the time between the provision of an effective dose of the mood preparation agent and rapidacting indolealkylamine.
  • the number of “blank” substrate layers may be varied to fine-tune the timing of provision of the effective dose of the mood preparation agent and rapid-acting indolealkylamine. For example, additional “blank” substrate layers may increase the time between the provision of effective doses and fewer “blank” substrate layers may decrease the time between the provision of effective doses. Likewise, for example, thicker “blank” substrate layers may increase the time between the provision of effective doses and thinner “blank” substrate layers may decrease the time between the provision of effective doses. The time between the provision of effective doses may additionally or alternatively be varied by the chemical composition of the “blank” substrate layers.
  • a single dose of 5-MeO-DMT is compared to a single dose of ketamine followed by a single dose of 5-MeO-DMT, administered sequentially, separated by either 5 min or 30 min in groups comprising 3-4 rodents (compared to a control group).
  • An ELISA assay for the stress marker cortisol is developed and used to measure cortisol in the blood over 6-8 time points.
  • a solid phase extraction method coupled with an optimal gradient elution is used for sample preparation and separation. Detection of 5-MeO-DMT and its metabolite bufotenine is accomplished using multiple reaction monitoring of m/z 219.2 ⁇ 174.2 and 205.2— >160.2, respectively, in the positive ion mode on a Waters Xevo triple quadrupole LC-MS/MS. 5- Methyl-N,N-dimethyltrypamine (m/z 203.2 ⁇ 158.3) is used as internal standard for quantification.
  • a solid phase extraction method coupled with an optimal gradient elution is used for sample preparation and separation. Detection of ketamine and its metabolite (2R,6R)- hydroxynorketamine is accomplished using multiple reaction monitoring of m/z 238 ⁇ 125, in the positive ion mode on a Waters Xevo triple quadrupole LC-MS/MS. H4-norketamine (m/z 228 ⁇ 129) is used as the internal standard for quantification.
  • Each group comprises 4-6 rats that are monitored over a 6 h pharmacokinetic study, during which 4-6 blood and saliva samples are taken.
  • the plasma is extracted from the blood samples and stored for analysis alongside the saliva samples.
  • the drug analytes 5-MeO-DMT, bufotenine, ketamine and (2R,6R)-hydroxynorketamine with the stress markers cortisol, alphaamylase, dehydroepiandrosterone (DHEA), noradrenaline are measured in the blood and saliva samples.
  • Administering ketamine prior to 5-MeO-DMT reduces the increase of the stress marker cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) or noradrenaline, compared with administering 5-MeO-DMT alone.
  • DHEA dehydroepiandrosterone
  • Combinations of ketamine, 5-MeO-DMT and a third agent, e.g., MDMA (or others, such as a further rapid-acting indolealkylamine, e.g. a further dose of 5-MeO-DMT) are administered sequentially separated by 5, 15 and 30 min to groups comprising 4-6 rodents.
  • the drug analytes with the stress markers cortisol, alpha-amylase, dehydroepiandrosterone (DHEA), noradrenaline are measured in the blood and saliva samples using appropriate LC-MS assays.
  • Administering ketamine, 5-MeO-DMT and a third agent, e.g., MDMA (or others, such as a further rapid-acting indolealkylamine, e.g. a further dose of 5-MeO-DMT) sequentially reduces the increase of the stress marker cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) or noradrenaline, compared with administering 5-MeO-DMT alone.
  • a third agent e.g., MDMA (or others, such as a further rapid-acting indolealkylamine, e.g. a further dose of 5-MeO-DMT) sequentially reduces the increase of the stress marker cortisol, alpha-amylase, dehydroepiandrosterone (DHEA) or noradrenaline, compared with administering 5-MeO-DMT alone.
  • DHEA dehydroepiandrosterone
  • a single dose of 20 mg 5-MeO-DMT is administered buccally to 4 healthy volunteers and 4 patients with major depressive disorder diagnosed according to DSM-5 diagnostic criteria.
  • a single dose of 250 mg of ketamine is administered buccally 20-25 minutes before a single dose of 20 mg 5-MeO-DMT administered buccally.
  • Patients are closely monitored in the hours and days following dosing. A control group without drug administration is also monitored.
  • a single dose of 20 mg 5-MeO-DMT is administered sublingually to 4 healthy volunteers and 4 patients with anxiety disorder diagnosed according to DSM-5 diagnostic criteria.
