Pharmaceutical compositions of 5-MEO-DMT for use in the treatment of alcohol use disorders

Abstract

The invention features methods for using 5-methoxy-N,N-dimethyltryptamine (5'MeO-DMT) in the treatment of substance use disorders (SUD), including specifically alcohol use disorder (AUD). Provided are specific therapeutically effective doses of 5-MeO-DMT which are well tolerated by patients and sufficient to induce a clinical response in the patient.

Description

[0001] PHARMACEUTICAL COMPOSITIONS OF 5-MEO-DMT AND USES THEREOF

[0002] BACKGROUND

[0003] This invention relates to dosage regimens of 5-methoxy-N,N-dimethyltryptamine (5-MeO- DMT), compositions of 5-MeO-DMT and uses thereof, particularly the use in the treatment of Alcohol Use Disorder (AUD) and related conditions

[0004] 5-MeO-DMT, a tryptamine alkaloid, is a short-acting serotonergic psychedelic that was first synthesised in 1936. 5-MeO-DMT has been found in a large number of plants and has also been identified as the primary psychoactive component of the parotid gland venom of Incilius alvarius (formerly Bufo alvarius), the Sonoran Desert toad. 5-MeO-DMT has been detected in blood, urine, and cerebrospinal fluid; however, its physiological role is unknown and more research is needed to definitively determine if 5-MeO-DMT is endogenously produced in humans.

[0005] 5-MeO-DMT is a serotonin (5-HT) receptor agonist with affinity to a variety of serotonin receptors. Its highest binding affinity is for the 5-HTIA receptor, with a 300-1000-fold higher selectivity compared with the 5-HT2A receptor. The behavioural effects and safety margins of 5-MeO-DMT have been best characterised in rodents.

[0006] 5-MeO-DMT is rapidly metabolised by monoamine oxidase enzymes in the gut and liver, and is orally inactive. It is therefore usually administered parenterally through smoking or inhalation of vapour, or less commonly via intravenous, intramuscular, rectal, sublingual, or intranasal applications.

[0007] 5-MeO-DMT induces profound alterations in consciousness including mystical experiences, has minimal visual effects and higher rates of ego-dissolution compared to other psychedelics. Data, mainly derived from psilocybin and LSD studies, suggests that a profound psychedelic effect might be a necessary precursor for psychiatric efficacy of psychedelics, suggesting that 5-MeO-DMT, given at the right dose could be a beneficial alternative to current psychedelics in clinical development. Furthermore, 5-MeO-DMT has a rapid onset and short duration of action, which might reduce the duration of treatment sessions and thus resource utilisation. The high first-pass effect demands nonparenteral delivery options (i.v., inhalation, intranasal absorption) and the intranasal route disclosed herein provides benefits regarding the ease of use and the clear regulatory pathway of a broadly utilised drug-device combination. A comprehensive review of all published pre-clinical and clinical data concluded that 5-MeO-DMT is a potentially useful addition to the psychedelic pharmacopoeia because of its short duration of action, relative lack of visual effects and putatively higher rates of ego-dissolution and mystical experiences.

[0008] Many people in the United States struggle with alcohol use disorder (AUD), a mental health condition marked by unhealthy drinking habits. This widespread disorder involves a range of symptoms and behaviours linked to alcohol misuse. AUD significantly impacts society, affecting not just individuals' health but also social interactions, the economy, and public health as a whole. There are very few approved treatments for AUD and there is therefore a need in the art for further clinical exploration of suitable treatments. The psychedelic compound psilocybin has been shown, in a double-blind randomised clinical trial wherein two different doses of psilocybin were administered in two different sessions, to significantly reduce the percentage of heavy drinking days compared with diphenhydramine. Psilocybin, however, has a long duration of activity (~6-8 hours) requiring very high healthcare resource utilisation. There is therefore a need in the art for the provision of a short-acting psychedelic compound suitable for the treatment of AUD from a single dose.

[0009] SUMMARY OF THE INVENTION

[0010] Disclosed herein is a rapid and sustained treatment of alcohol use disorder (AUD), said treatment comprising the administration 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. In an embodiment, the amount of 5-MeO-DMT is 8mg, 9mg, 10mg, 11 mg or 12mg of 5-MeO-DMT, or 8mg, 9mg, 10mg, 11 mg or 12mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. In an embodiment, there is provided a rapid and sustained treatment of AUD, with an improved tolerability profile, said treatment comprising the administration of 10mg of 5-MeO-DMT, or 10mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.

[0011] In an embodiment, there is provided a rapid and sustained treatment of a substance use disorder (SUD), said treatment comprising the administration of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. In an embodiment, the amount of 5-MeO-DMT is 8mg, 9mg, 10mg, 11 mg or 12mg of 5-MeO-DMT, or 8mg, 9mg, 10mg, 11 mg or 12mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof. In an embodiment, there is provided a rapid and sustained treatment of a SUD, with an improved tolerability profile, said treatment comprising the administration of 10mg of 5-MeO-DMT, or 10mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.

[0012] The Diagnostic and Statistical Manual of Mental Disorders, or DSM-5, defines Alcohol Use Disorder (AUD) as a condition with problematic alcohol consumption leading to noticeable problems or distress in a person's life. The severity of AUD can range from mild to severe, based on the number of symptoms experienced within the past year. Previously, AUD was referred to by various terms like alcohol abuse, dependence, addiction, or even the more general term, alcoholism. Mortality among patients with alcohol use disorder (AUD) increased by over 20% in 2020 and 2021 , during the COVID- 19 pandemic. The DSM-5 defines AUD as a problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least 2 of the following 11 symptoms occurring within a 12-month period. The number of symptoms determines the severity: 2 to 3 symptoms for mild AUD, 4 to 5 for moderate, and 6 or more for severe.

[0013] 1 . Alcohol is often taken in larger amounts or over a longer period than was intended.

[0014] 2. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use.

[0015] 3. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects.

[0016] 4. Craving, or a strong desire or urge to use alcohol.

[0017] 5. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. 6. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol.

[0018] 7. Important social, occupational, or recreational activities are given up or reduced because of alcohol use.

[0019] 8 Recurrent alcohol use in situations in which it is physically hazardous.

[0020] 9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol.

[0021] 10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. b. A markedly diminished effect with continued use of the same amount of alcohol. 1 Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol. b. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.

[0022] In an embodiment, there is provided a pharmaceutical composition comprising about 10mg 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 10mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a method of treating alcohol use disorder (AUD) in a patient in need thereof, optionally wherein, optionally, the patient has Abstinence as a goal, the method comprising the administration of the pharmaceutical composition to the patient, wherein:

[0023] (i) a clinically significant reduction in one or more of:

[0024] Alcohol Units / Day (UPD);

[0025] Drinking Days (DD);

[0026] Heavy Drinking Days (HDD);

[0027] Average number of standard units of alcohol consumed (UoAC), optionally per week;

[0028] Alcohol cravings, optionally as measured by the Alcohol Craving Questionnaire (ACQ), optionally the Alcohol Craving Questionnaire Short Form Revised (ACQ-SF-R);

[0029] Negative impacts of alcohol use, optionally as measured by The Drinker

[0030] Inventory of Consequences (DrlnC), optionally the Short Inventory of Problems (SIP);

[0031] Severity of AUD, optionally as measured by the Clinical Global Impression of Severity (CGIS) questionnaire;

[0032] Alcohol use as measured by ethyl glucuronide (EtG) in a sample, optionally urine, from the patient; and / or

[0033] Alcohol use as measured by carbohydrate deficient transferrin (CDT) in a sample, optionally blood, from the patient; and / or (ii) a clinically significant increase in one or more of:

[0034] Abstinent Days;

[0035] Longest duration of, optionally in days, of continuous abstinence; and / or Patient condition, optionally as measured by the Patient Global Impression of Change (PGIC) questionnaire and / or the 5-Level EQ-5D (EQ-5D-5L); is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration.

[0036] In some embodiments, the subject experiences a clinically significant response within 2 hours (e.g., within 90 minutes, within 1 hour, within 30 minutes, or within 10 minutes) after the administration of the pharmaceutical composition. In some embodiments, the subject experiences a clinically significant response within 12 hours after the administration of the pharmaceutical composition.

[0037] In some embodiments, the subject experiences a clinically significant response within 24 hours (e.g., within 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or 10 minutes) after the administration of the pharmaceutical composition. In some embodiments, the subject experiences a clinically significant response within 48 hours after the administration of the pharmaceutical composition. In some embodiments, the subject experiences a clinically significant response within 7 days after the administration of the pharmaceutical composition.

[0038] In some embodiment, a clinically significant response is experienced within 7 days (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 12 hours, 6 hours, 4 hours, 2 hours, or 1 hour), within 48 hours (e.g., within 48 hours, 46 hours, 44 hours, 42 hours, 40 hours, 38 hours, 36 hours, 34 hours, 32 hours, 30 hours, 28 hours, 26 hours, 24 hours, 22 hours, 20 hours, 18 hours, 16 hours, 14 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 30 minutes), within 24 hours (e.g., within 24 hours, 23 hours, 22 hours, 21 hours, 20 hours, 19 hours, 18 hours, 17 hours, 16 hours, 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or 10 minutes), within 12 hours (e.g., within 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 30 minutes, or 10 minutes) or within 2 hours (e.g., within 110 minutes, 100 minutes, 90 minutes, 80 minutes, 70 minutes, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, or 10 minutes), the method of treatment may be considered to be a rapid method of treatment.

[0039] In some embodiments, the pharmaceutical composition comprises between 5 mg and 15 mg, (e.g. about 5±1 mg, 6±1 mg, 7±1 mg, 8±1 mg, 9±1 mg, 10±1 mg, 11±1 mg, 12±1 mg, 13±1 mg, 14±1 mg, or 15±1 mg) of 5-MeO-DMT in the pharmaceutical composition. In some embodiments, the amount of 5-MeO-DMT refers to amounts of 5-MeO-DMT freebase, a pharmaceutically acceptable salt thereof, or 5-MeO-DMT freebase equivalent that is present in the pharmaceutical composition.

[0040] In an embodiment, the patient has abstinence as a goal.

[0041] In an embodiment, the clinically significant reduction is a reduction, compared with baseline, of at 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, the clinically significant increase is an increase, compared with baseline, of at 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%. In an embodiment, baseline may be the average value for a particular parameter / measure at any point in time prior to the administration of the pharmaceutical composition. In an embodiment, baseline may be the average value for a particular parameter / measure over 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or at least 20 weeks prior to the administration of the pharmaceutical composition. In an embodiment, baseline may be the average value for a particular parameter / measure over 85, or more, days prior to the administration of the pharmaceutical composition.

[0042] In an embodiment, the clinically significant response occurs not later than about 2 hours after the administration of the pharmaceutical composition.

[0043] In an embodiment, the clinically significant reduction in one or more of: UPD, DD, HDD, UoAC, alcohol cravings, negative impacts, severity of AUD, ETG and / or CDT is a reduction from baseline of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

[0044] In an embodiment, the clinically significant reduction in one or more of: UPD, DD, HDD, UoAC, alcohol cravings, negative impacts, severity of AUD, ETG and / or CDT is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration.

[0045] In an embodiment, the clinically significant increase in Abstinent Days and / or patient condition is an increase from baseline of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

[0046] In an embodiment, the clinically significant increase in Abstinent Days and / or patient condition is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration.

[0047] In an embodiment, the clinically significant change in one or more of the parameters is sustained for at least 85 days following a single administration of the pharmaceutical composition.

[0048] In an embodiment, a clinically significant increase in patient condition is achieved as indicated by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score.

[0049] In an embodiment, the Timeline Follow-Back (TLFB) interview is used to measure a clinically significant increase or reduction in one or more of the parameters.

[0050] In an embodiment, the patient is ready for discharge within 90, 100, 110, or 120 minutes following administration.

[0051] In an embodiment, the patient is diagnosed with AUD, mild AUD, moderate AUD or severe AUD, optionally by a licensed professional in accordance with accepted medical practice, as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

[0052] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support to the patient.

[0053] In an embodiment, psychological support is provided weekly for 1 month, once every other week for the following month and once per month thereafter.

[0054] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support to the patient, wherein the psychological support is provided:

[0055] Prior to administration of the pharmaceutical composition; During administration of the pharmaceutical composition; and / or After administration of the pharmaceutical composition.

[0056] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support to the patient, wherein the psychological support is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks prior to administration of the pharmaceutical composition.

[0057] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support to the patient, wherein the psychological support is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks following administration of the pharmaceutical composition.

[0058] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of at least 3 psychological support sessions over about 2 weeks prior to the administration of the pharmaceutical composition.

[0059] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of at least 3 psychological support sessions over about 2 weeks prior to the administration of the pharmaceutical composition, wherein the third of the 3 sessions takes place in a medical facility and / or clinic, optionally the same medical facility and / or clinic wherein administration of the pharmaceutical composition takes place.

[0060] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support by an AUD therapist a psychedelic assisted therapy therapist.

[0061] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of at least 3 psychological support sessions over about 2 weeks following the administration of the pharmaceutical composition.

[0062] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient.

[0063] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided:

[0064] Prior to administration of the pharmaceutical composition;

[0065] During administration of the pharmaceutical composition; and / or After administration of the pharmaceutical composition.

[0066] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks prior to administration of the pharmaceutical composition.

[0067] In an embodiment, the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks following administration of the pharmaceutical composition.

[0068] In an embodiment, the patient is ready for discharge within 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 minutes of the administration of the pharmaceutical composition.

[0069] In an embodiment, the pharmaceutical composition is administered under the supervision of one or more professionals.

[0070] In an embodiment, the pharmaceutical composition is administered under the supervision of one or more licensed professionals.

[0071] In an embodiment, the pharmaceutical composition is administered under the supervision of a cognitive behavioural therapist and a psychedelic assisted therapy therapist.

[0072] In an embodiment, the pharmaceutical composition is administered by the patient themselves or by a licensed professional.

[0073] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is administered by a licensed professional and the method comprises the steps of: the patient sits in an upright position; the patient blows their nose; the pharmaceutical composition is administered by a licensed professional to a single nostril; and the patient does not inhale through their nose during the administration.

[0074] In an embodiment, the pharmaceutical composition is for use in a method of treatment of a patient aged 18 to 64 years.

[0075] In an embodiment, the pharmaceutical composition is for use in a method of treatment of a patient who has a minimum of 4 heavy drinking days (HDD) in the 28 days prior to administration of the pharmaceutical composition.

[0076] In an embodiment, the pharmaceutical composition is for use in a method of treatment of a patient for whom no more than 14 days have elapsed since the last heavy drinking days (HDD) or completion of detoxification.

[0077] In an embodiment, the pharmaceutical composition is for use in a method of treatment of a patient who is willing to abstain from recreational drugs for the duration of their treatment with the pharmaceutical composition.

[0078] In an embodiment, the pharmaceutical composition is for use in a method of treatment of a patient who does not have one or more of: a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure (BP) and heart rate (HR), such as: severe coronary artery disease, history of myocardial infarction, unstable angina, cerebrovascular accident, aneurysm or revascularization procedure within the previous 12 months, significant valvular heart disease, heart failure of any etiology, history of a stroke or transient ischemic attack; a history of uncontrolled hypertension despite adequate therapy or any history of a hypertensive crisis or ongoing evidence of uncontrolled hypertension, optionally defined as repeated supine systolic BP 140 mmHg, or diastolic BP 90 mmHg; a history of seizures, including febrile and withdrawal seizures; uncontrolled or insulin-dependent diabetes; any clinically significant neurological, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, or any other major concurrent illness that, in the opinion of a licensed professional, may interfere with the treatment; any abnormal and, in the opinion of a licensed professional, clinically significant results on physical examination, vital signs, electrocardiogram (ECG), or laboratory tests prior to administration of the pharmaceutical composition; any signs of alcohol withdrawal prior to administration of the pharmaceutical composition, optionally as assessed by the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar); a positive test result for alcohol on the day of administration of the pharmaceutical composition; a positive urine drug screen for illicit drugs or drugs of abuse on the day of administration of the pharmaceutical composition; current use of monoamime oxidase inhibitors (MAO-I), tramadol, opioids, antiviral medication, cytochrome P4502D6 inhibitors, antidepressant medication, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, lithium, antipsychotic medications, triptans, tramadol, 5- hydroxytryptophan (5-HTP), herbal preparations containing 5-HTP, St John’s Wort, or any other medications or supplements that may affect serotonergic function or may interfere with 5-MeO-DMT; history of intolerance to 5-MeO-DMT, dimethyltryptamine (DMT), or related compounds; nasal obstruction, blockage, or symptoms of congestion; and / or personal or family history of malignant hyperthermia.

[0079] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 40 and 80 days after the first administration.

[0080] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 50 and 70 days after the first administration.

[0081] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 55 and 65 days after the first administration. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place 64 days, ±1 , 2, 3, 4, 5, 6 or 7 days, after the first administration.

[0082] In an embodiment, the patient has not taken one or more of the following for at least 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.

[0083] In an embodiment, the patient has not taken one or more of the following for at least 1 , 2, 3, 4, 5 or 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.

[0084] In an embodiment, the pharmaceutical composition is amorphous or crystalline.

[0085] In an embodiment, the pharmaceutical composition is formulated for intranasal administration.

[0086] The pharmaceutical composition use of any one preceding claim, wherein the pharmaceutical composition is formulated as a dry powder.

[0087] The pharmaceutical composition use of any one preceding claim, wherein the pharmaceutical composition is formulated as a dry powder, wherein the powder is characterised by one or more of: particles having a median diameter of less than 2000pm, 1000pm, 500pm, 250pm, 100pm, 50pm, or 1 pm; particles having a median diameter of less than 15, 14, 13, 12, 11 , or 10pm; particles having a median diameter of less than 9pm; particles having a median diameter of greater than 500pm, 250pm, 100pm, 50pm, 1 pm or 0.5pm; and / or a particle size distribution of d10=20-60pm, and / or d50=80-120pm, and / or d90=130-300pm.

[0088] In an embodiment, the pharmaceutical composition is formulated as a spray dried dry powder.

[0089] In an embodiment, the pharmaceutical composition is formulated as a dry blend dry powder.

[0090] In an embodiment, the pharmaceutical composition is formulated as a powder which is suitable for administration by inhalation / insufflation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler, a pressurised metered dose inhaler, a nasal delivery device, a nasal spray or an active nasal delivery device.

[0091] In an embodiment, the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 10mg 5-MeO-DMT freebase.

[0092] In an embodiment, the pharmaceutical composition comprises crystalline 5-MeO-DMT.

[0093] In an embodiment, the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 10mg 5-MeO-DMT freebase, wherein: the pharmaceutical composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.1°20 as measured using an x-ray wavelength of 1.5406 A; the pharmaceutical composition comprises crystalline 5-MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1 , 15.0, 18.5 and 19.5°±O.1 °20 as measured using an x-ray wavelength of 1 .5406 A; the pharmaceutical composition comprises crystalline 5-MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5O20±O.1°20 as measured using an x-ray wavelength of 1.5406 A; or the pharmaceutical composition comprises crystalline 5-MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1 °20 as measured using an x-ray wavelength of 1.5406 A.

[0094] In an embodiment, the pharmaceutical composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM / MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC), chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl- (QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), p-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, citric acid, a mucoadhesive enhancer, a penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.

[0095] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces a, optionally complete, mystical experience.

[0096] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces a, optionally complete, mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-claim revised Mystical Experience Questionnaire (MEQ30) and / or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, optionally the, optionally complete, mystical experience is induced within 5, 10, 15, 20, 25, or 30 minutes of administration of the pharmaceutical composition and optionally the, optionally complete, mystical experience is resolved within 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 300 minutes of administration of the pharmaceutical composition.

[0097] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces ego dissolution.

[0098] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces ego dissolution as identified by the Ego Dissolution Inventory (EDI), optionally the ego dissolution is induced within 5, 10, 15, 20, 25, or 30 minutes of administration of the pharmaceutical composition and optionally the ego dissolution is resolved within 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 300 minutes of administration of the pharmaceutical composition. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient is given a low-fat meal, such as water and fruit, at least 2 hours prior to treatment. In some embodiments, the low-fat meal includes less than 10 g, 9 g, 8 g, 7 g, 6 g, 5 g, 4 g, 3 g, 2 g, or 1 g of fat per serving. In some embodiments, the low-fat meal includes less than 3 g of fat per serving. In some embodiments, the low-fat meal includes 3 g of fat or less for every 100 calories. In some embodiments, the low-fat meal is a meal where less than 50%, 40%, 30%, 20%, or 10% of the calories in the meal come from fat. In some embodiments, the low-fat meal is a meal where less than 30% of the calories in the meal come from fat.

[0099] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours prior to treatment.

[0100] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour prior to treatment.

[0101] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour following treatment.

[0102] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours following treatment.

[0103] In an embodiment, the patient is monitored for symptoms of alcohol withdrawal.

[0104] In an embodiment, the patient is monitored for symptoms of alcohol withdrawal using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar).

[0105] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents.

[0106] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents wherein the one or more selected agents are nalmefene, fluoxetine, gabapentin, ondansetron, sertraline, topiramate, disulfiram, acamprosate and / or naltrexone.

[0107] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is acamprosate, optionally two 333 mg enteric-coated tablets three times per day.

[0108] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is disulfiram, optionally 250 mg or 500 mg once per day.

[0109] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is fluoxetine, optionally 20, 40, 60 or 80 mg once per day.

[0110] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD.

[0111] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 12 step program. In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 12 week program.

[0112] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 week program.

[0113] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a group program.

[0114] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more digital tools.

[0115] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more ai chatbots.

[0116] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more digital therapy tools.

[0117] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more ai therapists.

[0118] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises sessions which are 30-90 minutes in duration.

[0119] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises weekly sessions.

[0120] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises daily sessions.

[0121] In an embodiment, the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises one or more of individual treatments, group treatments, psychoeducational interventions, help to attend self-help groups, family and carer support and involvement, and case management.

[0122] In an embodiment, the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof.

[0123] In an embodiment, the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein the condition is diagnosed in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association, optionally by a licensed professional in accordance with accepted medical practice.

[0124] In an embodiment, the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein treatment of the one or more other conditions is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

[0125] In an embodiment, the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein treatment of the one or more other conditions is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration of the pharmaceutical composition.

[0126] In an embodiment, the method of treatment is a method of treatment of AUD and one or more other conditions selected from: a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, difficult to treat depression, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders, obsessive-compulsive disorder, a sleep disturbance, such as insomnia, hypersomnia, circadian rhythm disorder, parasomnia, sleep-related breathing disorder, sleep-related movement disorder, and / or an idiopathic sleep disturbance or bipolar disorder in a patient in need thereof.

[0127] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatmentresistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

[0128] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatmentresistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction in MADRS score is a reduction from baseline of at least 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 points.

[0129] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatmentresistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction is sustained following the administration of the pharmaceutical composition.

[0130] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment- resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction is sustained for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration of the pharmaceutical composition.

[0131] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as moderate to severe MDD, wherein the moderate to severe MDD is indicated by a Montgomery-Asberg depression / major depressive disorder Rating Scale (MADRS) score of 20 or more or by a 17-claim Hamilton depression / major depressive disorder Rating Scale (HAM-D) score of 17 or more.

[0132] In an embodiment, the method of treatment is a method of treatment of AUD and a depressive disorder, such as moderate to severe MDD, wherein the moderate to severe MDD is indicated by a a MADRS score of 35 or more or by a HAM-D score of 25 or more.

[0133] In an embodiment, the method of treatment is a method of treatment of AUD and suicidal ideation.

[0134] In an embodiment, the method of treatment is a method of treatment of AUD in a patient at imminent risk of suicide.

[0135] In an embodiment, the method of treatment is a method of treatment of AUD in a patient with suicidal ideation with intention to act.

[0136] In an embodiment, the method of treatment is a method of treatment comprises one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences.

[0137] In an embodiment, the method of treatment is a method of treatment comprises one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences, wherein the one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences occur prior to administration of the pharmaceutical composition and, optionally, said experiences are used to prepare the patient for treatment with the pharmaceutical composition resulting in increased patient tolerability to the treatment and treatment efficacy.

[0138] In an embodiment, the method of treatment is a method of treatment comprising one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences, wherein the one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences occur following administration of the pharmaceutical composition, and, optionally, said experiences are used to aid the patient with integrating following treatment with the pharmaceutical composition resulting in increased treatment efficacy.

[0139] In an embodiment, the pharmaceutical composition is for use in a method of preventing relapse in an AUD disorder patient in need thereof.

[0140] In an embodiment, the pharmaceutical composition is for use in a method of reducing the likelihood of relapse in an AUD disorder patient in need thereof. In an embodiment, the pharmaceutical composition is for use in a method of reducing alcohol cravings in a patient in need thereof.

[0141] In an embodiment, the pharmaceutical composition is for use in a method of reducing alcohol cravings in a patient in need thereof, as measured by the Alcohol Craving Questionnaire (ACQ).

[0142] In an embodiment, the pharmaceutical composition is for use in a method of reducing alcohol cravings in a patient in need thereof, as measured by the Alcohol Craving Questionnaire (ACQ) 1 , 7, 28, 56 and / or 84 days after administration of the pharmaceutical composition to the patient.

[0143] In an embodiment, the pharmaceutical composition is for use in a method of reducing alcohol consumption in a patient in need thereof.

[0144] In an embodiment, the pharmaceutical composition is for use in a method of reducing heavy drinking days in a patient in need thereof.

[0145] In an embodiment, the pharmaceutical composition is for use in a method of increasing alcohol free days in a patient in need thereof.

[0146] In an embodiment, the pharmaceutical composition is for use in a method of increasing the number of abstinent days in a patient in need thereof.

[0147] In an embodiment, the pharmaceutical composition is for use in a method of promoting abstinence from alcohol in a patient in need thereof.

[0148] In an embodiment, the pharmaceutical composition is for use in a method of preventing and / or treating one or more conditions associated with alcohol use disorder.

[0149] In an embodiment, the pharmaceutical composition is for use in a method of preventing one or more conditions associated with alcohol use disorder such as: high blood pressure, heart disease, stroke, liver disease, digestive conditions, cancer, wherein said cancer is optionally of the breast, mouth, throat, oesophagus, voice box, liver, colon and / or rectum, learning problems, memory problems, dementia and / or poor academic performance.

[0150] In an embodiment, the pharmaceutical composition is for use in a method of preventing the contraction of sexually transmitted infections.

[0151] In an embodiment, the pharmaceutical composition is for use in a method of preventing the contraction of one or more blood borne diseases.

[0152] In an embodiment, the pharmaceutical composition is for use in a method of preventing the contraction of HIV.

[0153] In an embodiment, the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device.

[0154] In an embodiment, the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device, wherein the single use intranasal delivery device is an active delivery device.

