5-methoxy-DMT for use in the treatment of depression

Abstract

Provided herein are compositions including 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) for the treatment of depression in a subject and methods of use thereof. The invention further provides methods for administering the 5-MeO-DMT to a subject over a period time which is 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 treatment-resistant depression (TRD) 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] Controlled clinical studies with 5-MeO-DMT in humans are lacking and there remains a need in the art for further clinical exploration of formulations of 5-MeO-DMT benzoate.

[0009] SUMMARY OF THE INVENTION

[0010] In an embodiment, there is provided a method of treating one or more psychological disorders in a patient in need thereof, the method comprising administering to the patient having one or more psychological disorders: a first pharmaceutical composition comprising: (i) about 8 or 12mg 5- methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 8 or 12mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients; and a second pharmaceutical composition comprising: (i) about 12mg 5-MeO-DMT, or about 12mg freebase equivalent of a pharmaceutically acceptable salt, prodrug, hydrate, ester, co-crystal or deuterated form thereof, and (ii) one or more pharmaceutically acceptable carriers or excipients, wherein the second pharmaceutical composition is administered to the subject within 4 weeks (e.g., within 1 week, within 2 weeks, within 3 weeks, or within 4 weeks) of administration of the first pharmaceutical composition.

[0011] In an embodiment, there is provided a method of treating depression in a patient in need thereof, the method comprising administering to the patient having depression a first pharmaceutical composition and a second pharmaceutical composition, wherein:

[0012] (a) the first pharmaceutical composition comprises about 8mg 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and the second pharmaceutical composition comprises about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients; or

[0013] (b) the first pharmaceutical composition comprises about 12mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and the second pharmaceutical composition comprises about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients; wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition.

[0014] In an embodiment, the second pharmaceutical composition is administered to the subject within 3 weeks of administration of the first pharmaceutical composition.

[0015] In an embodiment, the second pharmaceutical composition is administered to the subject within 2 weeks of administration of the first pharmaceutical composition.

[0016] In an embodiment, the second pharmaceutical composition is administered to the subject within 1 week of administration of the first pharmaceutical composition.

[0017] In an embodiment, the second pharmaceutical composition is administered to the subject 14 days after the administration of the first pharmaceutical composition.

[0018] In an embodiment, the patient is ready for discharge within about 90, 100, 110, 120, 130, 140, 150, 160, 170 or 180 minutes following administration of the pharmaceutical composition.

[0019] In an embodiment, the method further comprises the provision of psychological support to the patient.

[0020] In an embodiment, the method further comprises the provision of psychological support to the patient, wherein the psychological support is provided:

[0021] Prior to administration of the first or second pharmaceutical composition;

[0022] During administration of the first or second pharmaceutical composition; and / or After administration of the first or second pharmaceutical composition. In an embodiment, 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 first or second pharmaceutical composition.

[0023] In an embodiment, 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 first or second pharmaceutical composition.

[0024] In an embodiment, the method further comprises the provision of at least 2 psychological support sessions over about 2 weeks priorto the administration of the first pharmaceutical composition.

[0025] In an embodiment, the method further comprises the provision of at least 1 psychological support session following administration of the first pharmaceutical composition and priorto the administration of the second pharmaceutical composition.

[0026] In an embodiment, the method further comprises the provision of psychological support by a psychedelic assisted therapy therapist.

[0027] In an embodiment, the pharmaceutical compositions are administered under the supervision of one or more professionals.

[0028] In an embodiment, the pharmaceutical compositions are administered under the supervision of one or more licensed professionals.

[0029] In an embodiment, the pharmaceutical compositions are administered under the supervision of a cognitive behavioural therapist and a psychedelic assisted therapy therapist.

[0030] In an embodiment, the pharmaceutical compositions are administered by the patient themselves or by a licensed professional.

[0031] In an embodiment, 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.

[0032] In an embodiment, the method of treatment is a method of treatment of a patient aged 18 to 75 years.

[0033] In an embodiment, the method of treatment is 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; 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.

[0034] 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.

[0035] 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.

[0036] In an embodiment, the pharmaceutical composition is amorphous or crystalline.

[0037] In an embodiment, the pharmaceutical composition is formulated for intranasal administration.