  • a single dose of 250 mg of ketamine is administered sublingually 20-25 minutes before a single dose of 20 mg 5-MeO- DMT administered sublingually.
  • Patients are closely monitored in the hours and days following dosing.
  • a control group without drug administration is also monitored.
  • a single dose of 20 mg 5-MeO-DMT is administered in an orally dissolvable dosage form to 4 patients with post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • a single dose of 250 mg of ketamine is co-administered with two doses of 5-MeO-DMT in an orally dissolvable dosage form adapted to provide the single dose of ketamine to the subject 20-25 minutes before a first dose of 20 mg of 5-MeO-DMT, and to provide a second dose of 40 mg 5-MeO-DMT 5-10 minutes after the first dose of 5-MeO-DMT.
  • a placebo control e.g. saline
  • Patients in the control group report no change in symptoms.
  • Patients with PTSD with 5-MeO- DMT alone report variable outcomes with half the cohort showing improvements in their PTSD symptoms, while the other half show significant anxiety and/or stress-related adverse effects that may be associated to the treatment itself worsening their condition.
  • patients with PTSD given ketamine and two doses of 5-MeO-DMT thereafter report significant improvements in their PTSD symptoms with no intolerable side effects.
  • Brain scans of the patients show a before and after treatment comparison of the parts of the brain and neural pathways that are triggered by asking the patient about the same traumatic event in their life.
  • Patients in the control group show that the same parts of the brain are triggered post administration as before.
  • a human subject was administered a single dose of 250 mg of ketamine 20-25 minutes before being administered a single dose of 20 mg 5-MeO-DMT.
  • the subject noted a reduction in anxiety with no intolerable side effects.
  • Patient 1 presented with symptoms suggestive of mild neurosis, characterized by a challenge in releasing emotional control, a pronounced deficiency in trust, and heightened anxiety in response to their circumstances.
  • the patient was first administered a 250mg dose of ketamine, resulting in a profound shift from the patient’s cognitive state to a state of deep relaxation. Subsequently, their overt facial expressions evolved from expressions of distress to expressions of contentment. Approximately 20 minutes following the administration of ketamine, the patient exhibited readiness for a dose of 5-MeO-DMT.
  • the patient was next administered a 10mg dose of 5-MeO-DMT. After the patient fully inhaled the compound, they reclined peacefully and successfully navigated the most challenging phase of the experience, marked by ego dissolution, within the initial 3 minutes. During this phase, the patient extended their arms fully and expanded their chest. This was accompanied by a profound and exuberant smile, indicative of a sense of liberation and pleasure. Additionally, there was a coordinated pattern of bodily movements extending from head to toe, which appeared to activate their sexual energy along the spinal column.
  • the patient was administered a 50mg dose of ketamine. After a 15-minute interval, this initial dosage induced a mild calming effect.
  • Patient 3 had a desire to confront deep-seated issues that had been burdensome for quite some time. Their journey began with a careful introduction of ketamine into their system. The patient seemed to visibly relax, appearing almost weightless as the calmness settled in during the initial twenty minutes.
  • a method for treating a mental disorder comprising administering to a subject a mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a method for treating a mental disorder comprising providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine.
  • a method for treating a mental disorder comprising providing an effective dose of a rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • a method for treating a mental disorder comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for treating a mental disorder comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for treating a mental disorder comprising providing an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • a rapid-acting indolealkylamine for use in a method for treating a mental disorder comprising providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for treating a mental disorder comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of a mood preparation agent to a subject that will be provided with an effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing a subject with an effective dose of a mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent for use in a method for treating a mental disorder comprising administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent for use in a method for treating a mental disorder comprising providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent for use in a method for treating a mental disorder comprising providing an effective dose of a rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a mood preparation agent for use in a method for treating a mental disorder comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising administering to a subject the mood preparation agent and a rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of the mood preparation agent to a subject that will be provided with an effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing an effective dose of a rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a mood preparation agent in the manufacture of a medicament for treating a mental disorder, the treatment comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of a rapid-acting indolealkylamine.
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine for use in a method for treating a mental disorder comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to an effective dose of the rapid-acting indolealkylamine.
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine for use in a method for treating a mental disorder the method comprising providing a subject with an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine.
  • a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising providing an effective dose of a mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of a mood preparation agent.
  • a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapidacting indolealkylamine.