[0155] In an embodiment, the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device, wherein the single use intranasal delivery device is an active delivery device which does not require the patient to inhale through the nose to deliver the pharmaceutical composition. In an embodiment, the pharmaceutical composition is contained within, and administered from an intranasal delivery device wherein the delivery device is an active delivery device.

[0156] In an embodiment, the pharmaceutical composition is contained within, and administered from an intranasal delivery device wherein the delivery device is an active delivery device configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume having one or more of: a spray pattern of: a particle size distribution (at 40mm) of: D10 = 13 to 17, D50 = 35 to 60, DOO = 650 to 700, %<10 pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70mm) of: D10 = 13 to 17, D50 = 24 to 30, D90 = 540 to 610, %<10pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution of: D10 = 13 to 17, D50 = 22 to 27, DOO = 35 to 56, %<9 pm = <0.1-10%; or

[0157] % particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

[0158] A kit comprising the pharmaceutical for use as described in any one preceding, or subsequent, embodiment and instructions for use.

[0159] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treating alcohol use disorder in patients for whom abstinence is a goal.

[0160] In an embodiment, the treatment with the pharmaceutical composition provides a reduction in World Health Organization (WHO) risk level by 1 , 2, or 3 levels. Abstinence may be defined as no risk whilst, for men, low risk (level 1) is defined as s >0 g / d to 40 g / d (alcohol / day); moderate risk (level 2) as >40 g / d to 60 g / d; high risk (level 3) as >60 g / d to 100 g / d; and very high risk (level 4) as >100 g / d. Forwomen, low risk (level 1) is defined as >0 g / d to 20 g / d; moderate risk (level 2) as >20 g / d to 40 g / d; high risk (level 3) as >40 g / d to 60 g / d; and very high risk (level 4) as >60 g / d. Change in WHO risk level may be calculated in relation to drinking during the 12 weeks prior to treatment.

[0161] In an embodiment, there is provided the use of a pharmaceutical composition as described herein in a method of managing one or more symptoms of AUD withdrawal. In an embodiment, the one or more symptoms are selected from: tremors, sweating, elevated pulse and blood pressure, insomnia, anxiety, nausea or vomiting, seizures and / or delirium tremens. As used herein, the terms “approximately” and “about” generally should be understood to encompass ± 5% of a specified amount or value. In an embodiment, there is provided a pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients, wherein the composition comprises a dosage amount of 10mg 5-MeO-DMT.

[0162] In an embodiment, the composition comprises a salt of 5-MeO-DMT. In an embodiment, the composition comprises a crystalline salt of 5-MeO-DMT. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrobromide. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrobromide, characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT phosphate, characterised by one or more peaks in an XRPD diffractogram at 12.9, 20.4 and 23.1 °20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT fumarate, characterised by one or more peaks in an XRPD diffractogram at 13.0, 16.3 and 22.1 °20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT oxalate, characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1 °20 as measured by x-ray powder diffraction using an x- ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT tartrate, characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.6, and 2O.7°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT benzenesulfonate, characterised by one or more peaks in an XRPD diffractogram at 9.5, 21 .2, and 23.6°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT tosylate, characterised by one or more peaks in an XRPD diffractogram at 19.3, 23.6 and 24.1 °20±O.1 °20 as measured by x-ray powder diffraction using an x- ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT glycolate, characterised by one or more peaks in an XRPD diffractogram at 20.2, 21 .1 and 23.4°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT ketoglutarate, characterised by one or more peaks in an XRPD diffractogram at 14.4, 18.2 and 2O.9°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT malate, characterised by one or more peaks in an XRPD diffractogram at 18.3, 18.7 and 18.9°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT saccharinate, characterised by one or more peaks in an XRPD diffractogram at 8.7, 15.2 and 2O.9°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT hydrochloride, characterised by one or more peaks in an XRPD diffractogram at 9.2°±0.1 °, 12.2°±0.1 °, 14.1 °±0.1 °, 15.0°±0.1 °, 18.5°±0.1 °, and 19.5°±0.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided a crystalline form of 5-MeO-DMT benzoate, characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21 ,0°20±O.1 °20 as measured using an x-ray wavelength of 1 .5406 A.

[0163] The nature of a powder formulation can be adjusted to suit needs. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet. In an embodiment the 5-MeO-DMT salt is amorphous or crystalline. In an embodiment, the 5-MeO-DMT salt is in a polymorphic crystalline form. For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100mg dosage amount of 5-MeO-DMT corresponds to 117 mg of the hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt (i.e. 218.3 g / mol for the free base as compared to 254.8 g / mol for the salt). Similarly, for the deuterated or triturated version of 5-MeO-DMT (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.

[0164] In an embodiment, the pharmaceutical composition comprises an amount of 5-MeO-DMT, wherein the amount of 5-MeO-DMT is measured in terms of the amount of freebase of 5-MeO-DMT For example, a pharmaceutical composition comprising 12mg 5-MeO-DMT benzoate refers to a pharmaceutical composition comprising 18.7mg 5-MeO-DMT benzoate which equates to 12mg of 5- MeO-DMT freebase. In an embodiment, there is provided the use of about 15.59mg 5-MeO-DMT benzoate, or a pharmaceutical composition, thereof.

[0165] Amorphous and crystalline substances often show different chemical / physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical / physical properties. In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.

[0166] In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.05mg to 100mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.1 mg to 50mg. In an embodiment the composition comprises a dosage amount of 5- MeO-DMT in the range of 0.5mg to 25mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.5mg to 10mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 10mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 1 mg to 8mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 3mg to 15mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.005mg to 100mg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.001 mg to 10Omg. In an embodiment the composition comprises a dosage amount of 5-MeO-DMT in the range of 0.0005mg to 100mg. The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.

[0167] In an embodiment, there is provided a pharmaceutical composition comprising about 10mg 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 10mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a method of treatment of a disease or condition.

[0168] In an embodiment, the disease or condition is: conditions caused by dysfunctions of the central nervous system, conditions caused by dysfunctions of the peripheral nervous system, conditions benefiting from sleep regulation (such as insomnia), conditions benefiting from analgesics (such as chronic pain), migraines, trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)), conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson’s dementia), conditions benefiting from anti-inflammatory treatment, depression / major depressive disorder, treatment resistant depression / major depressive disorder, anxiety, substance use disorder, addictive disorder, gambling disorder, eating disorders, obsessive-compulsive disorders, or body dysmorphic disorders, optionally the condition is SUNCT and / or SUNA, alcohol-related diseases and disorders, eating disorders, impulse control disorders, nicotine-related disorders, tobacco-related disorders, methamphetamine- related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, benzodiazepine abuse or dependence related disorders, opioid-related disorders, tobacco addiction, alcohol abuse and / or addiction.

[0169] In an embodiment there is provided a method of use of the composition disclosed herein. In an embodiment, the method of use is a method of treatment. In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression / major depressive disorder and anxiety. In an embodiment the composition is administered one or more times a year. In an embodiment the composition is administered one or more times a month. In an embodiment the composition is administered one or more times a week. In an embodiment the composition is administered one or more times a day. In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis. In an embodiment the composition is administered together with a complementary treatment and / or with a further active agent. In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine. In an embodiment the further active agent is lysergic acid diethylamide (LSD), psilocybin, psilocin or a prodrug thereof. In an embodiment the further active agent is an antidepressant compound. In an embodiment the further active agent is selected from an SSRI, SNRI, TCA or other antidepressant compounds.

[0170] In an embodiment the further active agent is selected from Citalopram (Celexa, Cipramil), Escitalopram (Lexapro, Cipralex), Fluoxetine (Prozac, Sarafem), Fluvoxamine (Luvox, Faverin), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft, Lustral), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Venlafaxine (Effexor), Vilazodone (Viibryd), Vortioxetine (Trintellix), Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Vivalan), Bupropion (Wellbutrin), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibria), Clomipramine (Anafranil), Desipramine (Norpramin, Pertofrane), Dibenzepin (Noveril, Victoril), Dimetacrine (Istonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Imipramine (Tofranil), Lofepramine (Lomont, Gamanil), Melitracen (Dixeran, Melixeran, Trausabun), Nitroxazepine (Sintamil), Nortriptyline (Pamelor, Aventyl), Noxiptiline (Agedal, Elronon, Nogedal), Opipramol (Insidon), Pipofezine (Azafen / Azaphen), Protriptyline (Vivactil), Trimipramine (Surmontil), Amoxapine (Asendin), Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Isocarboxazid (Marplan), Phenelzine (Nardil), Tranylcypromine (Parnate), Selegiline (Eldepryl, Zelapar, Emsam), Caroxazone (Surodil, Timostenil), Metralindole (Inkazan), Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol), Toloxatone (Humoryl), Agomelatine (Valdoxan), Esketamine (Spravato), Ketamine (Ketalar), Tandospirone (Sediel), Tianeptine (Stabion, Coaxil), Amisulpride (Solian), Aripiprazole (Ability), Brexpiprazole (Rexulti), Lurasidone (Latuda), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Trifluoperazine (Stelazine), Buspirone (Buspar), Lithium (Eskalith, Lithobid), Modafinil (Provigil), Thyroxine (T4), Triiodothyronine (T3).

[0171] In an embodiment the further active agent is selected from Celexa (citalopram), Cymbalta (duloxetine), Effexor (venlafaxine), Lexapro (escitalopram), Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Remeron (mirtazapine), Savella (milnacipran), Trintellix (vortioxetine), Vestra (reboxetine), Viibryd (vilazodone), Wellbutrin (bupropion), Zoloft (sertraline). In an embodiment, one or more disorders or conditions in the patient have previously failed to be treated with one or more of the above treatments.

[0172] In an embodiment, there is provided a method, optionally a rapid and durable method, of improving one or more of: sexual functioning, anxiety, anhedonia, cognition and / or overall quality of life, in a patient in need thereof. In an embodiment, the improvement is assessed by one or more of: the Arizona Sexual Experiences Scale, the 7-item Generalised Anxiety Disorder Assessment (GAD- 7), difference in self-reported anhedonia symptoms, assessed by Snaith-Hamilton Pleasure Scale (SHAPS), the Cognitive Test Battery, Patient Global Impression of Change and / or improvement in self-reported quality of life, assessed by EuroQoL- 5 Dimension-5 Level (EQ-5D-5L).

[0173] In an embodiment, there is provided a method, optionally a rapid and durable method, of treating a patient in need thereof, wherein the patient is aged 18 to 75 years old. In an embodiment, the patient has AUD. In an embodiment, the patient has AUD and one or more other conditions, as disclosed herein. In an embodiment, the patient has at least moderate major depressive disorder (MDD), (single or recurrent episode as informed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5] criteria; if single episode, duration of >3 months and < 2 years) based on medical records, clinical assessment, and documented completion of the version 7.0.2 Mini International Neuropsychiatric Interview (MINI). In an embodiment, the patient is diagnosed with TRD defined as failure to respond to an adequate dose and duration of at least 2 pharmacological treatments, in the current episode, based on the MGH ATRQ assessment. In an embodiment, augmentation with an add-on treatment counts as a second treatment. In an embodiment, the patient has not failed more than 5 prior pharmacological treatments in the current episode. In an embodiment, psychotherapy is not counted towards treatment failure. In an embodiment, the patient has a Hamilton Depression Rating Scale (HDRS) (17 item) score >19 at baseline / prior to treatment.

[0174] In an embodiment, the patient has a CGI-S >4 at baseline / prior to treatment. In an embodiment, the patient does not have a current or past history of schizophrenia, post-traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder. In an embodiment, the patient does not have a current or past history of schizophrenia, post-traumatic stress disorder, psychotic disorder including psychotic depression, bipolar disorder, delusional disorder, schizoaffective disorder, or any other severe psychiatric disorder as assessed by medical history and a structured clinical interview (MINI). In an embodiment, the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, -obsessive compulsive). In an embodiment, the patient does not have a current personality disorders: Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, -obsessive compulsive) assessed via McLean Screening Instrument for Borderline Personality Disorder (MSI- BPD), MINI, and clinical judgement. In an embodiment, the patient does not have a first-degree family history of schizophrenia, bipolar disorder, delusional disorder, or schizoaffective disorder. In an embodiment, the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine). In an embodiment, the patient does not have current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine) according to DSM-5 and assessed by the MINI. In an embodiment, the patient has not at any time been unresponsive to ketamine or esketamine. In an embodiment, the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT). In an embodiment, the patient has not at any time been unresponsive to an adequate course of treatment with electroconvulsive therapy (ECT) defined as at least 7 treatments with unilateral / bilateral ECT, or has received vagal nerve stimulation or has received deep brain stimulation. In an embodiment, the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment. In an embodiment, the patient has not had suicidal ideation with some intent to act within 12 months prior to treatment, based on the C-SSRS, corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or any suicidal behavior prior to treatment. In an embodiment, the patient has not attempted suicide and / or any other self-injurious behaviour within 12 months prior to treatment. In an embodiment, the patient does not have a history of any medical condition that could make receiving a sympathomimetic drug harmful because of transient and marked increases in blood pressure and heart rate. In an embodiment, the patient does not have atherosclerotic cardiovascular disease, obstructive coronary artery disease, myocardial infarction, hospitalisation for unstable angina, stroke, hospitalisation for transient ischemic attacks, known aortic or cerebral aneurysm or revascularization procedure within 12 months prior to treatment. In an embodiment, the patient does not have significant valvular heart disease, history of hospitalisation for heart failure and / or history of hospitalisation for atrial or ventricular arrhythmias. In an embodiment, the patient does not have a history of uncontrolled hypertension despite antihypertensive therapy and / or any past history of a hospital admission for hypertension. In an embodiment, the patient does not have controlled hypertension on antihypertensive therapy with repeated clinic seated or semi-recumbent systolic blood pressure >130 mmHg or diastolic blood pressure > 80 mmHg.

[0175] In an embodiment, the patient does not have repeated clinic seated or semi-recumbent systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. In an embodiment, the patient does not have one or more of hypo / hyperthyroidism with abnormal thyroid stimulating hormone values, uncontrolled or insulin dependent diabetes with HbA1c >8, renal failure with Creatinine Clearance <45 mL / min. In an embodiment, the patient does not have any seizure disorder and / or any seizure within 2 years of treatment. In an embodiment, the patient does not have any clinically significant results on ECG or a QT interval corrected using Fridericia’s formula (QTcF) >450 msec for males or >470 msec for females prior to treatment. In an embodiment, the patient does not have any history of intolerance to 5-MeO-DMT or related compounds. In an embodiment, the patient does not have any nasal obstruction, blockage, or symptoms of congestion at the time of treatment. In an embodiment, the patient is not a female patient who is pregnant, lactating, or of childbearing potential who is not willing or able to use adequate forms of contraception during treatment. In an embodiment, the patient is not a male patient who is not willing or able to use adequate forms of contraception during treatment. In an embodiment, the patient does not have a personal or family history of malignant hyperthermia. In an embodiment, the patient has discontinued one or more of the following at least 5 half-lives prior to treatment: Medications that antagonise the serotonin 2A receptor, Medications with serotonergic activity (e.g., SSRIs, SNRIs, efavirenz, lithium), Tramadol, Opioids, Antiviral Medications, St. John’s Wort, Medications that inhibit UGT1A9 or UGT1A10 enzymes, Monoamine Oxidase Inhibitors (MAOIs) and / or Medications that inhibit aldehyde or alcohol dehydrogenase.

[0176] Definitions

[0177] As used herein, the term “12 step program” refers to a set of defined actions or changes in behaviour that correspond to recovery from a substance dependence, i.e. addiction, or any other behavioural problem. The actions involved directed self-reflection in a subject, wherein the subject may recognize the symptoms and effects of having alcohol use disorder, and thereafter change behaviours so as to remain abstinent. In some embodiments, a subject of the methods of treatment described herein participates in a 12-step program concurrently while receiving treatment and may continue to participate in such a program thereafter in order to maintain an abstinent state. A 12-step program may be a part of psychological support administered to the subject as a part of the methods of treatment. In some embodiments, the 12-step program is a group program, or it may be an individual program. For example, a 12 step program designed by Alcoholic Anonymous includes the steps of: 1 . Admit powerlessness over alcohol; 2 .Find hope by believing in a greater power; 3. Surrender; 4. Take inventory of oneself; 5. Share inventory with others the nature of one’s past wrongs; 6. Become ready to change; 7. Ask God for help in removing shortcomings; 8. Make a list of all those who have been harmed by one’s actions; 9. Make amends; 10. Continue inventory of wrongs, promptly admitted them; 11. Pray and meditate; 12. Help others:

[0178] As used herein, terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration.

[0179] As used herein, the term “about” refers to a value that is within 10% above or below the value being described. As used herein, the term “abstinence” refers to the state of a subject refraining from alcohol consumption, to not be actively consuming or have recently consumed alcohol. Subjects with alcohol use disorder will frequently pursue abstinence as a goal to alleviate symptoms associated with withdrawal. Subjects considered to be abstaining (i.e. abstinent) will be expected to have no heavy drinking days (HDD) in the previous 72 hours and no alcohol in the previous 24 hours.

[0180] As used herein, the terms “acute stress disorder” and “ASD” refer to a condition that arises as a response to a stressful event or situation of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Like PTSD, acute stress disorder is an anxiety disorder that involves a very specific reaction following exposure to a traumatic event or stressor. However, the duration of acute stress disorder is shorter than that for PTSD, such that the symptoms are present for at least one, two, or three days, but no more than four, five, or six weeks. In some embodiments, individuals exhibiting symptoms persisting for a longer period longer than 6 weeks, a diagnosis of PTSD may be warranted.

[0181] The term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical composition to a subject. The compound or pharmaceutical composition may be administered by the subject, a medical professional, or another person to the subject.

[0182] As used herein, the terms “Alcohol Craving Questionnaire,” “ACQ,” or “ACQ-NOW” refer to a 47-item questionnaire that may be administered to a subject in order to collect information regarding the subject’s cravings of alcohol. The items of the questionnaire are scored on a 7-point Likert-type scale ranging from “strongly disagree” to “strongly agree” and all relate to a subject’s desire to drink alcohol, intention to drink alcohol, lack of control regarding the use of alcohol, a positive outcome expectancy or anticipation of positive effects associated with alcohol consumption, or a subject’s expectation of relief from symptoms associated with withdrawal. The ACQ is sometimes administered as the short form version, the ACQ-SF or ACQ-SF-R, which features the 12 items most strongly correlated with total ACQ score.

[0183] As used herein, the terms “alcohol use disorder” and “AUD” refer to a mental health condition marked by unhealthy drinking habits and symptoms and behaviours linked to excessive consumption of alcohol. The severity of AUD can range from mild to severe, based on the number of symptoms experienced within the past year. AUD may be commonly referred to by various terms like alcohol abuse, dependence, addiction, or even the more general term, alcoholism. AUD may be diagnosed by a clinical professional using the criteria as described in the Diagnostic and Statistical Manual of Mental Disorders. Symptoms related to AUD are exemplified, but not limited to, any of the following: a. Alcohol is often taken in larger amounts or over a longer period than was intended. b. There is a persistent desire or unsuccessful efforts to cut down or control alcohol use. c. A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects. d. Craving, or a strong desire or urge to use alcohol. e. Recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school, or home. f. Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol. g. Important social, occupational, or recreational activities are given up or reduced because of alcohol use. h. Recurrent alcohol use in situations in which it is physically hazardous. i. Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol. j. Tolerance, as defined by either of the following: i. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect. ii. A markedly diminished effect with continued use of the same amount of alcohol. k. Withdrawal, as manifested by either of the following: i. The characteristic withdrawal syndrome for alcohol. ii. Alcohol (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.

[0184] As used herein, the terms “Altered States of Consciousness” or “ASC” refer to a scale comprising 94 items (e.g., visual analogue scales) which measures altered states of consciousness. Example dimensions encompassed by ASC questionnaires include oceanic boundlessness, dread of ego dissolution, or visionary restructuralization. Each of these five dimensions contain lower-order scales. In some embodiments, the subject receiving the methods of treatment of the invention experience report more than 60% of the maximum score on the oceanic boundlessness dimension of the ASC questionnaire.

[0185] As used herein, the term “baseline” refers to a score, evaluation, or measurement made for a subject prior to the first administration of any of the methods of treatment described herein. The subject has an original set of data representative of the symptoms associated with the diseases or conditions to be treated, such as alcohol use disorder. For example, the subject may initially be evaluated by a medical professional prior to receiving any of the methods of treatment of the invention through the Alcohol Craving Questionnaire, thereby providing a baseline for the medical professional to reference. Thereafter, the efficacy of the method of treatment may be determined by readministering the Alcohol Craving Questionnaire, or the same evaluation used to determine the baseline in the subject as appropriate. A comparison between the newly acquired scores or evaluations serves to determine the efficacy of the methods of treatment when compared to baseline. For example, a subject who experiences a reduction in MADRS score of 10 after 2 weeks following the first administration may be experiencing increased treatment efficacy than a subject who experiences a MADRS score reduction of only 7, and this may be due to additional treatment factors present such as additional participation by the first subject in group therapy or the use of digital tools in the first subject’s treatment routine. As used herein, the terms “carbohydrate deficient transferrin” and “CDT” refer to metabolites of transferrin that result from heavy alcohol consumption in a subject and serves as a reliable measure of identifying problem drinking in those with alcohol use disorder. Levels of CDT in a subject become elevated due to higher content of, for example, desialotransferrin or asialotransferrin. A CDT test may be administered to a subject, wherein a blood sample is taken, and quantitative detection of transferring glycosylation is performed, such as through the use of high performance liquid chromatography (HPLC).

[0186] As used herein, the terms “clinical global impression” and “CGI” refer to rating scales used to evaluate mental health disorders in subjects in terms of severity of symptoms, their response to treatment, and the efficacy of any psychiatric medications they may be receiving. For example, the severity scale, or clinical global impression - severity (CGI-S), refers to a 7-point scale that a physician, clinician, or other medical professional may use to evaluate the subject’s disease or condition based on observed behaviour, reported symptoms, and general function and well-being within the previous 7 days. Evaluations range from 1 , indicating normal health and absence of observable illness, to 7, indicating that the subject is among the most extremely ill. Other forms of the CGI include the clinical global impression - improvement (CGI-I, or sometimes Patient Global Impression of Change - PGIC), a 7-point scale administered by a medical professional that quantifies the change in baseline for a patient or subject’s average condition, and ranges from 1 , indicating the disease or condition has significantly improved, to 7, indicating the disease or condition has significantly worsened. A correlation between the CGI-S and other clinical evaluations or interviews has been observed. For example, a 1 -point improvement (i.e. reduction) in CGI-S scale as noted by a medical professional may correspond to a reduction in MADRS score by 6 or more.

[0187] As used herein, the terms “clinical institute withdrawal assessment” and “CIWA” refer to a 10- item scale administered to a subject by a clinical professional in order to evaluate alcohol withdrawal in a subject. Each item is scored independently, with higher aggregate scores indicating more severe alcohol withdrawal symptoms. The assessment evaluates nausea and vomiting, tremors, paroxysmal sweats, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headaches, and orientation and clouding of sensorium.

[0188] As used herein, "clinical response" and / or “clinically significant reduction” and / or “clinically significant increase” and / or “clinically significant response” includes, but is not limited to, improvements on rating scales such as the Clinical Global Impression - Severity scale (CGI-S), the Patient Global Impression - Severity scale (PGI-S), the Clinical Global Impression - Improvement scale (CGI-I) or the Patient Global Impression - Improvement scale (PGI-I) and further includes, but is not limited to, endpoints such as the Montgomery-Asberg depression / major depressive disorder Rating Scale (MADRS) or the 17-item Hamilton depression / major depressive disorder Rating Scale (HAM-D) for depression / major depressive disorder and persistent depressive disorder, anxiety symptoms e.g. as measured by the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Scale (HAM- A) or the State-Trait Anxiety Inventory (STAI) for anxiety disorder, the Clinician-Administered Posttraumatic Stress Disorder Scale (CAPS) for posttraumatic stress disorder, the Yale-Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder (BDD-YBOCS) for body dysmorphic disorder, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for obsessive- compulsive disorder, weight gain for anorexia nervosa, frequency of binge-purge episodes for bulimia nervosa, frequency of binge episodes for binge eating disorder, duration of abstinence or reduced substance use in psychoactive substance abuse and suicidality rating scales such as the Columbia- Suicide Severity Rating Scale (C-SSRS) or the suicidal thoughts item of the MADRS for suicidal ideation or the Clinical Global Impression - Severity of Suicidality - Revised (CGI-SS-R) scale (the CGI-SS-R is derived from the CGI-S, and is scored 0 = Normal, Not At All Suicidal; 1 = Questionably Suicidal; 2= Mildly Suicidal; 3 = Moderately Suicidal; 4 = Markedly Suicidal; 5 = Severely Suicidal; 6 = Extremely Suicidal). When assessing a clinical response at an early time point after drug administration (e.g. at 2 hours) based on endpoints which have been developed for a longer recall period, a rational modification of such endpoint (e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied.

[0189] As used herein, the term “concentration difficulties” refers to the subjective feeling of a subject experiencing challenges coalescing thoughts gathering their thoughts into coherent ideas. A subject experiencing difficulty concentrating may have a reduced ability to read or converse. Concentration difficulties in a subject may be self-assessed by the subject or by a clinical professional.

[0190] As used herein, the term “C-SSRS” refers to the Columbia Suicide Severity Rating Scale, a six-item questionnaire utilized for assessment of suicidal ideation or behavior. The items of the questionnaire are as follows:

[0191] 1 . Have you wished you were dead or wished you could go to sleep and not wake up?

[0192] 2. Have you had any thoughts about killing yourself?

[0193] 3. Have you been thinking about how you might do this?

[0194] 4. Have you had these thoughts and had some intention of acting on them?

[0195] 5. Have you started to work out or worked out the details of how to kill yourself? Did you intend to carry out this plan?

[0196] 6. Have you done anything, started to do anything, or prepared to do anything to end your life? (If yes, was this within the past 3 months?)

[0197] As used herein, the term “Drinker Inventory of Consequences” or “DrlnC” refers to a 50-item assessment related to evaluating a subject’s adverse consequences they may have experienced in relation to excessive alcohol consumption or alcohol use disorder. The DrlnC may be administered to evaluate both lifetime experiences with alcohol use stretching back to birth or may assess items with respect to a more recent time, e.g. the past month, 2 months, 3 months, 4 months, 5 months, 6 months, or 12 months, or since the previous administration of the assessment. Five subscales of the DrlnC evaluate the adverse experiences in a subject associated with physical consequences, intrapersonal consequences, interpersonal consequences, consequences related to impulse control, or consequences regarding social responsibilities. There is also one control subscale. The DrlnC may also be administered as the Short Index of Problems (SIP), a 15-item version derived from the highest correlated items for each of the above subscales. In some cases, the methods of treatment described herein may be applicable to other substance use disorders, in which an alternative from of the DrlnC, known as the “Inventory of Drug Use Consequences,” may be administered. As used herein, there term “particle size distribution” refers to the variability of particle sizes emitted in the plume of the intranasal delivery device which may be characterized as in terms of the diameter which 10% of the droplets in the plume have a smaller diameter than (D10), the diameter which 50% of the droplets in the plume have a smaller diameter than (D50), or the diameter which 90% of the droplets in the plume have a smaller diameter than (D90).