[0038] In an embodiment, the pharmaceutical composition is formulated as a dry powder.

[0039] In an embodiment, 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.

[0040] In an embodiment, the pharmaceutical composition is formulated as a spray dried dry powder.

[0041] In an embodiment, the pharmaceutical composition is formulated as a dry blend dry powder.

[0042] 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. In an embodiment, the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 8mg, 9mg, 10mg, 11 mg, 12mg, 13mg or 14mg 5-MeO-DMT freebase.

[0043] In an embodiment, the pharmaceutical composition comprises crystalline 5-MeO-DMT.

[0044] In an embodiment, the pharmaceutical composition comprises an amount of 5-MeO-DMT benzoate, hydrochloride, hydrobromide or oxalate equivalent to 8mg, 9mg, 10mg, 11 mg, 12mg, 13mg or 14mg 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.O°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 27.5°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.

[0045] 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.

[0046] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces a, optionally complete, mystical experience.

[0047] 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.

[0048] In an embodiment, administration of the pharmaceutical composition to the patient in need thereof induces ego dissolution.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] In an embodiment, the pharmaceutical composition is for use alongside one or more further active agents.

[0055] In an embodiment, the method of treatment is a method of treatment of a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, or difficult to treat depression.

[0056] In an embodiment, the method of treatment is a method of treatment of depression and one or more other conditions selected from: 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.

[0057] In an embodiment, the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device.

[0058] 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.

[0059] 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.

[0060] 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. 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

[0061] % particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

[0062] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants.

[0063] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the patient has been taking the one or more antidepressants for at least about 4, 5, 6, 7, 8, 9 or 10 weeks.

[0064] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the patient has been taking the one or more antidepressants for at least about 6 weeks.

[0065] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants are one or more selective serotonin reuptake inhibitors (SSRIs).

[0066] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants are citalopram, escitalopram, fluoxetine or sertraline.

[0067] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 10-40 mg daily.

[0068] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 40 mg daily. In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants,

[0069] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 20 mg daily.

[0070] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 10-20 mg daily.

[0071] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 20 mg daily.

[0072] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 10 mg daily.

[0073] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 20-60 mg daily.

[0074] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 60 mg daily.

[0075] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 40 mg daily.

[0076] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 20 mg daily.

[0077] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 50-200 mg daily.

[0078] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 200 mg daily.

[0079] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 150 mg daily.

[0080] In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 100 mg daily. In an embodiment, the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 50 mg daily.

[0081] In an embodiment, the method is a method of treating depression in a patient wherein the treatment comprises administering to the patient a 5-MeO-DMT dosing regimen, and the 5-MeO-DMT dosing regimen consists of administering (a) a first pharmaceutical composition comprising about 8mg 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and (b) a second pharmaceutical composition comprising about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition and wherein the 5-MeO-DMT dosing regimen includes no further 5-MeO-DMT administrations to the patient for a period of at least 1 month, 2 months, or 3 months following the administration of the first pharmaceutical composition.

[0082] In an embodiment, the method is a method of treating depression in a patient wherein the treatment comprises administering to the patient a 5-MeO-DMT dosing regimen, and the 5-MeO-DMT dosing regimen consists of administering (a) a first pharmaceutical composition comprising about 12mg 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and (b) a second pharmaceutical composition comprising about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition and wherein the 5-MeO-DMT dosing regimen includes no further 5-MeO-DMT administrations to the patient for a period of at least 1 month, 2 months, or 3 months following the administration of the first pharmaceutical composition.

[0083] 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.

[0084] In some embodiments, the subject experiences a clinically significant response within 24 (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) hours after the administration of the first or second 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. In some embodiments, the clinically significant response from administration of the first and second pharmaceutical compositions is sustained for a greater duration of time than that provided by a single administration of a pharmaceutical composition comprising 5-MeO-DMT.

[0085] The person skilled in the art will appreciate that the disclosure herein of one or more methods of treatment using one or more particular pharmaceutical compositions are also a disclosure of the use of said one or more particular pharmaceutical compositions in such one or more methods of treatment.

[0086] In some embodiments, the first 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 second 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.

[0087] 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.