  • a mood preparation agent for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine the method comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a mood preparation agent for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of a rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a mood preparation agent in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine, comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of a rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of the rapid-acting indolealkylamine comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of the rapid-acting indolealkylamine comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of the rapid-acting indolealkylamine comprising providing the effective dose of the rapid-acting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of the rapid-acting indolealkylamine comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising administering to a subject a mood preparation agent and the rapid-acting indolealkylamine, to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising providing an effective dose of the mood preparation agent to a subject that will be provided with the effective dose of the rapid-acting indolealkylamine.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising providing the effective dose of the rapidacting indolealkylamine to a subject that has been provided with an effective dose of the mood preparation agent.
  • a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of the rapid-acting indolealkylamine, comprising providing a subject with an effective dose of a mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine for use in a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), comprising administering to a subject the mood preparation agent and the rapid-acting indolealkylamine to provide an effective dose of the mood preparation agent to the subject prior to the effective dose of the rapid-acting indolealkylamine.
  • an adverse effect e.g. in a subject
  • an effective dose of a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine
  • a combination of a mood preparation agent and a rapid-acting indolealkylamine in the manufacture of a medicament for reducing or preventing an adverse effect (e.g. in a subject) associated with treatment with an effective dose of a rapid-acting indolealkylamine (e.g., a further effective dose of a rapid-acting indolealkylamine), comprising providing a subject with an effective dose of the mood preparation agent prior to the effective dose of the rapid-acting indolealkylamine.
  • a pharmaceutical composition for treating a mental disorder comprising a mood preparation agent and a rapid-acting indolealkylamine.
  • a dosage form for treating a mental disorder comprising a mood preparation agent and a rapid-acting indolealkylamine, wherein the dosage form is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • the dosage form comprises a first substrate with which the mood preparation agent is associated and a second substrate with which the rapid-acting indolealkylamine is associated, wherein the first substrate has a faster dissolution and/or disintegration rate in the subject (preferably in the mouth of the subject e.g., in the buccal cavity of the subject) than the second substrate.
  • (i) is hydrophilic or more hydrophilic than a polymer of the second layer, optionally is water soluble, and further optionally is poly(vinyl alcohol);
  • (ii) has a low molecular weight or a lower molecular weight than polymer of the second layer, and optionally has a molecular weight of 10,000-50,000 Mw;
  • (iii) comprises at least one disintegrant, optionally wherein the disintegrant comprises a cellulose derivative, starch derivative or crosslinked polyvinylpyrrolidone, and/or
  • (iv) is non-inert, e.g., is soluble and/or swellable, or is less inert, e.g., is more soluble and/or more swellable, than a polymer of the second layer, and optionally wherein the second polymer layer is formed from a polymer that:
  • (a) is hydrophobic or more hydrophobic than a polymer of the first layer, optionally is not water soluble, and further optionally is polyacrylic acid;
  • (b) has a high molecular weight or a higher molecular weight than a polymer of the first layer, and optionally has a molecular weight of >50,000 Mw;
  • (c) is inert, e.g., is non-soluble and/or non-swellable, or is more inert, e.g., less soluble and/or less swellable, than a polymer of the first layer.
  • a second substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); (iii) a third substrate layer associated with a rapid-acting indolealkylamine;
  • a fourth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • a fifth substrate layer that is associated with a third agent (e.g. a rapid-acting indolealkylamine);
  • a third agent e.g. a rapid-acting indolealkylamine
  • a sixth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent);
  • an eighth substrate layer that is not associated with (e.g. does not comprise) either a mood preparation agent or a rapid-acting indolealkylamine (or any further therapeutically or pharmacologically active agent); and
  • a method for treating disease comprising administering a pharmaceutical composition according to clause 51 or a dosage form according to any one of clauses 52- 56 to a subject.
  • a rapid-acting indolealkylamine e.g., a further effective dose of a rapid-acting indolealkylamine.
  • a method for treating a mental disorder comprising administering the pharmaceutical composition according to clause 51 or the dosage form according to any one of clauses 52-56 to a subject.
  • a method for reducing or preventing an adverse effect associated with treatment with an effective dose of a rapid-acting indolealkylamine comprising administering the pharmaceutical composition according to clause 51 or the dosage form according to any one of clauses 52-56 to a subject.
  • a pharmaceutical composition according to clause 51 or a dosage form according to any one of cluses 52-56 in the manufacture of a medicament for treating a mental disorder.