[0198] The terms “dysthymia” and “dysthymic disorder” refer to a chronically depressed mood that occurs for most of the day, more days than not, for at least two years. In children and adolescents, the mood may be irritable rather than depressed, and the required minimum duration is one year. During the two-year period (one year for children or adolescents), any symptom-free intervals last no longer than 2 months. During periods of depressed mood, at least two of the following additional symptoms are present: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self- esteem, poor concentration, or difficulty making decisions, and feelings of hopelessness. The symptoms cause clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning. The diagnosis of dysthymia is not made if: the individual has ever had a manic episode, a mixed episode, a hypomanic episode; has ever met the criteria for a cyclothymic disorder; the depressive symptoms occur exclusively during the course of a chronic psychotic disorder (e.g., schizophrenia); or if the disturbance is due to the direct physiological effects of a substance or a general medical condition. After the initial two-years of dysthymic disorder, major depressive episodes may be superimposed on the dysthymic disorder (“double depression”). Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th Edition, I 994. Diagnostic guidance for psychological disorders can be found, for example, in the ICD- 10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and the DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) Arlington, VA.; American Psychiatric Association, 2013).

[0199] As used herein, the terms“5-level EuroQol 5-Dimension” and “EQ-5D-5L” refer to a quality-of- life questionnaire focusing on health related matters, and is typically self-administered or selfassessed. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each level is rated on scale that describes the degree of problems in that area (i.e. I have no problems walking about, slight problems, moderate problems, severe problems, or unable to walk). This tool also may be used as an overall health scale where the rater selects a number between 1-100 to describe the condition of their health, 100 being the best imaginable.

[0200] As used herein, the term “ego dissolution” refers to the effect in a subject experiencing a psychological loss of self or identity. The subject may experience a reduction in self-centeredness. The subject undergoing ego dissolution may be characterized by a removal of previous reference points up to that time period in the subjects lived time. For example, the subject may experience a disconnection from their accumulated thoughts, emotions, and life occurrences, such that they no longer identify or recognize previously held personality traits in themselves. In some embodiments, dissolution of ego results in depersonalization, detachment from reality and dissociation, or even psychosis. In some embodiments, the subject’s ego dissolution is assessed by a clinical professional.

[0201] As used herein, the terms “Ego Dissolution Inventory” and “EDI” refer to a questionnaire used to evaluate ego dissolution in a subject, wherein each question is given a score on a scale of 0-100 in order to assess a psychedelic experience. There are 8 items of the inventory, giving a total possible score of 800. The scores range from 0 being no effect to 800 indicating a complete absence of being or feeling at one with the universe. In some embodiments of the invention, the subject receiving the methods of treatment of the invention experience ego dissolution as characterized by a score of 100, 200, 300, 400, 500, 600, 700 or higher on the EDI.

[0202] As used herein, the terms “evaluate” and “evaluation” refer to the process by which a physician or medical professional may diagnose conditions in a subject to be treated, such as through a structured clinical interview. In some cases, the evaluation may be through a diagnostic questionnaire. In some embodiments, the questionnaire may be self-administered. The evaluation may inform the physician or professional throughout the course of treatment as to how the subject is responding to treatment. The evaluation may be performed using one or more of the following assessments: the Columbia Suicide Severity Rating Scale (C-SSRS), the clinical global impression (CGI) rating scale, the Drinker Inventory of Consequences (DrlnC), the Patient Global Impression of Change (PGIC), the 5-Level EuroQol Five Dimension (EQ-5D-5L), the Timeline Follow-Back (TLFB) interview, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A) or revised version (CIWA-Ar), an altered states of consciousness (ASC) questionnaire, the Ego Dissolution Inventory (EDI), the Structure Clinical Interview for DSM-IV or DSM-V (SCID or SCID-5 / SCID-V), the MiniInternational Neuropsychiatric Interview (MINI), the World Health Organization Composite International Diagnostic Review (CIDI), the Schedules for Clinical Assessment in Neuropsychiatry (SCAN), the Diagnostic Interview for Genetic Studies (DIGS), the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CES-D), the EQ-5D or EQ-5D-Y, the Hamilton Rating Scale for Depression (abbreviated by any of HDRS, HRSD, or HAM-D), the Montgomery- Asberg Depression Rating Scale (MADRS), the Social Problem-Solving Inventory- Revised (SPSI-RTM) assessment in either long form (52 questions) or short form (25 questions), the Beck Hopelessness Scale, the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS- SR), the Patient Health Questionnaire (PHQ, usually version 9: PHQ-9), the Reminiscence Functions Scale (RFS), the Short Form Health Survey (SF-36), the Social Adjustment Scale-Self Report (SAS- SR), the Social Functioning Questionnaire (SFQ), the Geriatric Depression Scale (GDS), the Life Satisfaction Index (also known as the Life Satisfaction Ratings, LSR), the Alcohol Use Disorders Identification Test, or the Anorectic Behavior Observation Scale. It is contemplated that alternative or unlisted assessments utilized for analogous purposes (e.g. clinical assessment or evaluation) to those listed above may be utilized for the methods of treatment disclosed herein. In other embodiments, modified versions of any of the above assessments may be used. For example, the MINI may be administered as the MINI, or it may be administered as the MINI-Screen, the MINI-Tracking, or MINIKID variants of the assessment. Another example of an alternative assessment includes the selfrating version of the MADRS, the MADRS-S. In additional examples, the ACQ may be administered as the short form version, the Alcohol Craving Questionnaire Short Form Revised (ACQ-SF-R). In some embodiments, the results of the assessments are collected by a medical professional. In other embodiments, the results of the assessments are reported by the subject (i.e. self-reported). It is contemplated that the collection of responses to any of the above evaluations falls within the scope of “clinical assessment” for a subject for determining the need of utilizing the methods of treatment described herein.

[0203] As used herein, the term “first-degree relative” refers to a relative to a subject or patient having substantially similar genetic material and / or are directly blood-related. Examples of first-degree relatives include parents, siblings, or offspring.

[0204] By “freebase equivalent” is meant an amount corresponding to a free base equivalent in a mass of 5-MeO-DMT. For example, a freebase equivalent of 10 mg of 5-MeO-DMT is equal to 10 mg of 5-MeO-DMT in its free base form or equal to 15.59 mg of 5-MeO-DMT in its benzoate salt form to account for the mass contribution of the benzoic acid.

[0205] As used herein, the term “generalized anxiety disorder” refers to a condition characterized by excessive anxiety and worry (i.e., apprehensive expectation). Typically, the excessive anxiety and worry occur on more days than not for a period of time (e.g., one, two, three, or four months or more). The anxiety and worry can be associated with (i) restlessness, feeling keyed up, or on edge; and / or (ii) muscle tension. The anxiety and worry can be associated with (a) a marked avoidance of situations in which a negative outcome could occur; (b) a marked time and effort preparing for situations in which a negative outcome could occur; (c) a marked procrastination in behavior or decision-making due to worries; and (d) repeatedly seeking reassurance due to worries. The anxiety, worry, or physical symptoms can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in many, but not necessarily all individuals with GAD.

[0206] As used herein, the terms “Hamilton Rating Scale for Depression” and “HAM-D” refer to an evaluation tool for depression which contains 17 or 29 (depending on version) scored items, each on a 3- or 5-point per item basis. Levels of depression are determined following administration of the HAM-D, and scores indicate that a subject may be not depressed (0-7), have mild depression (8-13), have moderate depression (14-18), be severely depressed (19-22), or be very severely depressed (>23).

[0207] As used herein, a heavy drinking day (HDD) may be defined as >7 units per day for a woman and >9 units per day for a man.

[0208] As used herein, the term “hypertension” refers to the condition of experiencing high blood pressure in a subject, such that the subject has pressure in their arteries which is persistently elevated. An example of elevated blood pressure (BP) in a subject would be a subject having a systolic BP while in supine position of >140 mmHg, or a supine diastolic BP of >90 mmHg. Optionally, hypertension in a subject may be defined as repeated supine systolic BP of 140 mmHg, or diastolic BP of 90 mmHg.

[0209] As used herein, the term “inability to feel” refers to a subjective experience by a subject wherein they show reduced interest in activities that previously brought joy, happiness or pleasure. An inability to feel may be diagnosed as anhedonia in a subject. The feeling of disinterest may apply to the surroundings, and a subject may lack observation thereof. The inability to feel also manifests in a subject by causing a reduced ability to show emotion or a reduced ability to empathize. Symptoms associated with loss of ability to feel may be loss of joy associated with a subjects’ interests, loss of feeling for friends or acquaintances, or emotional paralysis. Emotional paralysis is indicated by the inability of a subject to experience anger, grief, pleasure, fear, or other emotions, or lacking the ability to empathize with friends and / or family.

[0210] As used herein, the term “increased treatment efficacy” refers to a subject experiencing clinically significant improvements that are increased in comparison to another subject or to another subject being administered the same method of treatment. In some embodiments of the invention, a subject that does not participate in virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences, wherein the one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) or spatial computing (SC) experience may be evaluated to have worse response to treatment than a subject who does. The subject participating in virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences alongside the methods of treatment described herein may report larger reductions in depressive or addictive symptoms. The subject participating in virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences may report reduced cravings for alcohol as compared to subjects who do not participate in these experiences.

[0211] As used herein, the term “MADRS” refers to the Montgomery-Asberg Depression Rating Scale, a ten-item questionnaire used by clinical professionals for assessing the severity of depression in a subject. The items of the assessment are divided by category to which the questions gauge symptoms, and are as follows:

[0212] 1 . apparent sadness

[0213] 2. reported sadness

[0214] 3. inner tension

[0215] 4. reduced sleep

[0216] 5. reduced appetite

[0217] 6. concentration difficulties

[0218] 7. lassitude

[0219] 8. inability to feel

[0220] 9. pessimistic thoughts

[0221] 10. suicidal thoughts

[0222] A subject may be evaluated in each item on a scale of 1 to 6 in the MADRS assessment, yielding an overall score totaling from 0 to 60. Higher scores indicate more severe depressive symptoms in a subject. For the purposes of the invention, subjects with an elevated MADRS score that becomes reduced to less than 9, following any of the methods of treatment disclosed herein, is considered to be in remission. A clinically significant reduction in MADRS score is a lowering by 6 or more points on the assessment scale. In some embodiments of the invention, the MADRS assessment is used to identify subjects in need of the methods of treatment disclosed herein. It is contemplated that the methods of treatment disclosed herein may be used as methods of treating a subject experiencing symptoms as described by some of the MADRS assessment items — subjects receiving the methods of treatment are expected to experience an alleviation of symptoms. Alleviation of symptoms in a subject may characterised, but not limited to, an improvement in mood or happiness (i.e., a reduction in sadness), a reduction of inner tension, an increase in the amount of quality of sleep, an improvement or increase in appetite, an improvement in concentration, a renewed interest in surroundings, or an increase in the enjoyment of life. Assessment of a subject by other evaluation tools as described above are expected, and symptoms are expected to be improved following treatment regardless of the evaluation tool utilized by the subject or medical professional. The symptoms are determined to be “reduced” or “increased” in a subject by comparing a baseline evaluation and subsequent evaluations of a subject. The skilled artisan recognizes the subjective nature of the symptoms as reported by the subject or evaluated by a medical practitioner.

[0223] As used herein, the term “malignant hyperthermia” refers to a condition in a subject wherein the subject experiences a severe reaction in response to being administered a drug or pharmaceutical composition that is characterized by overheating, and generally coincides with symptoms in a subject such as muscle rigidity, fever, and an elevated heart rate. Examples of compounds which may trigger a reaction through malignant hyperthermia as in the present invention include 5-MeO-DMT. A subject may have a familial history of malignant hyperthermia as characterized by first-degree relatives who have experienced the adverse reactions previously.

[0224] As used herein, the terms “Mystical Experience Questionnaire” and “MEQ30” refer to a 30- item questionnaire tool used to assess the response of subjects receiving methods of treatment that administer psychedelic drugs as active agents in the pharmaceutical compositions, such as those described by the methods of treatment disclosed herein. Each item of the evaluation touches on four dimensions selected from mystical, positive mood, transcendence of time and space, and ineffability, and seeks to identify the nature and intensity of the experiences; the experiences may be spontaneous or induced by previous administration of psychedelic substances.

[0225] As used herein, the term “nil by mouth” refers to a subject that has fasted of all food and fluids. In some embodiments, the subject has fasted of all food and fluids for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours, or in some further embodiments up to 48 hours.

[0226] As used herein, the terms “obsessive compulsive disorder,” “OCD,” and “anxiety and obsessive-compulsive spectrum disorders” refer to a condition characterized by obsessions and / or compulsions. Obsessions are recurrent and persistent thoughts, urges, or images that are experienced, at some time during the disturbance, as intrusive and unwanted and that usually cause marked anxiety or distress in which the obsessed individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with some other thought or action (i.e., by performing a compulsion). Compulsions are repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly. The behaviors or mental acts are aimed at preventing or reducing anxiety or distress, or preventing some dreaded event or situation; however, these behaviors or mental acts either are not connected in a realistic way with what they are designed to neutralize or prevent, or are clearly excessive. Typically the obsessions or compulsions are time consuming (for example, take more than 1 hour a day), or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0227] As used herein, the term “panic disorder” refers to a condition characterized by recurrent and unexpected panic attacks. Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia. Subjects with this condition can exhibit one or both of the following: (i) a persistent concern or worry about additional panic attacks or their consequences (e.g., losing control, having a heart attack, going crazy); and / or (ii) significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks), which may include agoraphobic avoidance.

[0228] As used herein, the term “patient” refers to a subject receiving any of the methods of treatment disclosed herein or being administered any of the pharmaceutical compositions described herein. The terms “patient” and “subject” may be interchangeable with respect to the methods of treatment herein described. As used in the context of the present invention, a patient to be treated is preferably a human subject who is diagnosed as suffering from one or more of the diseases / conditions / disorders, as disclosed herein, by a licensed professional in accordance with accepted medical practice.

[0229] As used herein, the terms “pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition, refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results. For example, in the context of treating depression, described herein, these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. The quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like. An “effective amount,” “pharmacologically effective amount,” or the like, of a composition of the present disclosure, also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).

[0230] As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of the compound of any of the compounds described herein. For example, pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid. The compounds described herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds described herein, be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Compounds of the present disclosure comprise analogues of dimethyltryptamine (DMT), which has an amine group capable of serving as a base for abstracting a proton from a suitably acidic functional group, thereby forming an acid addition salt. Nonlimiting examples of pharmaceutically acceptable salts that characterize compounds of the invention include, but are not limited to, metal salts (such as aluminum salt, iron salt, zinc salt, copper salt and nickel salt), inorganic salts (such as phosphate, sulfate, hydroxide, hydrochloride, hydrobromide, hydrobromate, or ammonium salt), organic acid salts (such as methanesulfonate, p-toluenesulfonate, lactate, acetate, trifluoroacetate, citrate, succinate, fumarate, maleate, tartrate, nicotinate, glutarate, and salicylate), or amino acid salts (such as glycine salt, lysine salt, arginine salt, ornithine salt, asparagine salt, aspartate, or glutamate). It is expected that the stoichiometry of the salt form may vary depending on the counterion chosen and conditions of formation. For example, in such cases where the acid added has more than one suitably acidic proton, the compound may be present in a 2 to 1 ratio to the counterion in the salt, such as with tartaric acid. It is also expected that the hydration state of all salts of the invention to be differentially hydrated. For example, the salt may be substantially free of water, e.g. anhydrous, or it may be a hemihydrate. The salt may also be substantially hydrated, providing a salt form that is a monohydrate, dihydrate, trihydrate, tetrahydrate, or pentahydrate.

[0231] As used herein, the term “pharmaceutically acceptable excipient” or “carrier” refers to an additive substance to a pharmaceutical composition which is not the active agent but assists with the delivery of the active compound such as through the control of release of the drug once administered, prevention of degradation of the drug prior to reaching a target site of action, or in improving the administration of the composition by changing of the physical characteristics (e.g. from a dry powder to a suspended formulation).

[0232] As used herein, the terms “plume geometry” and “geometry” when used in connection with a plume, means the measurement of the angle of the plume at its origin. Plume geometry can be measured at two distances from the origin of the plume, for example, at two side views 90° relative to each other. The plume geometry may be determined by measuring the angle between a first arm of the plume and a longitudinal access and a second arm of the plume that is 180° relative to the first arm in comparison to a longitudinal access, wherein the angle between the first arm of the plume and a longitudinal access and the angle between the second arm of the plume and a longitudinal access measure the total plume angle.

[0233] As used herein, the terms “post-traumatic stress disorder” and “PTSD” refer to a condition that arises as a delayed and / or protracted response to a stressful event or situation (either short- or long-lasting) of an exceptionally threatening or catastrophic nature, which is likely to cause pervasive distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the violent death of others, or being the victim of torture, terrorism, rape, or other crime). Predisposing factors such as personality traits (e.g., compulsive, asthenic) or previous history of neurotic illness may lower the threshold for the development of the condition or aggravate its course, but they are neither necessary nor sufficient to explain its occurrence. PTSD is a less frequent and more enduring consequence of psychological trauma than the more frequently seen acute stress response. PTSD has been recognized in the past as railway spine, stress syndrome, shell shock, battle fatigue, traumatic war neurosis, and post-traumatic stress syndrome. Diagnostic symptoms include reexperiencing original trauma(s), by means of flashbacks or nightmares; avoidance of stimuli associated with the trauma; and increased arousal, such as difficulty falling or staying asleep, anger, and hypervigilance. Formal diagnostic criteria (DSM-V, DSM-IV, and / or ICD-9) require that the symptoms last more than one month and cause significant impairment in social, occupational, or other important areas of functioning (e.g., problems with work and / or relationships). Formal diagnostic criteria can include: (i) intrusion symptoms that are associated with the traumatic event (e.g., (a) spontaneous or cued recurrent, involuntary, and intrusive distressing memories of the traumatic event; (b) recurrent distressing dreams in which the content and / or affect of the dream is related to the event; (c) dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event were recurring (such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings; (d) intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an embodiment of the traumatic event; and / or (e) marked physiological reactions to reminders of the traumatic event); (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that arouse recollections of the traumatic event; (b) activities, places, physical reminders, or times (e.g., anniversary reactions) that arouse recollections of the traumatic event; and / or (c) people, conversations, or interpersonal situations that arouse recollections of the traumatic event); (iii) negative alterations in cognitions and mood that are associated with the traumatic event (e.g., (a) inability to remember an important embodiment of the traumatic event (typically dissociative amnesia); (b) persistent and exaggerated negative expectations about one’s self, others, or the world; (c) persistent distorted blame of self or others about the cause or consequences of the traumatic event; (d) pervasive negative emotional state (e.g., fear, horror, anger, guilt, or shame); (e) markedly diminished interest or participation in significant activities; (f) feeling of detachment or estrangement from others; and / or (g) persistent inability to experience positive emotions (e.g., unable to have loving feelings, psychic numbing); and (iv) alterations in arousal (i.e., hyperarousal) and reactivity that are associated with the traumatic event (e.g., (a) irritable, angry, or aggressive behavior; (b) reckless or self-destructive behavior; (c) hypervigilance; (d) exaggerated startle response; (e) problems with concentration; and / or (f) sleep disturbance (e.g., difficulty falling or staying asleep, or restless sleep)). Formal diagnostic criteria can further include that the duration of disturbance is more than a certain period of time (e.g., one month, three months, or six months) and that the disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. In a small proportion of patients the condition may show a chronic course over many years and a transition to an enduring personality change. The three main symptoms associated with PTSD are (1) “reliving” the traumatic event, such as flashbacks, nightmares, intrusive thoughts and recollections, (2) avoidance behaviors and emotional numbing, and (3) hypersensitivity such as an inability to sleep, anxious feelings, overactive startle response, hyperarousal, hypervigilance, irritability, and outbursts of anger.

[0234] As used herein, the terms “psychological disorder” and “psychological condition” refer to a condition characterized by a disturbance in one’s emotional or behavioral regulation that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental function. Psychological disorders include, but are not limited to depressive disorders (major depression, treatment resistant depression, melancholic depression, atypical depression, or dysthymia), anxiety disorders (end of life anxiety, generalized anxiety disorder, panic disorder, social anxiety, post- traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, or social phobia), addictions (e.g., substance abuse, e.g., alcohol use disorder, tobacco abuse, or drug abuse)), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and binge eating disorder) and compulsive behavior disorders (e.g., primary impulse-control disorders or obsessive-compulsive disorder). Psychological disorders can be any psychological condition associated with one or more symptoms, e.g., somatic symptoms (e.g., chronic pain, anxiety disproportionate to severity of physical complaints, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or neurological conditions without identifiable cause), or psychosomatic symptoms (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome). Psychological disorders also include repetitive body-focused behaviors, such as tic disorders (e.g., Tourette's Syndrome, trichotillomania, nail-biting, temporomandibular disorder, thumb-sucking, repetitive oral-digital, lip-biting, fingernail biting, eye-rubbing, skin-picking, or a chronic motor tic disorder). In some cases, development of a psychological disorder is associated with or characterized by a prodromal symptom, such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, initial insomnia, middle insomnia, early waking, hypersomnia, decreased energy, decreased interest or pleasure, selfblame, decreased concentration, indecision, suicidality, psychomotor agitation, psychomotor retardation, crying more frequently, inability to cry, hopelessness, worrying / brooding, decreased self- esteem, irritability, dependency, self-pity, somatic complaints, decreased effectiveness, helplessness, and decreased initiation of voluntary responses.

[0235] As used herein, the term “recreational drug” refers to any pharmacologically active substance that may be taken by a subject outside the supervision of a medical practitioner for purposes unrelated to treatment of a disease or condition as described herein. Representative examples of recreational drugs include psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca. In some embodiments, a subject has not been administered a psychedelic recreational drug within the previous 6 months prior to the first administration of the pharmaceutical compositions as described in the methods of treatment of the invention. In some embodiments, the methods of treatment described herein are methods of treating diseases or conditions in subjects without concurrent or recent recreational drug use. In some embodiments, the subject abstains from consumption of recreational drugs for the duration of treatment with any of the pharmaceutical compositions as described herein. In some embodiments, a urine sample is collected from a subject prior to administering any of the methods of treatment described herein in order to verify that the subject has not recently taken an illicit drug substance or recreation drug of abuse.

[0236] As used herein, the term “relapse” refers to the state of a subject changing from being abstinent in consumption a substance, such as alcohol, to a state of having recently consumed said substance. In some embodiments, the subject is considered to have relapse if the subject consumes at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 20, 30, 40, or 50 drinks.

[0237] As used herein, the term “sensitivity” or “intolerance” refers to a subject being prone to having an adverse reaction or experiencing an adverse event as a result of exposure to a compound to which the subject has the sensitivity. Examples of the adverse reactions or adverse events the subject may experience as a result of the intolerance include but are not limited to panic, panic attacks, anxiety, confusion, agitation, disorientation, dysphoria, accidental self-injury, suicidal ideation, attempted suicide, violent behavior, psychosis, derealization or a disconnection from reality, mania, depersonalization, ego death, dissociation or non-responsiveness, fear, or terror in a subject.

[0238] As used herein, the term “substance use disorder” refers to a condition involving uncontrolled substance use or intense cravings for a substance. Substance use disorder exists on a spectrum and may be mild, moderate, or severe. Substance use disorder typically involves an overpowering desire to use the substance, increased tolerance to the substance and / or withdrawal symptoms when the substance is no longer being taken. A person may have more than one substance use disorder at a time. Substances involved in substance use disorder include any drug that has the potential to be addictive. For example, the substance involved in substance use disorder may be alcohol, caffeine, phenylcyclohexyl piperidine, hypnotics (e.g., sedatives and anxiolytics, e.g., benzodiazepine and barbiturates), inhalants (e.g., paint thinners, aerosol sprays, gases and nitrites), opioids (e.g., morphine, codeine, oxycodone, hydrocodone, fentanyl, and heroin), stimulants (e.g., amphetamine, dextroamphetamine, cocaine, and methamphetamine), and nicotine.

[0239] As used herein, the term “sympathomimetic drug” refers to the class of compounds that act as stimulants and mimic the effects of sympathetic nervous system agonists. Nonlimiting examples of sympathomimetic drugs include cocaine, methylenedioxy methamphetamine (MDMA), amphetamine, ephedrine, serotonin, norepinephrine, phenylephrine, isoproterenol, dobutamine, fenoldopam, propylhexedrine, salbutamol, or pseudoephedrine. The subject may experience adverse reactions associated with being administered a sympathomimetic drug, such as elevated heart rate, elevated force of cardiac contraction, or changes in blood pressure.

[0240] As used herein, the terms “timeline followback” and “TLFB” refer to the alcohol Timeline Follow-Back calendar prompt interview originally developed in 1992 was adapted from the Form 90 structured interview, developed in 1996, to indicate “active” recording of each day in the recall period (i.e., “abstinent” or “alcohol consumed”) with standard and high-strength beverage types typically consumed by the study clinical population before treatment to assist the interviewer record units consumed on a drinking day from the participant’s verbatim report. In some embodiments, the TLFB provides psychometric characteristics with a variety of drinker groups. In some embodiments, the TLFB generate variables that provide a wide range of information about an individual’s drinking (e.g., pattern, variability, and magnitude of drinking). Use of the TLFB may be recommended for use when relatively precise estimates of drinking are necessary, especially when a complete picture of drinking days (i.e., high- and low-risk days) is needed.

[0241] The subject diagnosed with a psychological condition may be diagnosed by evaluation of the subject’s symptoms by a physician, clinician, or therapist based on a physical examination. For example, a blood test may be used to evaluate blood concentration levels of certain biomarkers such as may indicate alcohol use disorder. Additionally, or alternatively, for patients with AUD a screening test may be performed by the physician, clinician, or therapist to aid in the diagnosis of AUD. In some embodiments, the methods described herein may be used to treat AUD. In some embodiments, the AUD is diagnosed by assistance of a clinical evaluation which utilizes the Alcohol Craving Questionnaire as an assessment tool.