[0088] In an embodiment, the clinically significant response occurs not later than about 2 hours after the administration of the first pharmaceutical composition.

[0089] In an embodiment, the clinically significant change in one or more of the parameters is sustained for at least 85 days following administration of the pharmaceutical composition.

[0090] 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.

[0091] In an embodiment, the patient is ready for discharge within about 90, 100, 110, 120, 130, 140, 150, 160, 170 or 180 minutes following administration.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] A kit comprising the pharmaceutical for use as described in any one preceding, or subsequent, embodiment and instructions for use.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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).

[0106] 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.

[0107] In an embodiment, there is provided a method, optionally a rapid and durable method, of improving one or more of: sexual functioning, anxiety, anhedonia, cognition and / or overall quality of life, in a patient in need thereof. In an embodiment, the improvement is assessed by one or more of: the Arizona Sexual Experiences Scale, the 7-item Generalised Anxiety Disorder Assessment (GAD- 7), difference in self-reported anhedonia symptoms, assessed by Snaith-Hamilton Pleasure Scale (SHAPS), the Cognitive Test Battery, Patient Global Impression of Change and / or improvement in self-reported quality of life, assessed by EuroQoL- 5 Dimension-5 Level (EQ-5D-5L). In an embodiment, there is provided a method, optionally a rapid and durable method, of treating a patient in need thereof, wherein the patient is aged 18 to 75 years old. In an embodiment, the patient has 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.

[0108] 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.

[0109] 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.

[0110] In some embodiments, the administering results in a decrease in reported sadness in the subject. In some embodiments, the administering results in a decrease in apparent sadness in the subject. In some embodiments, the administering results in a decrease in inner tension in the subject. In some embodiments, the administering results in an increase of the quality of sleep in the subject. In some embodiments, the administering results in an increase of appetite in the subject. In some embodiments, the administering results in a decrease in concentration difficulties in the subject. In some embodiments, the administering results in a decrease in lassitude in the subject. In some embodiments, the administering results in a decrease in the inability to feel in the subject. In some embodiments, the administering results in a decrease in pessimistic thoughts in the subject. In some embodiments, the administering results in a decrease in suicidal thoughts in the subject.

[0111] In some embodiments, the subject is suffering from inner tension, disrupted sleep, concentration difficulties, lassitude, an inability to feel, reduced appetite, pessimistic thoughts, or suicidal thoughts. In some embodiments, the subject is suffering from inner tension. In some embodiments, the subject is suffering from disrupted sleep. In some embodiments, the subject is suffering from concentration difficulties. In some embodiments, the subject is suffering from lassitude. In some embodiments, the subject is suffering from an inability to feel. In some embodiments, the subject is suffering from pessimistic thoughts. In some embodiments, the subject is suffering from suicidal thoughts.

[0112] In some embodiments, the subject is diagnosed as having inner tension, sleep disturbances, concentration difficulties, suicidal ideation, or reduced appetite. In some embodiments, the subject is diagnosed as having inner tension. In some embodiments, the subject is diagnosed as having sleep disturbances. In some embodiments, the subject is diagnosed as having concentration difficulties. In some embodiments, the subject is diagnosed as having suicidal ideation. In some embodiments, the subject is diagnosed as having reduced appetite.

[0113] Definitions

[0114] 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.

[0115] As used herein, the term “about” refers to a value that is within 10% above or below the value being described.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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:

[0123] 1 . Have you wished you were dead or wished you could go to sleep and not wake up?

[0124] 2. Have you had any thoughts about killing yourself?

[0125] 3. Have you been thinking about how you might do this?

[0126] 4. Have you had these thoughts and had some intention of acting on them?

[0127] 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?

[0128] 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?)

[0129] 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).

[0130] 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).

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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, 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), 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 MINI-KID variants of the assessment. Another example of an alternative assessment includes the self-rating version of the MADRS, the MADRS-S. 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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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).

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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:

[0143] 1 . apparent sadness

[0144] 2. reported sadness

[0145] 3. inner tension

[0146] 4. reduced sleep

[0147] 5. reduced appetite

[0148] 6. concentration difficulties

[0149] 7. lassitude

[0150] 8. inability to feel 9. pessimistic thoughts

[0151] 10. suicidal thoughts

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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. 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.