  • a method for manufacturing a pharmaceutical composition (e.g., according to clause 23), wherein the method comprises combining a mood preparation agent and a rapid-acting indolealkylamine.
  • a method for manufacturing a dosage form (e.g., according to any one of clauses 24- 28), wherein the method comprises combining a mood preparation agent and a rapid-acting indolealkylamine into a dosage form that is adapted to provide an effective dose of the mood preparation agent prior to an effective dose of the rapid-acting indolealkylamine when administered to a subject.
  • kits for treating a mental disorder comprising:
  • a tryptamine e.g., 5-methoxy-N,N- dimethyltry
  • d-lysergic acid diethylamide LSD
  • LSA ergine
  • a p- carboline e.g., harman, harmaline or harmine
  • the rapid-acting indolealkylamine comprises (more preferably is) 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a derivative thereof or a pharmaceutically acceptable salt thereof, more preferably wherein the rapid-acting indolealkylamine comprises (preferably is) 5-MeO-DMT
  • the mood preparation agent comprises (preferably is): ketamine or a derivative or analogue thereof (e.g., esketamine, arketamine, 6-hydroxynorketamine, 5-hydroxynorketamine, norketamine, 5,6-dehydronorketamine, 2-metoxyketamine, N-ethyl-norketamine, 2- fluorodeschloroketamine, 3-fluorodeschloroketamine, deschloroketamine, 2- bromodeschloroketamine, trifluoromethyldeschloroketamine, methoxetamine, or KEA-1010), an N-methyl-D-aspartate (NM
  • SDRA serotonin-dopamine releasing agent
  • SDRI serotonin-dopamine reuptake inhibitor
  • SRI serotonin reuptake inhibitor
  • citalopram or fluoexetine a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), TAK-653, Glutamic Acid, beta-caryophyllene, an anti-NMDA antibody [or antigen binding fragment])
  • arylcyclidine e.g., ethylcyclidine, methoxpropamine, ethoxmetamine, PCP phencyclidine (phenyl)cyclohexylpiperidine), (1-[1-(3- methoxyphenyl)cyclohexyl]piperidine, 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), methylenedioxyphencyclidine, hydroxetamine, methoxisopropamin, 3-methoxyeticyclidine, tenocyclidine, tiletamine, or rolicyclidine), an anxiolytic (e.g.
  • a fast-acting anxiolytic 3,4-Methyl enedioxymethamphetamine (MDMA), a cannabinoid (e.g. cannabidiol (CBD) or tetrahydrocannabinol (THC)), a substituted cathinone (e.g. 3-Methylmethcathinone (3mmC)), Valerian, a derivative thereof, an analogue thereof or a pharmaceutically acceptable salt thereof, preferably wherein the mood preparation agent comprises (more preferably is) ketamine, a derivative thereof or a pharmaceutically acceptable salt thereof, more preferably wherein the mood preparation agent comprises (preferably is) ketamine. 73.
  • the rapid-acting indolealkylamine comprises (preferably is) 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), a derivative thereof or a pharmaceutically acceptable salt thereof, preferably wherein the rapid-acting indolealkylamine comprises (preferably is) 5-MeO-DMT; and/or (preferably and)
  • the mood preparation agent comprises (preferably is) ketamine, a derivative thereof or a pharmaceutically acceptable salt thereof, preferably wherein the mood preparation agent comprises (preferably is) ketamine.
  • the effective dose of a rapid-acting indolealkylamine is 5-50 mg or 20-60 mg, preferably 20-40 mg, more preferably 20 mg;
  • the effective dose of a mood preparation agent is 50-350 mg, preferably 200-250 mg, more preferably 250 mg. 78.

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Abstract

La présente invention concerne le traitement de troubles mentaux. Par exemple, l'invention concerne une combinaison d'une indolealkylamine à action rapide et d'un agent de préparation d'humeur destinés à être utilisés dans un procédé de traitement d'un trouble mental, le procédé comprenant l'administration à un sujet de l'agent de préparation d'humeur et de l'indolealkylamine à action rapide pour fournir une dose efficace de l'agent de préparation d'humeur au sujet avant une dose efficace de l'indolealkylamine à action rapide. L'invention concerne également des procédés, des utilisations et des kits.
PCT/GB2023/052606 2022-10-06 2023-10-06 Traitement de troubles mentaux WO2024074850A1 (fr)

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