[0242] As used herein, the term “psychological support” may refer to one or more of the following: therapy, psychotherapy, talk therapy, cognitive behavioral therapy (CBT), counselling, guided selfhelp and / or group therapy. In some embodiments, the use of a computer-aided chat services, digital tools, or ai chatbots may be administered as psychological support. The support may be giving the in form of a program, wherein the subject has repeated experiences of support that is administered. For example, a subject being administered 5-MeO-DMT to treat alcohol use disorder according to the methods of treatment of the invention may also be required to attend group therapy sessions on a weekly basis, for at least one week, but more preferably 12 weeks. It is expected that within the scope of the invention, subjects are to be receiving psychological support as part of in-patient or out-patient treatment program, and that support may be administered both at a clinic or at a private practice or residence.

[0243] As used herein, the term “withdrawal” refers to the state of a subject that previously drank alcohol on a regular basis suddenly stopping the consumption of alcohol, thereby triggering withdrawal symptoms in the subject. Symptoms of withdrawal include, but are not limited to, trembling or tremors, insomnia, hallucinations, seizures, or delirium tremens (a mental disturbance or confusion caused by the withdrawal), headaches, anxiety, nausea, vomiting, sweating, elevated heart rate, high blood pressure (or hypertension), or fever.

[0244] BRIEF DESCRIPTION OF THE DRAWINGS

[0245] FIG. 1 is a flowchart depicting the study design and patient recruitment for a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0246] FIG. 2 is a graph depicting the average number of standard units of alcohol consumed per day (UPD) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate). FIG. 3 is a graph depicting the mean percentage of drinking days for the cohort in a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0247] FIG. 4 is a graph depicting the change in number of heavy drinking days (HDD) from baseline from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0248] FIG. 5 is a graph depicting the change in the percentage of heavy drinking days (HDD) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0249] FIG. 6. is a graph depicting the mean percentage of heavy drinking days (HDD) for the cohort in a phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0250] FIG. 7 is a graph depicting the change in the percentage of drinking days (DD) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0251] FIG. 8 is a graph depicting the change in the average number of standard units of alcohol consumed per week from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0252] FIG. 9 is a graph depicting the change in the maximum number of standard units of alcohol consumed on any one day from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0253] FIG. 10 is a graph depicting the change in the percentage of abstinent days from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0254] FIG. 11 is a graph depicting the mean percentage of abstinent days for the cohort in a phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0255] FIG. 12 is a chart depicting the daily units of alcohol consumed in each patient before and after BPL-003 (5-MeO-DMT benzoate) dosing in a phase Ila clinical trial.

[0256] FIG. 13 is a graph depicting MEQ-30 scores after administration of BPL-003 in a phase Ila clinical trial.

[0257] FIG. 14 is a chart depicting the Patient Global Impression of Changes (PGIC) scores at days 28, 56, and 84 for the patients in a phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0258] FIG. 15 is a graph depicting mean (± SEM) subjective intensity ratings after single doses of placebo or 8 mg, 10 mg and 12 mg BPL-003 (SEM, Standard error of the mean).

[0259] FIG. 16 is a graph depicting mean (± SEM) MEQ-30 scores after single doses of placebo or 8 mg, 10 mg and 12 mg BPL-003 (MEQ-30, Mystical Experience Questionnaire; SEM, Standard error of the mean. Dotted line indicates a meaningful threshold of >3).

[0260] FIG. 17 is a graph depicting the mean change from baseline in MADRS total score overtime (per protocol population) from a Phase Ila clinical trial of BPL-003 (5-MeO-DMT benzoate).

[0261] FIG. 18 shows the particle size distribution of a 5-MeO-DMT SDD as Bulk Material, analysed using the RODOS dry powder dispersion unit at 3 bar dispersal pressure (Gray); and ExDevice powder, by manual actuation into the laser diffractortip with the tip of the device positioned 3 cm from the mid-point of the laser (Black) as described in Example 6.

[0262] FIG. 19 is a graph depicting the nasal deposition profile for a 5-MeO-DMT SDD delivered via an active delivery nasal delivery device.

[0263] FIG. 20 is a graph depicting the nasal deposition profile for a 5-MeO-DMT SDD delivered via a passive delivery nasal delivery device. DETAILED DESCRIPTION OF THE INVENTION

[0264] The present disclosure includes the aspects described above and is further illustrated by the following examples. The examples are intended to illustrate the present disclosure without, however, being limiting in nature. It is understood that the present disclosure encompasses additional embodiments consistent with the foregoing description and following examples.

[0265] Methods of Administration

[0266] Other routes of administration may also be considered for administering the pharmaceutical compositions described herein to a subject in an appropriate amount. Nonlimiting examples of the routes of administration considered within the scope of the invention include, but are not limited to, oral, intravenous, subcutaneous, transdermal, topical, intranasal, or transmucosal. In some embodiments, the pharmaceutical compositions are self-administered. In other embodiments, the pharmaceutical compositions may be administered by a medical practitioner. Devices capable of delivering controlled doses of the pharmaceutical compositions over time to the subject are also contemplated to be within the scope of the present invention. For example, the pharmaceutical composition may be stored in a spray device design for nasal administration to a subject and is further characterized by a controlled spray pattern the delivers uniform actuations of the pharmaceutical compositions with each administration. For instance, the pharmaceutical composition may be formulated as a powder, such as a dry blend powder or spray dried powder, which is suitable for administration by inhalation / insufflation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler, a pressurised metered dose inhaler, a nasal delivery device, a nasal spray or an active nasal delivery device. The pharmaceutical compositions described herein are also contemplated to be in the form of a tablet suitable for oral administration to a subject. In some cases, administration of the pharmaceutical composition may be facilitated by a kit the provides the composition and a device for administration. In other embodiments, the kit contains instructions for use of the pharmaceutical composition.

[0267] The dosing schedule and frequency of administration corresponding to the methods of treatment disclosed herein may vary depending on considerations by a medical practitioner, as the skilled artisan recognizes. For example, the administration of the pharmaceutical composition may occur between once every day and once every 80 days, between once every 7 days and once every 60 days, or about once every 40 days. In some embodiments, the administration occurs once every week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, or once every twelve weeks. In some embodiments, the methods of treatment are methods of administering 5-MeO-DMT once every month, once every two months, or once every three months to a subject in order to treat alcohol use disorder. In some embodiments, the administration may occur more than once during any given administration period. In some embodiments, the administration is repeated between 40 and 80 days after the first administration. Pharmaceutical Formulations

[0268] The compounds used in the methods of treatment described herein may be administered in the form of pharmaceutical compositions, wherein the active drug substance is administered with one or more inactive agents such as excipients, carriers, adjuvants, or fillers. For example, an excipient may be, but is not limited to, HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM / MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC), chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), p-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, citric acid, a mucoadhesive enhancer, a penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides. Other examples of carriers, adjuvants, or fillers are contemplated to be for use in pharmaceutical compositions of the present invention, and are well known to the skilled artisan.

[0269] EXAMPLES

[0270] Example 1: An Open-Label , Phase Ila Single Dose Study in Patients with Alcohol Use Disorder (AUD)

[0271] A phase Ila clinical trial has been completed to evaluate the safety and tolerability of a single intranasal dose of BPL-003 (5-MeO-DMT benzoate) in patients with Alcohol Use Disorder (AUD). Further objectives of the clinical trial were:

[0272] • To assess the pharmacodynamics (PD; including psychological effects) of a single intranasal dose of BPL-003 in patients with AUD

[0273] • To assess the feasibility of the treatment model for BPL-003 combined with relapse prevention psychotherapy in patients with AUD

[0274] • To assess effects as determined by the Mystical Experience Questionnaire (MEQ30) and Ego Dissolution Inventory (EDI) after a single intranasal dose of BPL-003 in patients with AUD

[0275] • To explore the effects of a single intranasal dose of BPL-003 combined with relapse prevention psychotherapy in patients with AUD on alcohol use and related symptoms

[0276] • To explore the effects of BPL-003 combined with relapse prevention psychotherapy on health-related quality of life (QOL) in patients with AUD

[0277] • To explore exposure levels after a single intranasal dose of BPL-003 in patients with AUD

[0278] This study assessed a dry powder nasal spray formulation of 5-MeO-DMT benzoate (BPL- 003). Enrolment of up to 12 patients with AUD was planned. After completing the screening period, those patients who were confirmed as eligible participated in a minimum of 3 preparatory psychological support sessions over approximately 2 weeks before the BPL-003 treatment session. These sessions were conducted by a therapist with psychedelic knowledge and an AUD therapist. The last of the 3 sessions was conducted at the clinic where the dosing will occur so that patients could become familiar with the dosing room, clinic staff and a practice run with the nasal delivery system could be completed. Baseline assessments were completed on the BPL-003 treatment day, before BPL-003 administration. BPL-003 was administered on the treatment day in accordance with established safety practices for psychedelic research. A minimum of 3 integration sessions occurred over approximately 2 weeks after the treatment session, together with AUD relapse prevention psychotherapy that guided the patient through the 12-week post dose follow-up period.

[0279] The study visits and procedures are outlined below: Screening: Patients were screened up to 14 days before their psychedelic preparation session to confirm their eligibility for the study.

[0280] Patients were determined to be eligible if they met the following criteria: willing and able to give informed consent; age 18 to 64 years at Screening; diagnosed with moderate to severe AUD (based on DSM-5); minimum of 4 HDD in the 28 days before Screening; No more than 14 days after the last HDD or completion of detoxification (at point of screening), with no HDD in the 72 hours prior to dosing, and no alcohol at all in the 24 hours prior to dosing; willing to abstain from using recreational drugs from Screening until end of the study; willing to abstain from smoking during their time in the clinic on the day of drug administration as instructed by clinical staff; willing to refrain from psychedelic drug use (excluding the study drug) from Screening until the end of the study; able (in the Investigator’s opinion) and willing to undertake and comply with all study requirement, with the ability to complete all protocol-required assessment tools and to comply with all study visits; willing to allow their own general practitioner, and consultant if appropriate, to be informed of study participation; living in stable / secure accommodation in the community; and in possession of a personal mobile phone and able to nominate at least one locator individual (e.g., a family member, friend, or recovery mentor) with a verifiable address and a telephone number to assist with the arrangement of follow-up appointments.

[0281] Similarly, patients were excluded from the study if they met any one of the following general medical exclusion criteria: history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure (BP) and heart rate (HR). This includes, but is not limited to, severe coronary artery disease, history of myocardial infarction, unstable angina, cerebrovascular accident, aneurysm or revascularization procedure within 12 months before Screening, significant valvular heart disease, heart failure of any aetiology, history of a stroke or transient ischemic attack; history of uncontrolled hypertension despite adequate therapy or any history of a hypertensive crisis or ongoing evidence of uncontrolled hypertension (defined as repeated supine systolic BP >140 mmHg, or diastolic BP >90 mmHg). Participants with well-controlled hypertension that has been successfully treated with anti-hypertensive medicines may be enrolled if they pass additional screening to rule out underlying cardiovascular disease; uncontrolled or insulin- dependent diabetes; history of seizures (including febrile and withdrawal seizures); any other clinically significant neurological, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, or any other major concurrent illness that, in the opinion of the Investigator, may interfere with the interpretation of the study results or constitute a health risk for a participant if they take part in the study; abnormal and, in the opinion of the Investigator, clinically significant results on the physical examination, vital signs, electrocardiogram (ECG), or laboratory tests at Screening (Visit 1); participants who are exhibiting any signs of alcohol withdrawal at Day 0 as assessed by Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA Ar); positive for alcohol at Day 0; positive urine drug screen for illicit drugs or drugs of abuse; currently receiving monoamine oxidase inhibitors (MAO-I), tramadol, opioids, antiviral medication, cytochrome P4502D6 inhibitors, antidepressant medication, including selective serotonin reuptake inhibitors be enrolled if they pass additional screening to rule out underlying cardiovascular disease; currently receiving SSRIs and SNRIs, tricyclic antidepressants, lithium, antipsychotic medications, triptans, tramadol, 5 hydroxytryptophan (5-HTP), herbal preparations containing 5-HTP, St John’s Wort, or any other medications or supplements that may affect serotonergic function or may interfere with the study drug; history of intolerance to 5-MeO-DMT, dimethyltryptamine (DMT), or related compounds; any nasal obstruction, blockage, or symptoms of congestion; any personal or family history of malignant hyperthermia; disposition judged by the Investigator (or delegate) to be incompatible with establishment of rapport with study team and / or safe exposure to BPL-003; presence of acute or chronic illness or infection or history of chronic illness or infection sufficient to invalidate the participant’s participation in the study or make it unnecessarily hazardous; presence or history of severe adverse reaction to any drug or drug excipient; female participants who are pregnant or lactating or of childbearing potential and not willing to use adequate forms of contraception during the study and for 1 month after completion of the study; male participants who are sexually active and not willing to use adequate forms of contraception during the study and for 1 month after completion of the study; participants who have taken part in a clinical research study in the last 4 weeks, whether or not they received an investigational medicinal product as part of that research study; current criminal justice involvement with legal proceedings, which in the opinion of the Investigator means the participant may fail to complete the study protocol due to re-incarceration or relocation from the clinic’s catchment area; unable to communicate in English to a level required to accept standard care and psychosocial intervention; or participants who, in the opinion of the Investigator, are not suitable to participate in the study for any other reason not mentioned in the entry criteria.

[0282] An additional set of exclusion criteria was used that have a psychiatric basis as follows: personal or first-degree family history of schizophrenia, bipolar disorder, psychotic disorder (unless substance induced or due to a medical condition), delusional disorder, paranoid disorder, or schizoaffective disorder, as defined by DSM-5. Personal history determined by medical records and positive diagnoses on the Mini-International Neuropsychiatric Interview (MINI version 7.02) to be confirmed by the Investigator; any major psychiatric disorders, with the exception of mild or moderate anxiety and / or depression, as determined by a MINI and confirmed by the Investigator; a clinical diagnosis of post-traumatic stress disorder (as determined by MINI); psychological therapies other than those planned per protocol that are initiated or terminated within 21 days of baseline and for the duration of the study; has suicidal ideation with some intent to act within the 12 months before Screening, per the Investigator’s clinical judgment or based on the Columbia-Suicide Rating Scale (C- SSRS), corresponding to a response of “Yes” on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) for suicidal ideation on the C-SSRS, or a history of suicidal behaviour within the 12 months before Screening. Suicidal ideation with intent to act or suicidal behaviour as assessed on Day -3 should also be excluded; suicide attempts and / or self-injurious behaviour within 12 months before Screening; regular use of or dependence on other drugs other than caffeine or nicotine (Presence or history of substance use disorder (not including AUD) as defined by the DSM-5. The Investigator will evaluate the participant’s ability to abstain from using this substance during the study. The participant must have a negative recreational drug test on Day 0, before dosing); or any self-reported use of psychedelic compounds (phenethylamines, tryptamines, or dissociatives) in the past 6 months.

[0283] Abstinence: Patients were expected to have no HDD in the 72 hours prior to dosing, and no alcohol in the last 24 hours. If breath alcohol is not zero on dosing day, patients may reschedule once if they are deemed not to have completely relapsed; however, if they fail the second time, they were excluded from the study.

[0284] Psychedelic preparation visits: Following the initial Screening Visit, all patients participated in 3 preparatory sessions over approximately 2 weeks before being dosed (patients should not undertake preparation sessions if intoxicated (clinical judgement was applied to determine whether the patient was able to absorb the information and build a therapeutic alliance). The aim was to establish a therapeutic alliance with the therapists during the preparatory sessions so that patients were well prepared for the BPL-003 treatment session and received ongoing AUD relapse prevention psychotherapy.

[0285] Psychological change measures and semi-structured interviews (optional): if patients consented to these optional assessments, they were required to complete psychological change questionnaires at 5 visits during the study on Days -3, 1 , 7, 28 and 84, and 3 semi-structured interviews with a therapist on Days 1 , 28 and 84.

[0286] Dosing visit: After completion of the 3 preparatory sessions, patients attended the clinic fortheir dosing visit. Patients were resident at the clinic from the morning of Day 0 (dosing day) until at least 4 hours post dose. BPL-003 was administered to patients in the designated setting, and the therapist remained with patients while patients were in an altered state of consciousness. Blood samples were taken at 5, 15 and 60 minutes after dosing to confirm 5-MeO-DMT exposure. Plasma 5-MeO-DMT and active metabolite concentrations were quantified with a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) assay (Analytical Services International). References and internal standards (psilocybin D10) for 5-MeO-DMT and metabolites bioanalysis were supplied by Chiron or Cerilliant.

[0287] Qualitative interviews (optional): After returning to a usual state of consciousness after dosing, and provided they consented, patients were asked to have a one-to-one guided qualitative interview with independent researchers trained in microphenomenology methods to discuss their psychedelic experience. This was done either face to face at the clinic or via video call. Psychometric scales were then administered to provide quantitative measures of the patient’s psychedelic experience. All patients had their readiness for discharge assessed every 30 minutes starting 90 minutes after dosing before discharge on the dosing day. The earliest a patient could be discharged was 4 h after receiving the dose.

[0288] Follow-up (for 12 weeks post dose):

[0289] • Psychedelic integration sessions: Patients had at least 3 integration sessions, lasting approximately 60-90 min, over the 2 weeks following their dose to discuss their experience with the therapists.

[0290] • Relapse prevention psychotherapy: Participants were invited to attend 10 x 60-minute weekly sessions of individual CBT with the AUD therapist, as outlined in the CBT manual. Patients had weekly sessions following the dose of BPL-003 (can be either face to face or remote) with an AUD therapist.

[0291] BPL-003 was administered intranasally by a trained member of the study team using an Aptar Unidose (UDS) dry powder delivery system. Each dose is preloaded into the delivery device.

[0292] Ego Dissolution Inventory

[0293] The Ego Dissolution Inventory (EDI), is an 8-item self-report scale designed to measure egodissolution.

[0294] 5-Level EuroQol 5-Dimension

[0295] The EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each level is rated on scale that describes the degree of problems in that area (i.e. I have no problems walking about, slight problems, moderate problems, severe problems, or unable to walk). This tool also has an overall health scale where the rater selects a number between 1-100 to describe the condition of their health, 100 being the best imaginable.

[0296] Timeline Follow-Back

[0297] The alcohol Timeline Follow-Back (TLFB; calendar prompt interview) originally developed in 1992 was adapted from the Form 90 structured interview, developed in 1996, to indicate “active” recording of each day in the recall period (i.e., “abstinent” or “alcohol consumed”) with standard and high-strength beverage types typically consumed by the study clinical population before treatment to assist the interviewer record units consumed on a drinking day from the participant’s verbatim report. The TLFB has been shown to have good psychometric characteristics with a variety of drinker groups, and it can generate variables that provide a wide range of information about an individual’s drinking (e.g., pattern, variability, and magnitude of drinking). The method is recommended for use when relatively precise estimates of drinking are necessary, especially when a complete picture of drinking days (i.e., high- and low-risk days) is needed. Although TLFB summary data have been found to be generally reliable, as with all drinking assessment methods, exact day-by-day precision cannot be assumed or necessarily expected. Overall, the TLFB method provides a relatively accurate portrayal of drinking and has both clinical and research utility.

[0298] Qualitative Interview

[0299] After dosing, patients will be asked to take part in an optional qualitative interview. If they agree, they will have a one-to-one guided interview with independent researchers trained in microphenomenology methods to discuss their psychedelic experience. This will be done either face to face at the clinic or via video call. The qualitative interview will provide a more nuanced understanding of the phenomenology of BPL-003 effects compared with the questionnaires used in this study. Data from this interview will help inform future clinical studies of this compound.

[0300] Optional Semi-Structured Interview & Psychological Change Measures

[0301] The optional semi-structured interviews will take place on Days 1 and 84. These interviews will be topic-guided, audio-recorded, qualitative interviews to understand a patient’s psychological changes from shortly after dosing (Day 1) until Day 84. Patients will be invited to complete an optional online psychological change questionnaire on Days -3, 1 , 28, and 84. The questionnaire will consist of validated scales measuring psychological changes such as personality traits, anxiety traits and avoidance, beliefs about self, others and environment, suggestibility, absorption, expectations about the treatment, and wellbeing and resilience pre- and post dosing, to understand the potential effect of BPL-003 dosing combined with relapse prevention psychotherapy.

[0302] Montgomery-Asberg Depression Rating Scale (MADRS)

[0303] Via the electronic Clinical Outcome Assessment (eCOA), an appropriately trained member of the study team will use a Structured Interview Guide for the MADRS (SIGMA) to interview the subject moving from broad questions about symptoms to more detailed ones which allow the precise rating of symptom severity. The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. A higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The questionnaire includes questions on the following symptoms: (1) apparent sadness, (2) reported sadness, (3) inner tension, (4) reduced sleep, (5) reduced appetite, (6) concentration difficulties, (7) lassitude, (8) inability to feel, (9) pessimistic thoughts, and (10) suicidal thoughts. The usual cutoff points are: 0 to 6 = normal / symptom absent, 7 to 19 = mild depression, 20 to 34 = moderate depression, >34 = severe depression.

[0304] Alcohol Craving Questionnaire

[0305] The Alcohol Craving Questionnaire Short Form Revised (ACQ-SF-R) will be completed at Baseline (pre-dose on Day 0) and at the visits on Days 1 , 7, 28, 56, and 84. Craving Visual Analogue Scale

[0306] A Craving VAS will be used on dosing day to assess the relative craving status of the patient before discharge on Day 0 dosing compared to prior to dosing. The scale will be completed on admission (A) and again at the point of discharge (B). If the rating at B is greater than at A, then an additional craving talk down procedure will be implemented and VAS B repeated. Patients will be discharged only when their VAS rating at B is the same or lower than at A.

[0307] Clinical Global Impression of Severity

[0308] A brief Clinical Global Impression of Severity (CGIS) questionnaire of the patient’s condition will be completed. The CGIS uses a 7-item scale to rate total severity whether or not, in the Investigator’s judgment, it is due entirely to drug treatment. This rating is based upon observed and reported symptoms, behaviour, and function. The Investigator will compare the patient’s current condition to that at Screening and determine how much the patient has changed on the following scale: 0 = not assessed, 1 = normal, not at all ill, 2 = borderline ill, 3 = mildly ill, 4 = moderately ill, 5 = markedly ill, 6 = severely ill, 7 = among the most extremely ill patients.

[0309] Patient Global Impression of Change

[0310] A brief PGIC will be completed. The PGIC uses a 7-item scale to rate total improvement reported by patient whether or not it is due to drug treatment. The patient will report their own current condition compared to that at Screening on the following scale: 0 = Not assessed, 1 = Very much improved. 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, 7 = Very much worse.

[0311] Clinical Institute Withdrawal Assessment for Alcohol-Revised

[0312] The Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) is a 10-item scale used in the assessment and management of alcohol withdrawal. Each item on the scale is scored independently, and the summation of the scores yields an aggregate value that correlates to the severity of alcohol withdrawal. The ranges of scores are designed to prompt specific management decisions such as the administration of benzodiazepines. The maximum score is 67; mild alcohol withdrawal is defined by a score <10, moderate by scores 11 to 15, and severe by any score >16.

[0313] Short Inventory of Problems

[0314] The Drinker Inventory of Consequences (DrlnC) was developed to assess consequences of alcohol use; it contains 50 items, 45 of which measure consequences in 5 domains: interpersonal, intrapersonal, physical, impulse control, and social. In the briefer 15-item version of this measure, the Short Inventory of Problems (SIP), 3 items from each of the 5 domains based on the strongest itemsubscale correlations were selected. Revised versions use the 15 items with the strongest item-total correlations. The version used in this study is the SIP-2R developed by the Center on Alcohol, Substance use, And Addictions (CASAA) at the University of New Mexico.

[0315] Readiness for discharge questionnaire

[0316] An appropriately trained member of the site team will complete the readiness to discharge questionnaire to determine the earliest time point the patient is able to leave the clinical study site safely. The post dose vital signs (HR, BP and temperature), done every 30 min, are included as part of this questionnaire. Patients will have their readiness for discharge assessed every 30 min starting 90 min after dosing, up to the point the patient has been deemed safe to leave the clinical study site. The final readiness to discharge questionnaire will be verified by a suitable physician. If the final readiness to discharge is before the 4 h post dose timepoint the patient will remain until 4 h post dose as per this protocol. Completion of the readiness to discharge questionnaire can stop once the patient has been deemed safe to leave the clinical study site as per the questionnaire. If the patient is not ready for discharge at 4 hours post dose then the questionnaire will be repeated again at the point Investigator believes the patient may be ready for discharge.

[0317] Each question must be answered with YES in order to be able to discharge the patient safely from care. Once all items are checked as a YES the last question to confirm that the patient is ready for discharge can be completed and no further reviews every 30 minutes are required. If this occurs before 4 hours post dose the patient will remain until the completion of 4 hours waiting period before actually being discharged. If the patient is not ready to be discharged at 4 hours post dose the every 30 minute assessments will stop but a final questionnaire will be completed once the Investigator is satisfied that the patient is ready prior to discharge.

[0318] (1) The patient is fully responsive, aware of their surroundings, and reacts adequately

[0319] (2) The acute psychedelic effects of the drug have completely subsided

[0320] (3) The patient is fully orientated (name, location, time)

[0321] (4) Blood pressure and pulse rate have returned to normal or only slightly elevated levels

[0322] (5) The breathing frequency and body temperature are normal

[0323] (6) The patient has a stable gate and normal muscle coordination and can walk safely

[0324] (7) Potential side effects are mild to moderate in intensity and do not need to be medically monitored

[0325] (8) The patient has no acute suicidal ideations or suicidal intentions

[0326] (9) Possible distress or feelings of being overwhelmed have sufficiently subsided to a degree that the patient themselves feel safe to be discharged

[0327] After all prior assessments have been answered with YES the final question can be completed. The last question cannot be ticked as yes until all the proceeding questions are yes.

[0328] (10) In the opinion of the assessor, the patient is now safe to be discharged. Biomarkers

[0329] Ethyl Glucuronide

[0330] Ethanol is excreted from the body in a variety of ways, including (1) Direct excretion of ethanol (5%-10%) in urine, sweat, and breath, (2) Metabolic excretion by conversion to acetaldehyde or acetic acid (>90%) and (3) Metabolic excretion by conversion to ethyl glucuronide (EtG) and ethyl sulfate (<0.1%), both of which are readily eliminated through urination.

[0331] While most of these excretory products are detectable in urine for very short periods of time (<24 hours), EtG has a longer half-life and may be detectable in urine for up to 72 hours after consumption, depending on the dose taken prior to specimen collection. Although higher amounts of EtG might indicate greater alcohol consumption, the exact EtG number is influenced by several factors, including how recently alcohol was consumed. The presence of EtG in urine indicates only that the individual was exposed to ethanol at some point in the recent past before testing, typically within the preceding 72 hours. The EtG test accurately detects a person who recently consumed alcohol 70% or more of the time. One study showed that for moderate to heavy drinking, this value increases to 85%.