[0156] 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.

[0157] 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.

[0158] 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).

[0159] 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.

[0160] 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).

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] As used herein, the term “psychological support” may refer to one or more of the following: therapy, psychotherapy, talk therapy, cognitive behavioral therapy (CBT), counseling, guided self-help and / or group therapy. In some embodiments, the use of computer-aided chat services, digital tools, or Al chatbots may be administered as psychological support. The support may be given in the form of a program, wherein the subject has repeated experiences of support that is administered.

[0170] 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.

[0171] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0172] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0173] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT ; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0174] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure a first time; b) administering to the patient / subject 10 mg of 5-MeO-DMT intranasally; c) measuring the patient / subject’s blood pressure a second time; d) discharging the patient / subject if the patient / subject’s blood pressure at the second time is about the same as the patient / subject 's blood pressure at the first time, wherein the patient / subject is discharged within 90 minutes of step (b).

[0175] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0176] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) 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.

[0177] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0178] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) measuring the patient / subject’s blood pressure; b) intranasally administering to the patient / subject 10 mg of 5-MeO-DMT if the patient / subject’s systolic blood pressure is less than 130 mmHg and / or subject’s diastolic blood pressure is less than 80 mmHg.

[0179] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient / subject for relapse of one or more depressive symptoms; c) administering to the patient / subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0180] In an embodiment, there is provided a method of treating depression in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient / subject for relapse of one or more depressive symptoms; c) administering to the patient / subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0181] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT; b) monitoring the patient / subject for relapse of one or more depressive symptoms; c) administering to the patient / subject a second dose of 5-MeO-DMT, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0182] In an embodiment, there is provided a method of treating treatment-resistant depression in a patient / subject in need thereof, wherein the method comprises: a) administering to the patient / subject a first dose of 10 mg of 5-MeO-DMT intranasally; b) monitoring the patient / subject for relapse of one or more depressive symptoms; c) administering to the patient / subject a second dose of 5-MeO-DMT intranasally, wherein the second dose is administered at least 28 days after the first dose is administered to the patient / subject.

[0183] BRIEF DESCRIPTION OF THE DRAWINGS

[0184] FIG. 1 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).

[0185] FIG. 2 Shows a comparison of the change from baseline in the MADRS score for patients who received a single 8 mg BPL-003 dose administered in a Phase 2b trial in patients with TRD compared to a cohort who received an 8 mg dose of BPL-003 followed two weeks later by 12 mg.

[0186] FIG. 3 Shows a comparison of the change from baseline in the MADRS score for patients who received a single 10 mg BPL-003 dose administered in a Phase 2b trial in patients with TRD compared to a cohort who received an 8 mg dose of BPL-003 followed two weeks later by 12 mg.

[0187] FIG. 4 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). FIG. 5 is a graph depicting the nasal deposition profile for a 5-MeO-DMT SDD delivered via an active delivery nasal delivery device.

[0188] FIG. 6 is a graph depicting the nasal deposition profile for a 5-MeO-DMT SDD delivered via a passive delivery nasal delivery device.

[0189] DETAILED DESCRIPTION OF THE INVENTION

[0190] 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.

[0191] Methods of Administration

[0192] 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.

[0193] 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 depression. 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.

[0194] Pharmaceutical Formulations

[0195] 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.

[0196] EXAMPLES

[0197] Example 1: Results of a Phase Ila study into 5-MeO-DMT for Treatment Resistant depression / major depressive disorder (TRD)

[0198] 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.

[0199] 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.

[0200] 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. 75% of subjects were assessed as being ready for discharge at the first assessment time of 90 minutes, confirming the potential for a short treatment duration, fast discharge and low resource burden with BPL-003.

[0201] 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

[0202] 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.

[0203] 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,

[0204] 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.

[0205] 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.

[0206] The mean change from baseline in MADRS total score overtime (per protocol population) can be seen in Figure 1 . 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. 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 shortterm and long-term clinical symptom improvement.

[0207] The results for each of the 10-items of the MADRS for the per protocol population (PPP) can be seen in Tables 1a-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.

[0208] Table 1a: Average MADRS scores reported by subjects Pre- and Post-BPL-003 administration.

[0209] Table 1b: 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.

[0210] 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.

[0211] Example 2: An Open-Label, Phase 2a Study to Evaluate the Safety Tolerability and Pharmacodynamics of BPL-003 in Patients with Treatment Resistant Depression

[0212] A phase Ila clinical trial is underway to evaluate the safety and tolerability of a two dose treatment of BPL-003 (5-MeO-DMT benzoate) in patients with treatment-resistant depression (TRD). This trial is Part 2 of the trial described in Example 1 , which investigated a single intranasal dose of BPL-003 in patients with TRD.

[0213] Patients will receive 2 doses, given 2 weeks apart (on Day 1 and Day 15), with an 8mg freebase equivalent of BPL-003 given on Day 1 and a 12mg freebase equivalent of BPL-003 given 2 weeks later on Day 15.

[0214] BPL-003 will be 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.

[0215] A cohort comprising patients on a stable dose of citalopram, escitalopram, sertraline or fluoxetine will also be investigated.

[0216] Objectives:

[0217] All objectives, unless stated otherwise, are for patients with treatment resistant depression (TRD) who received BPL-003.

[0218] Primary objective

[0219] • To assess the safety and tolerability of multiple intranasal doses of BPL-003 given with psychological support in patients with TRD.

[0220] Exploratory objectives

[0221] • To explore the efficacy of multiple intranasal doses of BPL-003 given with psychological support in patients with TRD.

[0222] • To assess the pharmacodynamics (PD; including psychological effects) of multiple intranasal doses of BPL-003 given with psychological support in patients with TRD.

[0223] • To explore the association between dose and mystical experiences elicited after multiple intranasal doses of BPL-003 and the antidepressant efficacy in patients with TRD.

[0224] • To assess the feasibility of the treatment model for BPL-003 combined with psychological support in TRD patients.

[0225] • To assess the qualitative psychological effects of BPL-003 combined with psychological support in TRD patients.

[0226] • To collect population pharmacokinetic (PK) measures through blood draws.

[0227] • To assess plasma levels of brain-derived neurotrophic factor (BDNF).

[0228] Study Design:

[0229] Screening: patients will be screened within 56 days before their dose of study drug, to confirm their eligibility for the study.

[0230] Washout: patients who take prohibited antidepressant medication will be requested to discontinue that medication, in agreement with their General Practitioner (GP) or other mental health professional. The Washout Period may last up to 6 weeks depending on the medication and the choice of tapering rate advised by the site physician and preference of the patient. The washout period must finish at least 14 days (Day -14) before dosing on Day 1 . During the Washout Period, weekly calls will be conducted by the study physician or appropriate study team members, and the patients will be offered medical advice with regards to discontinuing their antidepressant medication, monitoring and management of potential withdrawal symptoms and ongoing safety monitoring.

[0231] Psychedelic preparation visits: Patients will participate in a minimum of 2 preparatory sessions before the first dose, and 1 before the second dose. The psychedelic preparation sessions will last approximately 60-90 min and may be done via video call or in the clinic. During the preparatory sessions, a therapeutic alliance with the therapist will be established, and patients will receive advice on what to expect and how to respond to the psychedelic experience.

[0232] Psychological change measures and semi-structured interviews: patients will complete psychological change questionnaires at 5 visits on Days -3, 2, 16, 29 and 85. Patients will complete semi-structured interviews with a therapist on Days 2, 16, 29, and 85.

[0233] Dosing visit: after completion of the preparatory meetings, patients will attend the clinic for their dosing visit. Patients will be resident at the clinic from the morning of Day 1 (the dosing day) until at least 4 h post dose. Patients will complete the above on Day 1 (first dosing day), and they will also be resident at the clinic from the morning of Day 15 (second dosing day) until at least 4 h post dose.

[0234] For all doses, BPL-003 will be administered to patients in the designated setting, and the therapist will remain with the patients while patients are in an altered state of consciousness.

[0235] Qualitative interviews: after returning to a usual state of consciousness after each dosing, patients will have a one-to-one guided qualitative 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 on Day 1 and Day 15.