[0332] Carbohydrate Deficient Transferrin

[0333] Chronic alcohol use causes a transient change in the glycosylation pattern of transferrin, where the relative amounts of disialo- and asialotransferrin (carbohydrate deficient transferrin [CDT]) are increased over the amount of normally glycosylated tetrasialotransferrin. CDT can be used to detect whether someone is a binge drinker or a daily heavy drinker (4 or more drinks a day). It can even be used to determine AUD relapse. Generally, CDT levels will return to normal within several weeks of abstinence from alcohol use. CDT testing alone is not recommended for general screening for AUD; however, when combined with other assessments (e.g.: gamma-glutamyl transpeptidase [GGT], alanine aminotransferase [ALT], aspartate aminotransferase [AST], mean corpuscular volume [MCV], EtG, and patient self reporting), clinicians can expect to identify the majority of patients with AUD.

[0334] Haematology and Clinical Chemistry

[0335] Changes in the reported values of MCV (mean corpuscular volume), ALT (alanine aminotransferase), AST (aspartate aminotransferase), and GGT (gamma-glutamyl transpeptidase) will also be used to monitor for signs of relapse.

[0336] Results

[0337] 12 patients were administered 10 mg BPL-003 and completed follow-up as described in Figure 1 ; selected results are disclosed and discussed below.

[0338] During BPL-003 dosing, transient increases in systolic blood pressure occurred, peaking at about 15 minutes and returning to the reference range by 210 minutes. Mean (SD) 5-MeO-DMT plasma levels were 12.2 (8.86) ng / mL at 5 minutes, increasing to 18.3 (11 .10) ng / mL at 15 minutes and decreasing to 4.00 (4.57) ng / mL by 60 minutes post dose. Exposure was confirmed in all participants on active drug, with levels broadly consistent with expectations for the dose delivered. Bufotenine levels were all below the limit of quantification.

[0339] There were no post-dose clinically significant abnormal findings in laboratory values, physical examination, cardiac telemetry, or ECG values. The median readiness for discharge assessment time was 2.1 hours (range: 1 .4-3.8 hours) post dose.

[0340] Eleven (84.6%) of 13 participants in the safety analysis set reported at least one TEAE. A total of 41 TEAEs were reported (22 were mild; 19 were moderate). One participant (7.7%) experienced mild suicidal ideation, which was judged unrelated to the study drug. No participants were withdrawn from the study due to TEAEs.

[0341] Most TEAEs occurred on the day of dosing, and participants recovered from the effects of the study drug within a short time frame. The most frequently occurring treatment-related AEs were drug administration site pain in four (30.8%) participants, transient elevations in blood pressure in four (30.8%) participants, nightmares in two (15.4%) participants, and vomiting in two (15.4%) participants . Of the four participants who experienced administration site pain, nasal pain began within 30 minutes of dosing and lasted between 40 and 195 minutes.

[0342] Two (15.4%) participants reported re-experiencing certain elements of the drug-induced state after the drug effects had worn off (reactivations). These experiences were coded as flashback AEs. On waking during two nights in the week following dosing, one participant - who remained continuously abstinent during follow-up - described seeing lights and experiencing non-distressing fleeting physical sensations, which they associated with BPL-003. The other participant reported a single event 22 days after dosing, in which they felt they could see inside their body while in the bath. The event lasted approximately two minutes and resolved completely. Both participants were aware of their surroundings during the reactivation events.

[0343] All measures of alcohol use were reduced over the 12-week follow-up period. The alcohol biomarker analysis showed that all six abstinent participants had CDT levels <0.8% on Day 84, and all participants who reported drinking during the follow-up period had CDT levels >0.8% on Day 84. Abstinent participants had EtG <60 pg / L at all post-dose assessments, as did one participant who reported drinking on one day only during the follow-up period. For the remaining five participants who reported drinking, the mean EtG on Day 84 was 42,553.8 pg / L. Two participants had higher EtG levels at Day 84 than at screening. This was reflective of the TLFB results, which showed that both reported increased drinking towards the end of the study.

[0344] Table 1 below, and Figure 2, show the average alcohol units / day (UPD) for the 12 patients.

[0345] Table 1. Average Units Per Day

[0346] *This patient's stated goal was not abstinence. All other patients stated their goal was abstinence.

[0347] The average daily alcohol consumption among patients declined from 9.3 units / day prior to dosing, to 2.2 units / day in the period from 56 to 84 days post-treatment. This represents a 76% average reduction in alcohol consumption. Excluding the patient for whom abstinence was not a goal further increases the average reduction in alcohol consumption to 84%. A reduction in the mean number of drinking days for these patients before and after BPL-003 dosing is shown in Figure 3.

[0348] As can be seen, there is a clear and sustained drop in UPD for the patient cohort when taken as a whole. The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0349] Table 2 below, and Figure 4, show the number of Heavy Drinking Days (HDD) for the 12 patients.

[0350] Table 2. Heavy Drinking Days (HDD) As can be seen, there is a clear and sustained drop in HDD for the patient cohort when taken as a whole. The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0351] Table 3 below, and Figure 5, show the percentage Heavy Drinking Days (PHDD) for the 12 patients.

[0352] Table 3. Percentage Heavy Drinking Days (PDD)

[0353] As can be seen, there is a clear and sustained drop in PHDD for the patient cohort when taken as a whole (Figure 6). The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0354] Table 4 below, and Figure 7, show the percentage of Drinking Days (DD) for the 12 patients.

[0355] Table 4. Percentage Drinking Days (DD)

[0356] As can be seen, there is a clear and sustained drop in percentage drinking days for the patient cohort when taken as a whole. The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0357] Table 5 below, and Figure 8, show the number of standard units of alcohol consumed per week for the 12 patients.

[0358] Table 5. Number Of Standard Units Of Alcohol Consumed Per Week

[0359] The average weekly alcohol consumption among patients, measured in standard units, declined from 65 units / week prior to dosing (in the period 3 days before treatment to 85 days before that), to 15 units / week in the period from 56 to 84 days post-treatment. This represents a 77% average reduction in alcohol consumption. Excluding the patient for whom abstinence was not a goal further increases the average reduction in alcohol consumption to 85%.

[0360] As can be seen, there is a clear and sustained drop in average weekly alcohol consumption for the patient cohort when taken as a whole. The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0361] Table 6 below, and Figure 9, show the maximum number of standard units of alcohol consumed on any one day for the 12 patients. Table 6. Maximum Number Of Standard Units Of Alcohol Consumed On Any One Day

[0362] The average maximum number of standard units of alcohol consumed on any one day among patients declined from 22.1 units prior to dosing, to 10.2 units in the period from 56 to 84 days post- treatment. This represents a 53.8% reduction on average.

[0363] Excluding the patient for whom abstinence was not a goal further increases the average reduction in maximum units per day to 57.3%.

[0364] As can be seen, there is a clear and sustained drop in average maximum number of standard units of alcohol consumed on any one day for the patient cohort when taken as a whole. The results are even more promising if the patient for whom abstinence was not a goal was to be excluded.

[0365] Table 7 below, and Figure 10, show the percentage of abstinent days for the 12 patients.

[0366] Table 7. Percentage Of Abstinent Days

[0367] As can be seen, there is a clear and sustained increase in the percentage of abstinent days for the patient cohort when taken as a whole (Figure 11). The results are even more promising if the patient for whom abstinence was not a goal was to be excluded, with 6 / 12 patients completely abstinent during the period following dosing (Figure 12).

[0368] The person skilled in the art will appreciate that these results are unprecedented when compared with approved treatments for AUD.

[0369] For example, naltrexone, when given daily at a dose of 100mg for 16 weeks reduced the risk of a heavy drinking day to 66.2% (NCT00006206) whereas a single dose of BPL-003 reduced the % heavy drinking days to 6.5%, 8.0%, 11.3% and 13.2% over days 1-14, 15-28, 29-56 and 57-84 postdose, respectively.

[0370] In a meta-analysis of 50 randomized trials with 7793 subjects with alcohol use disorder, naltrexone decreased total drinking days by approximately 4% (Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, Kim MM, Shanahan E, Gass CE, Rowe CJ, Garbutt JC. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014 May 14;311(18):1889-900. doi: 10.1001 / jama.2014.3628. PMID: 24825644.), whereas a single dose of BPL-003 reduced the percentage of drinking days (compared to the period 3 days before treatment to 85 days before that) by 84.85%, 83.08%, 75.75% and 71.20% for days 1-14, 15-28, 29-56 and 57-84 post-dose, respectively.

[0371] Figure 13 shows the MEQ-30 results for the 12 patients.

[0372] The results herein disclosed show that treatment with BPL-003 can induce sustained reductions in alcohol use and Heavy Drinking Days (HDDs) for up to 3 months following a single dose.

[0373] Participant and investigator ratings of disease severity showed improvement (Table 8, Figure 14). The mean total MADRS scores fell within the normal range at all time points (Table 8). Two participants with a reported history of Major Depressive Disorder had elevated MADRS scores at various timepoints, one with a score of 21 at Day 84 and the other with scores of 12 at Days 28 and 56, and 8 at Day 84. Throughout the study, no participants reported PGIC scores >3.

[0374] Participants rated their quality of life high at baseline with regards to their mobility, self-care, usual activities and levels of pain or discomfort, as assessed using the EQ-5D-5L (Table 9); however, around a third of participants said they were slightly or moderately depressed or anxious. EQ-5D-5L scores did not differ greatly during the study, although there was a numerical increase in mean (SD) score for the EQ-VAS from 72.2 mm at baseline to 77.3 mm at Day 84.

[0375] Table 8. Summary of exploratory efficacy outcomes (efficacy analysis set). Table 9. Summary of 5-Level EuroQol 5-Dimension (EQ_5D-5L) results (efficacy analysis set).

[0376] Item assessed Time point Question n (%)

[0377] EQ-5D descriptive

[0378] Mobility (%) Screening 1 have no problems walking 12 (100.0)

[0379] Day 28 I have no problems walking 12 (100.0)

[0380] Day 84 I have no problems walking 12 (100.0)

[0381] Self-care (%) I have no problems washing or dressing

[0382] 11 (91.7) myself Screening

[0383] I have slight problems washing or

[0384] 1 (8.3) dressing myself

[0385] I have no problems washing or dressing

[0386] Day 28 12 (100.0) myself

[0387] I have no problems washing or dressing

[0388] Day 84 12 (100.0) myself

[0389] Usual activities (%) I have no problems doing my usual

[0390] 9 (75.0) activities

[0391] I have slight problems doing my usual Screening 2 (16.7) activities

[0392] I have moderate problems doing my usual

[0393] 1 (8.3) activities

[0394] I have no problems doing my usual

[0395] 11 (91.7) activities

[0396] Day 28

[0397] I have slight problems doing my usual

[0398] 1 (8.3) activities

[0399] I have no problems doing my usual

[0400] Day 84 12 (100.0) activities have no pain or discomfort 10 (83.3)

[0401] Screening I have slight pain or discomfort 1 (8.3)

[0402] I have moderate pain or discomfort 1 (8.3)

[0403] I have no pain or discomfort 9 (75.0)

[0404] Day 28

[0405] I have slight pain or discomfort 3 (25.0)

[0406] I have no pain or discomfort 11 (91 .7)

[0407] Day 84

[0408] I have slight pain or discomfort 1 (8.3)

[0409] Anxiety / depression I am not anxious or depressed 8 (66.7)

[0410] Screening I am slightly anxious or depressed 3 (25.0)

[0411] I am moderately anxious or depressed 1 (8.3) Item assessed Time point Question n (%)

[0412] I am not anxious or depressed 9 (75.0)

[0413] Day 28 I am slightly anxious or depressed 2 (16.7)

[0414] I am moderately anxious or depressed 1 (8.3)

[0415] I am not anxious or depressed 9 (75.0)

[0416] Day 84 I am slightly anxious or depressed 2 (16.7)

[0417] I am moderately anxious or depressed 1 (8.3)

[0418] EQ-VAS

[0419] Item assessed Time point n Mean (SD)

[0420] How good or bad your Screening 12 72.2 (10.05) health is today Day 28 12 77.0 (4.22)

[0421] Day 84 12 77.3 (16.60)

[0422] Abbreviations: EQ-5D-5L, 5-level EuroQol-5 Dimension; EQ-VAS, EuroQol visual analogue scale; n, number of participants; SD, standard deviation.

[0423] Initial findings show that BPL-003 induced a sustained reduction in alcohol use, with the mean number of alcohol units per day decreasing from 9.3 at the start of the study to 2.2 in the 12 weeks following dosing. The mean percentage of Heavy Drinking Days dropped from 56% pre-dose to 13% at the end of the 12 week evaluation period, whilst the number of abstinent days increased from 33% to 81%. Furthermore, 50% of participants remained completely abstinent during the 12-week followup period following a single dose.

[0424] Overall, participants had positive expectations of treatment; at pre-dose (Day -7), the mean (SD) SETS score for positive expectancy was 4.2 (1 .0) and 1 .8 (1 .5) for negative expectancy. The sample size was insufficient to assess if there was an association between treatment expectations and outcomes. On the day of dosing, a complete mystical experience (defined as reaching or exceeding a score of 3 on all four sub-domains of the scale) was reported by 4 of the 12 participants (33.3%). The mean total MEQ-30 score was 3.0 (SD 1 .0), with mean subdomain scores for positive mood, transcendence of time and space and ineffability scores all >3. The mean total EDI score was 51 .0 (SD 24.2). Tables 10 and 11 , below, show the mean MEQ-30 and EDI scores across these patients over the course of the study.

[0425] Table 10. MEQ-30 scores at day 0 and post dose

[0426] Score n Mean (SD) Median (min, max)

[0427] Mystical subdomain 12 2.67 (1.15) 2.60 (0.40, 4.60)

[0428] Positive mood subdomain 12 3.22 (1 .20) 3.50 (1 .00, 4.67)

[0429] Transcendence of time and space 12 3.42 (1 .49) 3.92 (0.67, 5.00) subdomain

[0430] Ineffability subdomain 12 3.67 (1.10) 3.84 (1.00, 5.00) Total MEQ score 12 3.03 (1.03) 3.07 (0.63, 4.67)

[0431] Abbreviations: MEQ-30, Mystical Experience Questionnaire; n, number of participants; SD, standard deviation.

[0432] Table 11. EDI scores at day 0 and post dose

[0433] Domain n Mean (SD) Median (min, max)

[0434] Experienced dissolution of 'self / ego 12 64.3 (40.9) 80.0 (0, 100)

[0435] I felt at one with the universe 12 59.8 (38.7) 75.0 (1 , 100)

[0436] I felt a sense of union with others 12 59.4 (26.7) 70.0 (1 , 90)

[0437] Experienced drop in self-importance 12 50.6 (36.0) 52.5 (0, 100)

[0438] Experienced disintegration of self / ego 12 40.2 (35.3) 39.5 (0, 100)

[0439] Less absorbed by my issues / concerns 12 49.7 (34.9) 50.0 (0, 100)

[0440] I lost all sense of ego 12 41.4 (35.3) 32.5 (0, 100)

[0441] All notion of self / identity dissolved 12 42.6 (31.3) 50.0 (0, 90)

[0442] Total EDI Score 12 51.0 (24.2) 52.4 (6, 82)

[0443] Abbreviations: EDI, Ego Dissolution Inventory; max, maximum; min, minimum; MEQ, mystical experience questionnaire; n, number of participants; SD, standard deviation.

[0444] BPL-003 was shown to be well-tolerated with adverse events (AEs) being reported as mild or moderate and there were no serious or severe adverse events reported. Most patients were also assessed as ready for discharge within approximately 2 hours.

[0445] Example 2: A. double-blind, randomised. Phase I, single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate (BPL-003) in healthy subjects

[0446] A single ascending dose study to evaluate the safety, tolerability and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate (BPL-003) was performed. The doses tested were 1 mg, 2.5mg, 4mg, 6mg, 8mg, 10mg and 12mg. The pharmacokinetics were shown to be approximately dose linear. No dose exceeded the maximum exposure limits defined by previous preclinical work in dogs: Cmax: 421 ng / mL or AUC 220 h.ng / mL. The mean Cmax was 29ng / mL for the 12 mg dosage. The mean Tmax was 9.5 minutes whilst the mean half-life (T1 / 2) was 21 minutes. Bufotenin, the O- demethylated metabolite of 5-MeO-DMT, was only detected at very low levels at the 6mg dose level after the 16 minutes time point.

[0447] Subjective Drug Intensity (SDI)

[0448] The intensity of BPL-003 subjective effects were rated by the participant and psychedelic monitor using the SDI, a Likert Scale of 0-10, where 0 was ‘definitely no effect’ and 10 was ‘the strongest effect imaginable for 5-MeO-DMT’. The assessment was performed every 2 minutes for up to 90 minutes post-dose, and if the trial participants were not responsive, the psychedelic monitor would assess the rating to be 10.

[0449] Mystical Experiences Questionnaire (MEQ-30) The M EQ-30 is a 30-item questionnaire to evaluate mystical experiences, with subdomains to measure mystical, positive mood, transcendence, and ineffability factors. Participants rated the degree to which they experienced each of the 30 phenomena using the following scale: 0 (none; not at all), 1 (so slight cannot decide), 2 (slight), 3 (moderate), 4 (strong [equivalent in degree to any other strong experience]) or 5 (extreme [more than any other time in my life and stronger than 4]). Means were calculated for each subdomain and a total overall score. The % of participants experiencing a “complete mystical experience” in each dose cohort was assessed by calculating the number of participants that scored 3 and above (>60% of the attainable value) in all of the four subdomains of the M EQ-30.

[0450] Subjective Experience Data via Qualitative Interview

[0451] A description of the BPL-003 subjective experience data was gained from a qualitative interview utilising the “micro-phenomenology” interview technique. Participants were asked to take part in this optional qualitative interview. If they agreed, the interview commenced on cessation of the psychedelic experience and before any post-dose questionnaires were completed.

[0452] Challenging Experience Questionnaire (CEQ)

[0453] The CEQ has been used to characterise challenging experiences with psilocybin and is used in this trial to characterise and quantify any potentially challenging experiences with BPL-003. The questionnaire is grouped into 7 factors with 26 questions rated 0 (none / not at all) to 5 (extreme / more than ever before). Means % scores were calculated for each factor and total overall % score.

[0454] Results

[0455] Safety and Tolerability:

[0456] Overall, 21 participants (47.7%) had TEAEs across all cohorts; 19 participants (61.3%) that received BPL-003 and 2 participants (15.4%) that received placebo. The incidence of TEAEs in participants that received BPL-003 did not appear to correlate with dose. Most TEAEs 34 out of 38 (89.5%) were mild in severity; 4 out of 38 (10.5%) were moderate in severity. There were no severe or serious TEAEs, or any TEAEs leading to withdrawal from the trial. All TEAEs and the number of times each event occurred are shown in Table 12 below. The most frequently reported TEAEs were nasal discomfort (10 participants [26.3%]; all taking BPL-003 [2.5-8 mg and 12 mg]), nausea (7 participants [18.4%]; all taking BPL-003 [4-12 mg]), vomiting (5 participants [13.2%]; all taking BPL-003 [4, 8 and 12 mg]), and headache (4 participants [10.5%]; 1 [7.7%] taking placebo vs. 3 [9.7%] taking BPL-003 [4 and 8 mg]).

[0457] It was surprisingly found that the number of reported TEAEs for the 10 mg dose were half that reported for the 8mg dose. No participants receiving the 10mg dose reported nasal discomfort, whereas nasal discomfort was reported in at least 1 participant receiving any of the 2.5mg, 4mg, 6mg, 8 mg and 12 mg doses. No vomiting was reported for participants receiving the 10mg dose, whereas vomiting was reported for 40% of those receiving the 12 mg dose and 20% of those receiving the 8mg dose. There is therefore provided a pharmaceutical composition comprising 10mg 5-MeO-DMT wherein said composition has an improved side effect profile. There is therefore provided a pharmaceutical composition comprising 10mg 5-MeO-DMT wherein said composition has an improved tolerability profile.

[0458] Table 12: Summary of treatment-emergent adverse events.

[0459] There were no clinically significant findings for laboratory parameters, vital signs, ECGs, or physical examinations. There were transient increases in blood pressure and heart rate which began soon after BPL-003 treatment but recovered within the 90-minute observation period without intervention. None were considered clinically significant or assessed as AEs by the Investigator.

[0460] Pharmacodynamics

[0461] BPL-003 SDI

[0462] Overall, both monitor and participant drug intensity ratings increased with BPL-003 dose, indicating stronger subjective experience of BPL-003 with increasing dose. SDI onset was rapid, generally within 2-10 minutes and short-lasting, generally resolving completely within 45-90 minutes. Mean subjective intensity scores of participants in the placebo and the highest three BPL-003 doses are shown in Figure 15. The SDI scale has a maximum score of 10, and the mean maximum SDI score achieved by participants increased up to 6 mg BPL-003, after which it plateaued.

[0463] Effects by MEQ-30

[0464] Generally, the Mystical Experience Questionnaire-30 subdomain and total scores increased with BPL-003 dose, with the highest total score of 3.7 at the highest (12 mg) BPL-003 dose level and the lowest total score of 0.58 with placebo (Figure 16 and Table 13). A complete mystical experience, defined by reaching or exceeding a score of 3 on all four subdomains of the scale, was reported in 3 out of 5 participants (60%) at both the 10 mg and 12 mg doses; for lower doses a maximum of 1 participant had a complete mystical experience (<25%).

[0465] Table 13: Summary of MEQ-30 scores

[0466] MEQ, mystical experience questionnaire; SEM, standard error of the mean

[0467] There is therefore provided a pharmaceutical composition comprising 10mg 5-MeO-DMT wherein said composition has an improved side effect profile and produces a complete mystical experience. There is therefore provided a pharmaceutical composition comprising 10mg 5-MeO-DMT wherein said composition has an improved tolerability profile and produces a complete mystical experience. Effects by CEQ

[0468] Challenging Experience Questionnaire scores were generally less than 40% across the 7 subdomains, with total CEQ scores ranging from 20-37% for BPL-003 of 4 mg to 12 mg.

[0469] BPL-003 Subjective Experiences by Qualitative Interview

[0470] The common psychedelic experiences that were reported during the qualitative interviews highlighted the dynamic temporal progression of the subjective effects. Generally, participants described a rapid onset of the psychedelic effects, followed by inward focussed attention, altered sense of time, intense emotions, with various degrees of fear or discomfort, as well as a psychological struggle to “let go and surrender” to the experience. If participants were able to relax into the experience and “let go”, the sensation of floating in space, an ocean or void often followed, with feelings of peacefulness, calmness, relaxation or bliss. At the higher doses (10 mg and 12mg of BPL- 003) most participants appeared to experience a complete mystical experience. Gradually external awareness returned, and participants stated this allowed them to reflect on their experiences, often recounting meaningful insights. Many participants emphasised the importance of the psychological preparation, and the rapport and trust they built with the psychedelic monitors which they said helped participants to feel safer during the experience. Even participants who had challenging experiences, reported having benefited from these, as new insights or learnings about overcoming difficulties, or processing repressed or avoided memories justified the challenge.

[0471] Example 3: Results of a Phase Ila study into 5-MeO-DMT for Treatment Resistant depression / major depressive disorder (TRD)

[0472] In an open-label Phase Ila study, patients with moderate-to-severe TRD symptoms who were not taking concomitant antidepressants were given a single 10mg dose of BPL-003 (5-MeO-DMT benzoate) alongside psychological support in order to explore the safety, efficacy and pharmacokinetics of the treatment. 12 subjects were dosed, and 11 met the criteria for per-protocol analysis.

[0473] 12 patients, 83% male, 83% white, with a mean age of 42 (31-55) years received 10mg BPL- 003. The mean number of failed antidepressants in the current episode was 3.2 (range of 2-5), with citalopram and sertraline the most frequently failed antidepressants. 2 (17%) of the patients washed out their antidepressants during screening.

[0474] Patients were followed for 12 weeks post-dosing, with assessments conducted at multiple points throughout the period. A single dose of BPL-003 was shown to deliver a rapid response in 55% of patients with TRD by day 2, with 55% of patients in remission at day 29 and 45% of patients in remission at day 85. This is the longest-known follow-up of improvement in depression / major depressive disorder outcomes for a clinical study of 5-MeO-DMT.

[0475] 75% of subjects were assessed as being ready for discharge at the first assessment time of

[0476] 90 minutes, confirming the potential for a short treatment duration, fast discharge and low resource burden with BPL-003. Analysis of the per-protocol population (n=11) shows that a single 10mg dose of BPL-003 rapidly induced a clinically significant 12.7 point mean reduction in the Montgomery-Asberg depression / major depressive disorder Rating Scale (MADRS) score in TRD patients from as early as

[0477] I day post-dose and a response was sustained up to day 85 post-dose (13 point mean reduction from baseline). BPL-003 demonstrated good tolerability, with convenient nasal administration and no serious adverse events reported. Most reported events were mild-to-moderate and resolved themselves within the dosing session, which is broadly consistent with Phase I findings (see Example 2).

[0478] BPL-003 was well tolerated with no serious adverse events (AEs) or withdrawals due to AEs. Overall, 10 patients (83%) reported 22 treatment-emergent AEs (TEAEs); 10 TEAEs were rated mild,

[0479] I I moderate, and 1 severe. The most frequently reported TEAEs were nasal discomfort (4 patients; 33%), nausea (4 patients; 33%s), vomiting (2 patients; 17%) and headache (2 patients; 17%). 9 patients (75%) reported 16 TEAEs on Day 1 , with the remaining 6 TEAEs reported on Day 2 or later.

[0480] BPL-003 was also shown to produce a rapid onset and timely offset of psychedelic experiences, which have previously been shown to correlate with positive clinical improvement. 9 / 12 subjects were assessed as being ready for discharge at the first assessment time of 90 minutes, with a mean readiness for discharge time for all 12 subjects of 107 minutes. This signals the potential for a shorter treatment duration and reduced resource burden for healthcare systems compared to other psychedelic treatments currently under development.

[0481] The mean change from baseline in MADRS total score overtime (per protocol population) can be seen in Figure 17. The mean MADRS total score of 27.5±0.97 at Baseline was reduced to 14.8± 8.99 at Day 2 and to 14.5±11 .54 at Day 85. This represents a reduction of 12.6 MADRS points at Day 2, and 13.0 MADRS points at Day 85. The responder rate was 55% at Day 2, which was sustained at 55% at Day 85. The remitter rate was 36% at Day 2 and increased to 45% by Day 85, BPL-003 was administered as a dry powder from a single-use FDA-approved intranasal delivery device. The acute subjective experience in TRD patients was comparable to the findings of the Phase I clinical trial described in Example 2. Both groups of subjects were able to reach a score of equal to or greater than 3 out of 5 (as measured by the MEQ-30), which has previously been shown to correlate with short-term and long-term clinical symptom improvement.

[0482] The results for each of the 10-items of the MADRS for the per protocol population (PPP) can be seen in Tables 14a-b below. As can be seen, a single administration of BPL-003 leads to reductions in the scores of each of the 10-items, said reductions being present from day 2 and being sustained out to day 85. Surprisingly, it can be seen that reductions in each of “inability to feel”, “reduced sleep”, “reduced appetite”, “apparent sadness”, “lassitude” and “concentration” are larger at day 85 compared with day 2.

[0483] Table 14a: Average MADRS scores reported by subjects Pre- and Post-BPL-003 administration.

[0484] Table 14b: Average MADRS scores reported by subjects Pre- and Post-BPL-003 administration. In an embodiment, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients and wherein following a single dose of 5-MeO-DMT, an antidepressant response is sustained. In an embodiment, an antidepressant response may be an improvement in one or more of the 10-items of the MADRS.

[0485] The person skilled in the art will appreciate that the examples provided herein are supportive of claims to the use of 5-MeO-DMT pharmaceutical compositions in the rapid and sustained treatment of both depressive disorders such as treatment resistant major depressive disorder and substance use disorders, such as alcohol use disorder. In an embodiment, an antidepressant response is sustained for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ,

[0486] 12, 13, 14 or 15 or more weeks. In an embodiment, an antidepressant response is defined as a reduction in MADRS score (from baseline) of 5, 6, 7, 8, 9, 10, 11 , 12 or 13 points or more. In an embodiment, the antidepressant response is defined by one or more of the alternative measures known to the person skilled in the art for the definition of antidepressant response. In an embodiment, a rapid method of treatment of depression / major depressive disorder is a treatment wherein a patient / subject reports a reduction in MADRS score (from baseline) of 5, 6, 7, 8, 9, 10, 11 , 12 or 13 points or more, within 1 , 2, 3, 4, 5, 6 or 7 days of treatment. In an embodiment, there is provided a pharmaceutical composition, wherein the pharmaceutical composition comprises 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients and wherein following a single dose of 5-MeO-DMT, an antidepressant response is sustained for 12 weeks or more.

[0487] In an embodiment, the composition comprises 5-MeO-DMT benzoate. In an embodiment, the composition comprises amorphous 5-MeO-DMT benzoate. In an embodiment, the composition comprises crystalline 5-MeO-DMT benzoate. In an embodiment, the composition comprises 10mg of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. In an embodiment, the composition comprises 10mg of 5-MeO-DMT benzoate.

[0488] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving concentration in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving concentration in a treatment resistant major depressive disorder patient.

[0489] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing pessimistic thoughts in a treatment resistant major depressive disorder patient.

[0490] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing apparent sadness in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing apparent sadness in a treatment resistant major depressive disorder patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing an inability to feel in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing an inability to feel in a treatment resistant major depressive disorder patient.

[0491] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving sleep quality in a treatment resistant major depressive disorder patient.

[0492] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing sadness in a treatment resistant major depressive disorder patient.

[0493] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing lassitude in a treatment resistant major depressive disorder patient.

[0494] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing inner tension in a treatment resistant major depressive disorder patient.

[0495] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of reducing suicidal thoughts in a treatment resistant major depressive disorder patient.

[0496] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in in a patient in need thereof. In an embodiment, the patient is a depressed patient. In an embodiment, the patient is a treatment resistant depressed patient. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of improving appetite in a treatment resistant major depressive disorder patient.

[0497] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression / major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression / major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression / major depressive disorder. In an embodiment, there is provided the use of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression / major depressive disorder.

[0498] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of treatment resistant depression / major depressive disorder in a patient in need thereof, wherein the treatment resistant depression / major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and / or quetiapine.

[0499] In an embodiment, the treatment resistant depression / major depressive disorder has failed to be treated with one or more of the following: citalopram, sertraline, mirtazapine, escitalopram, venlafaxine, fluoxetine, paroxetine, amitriptyline and / or quetiapine, in the current episode.

[0500] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression / major depressive disorder, or treatment resistant depression / major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose.

[0501] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression / major depressive disorder, or treatment resistant depression / major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the pharmaceutical composition is as described herein and wherein the method is a as described herein.

[0502] In an embodiment, there is provided the use of a pharmaceutical composition comprising 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, in a method of treatment of depression / major depressive disorder, or treatment resistant depression / major depressive disorder, wherein the method is a rapid method of treatment which produces sustained results from a single dose, wherein the depression / major depressive disorder or treatment resistant depression / major depressive disorder, is treated within 1 day of the single dose and wherein the response is sustained for 12 weeks or more.

[0503] In an embodiment, there is provided a method as disclosed herein wherein the disease / condition to be treated has previously failed to be treated with one or more treatments. In an embodiment, the disease / condition has previously failed to be treated with one or more antidepressants, such as citalopram and / or sertraline. In an embodiment, the disease / condition has previously failed to be treated with one or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with two or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with three or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with four or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with five or more treatments, in the current episode of the disease / condition. In an embodiment, the one or more treatments were administered at an adequate dose for an adequate length of time.

[0504] In an embodiment, there is provided the use of a pharmaceutical composition as described herein wherein the disease / condition to be treated has previously failed to be treated with one or more treatments. In an embodiment, the disease / condition has previously failed to be treated with one or more antidepressants, such as citalopram and / or sertraline. In an embodiment, the disease / condition has previously failed to be treated with one or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with two or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with three or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with four or more treatments, in the current episode of the disease / condition. In an embodiment, the disease / condition has previously failed to be treated with five or more treatments, in the current episode of the disease / condition. In an embodiment, the one or more treatments were administered at an adequate dose for an adequate length of time.

[0505] In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, not more often than once every 1 , 2 or 3 months. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, once every three months. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, at a frequency of once per three months.

[0506] In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, not more often than once every 4, 8 or 12 weeks. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, once every 12 weeks. In an embodiment, the method of treatment comprises the administration of a pharmaceutical composition comprising 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, at a frequency of once per 12 weeks.

[0507] In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 90 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 100 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 110 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 120 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 130 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 140 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 150 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 160 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 170 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 180 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 190 minutes post-dose. In an embodiment, the pharmaceutical composition is for use in a method of treatment wherein the patient / subject is ready for discharge within 200 minutes post-dose.

[0508] In an embodiment, the patient / subject is assessed as being ready for discharge depending on the results of one or more discharge questionnaires. In an embodiment, a discharge questionnaire may be utilised by a professional. In an embodiment, this professional is a licensed medical professional. In an embodiment, a discharge questionnaire may include one or more of the following statements, which must be agreed with in order for a patient / subject to be assessed as ready for discharge: The patient / subject is fully responsive, aware of their surroundings, and reacts adequately; The acute psychedelic effects of the drug have completely subsided; The patient / subject is fully orientated (e.g. name, location, time); Blood pressure and pulse rate have returned to normal or only slightly elevated levels. The breathing frequency and body temperature are normal; The patient / subject has a stable gate and normal muscle coordination and can walk safely; Potential side effects are mild to moderate in intensity and do not need to be medically monitored; The patient / subject has no acute suicidal ideations or suicidal intentions; Possible distress or feelings of being overwhelmed have sufficiently subsided to a degree that the patient / subject themselves feel safe to be discharged; In the opinion of the assessor, the patient / subject is safe to be discharged. In some embodiments of the invention, the suicidal ideation is determined by a clinical professional. In some embodiments, the suicidal ideation is determined using a MADRS score. In some embodiments, the suicidal ideation is self-reported by the subject.

[0509] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration.

[0510] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the patient / subject and wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration and wherein the clinical significant reduction is sustained for at least 12 weeks.

[0511] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0512] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0513] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 10mg of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0514] In an embodiment, there is provided a pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0515] In an embodiment, there is provided a pharmaceutical composition comprising 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0516] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 8mg, 10mg, 12mg or 14mg of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0517] In an embodiment, there is provided a dry powder intranasal pharmaceutical composition comprising 8mg, 10mg, 12mg or 14mg of 5-MeO-DMT benzoate, and one or more pharmaceutically acceptable carriers or excipients, for use in a rapid method of treatment of treatment resistant depression / major depressive disorder in a patient / subject in need thereof, the method comprising a single intranasal administration of the composition to a single nostril of the subject, wherein a clinically significant reduction in MADRS score is obtained within 1 day of said administration, wherein the clinical significant reduction is sustained for at least 12 weeks and wherein said patient / subject is ready for discharge within 90 minutes post-administration.

[0518] In an embodiment, the patient does not inhale during the administration. In an embodiment, the patient experiences greater than 5% 5-MeO-DMT exposure to the turbinates following administration of any of the pharmaceutical compositions described herein. In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the 5-MeO-DMT of the present pharmaceutical compositions reaches the turbinates. In an embodiment, the patient experiences a plasma exposure of between 1-46 ng / mL to 5-MeO-DMT. In some embodiments, the plasma exposure is between 1-46 ng / mL, between 5-40 ng / mL, between 10-35 ng / mL, or between 25-32 ng / mL. In some embodiments, the plasma exposure is at least 25 ng / mL. In some embodiments, the licensed physician overseeing the administration to the patient uses the plasma exposure to adjust dosing. In some embodiments, the subsequent dose received by a patient is 12 mg of 5-MeO-DMT if the plasma exposure was less than 25 ng / mL at the 10 mg dose.

[0519] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT ; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0520] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0521] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT ; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0522] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0523] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0524] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) intranasally administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0525] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0526] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) intranasally administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0527] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient / subject for relapse of one or more symptoms associated with alcohol use disorder; c) administering to the patient / subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0528] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient / subject for relapse of one or more symptoms associated with alcohol use disorder; c) administering to the patient / subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0529] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient / subject for relapse of one or more symptoms associated with alcohol use disorder ; c) administering to the patient / subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0530] In an embodiment, there is provided a method of treating alcohol use disorder in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient / subject for relapse of one or more symptoms associated with alcohol use disorder ; c) administering to the patient / subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0531] In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein said method further comprises psychotherapy. In an embodiment, the psychotherapy is provided prior to administration of the composition. In an embodiment, psychotherapy is provided during administration of the composition. In an embodiment, psychotherapy is provided after administration of the composition. In an embodiment, psychotherapy is provided prior to, during and after administration of the composition.

[0532] In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein said method further comprises psychological support. In an embodiment, the psychological support is provided prior to administration of the composition. In an embodiment, the psychological support is provided during administration of the composition. In an embodiment, the psychological support is provided after administration of the composition. In an embodiment, the psychological support is provided prior to, during and after administration of the composition.

[0533] In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein the method does not comprise the concurrent use of other antidepressant treatments. In an embodiment, the method does not comprise the concurrent use of SSRIs.

[0534] In an embodiment of the present invention there is provided a pharmaceutical composition as described herein for use in a method as described herein wherein the method comprises the concurrent use of other antidepressant treatments. In an embodiment, the method comprises the concurrent use of SSRIs.

[0535] In an embodiment, there is provided a rapid method of treating one or more mental health diseases or conditions as described herein, in a patient / subject in need thereof, wherein the rapid method produces a sustained / durable treatment from a single administration, the method comprising the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject.

[0536] In an embodiment, there is provided a rapid method of treating one or more mental health diseases or conditions as described herein, in a patient / subject in need thereof, wherein the rapid method produces a sustained / durable treatment from a single administration, the method comprising the induction of a, optionally complete, mystical experience in the patient / subject by the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof, to the subject.

[0537] In an embodiment, there is provided a rapid and sustained / durable treatment method of one or more mental health diseases or conditions as described herein, in a patient / subject in need thereof, said treatment method comprising the administration of a single dose of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject. In an embodiment, the rapid method comprises the administration of a single dose of 10mg 5- MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, to the subject. In an embodiment, the rapid method comprises the administration of 10mg 5-MeO-DMT benzoate. The skilled person will understand that 10mg of a 5-MeO-DMT salt, as described herein, refers to the weight of such a salt required to provide a 10 mg free base when the salt is taken / administered. In an embodiment, there is therefore provided a rapid method that comprises the administration of about 15.59mg 5-MeO-DMT benzoate, which is equivalent to 10mg 5- MeO-DMT freebase.

[0538] In an embodiment, there is provided a method of rapidly treating one or more mental health conditions or diseases, as described herein, in a patient / subject in need thereof, comprising inducing a complete mystical experience in a patient / subject by the single administration of a pharmaceutical composition comprising 10mg 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, wherein said rapid treatment is sustained for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks following the single administration.

[0539] In an embodiment, there is provided a method of rapidly treating one or more of cognitive dysfunction, negative thinking, bipolar disorder, postnatal depression / major depressive disorder, postpartum depression / major depressive disorder, social / emotional withdrawal of detachment, psychomotor retardation, anxiety and / or sleep disturbance.

[0540] In an embodiment, there is provided a method of rapidly treating a sleep disturbance, such as insomnia, hypersomnia, circadian rhythm disorder, parasomnia, sleep-related breathing disorder, sleep-related movement disorder, and / or an idiopathic sleep disturbance. In an embodiment, the patient is suffering from: one or more mental or nervous system disorders associated with the sleep disturbance, or a treatment resistant form thereof, selected from one or more of: a disorder characterised by depressive episodes associated with the sleep disturbance, major depressive disorder (MDD) associated with the sleep disturbance, postpartum depression (PPD) associated with the sleep disturbance, compromised maternal functioning, compromised maternal functioning wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 80 or below, such as 65 or below, compromised maternal functioning wherein the treatment improves maternal functioning, compromised maternal functioning wherein the treatment improves maternal functioning reflected by an improvement of the BIMF total score by 10% or more, preferably by 20 % or more, compromised maternal functioning wherein the treatment improves maternal functioning reflected by at least an improvement in the BIMF total score on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, by at least an improvement in the BIMF total score on day 1 , 2, 3, 4, 5, 6 and / or 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT, bipolar disorder associated with the sleep disturbance, bipolar II disorder associated with the sleep disturbance, bipolar I disorder associated with the sleep disturbance, a current major depressive episode, seasonal affective disorder associated with the sleep disturbance, persistent depressive disorder associated with the sleep disturbance, anxiety disorder associated with the sleep disturbance, separation anxiety disorder associated with the sleep disturbance, agoraphobia associated with the sleep disturbance, generalised anxiety disorder (GAD) associated with the sleep disturbance, social anxiety disorder (SAD) associated with the sleep disturbance, panic disorder associated with the sleep disturbance, phobia associated with the sleep disturbance, substance / medication induced anxiety disorder associated with the sleep disturbance, somatic symptom disorder associated with the sleep disturbance, an obsessive compulsive or related disorder associated with the sleep disturbance, body dysmorphic disorder (BDD) associated with the sleep disturbance, post-traumatic stress disorder (PTSD) associated with the sleep disturbance, a pain disorder associated with the sleep disturbance, chronic pain associated with the sleep disturbance, fibromyalgia associated with the sleep disturbance, migraine associated with the sleep disturbance, a mental and behavioural disorder due to psychoactive substance use associated with the sleep disturbance, substance use disorder (SUD) associated with the sleep disturbance, a psychotic disorder associated with the sleep disturbance, schizophrenia associated with the sleep disturbance, Huntington’s disease associated with the sleep disturbance, Parkinson’s disease associated with the sleep disturbance, dementia associated with the sleep disturbance, Alzheimer’s dementia associated with the sleep disturbance, Parkinson’s disease dementia associated with the sleep disturbance, dementia with Lewy Bodies associated with the sleep disturbance, vascular dementia associated with the sleep disturbance, fronto-temporal dementia associated with the sleep disturbance, eating disorder associated with the sleep disturbance, an eating disorder suffers from a treatment resistant form of the disorder, attention deficit hyperactivity disorder (ADHD) associated with the sleep disturbance, a personality disorder associated with the sleep disturbance, schizotypal personality disorder associated with the sleep disturbance, a borderline personality disorder (BPD) associated with the sleep disturbance, an autism spectrum disorder (ASD) associated with the sleep disturbance and / or chronic fatigue syndrome associated with the sleep disturbance.

[0541] In an embodiment, there is provided a method of rapidly treating bipolar disorder in a patient in need thereof. In an embodiment, the bipolar disorder is bipolar I or bipolar II. In an embodiment, the patient: suffers from a current major depressive episode, the patient has a Montgomery- As berg Depression Rating Scale (MADRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37, the patient has a Bipolar Depression Rating Scale (BDRS) total score of equal to or greater than 19, such as equal to or greater than 24, in particular equal to or greater than 37, the patient had no adequate improvement after at least two adequate courses of therapy, the patient had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy, the patient has a Young Mania Rating Scale (YMRS) total score less than or equal to 8 and / or the 5-MeO-DMT or salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a, optionally complete, mystical experience.

[0542] In an embodiment, there is provided a method of rapidly treating anxiety in a patient in need thereof. In an embodiment, the patient: is suffering from is a subthreshold anxiety, has a comorbidity of anxiety and a further diagnosed disorder, is also suffering from a mental or nervous system disorder, is also suffering from a mental or nervous system disorder suffers from a treatment resistant form of the disorder, is also suffering from a disorder characterised by depressive episodes, is also suffering from major depressive disorder (MDD), is also suffering from postpartum depression (PPD), suffers in addition from compromised maternal functioning, has a Barkin Index of Maternal Functioning (BIMF) score of 80 or below, such as 65 or below. In an embodiment, the patient is suffering from a treatment resistant form of one or more of the above conditions or disorders.

[0543] In an embodiment, there is provided a method of rapidly treating one or more as disorders characterised by depressive episodes for example, Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Dis-order and Bipolar II Disorder; Anxiety Disorder, for example Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobias, and Substance / Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); Post-Traumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain, Fibromyalgia and Migraine; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Parkinson's Disease; Dementia, for example Alzheimer’s Dementia (AD), Parkinson’s Disease Dementia (PDD), Dementia with Lewy Bodies, Vascular Dementia, Fronto-Temporal Dementias; Eating Disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality Disorders, for example Schizotypal Personality Disorder and Borderline Personality Disorder; Autism Spectrum Disorder; Chronic Fatigue Syndrome; or a medical health condition leading to an associated mental or nervous system condition, for example anxiety due to Traumatic Brain Injury (TBI), HIV infection, or post COVID condition.

[0544] Treatment as indicated herein with 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof (or a pharmaceutical composition comprising said compound or salt) leads to a clinical response. The response may be assessed by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, which improvement preferably occurs not later than about 2 hours after the single administration of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof.

[0545] The clinical response, as assessed by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists until at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks after the single administration of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. The clinical response may also be assessed by improvement of the MADRS or HAM-D score, compared to the respective score prior to the single administration of 5-MeO-DMT. The clinical response may be assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to the single administration of 5-MeO-DMT.

[0546] This response preferably occurs not later than about 2 hours after the single administration of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. Further, a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, preferably occurs not later than about 2 hours after the single administration of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof. The clinical response, as may be assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, preferably persists until at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks after the single administration of 5-MeO-DMT, or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form thereof.

[0547] Diagnosis of one or more of the diseases / conditions / disorders, as disclosed herein, optionally a mental disorder or a nervous system disorder can, for instance, be in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association. In some instances, as is apparent from the discussion of specific conditions below, the criteria may be modified or supplemented to better define patients or patient groups particularly benefiting from a treatment according to the invention. The diagnosis will in any event be by a physician or a psychologist. It is not sufficient that the human subject himself / herself considers that he / she is suffering from the disorder.

[0548] As used in the context of the present invention, unless otherwise noted, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or eliminate the disease, condition, or disorder. "Treatment of one or more of the diseases / conditions / disorders, as disclosed herein" shall include the management and care of a patient for the purpose of combating negative thinking and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the one or more of the diseases / conditions / disorders, as disclosed herein.

[0549] The patient may suffer from treatment resistant disease. Treatment resistance means that the patient had no adequate improvement after at least two adequate courses of therapy. The patient in particular had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy; for instance, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy. The at least two prior courses of treatment were in particular administered in the current episode of the disease, for instance, if the patient suffers from a disorder characterised by depressive episodes, in the current episode of depression.

[0550] As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" shall mean the amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of the signs and / or symptoms of the one or more of the diseases / conditions / disorders, as disclosed herein. The terms “pharmacologically effective amount,” “therapeutically effective amount,” and the like, when used in reference to a therapeutic composition, refer to a quantity sufficient to, when administered to the subject, including a mammal, for example a human, effect beneficial or desired results, such as clinical results. For example, in the context of treating depression, described herein, these terms refer to an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. The quantity of a given composition described herein that will correspond to such an amount may vary depending upon various factors, such as the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like. An “effective amount,” “pharmacologically effective amount,” or the like, of a composition of the present disclosure, also include an amount that results in a beneficial or desired result in a subject as compared to a control (e.g., a decrease in the score on the Montgomery-Asberg Depression Rating Scale).

[0551] The severity of a condition as well as changes of the severity can be assessed by the Clinical Global Impression (CGI) rating scales which are measures of symptom severity, treatment response and the efficacy of treatments.

[0552] The CGI rating scales were developed to provide a brief, stand-alone assessment of the clinician’s view of the patient’s global functioning prior to and after a treatment (Busner, J. and Tagrum, S. D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0553] The CGI-Severity (CGI-S) is based on one question the clinician has to answer: "Considering your total clinical experience with this particular population, how mentally ill is the patient at this time?" This is rated on the following seven-point scale: 1 =normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.

[0554] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0555] A clinical response may be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 . Preferably, the CGI-S is reduced by at least 2 and / or to a score of 0. It is especially preferred if the CGI-S is reduced by at least 3 and / or to a score of 0.

[0556] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which is similarly simple in its format. After the treatment, the clinician compares the patient's overall clinical condition to the one prior to the treatment (the so-called baseline value). Again, only one query is rated on a seven-point scale: "Compared to the patient's condition at admission to the project [prior to medication initiation], this patient's condition is: 1 =very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment." The Patient Global Impression scale (PGI), also known as Subject Global Impression (SGI), is the counterpart to the Clinical Global Impressions scale (CGI). It consists of one item based on the CGI and adapted to the patient. It can measure disease severity (PGI- S) or disease improvement (PGI-I).

[0557] Individual items of scales as described herein as well as sub-combinations of individual items may be used to assess specific disease aspects. Numerous scales have been suggested to assess severity of one or more conditions or disorders, such as one or more conditions or disorders, such as one or more conditions or disorders, such as a mental disorder or a nervous system disorder. Such scales are based on tests which may be self-administered or administered by a clinician / physician. Scales which may be used according to the invention include those known in the art for diagnosis and / or monitoring the one or more conditions or disorders, such as a mental disorder or a nervous system disorder are discussed in more detail herein. Treatment outcome is assessed by using one or more indices or scales at one or more time points after completion of a treatment course.

[0558] The assessment may be carried out after the complete mystical experience has subsided. An appropriate point in time for an early assessment is generally about 2 to 3 hours after the last administration. An early assessment may generally be carried out, for instance, about 2 hours or about 3 hours after the last administration. An assessment of an effect on, for example, sleep disturbance can, however, be carried out at the earliest on the day after the treatment (i.e., on day 1) so that the treated patient / subject had the opportunity to sleep for at least one night.

[0559] Thus, an assessment at day 1 or on day 1 means an assessment on the day following the administration. The assessment may be carried out not earlier than 12 hours after the last administration and in any event optionally not earlier than one night after the last administration and not later than 36 hours after the last administration. The assessment may be carried out after about 24 hours. An assessment at day 7 or on day 7 means an assessment on the seventh day following the administration (the day of administration is day 0). Analogous definitions apply for other assessment timings measured in days.

[0560] When assessing a clinical response, for instance, using one of the scales to assess severity of one or more conditions or disorders, such as a mental disorder or a nervous system disorder, at an early time point after drug administration (e.g. at 1 , 2 or 3 hours) based on endpoints which have been developed for a longer recall period (e.g. normally 7 days for the MADRS), a rational modification of such endpoint (e.g. changing the MADRS recall period to 1 , 2 or 3 hours and carrying forward the sleep item recorded at baseline before drug administration) may be applied. The same applies with respect to any other scale applied herein, unless a recall period is specifically indicated. The considerations outlined apply for early time points because, on the one hand, in order to assess a clinical response, the influence of the patient's status before the treatment on any score recorded after treatment should be kept as low as possible, whereas on the other hand the sleep item cannot be assessed 1 , 2 or 3 hours after drug administration. At later time points, for instance, on day 1 or later, typically all items of the relevant scales to assess a clinical response may be assessed, using, if necessary, an adapted recall period, so that it is not necessary to carry forward any pre-treatment score.

[0561] There are two fundamental types of sleep: rapid eye movement (REM) sleep and non- REM sleep. Non-REM sleep may be divided into four stages (l-IV). These non-REM stages correspond to an increasing depth of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. During the earlier proportion of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, particularly within the first cycle of sleep. As the night progresses, non- REM sleep becomes shallow and more of each cycle is allocated to REM sleep.

[0562] Normal healthy sleep consists of different phases as outlined above that proceed in successive, tightly regulated order through the night. Disruption of this tight regulation results in sleep disturbances. Sleep disturbance refers to conditions, whether idiopathic or occurring in the context of a medical condition such as for example one or more conditions or disorders, such as one or more conditions or disorders, such as a mental disorder or a nervous system disorder, that affect sleep quality, timing, or duration. It impacts a person’s ability to properly function while the person is awake.

[0563] Common forms of sleep disturbances encompass disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep wake schedule (circadian rhythm disorders), dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia), disorders characterised by respiratory disturbance during sleep (sleep-related breathing disorders) and disorders characterised by abnormal movements during sleep (sleep-related movement disorders). Insomnia is a sleep disturbance where people have difficulty falling or staying asleep. People with insomnia have difficulty falling asleep; wake up often during the night and have trouble going back to sleep; wake up too early in the morning; have unrefreshing sleep; and / or have at least one daytime problem such as fatigue, sleepiness, problems with mood, concentration, accidents at work or while driving, etc. due to poor sleep.

[0564] Hypersomnia is characterised by excessive daytime sleepiness, and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomnia patients / subjects. It is a difficulty transitioning from sleep to wake. Individuals experiencing sleep drunkenness report waking with confusion, disorientation, slowness and repeated returns to sleep.

[0565] Circadian rhythm disorders are characterised by chronic or recurring sleep disturbances due to alterations of the individual’s internal circadian rhythm or due to misalignments between their circadian rhythm and their desired or required work or social schedule. This dyssynchrony may be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are usually shortened and disrupted, performance during the desired waking state is impaired, and temporary opportunities to revert to a regular sleep schedule are unsuccessful.

[0566] Parasomnia designates various forms of sleep disturbance characterised by abnormal behavioural or physiological activity (such as sleepwalking or nightmares) that people experience prior to falling asleep, while asleep, or during the arousal period between sleep and wakefulness. There are considerable variations in terms of characteristics, severity, and frequency. Parasomnia may compromise the quality of sleep.

[0567] Sleep-related breathing disorders are characterised by abnormal and difficult respiration during sleep. Respiration is a complex process that relies heavily on the coordinated action of the muscles of respiration and the (control centre in the) brain. One form of a sleep-related breathing disorder is central sleep apnoea. It occurs when the brain stops sending signals that control breathing, for instance, based on an underlying health condition. Central sleep apnoea has a potentially serious impact on sleep and the balance of oxygen and carbon dioxide in the blood. The reduction of airflow leads to intermittent hypoxia which in leads to sleep fragmentation due to microarousals or awakenings. A consequence may be excessive daytime sleepiness.

[0568] In sleep-related movement disorders repetitive, relatively simple, usually stereotyped, movements interfere with sleep or its onset. The most common of these are restless leg syndrome (RLS) and periodic limb movement disorder (PLMD). Not getting the proper amount or quality of sleep may lead to personality changes and may not only exacerbate existing mental illness, but also be a trigger for the development of mental illness. Sleep disturbance may also interfere with cognitive function and lead to memory impairment. A patient / subject who is deprived of sleep may experience difficulty making decisions, irritability, have problems with performance, and may have slower reaction times. Sleep loss may also adversely affect life by contributing to the development of obesity, diabetes, and heart disease.

[0569] Treatment of sleep disorders varies depending on the type and underlying cause. Maintenance of good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered as first-line treatment. If not successful, treatment also involves pharmacotherapy or psychotherapy. Available treatments are not successful in all patients / subjects, may be associated with side effects and / or require treatment over a long period of time to achieve a relevant treatment effect. In patients / subjects suffering from sleep disturbance in association with one or more conditions or disorders, such as a mental disorder or a nervous system disorder known treatments of the mental or nervous system disorder do not necessarily improve the sleep disturbance.

[0570] For instance, sleep disturbance is frequently associated with mental disorders, such as depression. However, treatment of depression does not necessarily lead to an improvement of the concomitant sleep disturbances. While most antidepressants have been proven to influence the sleep architecture, some classes of antidepressants improve sleep, but others may cause sleep impairment.Sleep may be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of awakenings throughout the night. The quantitative metrics may be measured using objective methods, including polysomnography, actigraphy, and the determination of sleep latency, or by way of self reported measures (questionnaires).

[0571] Polysomnography is a technique requiring that a patient / subject is monitored overnight at a specialised clinic. A variety of functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body positioning and movements, snoring, and heart rate. Another quantitative measurement is actigraphy. An actimetry sensor is worn to measure motor activity, which is recorded continually and used to assess sleepwake cycles. This technique allows the patient / subject to continue normal routines while the required data are being recorded in a natural sleep environment.

[0572] Sleep latency may be measured by the multiple sleep latency test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep across a multiplicity of test naps. An average sleep latency of approximately 10 minutes is considered to be normal; less than eight minutes is indicative of sleep disturbance (excessive daytime sleepiness). Accompanying analysis of brain activity may assist in the further diagnosis of the sleep disturbance.

[0573] Sleep-rating questionnaires capture ratings of components of sleep quality, such as perceptions of sleep depth, rousing difficulties, and restfulness after sleep, in addition to other factors that could affect sleep quality, such as comorbid conditions and medication use. The evaluation of the qualitative aspects of sleep experience is important, as sleep complaints may often persist despite normal values for quantitative measures of sleep. Questionnaires not only facilitate a quick and accurate assessment of a complex clinical problem, but they are potentially also helpful fortracking a patient's progress.

[0574] Various sleep quality indexes are known. The following indexes include examples of questionnaires to assess sleep in general and questionnaires to assess in particular insomnia, hypersomnia, circadian rhythm disorders and parasomnia, respectively. The invention is, however, not limited to the use of a particular index or questionnaire.

[0575] Some questionnaires rely on recall periods (recall windows) of several days or even weeks. While this may be appropriate for diagnosing sleep disturbances, it is not always appropriate for assessing treatment effects, in particular rapid onset of effect after treatment. For several of the questionnaires the recall period may be modified so that the scores obtained reflect a period after treatment. Questionnaires specifically discussed herein to assess effects of a treatment on sleep in patients / subjects suffering from specific conditions rely on a recall period that does not start earlier than the time point when complete mystical experiences have subsided after the last administration. To meet this criterion, the normally applied recall period is modified if necessary.

[0576] Sleep quality in general may be assessed, for instance, with the Sleep-50 questionnaire. The SLEEP-50 questionnaire consists of 50 items designed to screen for a variety of sleep disorders in the general population. The scale consists of nine subscales, reflecting some of the most common disorders and complaints related to sleep and the factors required for diagnosis such as sleep apnoea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors influencing sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a scale ranging from 1 ("not at all") to 4 ("very much") and are asked to indicate the extent to which the statement has matched their experience over the previous month or another appropriate recall window.

[0577] For diagnosing a sleep disorder not only the specific subscale (e.g., insomnia) must exceed a certain cut-off point, but respondents must also meet a cut-off of at least 3 or 4 (“rather much” or “very much”, respectively) on the subscale evaluating the impact of sleep complaints on daily functioning.

[0578] Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value. A common questionnaire assessing sleep disturbance is the Pittsburgh Sleep Quality Index. Other instruments are the insomnia severity index, the Espie sleep disturbance questionnaire and the patient / subject Reported Outcomes Measurement Information System (PROMIS®) Sleep Disturbance.

[0579] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and disturbances. The PSQI is a self-rated questionnaire comprising 19 questions. Respondents are asked to indicate how frequently they have experienced certain sleep difficulties over the past month or another appropriate recall window. The 19 self-rated questions assess a wide variety of factors relating to sleep quality, including estimates of sleep duration and latency and of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1 ) patient / subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping medication; (7) daytime dysfunction. Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances.

[0580] The seven component scores are then summed to yield one global score, with a range of CI- 21 points, "0" indicating no difficulty and "21 " indicating severe difficulties in all areas. A global score cut-off of 5 distinguishes poor from good sleepers. A global score > 5 indicates that a patient / subject is having severe difficulties in at least two areas, or moderate difficulties in more than three areas. If treatment outcome is assessed using the PSQI, treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 5 or below.

[0581] The insomnia severity index (ISI) is a short questionnaire relating to patient / subjective sleep quality, severity of symptoms, patient / subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how noticeable the respondent feels his or her insomnia is compared to others, and the overall level of distress created by the sleep problem. Individual responses may be scored from 0 (=none) to 4 (=very); a higher total score corresponds to more severe insomnia. A total score of 0-7 indicates "no clinically significant insomnia," 8-14 means "subthreshold insomnia," 15-21 is "clinical insomnia (moderate severity)," and 22-28 means "clinical insomnia (severe)". The recall window is two weeks. Another appropriate recall window may also be used. Treatment success may be indicated (i) by a decrease of the score, for instance, by > 7 points, in particular > 8 point; preferably (ii) by a decrease to below the cut-off value for clinically significant insomnia.

[0582] The Espie sleep disturbance questionnaire (SDQ) evaluates patient / subjective experiences of insomnia. With ratings on restlessness / agitation, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ is concerned specifically with beliefs about the sources of sleep issues. Respondents use a five-point scale to indicate how often certain statements about insomnia are representative of their experience. 1 means "never true," while 5 means "very often true." Higher scores are indicative of more dysfunctional beliefs about the causes and correlates of insomnia.

[0583] Treatment success may be indicated by a decrease of the score. The Patient- Reported Outcomes Information System (PROMIS)® Sleep Disturbance instrument is a universal measure to evaluate sleep disturbances. The instrument is available as a long form and 4 different short forms (e.g., 4-, 6-, and 8- items) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulties related to getting and staying asleep over a 7-day period. Each item on the measure is rated on a 5-point scale. The raw scores on the items are summed to obtain a total raw score. Total raw scores are then converted into a standardised T-score using conversion tables. Treatment success may be indicated by a decrease of the T-score.

[0584] Hypersomnia or hypersomnolence may be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity scale. The Epworth Sleepiness Scale (ESS) evaluates overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations representing a moment of relative inactivity, such as a nap in the afternoon or sitting in a car stopped in traffic. Using a scale of 0-3 (with 0 meaning "would never doze" and 3 meaning "high chance of dozing"), respondents rate their likelihood of falling asleep. Scoring ranges from 0-24; the higher the score, the higher the severity of daytime sleepiness. A cut-off score of 10 identifies daytime sleepiness at a potentially clinical level. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to 10 or below.

[0585] The Stanford Sleepiness Scale is a patient / subjective measure of sleepiness, evaluating sleepiness at specific moments in time. Consisting of only one item, the scale requires respondents to select one of seven statements best representing their current level of perceived sleepiness. A scale from 1 (=Feeling active and vital; alert; wide awake) to 7 (=Almost in reverie; sleep onset soon; lost struggle to remain awake) is used to assess the level of sleepiness. Treatment success may be indicated by a decrease of the score. Parasomnias may be evaluated by the Paris Arousal Disorders Severity Scale (PADSS). The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale listing parasomniac behaviours, assessing their frequency and includes an evaluation of consequences. Treatment success may be indicated (i) by a decrease of the score, preferably (ii) by a decrease to below the cut-off value.

[0586] A common questionnaire that assesses sleep-related breathing disorders is the Berlin Questionnaire. An appropriate recall period may also be chosen. Treatment success may be indicated by a decrease of the score. A common questionnaire that assesses sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire asks respondents to use Likert-type ratings to indicate how acutely the disorder has affected them over the course of the past week. Questions may be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their impact (sleep issues, disturbances in daily functioning, and resultant changes in mood. Each of the ten questions requires respondents to rate their experiences with RLS on a scale from 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least. Total scores may range from 0 to 40. As a brief scale with excellent psychometric qualities, the instrument may be suitable for a variety of research and clinical purposes, including screening and assessment of treatment outcomes. Treatment response may be assessed by a decrease of the score.

[0587] Bipolar disorder (BD) has various aspects and is characterised by various symptoms. The predominant psychopathology is depression, and the presentation of a patient / subject experiencing a depressive phase may initially result in the diagnosis of that patient / subject as having major depressive disorder (MDD). However, BD possesses multiple characteristics that define it as distinct from the latter even during the depressive phase.

[0588] Of particular interest here are the symptoms that are more strongly associated with BD compared to other psychiatric disorders, as these are the metrics against which patient / subject treatment is assessed. Notwithstanding that many symptoms may be said to straddle multiple disorders, much work has been done to identify several symptoms that present strongly in BD patients / subjects: sleep disturbance, psychomotor retardation (reduced energy and activity and reduced motivation), negative thinking (feelings of worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory) and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal and affective flattening). Characteristic symptoms further include suicidal ideation. Still further, characteristic symptoms include mixed symptoms (psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation).

[0589] Clinical assessment tools such as the Bipolar Depression Rating Scale (BDRS) have been developed and validated for use in BD, which take into account these symptoms. The Bipolar Depression Rating Scale (BDRS) is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS is validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and / or mixed symptoms expressed by patients / subjects currently and during the past few days. If there is a discordance between symptoms currently and the last few days, the rating should reflect current symptoms. The scale contains 20 questions and the maximum score possible is 60. Higher scores indicate greater severity.

[0590] The questions address depressed mood; sleep disturbance; appetite disturbance; reduced social engagement; reduced energy and activity; reduced motivation; impaired concentration and memory; anxiety; anhedonia; affective flattening; feelings of worthlessness; feelings of helplessness and hopelessness; suicidal ideation; feelings of guilt; psychotic symptoms; irritability; lability; increased motor drive; increased speech; agitation. Each of these aspects is assessed and assigned a score of 0, 1 , 2 or 3.

[0591] Depressed mood is scored as 0 if there is no self-reported and / or observed depression as evidenced by gloom, sadness, pessimism, hopelessness, and helplessness; 1 (mild) in case of brief or transient periods of depression, or mildly depressed mood; 2 (moderate) in case a depressed mood is clearly but not consistently present and other emotions are expressed, or depression is of moderate intensity; 3 (severe) in case of pervasive or continuous depressed mood of marked intensity.

[0592] Sleep disturbance (sleep dysregulation) is assessed based on the change in total amount of sleep over a 24-hour cycle, rated independent of the effect of external factors. It may either take the form of insomnia (reduction in total sleep time) or the form of hypersomnia (increase in total sleep time, inclusive of daytime sleep). The rating for insomnia involves scores of 0 (no reduction in total sleep time); 1 (mild; reduction up to 2 hours); 2 (moderate; 2 - 4 hours); 3 (severe; more than 4 hours).

[0593] The alternative rating for hypersomnia involves scores of 0 (no increase in total sleep time, inclusive of daytime sleep); 1 (mild; less than 2 hours, or normal amount but nonrestorative); 2 (moderate; 2 - 4 hours); 3 (severe; greater than 4 hours).

[0594] Appetite disturbance is assessed based on the change in appetite and food consumption, rated independent of the effect of external factors. It may either take the form of loss of appetite or the form of increase in appetite. The rating for loss of appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but has to push self to eat or reports that food has lost taste); 2 (moderate; some decrease in food intake); 3 (marked decrease in food intake, hardly eating). The alternative rating for increase in appetite involves scores of 0 (no change in appetite and food consumption); 1 (mild; no change in food intake, but increased hunger); 2 (moderate; some increase in food intake, e.g., comfort eating); 3 (marked increase in food intake or cravings).

[0595] Reduced social engagement is scored as 0 if there are no patient / subjective reports of reduced social and interpersonal engagement or interactions; 1 (mild) in case of slight reduction in social engagement with no impairment in social or interpersonal function; 2 (moderate) in case of clear reduction in social engagement with some functional sequelae, e.g., avoiding some social engagements or conversations; and 3 (severe) in case of marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusing to answer the phone or see friends or family.

[0596] Reduced energy and activity is scored as 0 if there is no reduced energy, drive or goal directed behaviour; 1 (mild) in case of ability to engage in usual activities but with increased effort; 2 (moderate) in case of significant reduction in energy leading to reduction of some role-specific activities; and 3 (severe) in case of leaden paralysis or cessation of almost all role specific activities, (e.g., spending excessive time in bed, avoiding answering the phone, poor personal hygiene).

[0597] Reduced motivation is scored as 0 if there are no reports of patient / subjective reduction in drive, motivation, and consequent goal directed activity; 1 (mild) in case of a slight reduction in motivation with no reduction in function; 2 (moderate) in case of a reduced motivation or drive with significantly reduced volitional activity or requiring substantial effort to maintain usual level of function; and 3 (severe) in case of reduced motivation or drive such that goal directed behaviour or function is markedly reduced.

[0598] Impaired concentration and memory are scored as 0 if there are no patient / subjective reports of reduced attention, concentration, or memory, and consequent functional impairment; 1 (mild) in case of slight impairment of attention, concentration, or memory with no functional impairment; 2 (moderate) in case of significant impairment of attention, concentration, or forgetfulness with some functional impairment; 3 (severe) in case of marked impairment of concentration or memory with substantial functional impairment, e.g., unable to read or watch TV).

[0599] Anxiety is scored as 0 if there are no patient / subjective reports of worry, tension, and / or somatic anxiety symptoms e.g., tremor, palpitations, dizziness, light-headedness, pins and needles, sweating, dyspnoea, butterflies in the stomach, or diarrhoea; 1 (mild; transient worry or tension about minor matters); 2 (moderate; significant anxiety, tension, or worry, or some accompanying somatic features); 3 (severe; marked continuous anxiety, tension, or worry that interferes with normal activity; or panic attacks).

[0600] Anhedonia is scored as 0 (no patient / subjectively reduced ability to experience pleasure in usual activities); 1 (mild; slight reduction in pleasure from usually pleasurable activities); 2 (moderate; significant reduction in pleasure from usually pleasurable activities; some pleasure from isolated activities retained); or 3 (severe; complete inability to experience pleasure). Affective flattening is scored as 0 if there is no patient / subjective sense of reduced intensity or range of feelings or emotions; 1 (mild) in case of slight constriction of range of affect, or transient reduction in range or intensity of feelings; 2 (moderate) in case of significant constriction of range or intensity of feelings with preservation of some emotions, e.g., inability to cry; and 3 (severe) in case of marked and pervasive constriction of range of affect or inability to experience usual emotions.

[0601] Feelings of worthlessness (also simply referred to as worthlessness) are scored as 0 (no patient / subjective sense, or thoughts, of decreased self-value or self-worth); 1 (mild; slight decrease in sense of self-worth); 2 (moderate; some thoughts of worthlessness and decreased self-worth) 3 (severe; marked, pervasive, or persistent feelings of worthlessness, e.g., feels others better off without them, unable to appreciate positive attributes).

[0602] Feelings of helplessness and hopelessness (also simply referred to as helplessness and hopelessness) characterise the patient / subjective sense of pessimism or gloom regarding the future, inability to cope, or sense of loss of control. If this is absent, the score is 0. The score is 1 (mild) in case of occasional and mild feelings of not being able to cope as usual, or pessimism; it is 2 (moderate) in case the patient / subject often feels unable to cope, or has significant feelings of helplessness or hopelessness which lift at times; it is 3 (severe) if there are marked and persistent feelings of pessimism, helplessness, or hopelessness.

[0603] Suicidal ideation relates to thoughts or feelings that life is not worthwhile; thoughts of death or suicide and is scored 0 if such thoughts are absent; 1 (mild) in case of thoughts that life is not worthwhile or is meaningless; 2 (moderate) in case of thoughts of dying or death, but with no active suicide thoughts or plans; 3 (severe) in case of thoughts or plans of suicide. Feelings of guilt (also simply referred to as guilt) are scored as 0 if there is no patient / subjective sense of self blame, failure, or remorse for real or imagined past errors; 1 (mild) in case of slight decrease in self-esteem or increased self-criticism; 2 (moderate) in case of significant thoughts of failure, self-criticism, inability to cope, or ruminations regarding past failures and the effect on others; able to recognise as excessive; 3 (severe) in case of marked, pervasive, or persistent guilt, e.g., feelings of deserving punishment; or does not clearly recognise as excessive.

[0604] Psychotic symptoms are scored as 0 if overvalued ideas, delusions, or hallucinations are absent; 1 (mild) in case of mild overvalued ideas, e.g., self-criticism or pessimism without clear effect on behaviour; 2 (moderate) in case of significant overvalued ideas with clear effect on behaviour, e.g., strong guilt feelings, clear thoughts that others would be better off without them; 3 (severe) in case of clear psychotic symptoms, e.g., delusions or hallucinations.

[0605] Irritability reports uncharacteristic patient / subjective irritability, short fuse, easily angered, manifested by verbal or physical outbursts and is scored 0 if absent; 1 (mild) in case of slight patient / subjective irritability which may not be overtly present; 2 (moderate) in case of verbal snappiness and irritability that is clearly observable in the interview; 3 (severe) in case of reports of physical outbursts, e.g., throwing / breaking objects, or markedly abusive verbal outbursts. Lability is scored 0 if there are no observed mood lability or reported mood swings. It is scored 1 (mild) in case of patient / subjective reports of mild increase in mood lability; 2 (moderate) if mood lability is clearly observable, moderate in intensity; 3 (severe) in case of marked and dominant mood lability, frequent or dramatic swings in mood. Increased motor drive relates to patient / subjective reports and objective evidence of increased motor drive and motor activity. It is scored 0 in case of normal motor drive: 1 (mild) in case of a slight increase in drive, not observable in the interview; 2 (moderate) in case of clear and observable increase in energy and drive; 3 (severe) if there is a marked or continuous increase in drive. Increased speech relates to an observed increase in either the rate or quantity of speech, or observed flight of ideas. This item is scored 0 if such observations are absent; 1 (mild) if there is a slight increase in the rate or quantity of speech; 2 (moderate) in case of racing thoughts, or if the patient / subject is significantly more talkative, clearly distractible, or in case of some circumstantiality; wherein this does not impede the interview; 3 (severe) in case of flight of ideas; which interferes with the interview.

[0606] Agitation is scored 0 if there is no observed restlessness or agitation; 1 (mild) in case of slight restlessness; 2 (moderate) in case of clear increase in level of agitation; 3 (severe) in case of marked agitation, e.g., near continuous pacing or wringing hands. While a higher score on the BDRS scale indicates more severe disease, there are no generally accepted limits for when a patient / subject is to be considered moderately or severely ill. BDRS score ranges used herein for indicating the severity of depressive episodes in patients / subjects with bipolar disorder are 13-18 for "mildly ill", 19-23 for "moderately ill", 24-36 for "markedly ill", 37-39 for "severely ill", and * 40 for "extremely ill". Various other scales are also useful to assess the severity of disease as well as the clinical outcome of treatments.

[0607] Anxiety is sometimes defined as an "apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic symptoms of tension". Anxiety is characterised by an intense, excessive, and persistent worry and fear about a situation that is only patient / subjectively seen as menacing and is often accompanied by muscular tension, restlessness, fatigue, inability to catch one's breath, tightness in the abdominal region, nausea, and problems in concentration.

[0608] In anxiety disorders or other mental or nervous system disorders associated with anxiety, the feelings of anxiety are difficult to control and interfere with daily activities. Anxiety is a core feature of anxiety disorders, including separation anxiety disorder, specific phobia, social anxiety disorder (social phobia), panic disorder, generalised anxiety disorder (GAD), agoraphobia, and substance / medication-induced anxiety disorder. Anxiety is moreover associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disturbance.

[0609] Several rating scales to assess anxiety are known on the art, and anxiety symptoms are furthermore assessed as part of various rating scales used to assess mental and nervous system disorders. The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. The scale is clinician / physician-administered. It has 14 items which may be divided into a group of psychic items (1 -6 and 14) measuring in particular mental agitation and psychological distress and into a group of somatic items (items 7-13) measuring in particular physical complaints related to anxiety.

[0610] Each item is rated by the interviewer on a scale from 0 to 4: 0 = Not present, 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Very severe. A total score is obtained by summing the 14 items. The total score range is 0-56. Higher scores indicate more anxiety. A score <7 is considered to represent no or minimal anxiety; a score of 8-14 mild anxiety; a score of 15-23 moderate anxiety; a score > 24 severe anxiety.

[0611] The Beck Anxiety Inventory (BAI) is a 21 -item self-report questionnaire developed to assess anxiety, with a focus on somatic symptoms. The items are rated on a four-point Likert scale ranging from zero (not at all) to three (severely: I could barely stand it). The total score ranges from 0 to 63. Subthreshold anxiety as the term is used herein in particular means that the patient / subject has a Hamilton Rating Scale for Anxiety (HAM-A) score of at least 9 but of less than 18 and / or a Beck Anxiety Inventory (BAI) score of at least 1 1 but of less than 16.

[0612] Negative thinking or individual aspects thereof, such as worthlessness, helplessness and hopelessness, and guilt, may be evaluated by different instruments, such as questionnaires or scales. Questionnaires assess the mental status of a patient / subject based on observations made by the patient / subject himself / herself, caregivers or the clinician / physician administering the questionnaire. Questionnaires used to assess whether a patient / subject suffers from a particular mental or nervous system disorder may comprise items related to negative thinking. Instruments evaluating relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule - Expanded Form (PANAS-X) or the State Hope Scale (SHS).

[0613] The State Shame and Guilt Scale (SSGS) is a self-rating scale of in-the-moment (state) feelings of shame, and guilt experiences. It comprises two subscales, a shame and a guilt subscale. The shame subscale comprises items 1 , 3, 5, 7, 9. The guilt subscale comprises items 2, 4, 6, 8, 10. All items are scored in a positive direction and are rated on a 5-point Likert scale. It contains some statements which may or may not describe how the patient / subject is feeling right now. A higher score indicates a more intense feeling of shame or guilt. The Positive and Negative Affect Schedule - Expanded Form (PANAS-X) is a 60-item, expanded version of the PANAS. The PANAS-X measures 11 specific affects: Fear, Sadness, Guilt, Hostility, Shyness, Fatigue, Surprise, Joviality, Self- Assurance, Attentiveness, and Serenity. The PANAS-X thus provides for mood measurement at two different levels. The basic negative emotion scales are fear, hostility, guilt and sadness, while the scale of guilt encompasses six items: guilty, ashamed, blameworthy, angry at self, disgusted with self, dissatisfied with self. Each answer should be scored as 1 = very slightly or not at all; 2= a little; 3= moderately; 4= quite a bit; or 5= extremely. However, investigators facing more severe time constraints may select and assess only those scales that are most relevant to their research.

[0614] More intense feelings of guilt are reflected by a higher score on the guilt scale. The PANAS-X is simple and easy to administer. Most patients / subjects complete the entire 60- item schedule in 10 minutes or less. This scale consists of a number of words and phrases that describe different feelings and emotions. While it should be indicated to what extent the patient / subject has felt this way during the past few weeks, it has been found that the trait scores on the PANAS-X scales are stable over time, including “at the present moment”, “today” and during “the past few days”, indicating that an appropriate shorter recall period may be applied. The State Hope Scale (SHS) has three agency and three pathways items to which respondents describe themselves in terms of how they are "right now." The agency subscale score is derived by summing items 2, 4 and 6, relating to the perceived capacity to use one's pathways to reach desired goals; the pathways subscale score is derived by adding the items 1 , 3 and 5, relating to thinking that is used to identify possible ways to achieve a goal. The total State Hope Scale score is derived by summing the three agency and the three pathways items. Scores may range from a low of 6 to a high of 48, wherein higher hope is reflected by a higher score on this scale. Negative thinking or aspects thereof are also reflected in other scales such as HAM-D, the MADRS, the BPRS or the BDRS, wherein relevant items thereof may be commonly applicable for assessing negative thinking or aspects thereof.

[0615] Cognition includes the skills needed for thinking, remembering, paying attention, and solving problems. Loss or decline of these skills leads to cognitive dysfunction, a term used herein to refer to a deficit in, or an impairment of, any domain of cognition. Cognitive dysfunction may be one of the manifestations of a patient's underlying condition.

[0616] The DSM-5 defines six key domains of cognitive function, namely complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. Cognitive dysfunction may impact one or more of those domains. In fact, cognitive abilities are highly interrelated, and it is not unusual that more than one domain is affected. For instance, the domain complex attention has the subdomains sustained attention (commonly referred to as 'concentration' or 'focus'), divided attention, selective attention, and processing speed.

[0617] Thus, complex attention evidently encompasses aspects which are critical for a variety of cognitive tasks, such as executive function and learning and memory. Cognitive control or executive function is intrinsically attentional. Also, perception, and decision-making are profoundly influenced by attention abilities. As a consequence, attention is not only tested for in isolation, but for example, also tested by cognitive control tasks / executive function. If attention is impaired, other types of cognitive abilities will likely also be impaired. Before language may be comprehended, visual- spatial relationships perceived, information remembered or problems solved, the stimuli must be attended to.

[0618] Cognitive dysfunction, which term herein means an acquired condition and thus represents a decline from a previously attained level of functioning, may be associated with various processes. In a healthy individual, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained upon ageing and may even improve over time. However, even in the absence of any pathological condition, ageing leads to declines in abilities like thinking abstractly, reasoning, and decision-making. These deteriorations are linked to underlying age-related deficits in processing speed, attention, memory, and executive function, which are indicative of cognitive ageing.

[0619] Independent of normal ageing, cognitive dysfunction may be associated with one or more conditions or disorders, such as a mental disorder or a nervous system disorder or some other medical conditions. Mental or nervous system disorders which lead to, or are associated with, cognitive dysfunction include disorders characterised by depressive episodes, for example, Major Depressive Disorder (MDD), Postpartum Depression (PPD), Persistent Depressive Disorder, Seasonal Affective Disorder and Bipolar Disorder (BD), such as Bipolar I Disorder and Bipolar II Disorder; Anxiety Disorder, for example Separation Anxiety Disorder, Agoraphobia, Generalised Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder, Phobia, and Substance / Medication Induced Anxiety Disorder; Somatic Symptom Disorder; Obsessive Compulsive and Related Disorders, for example, Obsessive Compulsive Disorder (OCD) and Body Dysmorphic Disorder (BDD); PostTraumatic Stress Disorder (PTSD); Pain Disorders, for example Chronic Pain, Fibromyalgia and Migraine; Mental and Behavioural Disorders due to Psychoactive Substance Use, for example, Substance Use Disorder (SUD); Psychotic Disorders, for example Schizophrenia; Huntington's Disease; Parkinson's Disease; Dementia, for example Alzheimer’s Dementia (AD), Parkinson’s Disease Dementia (PDD), Dementia with Lewy Bodies, Vascular Dementia, FrontoTemporal Dementia; Eating Disorders; Attention Deficit Hyperactivity Disorder (ADHD); Personality Disorders, for example Schizotypal Personality Disorder and Borderline Personality Disorder; Chronic Fatigue Syndrome; one or more conditions or disorders, such as a mental disorder or a nervous system disorder associated with HIV, Traumatic Brain Injury or Post COVID Condition. The cognitive dysfunction may also occur in a patient / subject suffering from sleep disturbance, for instance, insomnia.

[0620] Cognitive dysfunction furthermore occurs in disorders showing symptoms characteristic of a neurocognitive disorder that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning but do not meet the full criteria for any aetiology-related disorder. Cognitive dysfunction may take the form of a neurocognitive disorder. Mild neurocognitive disorder, also referred to as mild cognitive impairment, is characterised by a modest cognitive decline from a previous level of performance in one or more of the cognitive domains. Affected patients / subjects are still able to stay independent and do daily tasks. However, the patient / subject usually functions at a suboptimal level. Everyday tasks become more effortful owing to the engagement of compensatory strategies to maintain independence. In major neurocognitive disorder, a significant cognitive decline from a previous level of performance in one or more of the cognitive domains is observed. The cognitive deficits interfere with independence in everyday activities.

[0621] Cognitive dysfunction may be evaluated by questionnaires or by neuropsychological assessments. Questionnaires assess the mental status of a patient / subject based on observations made by the patient / subject himself, caregivers or the clinician / physician administering the questionnaire. Questionnaires used to assess whether a patient / subject suffers from a particular mental or nervous system disorder may comprise items related to cognitive function. A neuropsychological assessment is a process by which a person’s cognitive, psychological / emotional and behavioural functioning is comprehensively evaluated. A core part of neuropsychological assessment is the administration of neuropsychological tests for the formal assessment of cognitive function.

[0622] Performance in these tests is compared with norms appropriate to the patient's age, educational attainment, and cultural background. Testing often uses a set of performance-based questions, also known as a neuropsychological test battery. The abilities tested include language processing, visuospatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive functions, speed of processing, and sensory-perceptual functions. Common tests that assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screen for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB). The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses different cognitive domains: short-term memory; visuospatial abilities; executive functions; attention, concentration and working memory; language; orientation to time and space. The total possible score is 30 points; a score of 26 or above is considered normal; a score of 18-25 is considered mild cognitive impairment, a score of 10-17 is considered moderate cognitive impairment and a score less than 10 is considered severe cognitive impairment.

[0623] The Mini-Mental State Examination (MMSE) is an 11 -question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The maximum score is 30. The raw score may also need to be corrected for educational attainment and age. Four cut-off levels are employed herein to classify the severity of cognitive impairment: 24-30 means no cognitive impairment; 19-23 means mild cognitive impairment; 10-18 means moderate cognitive impairment; and * 9 means severe cognitive impairment. Used repeatedly, the MMSE is suitable to measure changes in cognitive status. The Mini-Cog™ is a short cognitive impairment screening questionnaire. It combines a 3-word recall with a clock drawing test. The clock drawing test assesses many cognitive areas that may be affected, such as executive function, visuospatial abilities, motor programming, and attention. One point is given for each of the three words correctly recalled after performing the clock drawing test; a correctly drawn clock is worth two points. A score of <4 indicates cognitive impairment.

[0624] The Screen for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening instrument for the examination of cognitive performance in psychiatric patients / subjects. The SCIP consists of five subscales: verbal learning test - immediate (VLT-I), working memory test (WMT), verbal fluency test (VFT), verbal learning test - delayed (VLT-D) and processing speed test (PST). There are three different test forms to facilitate test repetition and therefore reducing learning effect. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score of less than 70 indicates cognitive dysfunction.

[0625] Cognitive dysfunction may also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of the various subtests. The subtests are: Trail Making Test, Part A (testing speed of processing); Brief Assessment of Cognition in Schizophrenia, symbol coding subtest (speed of processing); Hopkins Verbal Learning Test-Revised, immediate recall, three learning trials only (verbal learning); Wechsler Memory Scale, 3rd ed., spatial span subtest (working memory (nonverbal)); Letter-Number Span test (working memory (verbal)); Neuropsychological Assessment Battery, mazes subtest (reasoning and problem solving); Brief Visuospatial Memory Test-Revised (visual learning); Category fluency test, animal naming (speed of processing); Mayer-Salovey-Ca-ruso Emotional Intell...

Claims

CLAIMSWhat is claimed is:1 . A method of treating alcohol use disorder (AUD) in a subject in need thereof, the method comprising administering to the subject having AUD a pharmaceutical composition comprising: (i) about 10mg 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 10mg freebase equivalent of a pharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients.

2. The method of claim 1 , wherein the patient has abstinence as a goal.

3. The method of claim 1 or claim 2, wherein the subject experiences a clinically significant response after administration of the pharmaceutical composition.

4. The method of claim 3, wherein the clinically significant response comprises:(i) a clinically significant reduction in one or more of:Alcohol Units / Day (UPD);Drinking Days (DD);Heavy Drinking Days (HDD);Average number of standard units of alcohol consumed (UoAC), optionally per week;Alcohol cravings, optionally as measured by the Alcohol Craving Questionnaire (ACQ), optionally the Alcohol Craving Questionnaire Short Form Revised (ACQ-SF-R);Negative impacts of alcohol use, optionally as measured by The Drinker Inventory of Consequences (DrlnC), optionally the Short Inventory of Problems (SIP);Severity of AUD, optionally as measured by the Clinical Global Impression of Severity (CGIS) questionnaire;Alcohol use as measured by ethyl glucuronide (EtG) in a sample, optionally urine, from the patient; and / orAlcohol use as measured by carbohydrate deficient transferrin (CDT) in a sample, optionally blood, from the patient; and / or(ii) a clinically significant increase in one or more of:Abstinent Days;Longest duration of, optionally in days, of continuous abstinence; and / or Patient condition, optionally as measured by the Patient Global Impression of Change (PGIC) questionnaire and / or the 5-Level EQ-5D (EQ-5D-5L); wherein the subject experiences a clinically significant response within 1 , 2, 3, 4, 5, 6 or 7 days of the administration.

5. The method of claim 4, wherein the subject experiences a clinically significant response within 2 hours after the administration of the pharmaceutical composition.

6. The method of claim 4, wherein the subject experiences a clinically significant response within 24 hours after the administration of the pharmaceutical composition.

7. The method of claim 4, wherein the subject experiences a clinically significant response with 48 hours after the administration of the pharmaceutical composition.

8. The method of claim 4, wherein the subject experiences a clinically significant response within 7 days after administration of the pharmaceutical composition.

9. The method of any one of claims 4 to 8, wherein the clinically significant reduction in one or more of: UPD, DD, HDD, UoAC, alcohol cravings, negative impacts, severity of AUD, ETG and / or CDT is a reduction from baseline of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

10. The method of any one of claims 4 to 9, wherein the clinically significant reduction in one or more of: UPD, DD, HDD, UoAC, alcohol cravings, negative impacts, severity of AUD, ETG and / or CDT is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration.11 . The method of any one of claims 4 to 10, wherein the clinically significant increase in Abstinent Days and / or patient condition is an increase from baseline of at least 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100%.

12. The method of any one of claims 4 to 11 , wherein the clinically significant increase in Abstinent Days and / or patient condition is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration.

13. The method of any one of claims 4 to 12, wherein the clinically significant change in one or more of the parameters is sustained for at least 85 days following a single administration of the pharmaceutical composition.

14. The method of any one preceding claim, wherein a clinically significant increase in patient condition is achieved as indicated by at least a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score.

15. The method of any one preceding claim, wherein the Timeline Follow-Back (TLFB) interview is used to measure a clinically significant increase or reduction in one or more of the parameters.

16. The method of any one preceding claim, wherein the patient is ready for discharge within 90, 100, 110 or 120 minutes following administration.

17. The method of any one preceding claim, wherein the patient is diagnosed with AUD, mild AUD, moderate AUD or severe AUD, optionally by a licensed professional in accordance with accepted medical practice, as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5).

18. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a rapid method of treating AUD in a patient in need thereof, wherein the method further comprises the provision of psychological support to the patient.

19. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method further comprisesthe provision of psychological support to the patient, wherein the psychological support is provided:Prior to administration of the pharmaceutical composition;During administration of the pharmaceutical composition; and / or After administration of the pharmaceutical composition.

20. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method further comprises the provision of psychological support to the patient, wherein the psychological support is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks prior to administration of the pharmaceutical composition.

21. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method further comprises the provision of psychological support to the patient, wherein the psychological support is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks following administration of the pharmaceutical composition.

22. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method further comprises the provision of at least 3 psychological support sessions over about 2 weeks prior to the administration of the pharmaceutical composition.

23. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of at least 3 psychological support sessions over about 2 weeks prior to the administration of the pharmaceutical composition, wherein the third of the 3 sessions takes place in a medical facility and / or clinic, optionally the same medical facility and / or clinic wherein administration of the pharmaceutical composition takes place.

24. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of psychological support by an AUD therapist and a psychedelic assisted therapy therapist.

25. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of at least 3 psychological support sessions over about 2 weeks following the administration of the pharmaceutical composition.

26. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient.

27. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided:Prior to administration of the pharmaceutical composition;During administration of the pharmaceutical composition; and / or After administration of the pharmaceutical composition.

28. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks prior to administration of the pharmaceutical composition.

29. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treating AUD in a patient in need thereof, wherein the method comprises the provision of relapse prevention psychotherapy to the patient, wherein the relapse prevention psychotherapy is provided for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks following administration of the pharmaceutical composition.

30. The method of any one preceding claim, wherein the patient is ready for discharge within 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 minutes of the administration of the pharmaceutical composition.

31. The method of any one preceding claim, wherein the pharmaceutical composition is administered under the supervision of one or more professionals.

32. The method of any one preceding claim, wherein the pharmaceutical composition is administered under the supervision of one or more licensed professionals.

33. The method of any one preceding claim, wherein the pharmaceutical composition is administered under the supervision of a cognitive behavioural therapist and a psychedelic assisted therapy therapist.

34. The method of any one preceding claim, wherein the pharmaceutical composition is administered by the patient themselves or by a licensed professional.

35. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the pharmaceutical composition is administered by a licensed professional and the method comprises the steps of: the patient sits in an upright position; the patient blows their nose; the pharmaceutical composition is administered by a licensed professional to a single nostril; and the patient does not inhale through their nose during the administration.

36. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment of a patient aged 18 to 64 years.

37. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment of a patient who has a minimum of 4 heavy drinking days (HDD) in the 28 days prior to administration of the pharmaceutical composition.

38. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment of a patient for whom no more than 14 days have elapsed since the last heavy drinking days (HDD) or completion of detoxification.

39. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment of a patient who is willing to abstain from recreational drugs for the duration of their treatment with the pharmaceutical composition.

40. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment of a patient without: a history of any medical condition that could make receiving a sympathomimetic drug harmful because of increases in blood pressure (BP) and heart rate (HR), such as: severe coronary artery disease, history of myocardial infarction, unstable angina, cerebrovascular accident, aneurysm or revascularization procedure within the previous 12 months, significant valvular heart disease, heart failure of any etiology, history of a stroke or transient ischemic attack; a history of uncontrolled hypertension despite adequate therapy or any history of a hypertensive crisis or ongoing evidence of uncontrolled hypertension, optionally defined as repeated supine systolic BP 140 mmHg, or diastolic BP 90 mmHg; a history of seizures, including febrile and withdrawal seizures; uncontrolled or insulin-dependent diabetes; any clinically significant neurological, cardiovascular, pulmonary, gastrointestinal, hepatic, renal, or any other major concurrent illness that, in the opinion of a licensed professional, may interfere with the treatment; any abnormal and, in the opinion of a licensed professional, clinically significant results on physical examination, vital signs, electrocardiogram (ECG), or laboratory tests prior to administration of the pharmaceutical composition; any signs of alcohol withdrawal prior to administration of the pharmaceutical composition, optionally as assessed by the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar); a positive test result for alcohol on the day of administration of the pharmaceutical composition; a positive urine drug screen for illicit drugs or drugs of abuse on the day of administration of the pharmaceutical composition; current use of monoamime oxidase inhibitors (MAO-I), tramadol, opioids, antiviral medication, cytochrome P4502D6 inhibitors, antidepressant medication, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, lithium, antipsychotic medications, triptans, tramadol, 5- hydroxytryptophan (5-HTP), herbal preparations containing 5-HTP, St John’s Wort, or any other medications or supplements that may affect serotonergic function or may interfere with 5-MeO-DMT;history of intolerance to 5-MeO-DMT, dimethyltryptamine (DMT), or related compounds; nasal obstruction, blockage, or symptoms of congestion; and / or personal or family history of malignant hyperthermia.

41. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 40 and 80 days after the first administration.

42. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 50 and 70 days after the first administration.

43. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place between 55 and 65 days after the first administration.

44. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the comprises at least two administrations of the pharmaceutical composition, with the second administration taking place 64 days, ±1 , 2, 3, 4, 5, 6 or 7 days, after the first administration.

45. The method of any one preceding claim, wherein the patient has not taken one or more of the following for at least 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.

46. The method of any one preceding claim, wherein the patient has not taken one or more of the following for at least 1 , 2, 3, 4, 5 or 6 months prior to treatment: psychedelics, such as psilocybin, psilocin, DMT, 5-MeO-DMT, LSD, NMDA, mescaline or ayahuasca.

47. The method of any one preceding claim, wherein the pharmaceutical composition is amorphous or crystalline.

48. The method of any one preceding claim, wherein the pharmaceutical composition is formulated for intranasal administration.

49. The method of any one preceding claim, wherein the pharmaceutical composition is formulated as a dry powder.

50. The method of any one preceding claim, wherein the pharmaceutical composition is formulated as a dry powder, wherein the powder is characterised by one or more of: particles having a median diameter of less than 2000pm, 1000pm, 500pm, 250pm, 100pm, 50pm, or 1 pm; particles having a median diameter of less than 15, 14, 13, 12, 11 , or 10pm; particles having a median diameter of less than 9pm; particles having a median diameter of greater than 500pm, 250pm, 100pm, 50pm, 1 pm or 0.5pm; and / or a particle size distribution of d10=20-60pm, and / or d50=80-120pm, and / or d90=130-300pm.

51. The method of any one preceding claim, wherein the pharmaceutical composition is formulated as a spray dried dry powder.

52. The method of any one preceding claim, wherein the pharmaceutical composition is formulated as a dry blend dry powder.

53. The method of any one preceding claim, wherein the pharmaceutical composition is formulated as a powder which is suitable for administration by inhalation / insufflation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler, a pressurised metered dose inhaler, a nasal delivery device, a nasal spray or an active nasal delivery device.

54. The method of any one preceding claim, wherein the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 10mg 5-MeO-DMT freebase.

55. The method of any one preceding claim, wherein the pharmaceutical composition comprises crystalline 5-MeO-DMT.

56. The method of any one preceding claim, wherein the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 10mg 5-MeO-DMT freebase, wherein: the pharmaceutical composition comprises crystalline 5-MeO-DMT benzoate as characterised by one or more peaks in an XRPD diffractogram at 17.5, 17.7 and 21 ,0°20±O.1 °20 as measured using an x-ray wavelength of 1 .5406 A; the pharmaceutical composition comprises crystalline 5-MeO-DMT hydrochloride as characterised by one or more peaks in an XRPD diffractogram at 9.2, 12.2, 14.1 , 15.0, 18.5 and 19.5°±0.1 °20 as measured using an x-ray wavelength of 1 .5406 A; the pharmaceutical composition comprises crystalline 5-MeO-DMT hydrobromide as characterised by one or more peaks in an XRPD diffractogram at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°20±O.1 °20 as measured using an x-ray wavelength of 1 .5406 A; or the pharmaceutical composition comprises crystalline 5-MeO-DMT oxalate as characterised by one or more peaks in an XRPD diffractogram at 13.0, 19.9 and 26.O°20±O.1 °20 as measured using an x-ray wavelength of 1 .5406 A.

57. The method of any one preceding claim, wherein the pharmaceutical composition comprises one or more of: HPMC, carbomers, xanthan gum, carrageenan, copolymers of methyl vinyl ether and maleic anhydride (PVM / MA), hydroxypropyl cellulose (HPC) or sodium carboxymethylcellulose (Na-CMC), chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N.N- dimethyl chitosan, chitosan chloride), p-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phosphatidyl choline, soybean lecithin, lysophosphatidylcholine,dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, citric acid, a mucoadhesive enhancer, a penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.

58. The method of any one preceding claim, wherein administration of the pharmaceutical composition to the patient in need thereof induces a, optionally complete, mystical experience.

59. The method of any one preceding claim, wherein administration of the pharmaceutical composition to the patient in need thereof induces a, optionally complete, mystical experience as identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-claim revised Mystical Experience Questionnaire (MEQ30) and / or through achievement of at least 60% of the maximum possible score of the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, optionally the , optionally complete, mystical experience is induced within 5, 10, 15, 20, 25, or 30 minutes of administration of the pharmaceutical composition and optionally the , optionally complete, mystical experience is resolved within 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 300 minutes of administration of the pharmaceutical composition.

60. The method of any one preceding claim, wherein administration of the pharmaceutical composition to the patient in need thereof induces ego dissolution.

61. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is given a low-fat meal, such as water and fruit, at least 2 hours prior to treatment.

62. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours prior to treatment.

63. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour prior to treatment.

64. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 1 hour following treatment.

65. The method of any one preceding claim, wherein the pharmaceutical composition is for use in a method of treatment wherein the patient is nil by mouth for at least 2 hours following treatment.

66. The method of any one preceding claim, wherein the patient is monitored for symptoms of alcohol withdrawal.

67. The method of any one preceding claim, wherein the patient is monitored for symptoms of alcohol withdrawal using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar).

68. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside one or more further active agents.

69. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside one or more further active agents wherein the one or more selected agents are nalmefene, fluoxetine, gabapentin, ondansetron, sertraline, topiramate, disulfiram, acamprosate and / or naltrexone.

70. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is acamprosate, optionally two 333 mg enteric-coated tablets three times per day.71 . The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is disulfiram, optionally 250 mg or 500 mg once per day.

72. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside one or more further active agents wherein one of the one or more further active agents is fluoxetine, optionally 20, 40, 60 or 80 mg once per day.

73. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD.

74. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 12 step program.

75. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 12 week program.

76. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 or 52 week program.

77. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program is a group program.

78. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more digital tools.

79. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more ai chatbots.

80. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more digital therapy tools.

81. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises the use of one or more ai therapists.

82. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises sessions which are 30-90 minutes in duration.

83. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises weekly sessions.

84. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises daily sessions.

85. The method of any one preceding claim, wherein the pharmaceutical composition is for use alongside an in-patient treatment or out-patient treatment program, optionally for AUD, wherein the program comprises one or more of individual treatments, group treatments, psychoeducational interventions, help to attend self-help groups, family and carer support and involvement, and case management.

86. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof.

87. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein the other conditions are diagnosed in accordance with the Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) published by the American Psychiatric Association, optionally by a licensed professional in accordance with accepted medical practice.

88. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein treatment of the one or more other conditions is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

89. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and one or more other conditions, in a patient in need thereof, wherein treatment of the one or more other conditions is sustained, optionally for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration of the pharmaceutical composition.

90. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and one or more other conditions selected from: a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, difficult to treat depression, anxiety, treatment-resistant anxiety, end of life anxiety, generalised anxiety disorder, panic disorder, social anxiety, post-traumatic stress disorder, acute stress disorder, obsessive compulsive disorder, social phobia, substance abuse, tobacco abuse, drug abuse, anorexia nervosa, bulimia nervosa, binge eating disorder, primary impulse-control disorders,obsessive-compulsive disorder, a sleep disturbance, such as insomnia, hypersomnia, circadian rhythm disorder, parasomnia, sleep-related breathing disorder, sleep-related movement disorder, and / or an idiopathic sleep disturbance or bipolar disorder in a patient in need thereof.

91. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition.

92. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction in MADRS score is a reduction from baseline of at least 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 points.

93. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction is sustained following the administration of the pharmaceutical composition.

94. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, in a patient in need thereof, wherein a clinically significant reduction in MADRS score is present within 1 , 2, 3, 4, 5, 6 or 7 days of the administration of the pharmaceutical composition and the clinically significant reduction is sustained for 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or more weeks following the administration of the pharmaceutical composition.

95. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as moderate to severe MDD, wherein the moderate to severe MDD is indicated by a Montgomery-Asberg depression / major depressive disorder Rating Scale (MADRS) score of 20 or more or by a 17-claim Hamilton depression / major depressive disorder Rating Scale (HAM-D) score of 17 or more.

96. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and a depressive disorder, such as moderate to severe MDD, wherein themoderate to severe MDD is indicated by a a MADRS score of 35 or more or by a HAM-D score of 25 or more.

97. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD and suicidal ideation.

98. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD in a patient at imminent risk of suicide.

99. The method of any one preceding claim, wherein the method of treatment is a method of treatment of AUD in a patient with suicidal ideation with intention to act.

100. The method of any one preceding claim, wherein the method further comprises having the subject participate in one or more of virtual reality (VR), augmented reality (AR), virtual experience (VE) or spatial computing (SC) experiences.101 . The method of any one preceding claim, wherein the method further comprises having the subject participate in one or more of virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences, wherein the one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) or spatial computing (SC) experiences prior to administration of the pharmaceutical composition and, optionally, said experiences are used to prepare the patient for treatment with the pharmaceutical composition resulting in increased patient tolerability to the treatment and treatment efficacy.

102. The method of any one preceding claim, wherein the method of further comprises having the subject participate in one or more of virtual reality (VR), augmented reality (AR), virtual experience (VE) and / or spatial computing (SC) experiences, wherein the one or more virtual reality (VR), augmented reality (AR), virtual experience (VE) or spatial computing (SC) experiences following administration of the pharmaceutical composition, and, optionally, said experiences are used to aid the patient with integrating following treatment with the pharmaceutical composition resulting in increased treatment efficacy.

103. The method of any one of the preceding claims, wherein the method of prevents relapse in the subject having AUD.

104. The method of any one of the preceding claims, wherein the method of reduces the likelihood of relapse in the subject having an AUD disorder.

105. The method of any one of the preceding claims, wherein the method of reduces alcohol cravings in the subject having AUD.

106. The method of any one of the preceding claims, wherein the method reduces alcohol cravings in a patient in need thereof, as measured by the Alcohol Craving Questionnaire (ACQ).

107. The method of any one of the preceding claims, wherein the method reduces alcohol cravings in a patient in need thereof, as measured by the Alcohol Craving Questionnaire (ACQ) 1 , 7, 28, 56 and / or 84 days after administration of the pharmaceutical composition to the patient.

108. The method of any one of the preceding claims, wherein the method reduces alcohol consumption in a patient in need thereof.

109. The method of any one of the preceding claims, wherein the method reduces heavy drinking days in a patient in need thereof.

110. The method of any one of the preceding claims, wherein the method increases alcohol free days in a patient in need thereof.

111. The method of any one of the preceding claims, wherein the method increases the number of abstinent days in a patient in need thereof.

112. The method of any one of the preceding claims, wherein the method promotes abstinence from alcohol in a patient in need thereof.

113. The method of any one of the preceding claims, wherein the method prevents and / or treats one or more conditions associated with alcohol use disorder.

114. The method of any one of the preceding claims, wherein the method prevents one or more conditions associated with alcohol use disorder, wherein the one or more conditions associated with alcohol use disorder comprises high blood pressure, heart disease, stroke, liver disease, digestive conditions, cancer, wherein said cancer is optionally of the breast, mouth, throat, oesophagus, voice box, liver, colon and / or rectum, learning problems, memory problems, dementia and / or poor academic performance.

115. The method of any one of the preceding claims, wherein the method prevents the contraction of sexually transmitted infections.

116. The method of any one of the preceding claims, wherein the method prevents the contraction of one or more blood borne diseases.

117. The method of any one of the preceding claims, wherein the method prevents the contraction of HIV.

118. The method for use as claimed in any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device.

119. The method for use as claimed in any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device, wherein the single use intranasal delivery device is an active delivery device.

120. The method for use as claimed in any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device, wherein the single use intranasal delivery device is an active delivery device which does not require the patient to inhale through the nose to deliver the pharmaceutical composition.121 . The method for use as claimed in any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from an intranasal delivery device wherein the delivery device is an active delivery device.

122. The method for use as claimed in any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from an intranasal delivery device wherein the delivery device is an active delivery device configured to deliver theparticles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume having one or more of: a spray pattern of:a particle size distribution (at 40mm) of: D10 = 13 to 17, D50 = 35 to 60, DOO = 650 to 700, %<10 pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70mm) of: D10 = 13 to 17, D50 = 24 to 30, D90 = 540 to 610, %<10pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution of: D10 = 13 to 17, D50 = 22 to 27, DOO = 35 to 56, %<9 pm = <0.1-10%; or% particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

123. The method of any one preceding claim, wherein the administration to the subject having alcohol use disorder is once every month.

124. The method of any one preceding claim, wherein the administration to the subject having alcohol use disorder is once every two months.

125. The method of any one preceding claim, wherein the administration to the subject having alcohol use disorder is once every three months.

126. A kit comprising the pharmaceutical for use as claimed in any one preceding claim and instructions for use.

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