[0236] Psychometric scales will then be administered to provide quantitative measures of the patient’s psychedelic experience and depression symptoms. Starting 90 min after dosing, patients will have their readiness for discharge assessed every 30 min. The earliest a patient can be discharged will be 4 h after receiving the dose.

[0237] Psychedelic integration visits: patients will have 1 integration session after the first dose (Day 2) and 2 integration sessions after the second dose (Days 16 and 22). The integration session on Day 22 may be done via video call or in-clinic.

[0238] Follow-up Visits: patients will have Follow-up Visits every 2 weeks for up to 10 weeks after the last dose. The visit on Day 85 will be held in clinic. Visits on Days 29, 43, 57 and 71 can be done via video call or in clinic.

[0239] Diagnosis and main criteria for inclusion:

[0240] To be eligible to participate in this study, patients must meet the following criteria: Inclusion criteria

[0241] • Willing and able to give informed consent.

[0242] • Age 18-75 at the time of Screening.

[0243] • Diagnosed with Major Depressive Disorder (MDD) based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria confirmed via structured clinical interview (version 7.0.2 Mini International Neuropsychiatric Interview [MINI]). • Diagnosed with TRD defined as failure to respond to an adequate dose and duration of at least 2 pharmacological treatments in the past 5 years prior to screening, at least one of which is during the current episode. However, patients must not have failed more than 5 prior pharmacological treatments in the current episode (psychotherapy is not counted towards treatment failure).

[0244] • Montgomery-Asberg Depression Rating Scale (MADRS) score >24 at Screening and Day -3.

[0245] • Clinical Global Impression - Severity (CGI-S) >4 at Screening and Day -3.

[0246] • Comply with restrictions in use of anti-depressants as follows: willing and able to discontinue current pharmacological anti-depressant therapy including selective serotonin reuptake inhibitors (SSRIs) (with the exception of a stable dose of citalopram, escitalopram, sertraline, or fluoxetine for at least 6 weeks prior to Screening, for the adjunctive therapy cohort), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) per recommended washout protocols.

[0247] • Able (in the Investigator’s opinion) and willing to undertake and comply with all study requirements including ability to complete all protocol required assessment tools and to comply with all study visits in language used by the study site.

[0248] • Willing to abstain from alcohol from 48 h before and on Day 1 , and 48 h before and on Day 15.

[0249] • Willing to abstain from recreational / illicit drugs from Screening until the end of the study.

[0250] • Willing to abstain from smoking or vaping during their time in the clinic on the day of drug administration as instructed by clinical staff.

[0251] • Willing to allow their own GP or other mental health professional, to be informed of study participation and that the patient may be withdrawing from their current medication.

[0252] Exclusion criteria:

[0253] Psychiatric Exclusion Criteria:

[0254] • Current or history of schizophrenia, 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).

[0255] • Current personality disorders Cluster A (paranoid, schizoid, schizotypal), Cluster B (antisocial, borderline, histrionic, narcissistic), or Cluster C (avoidant, dependent, obsessive-compulsive) as assessed via McLean Screening Instrument for Borderline Personality Disorder (MSI- BPD), MINI and clinical judgement.

[0256] • First-degree family history of schizophrenia, bipolar disorder, delusional disorder, personality disorders or schizoaffective disorder.

[0257] • Current (within the last year) alcohol or substance use disorder (other than caffeine or nicotine) as according to DSM 5, and assessed by the MINI at Screening that the Investigator judges to be a safety concern for enrolment in the study or that could interfere with the therapeutic process or with other aspects of study participation. Any patient who is not able to agree or adhere to a plan to reduce and manage use will be excluded.

[0258] • A patient that at any time, has been unresponsive to ketamine or esketamine, or 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 (VNS) or deep brain stimulation (DBS).

[0259] • Currently taking prohibited antidepressant medication, including augmentation or combination therapies and not willing to washout.

[0260] • Patients taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg / day of lorazepam) and / or non-benzodiazepine sleep medications (eg, zolpidem, zaleplon eszopiclone, and ramelteon) during Screening can continue taking these medications during the study. Benzodiazepines and non-benzodiazepine sleeping medication are prohibited within 12 h prior to dosing.

[0261] • Currently receiving lithium.

[0262] • Currently receiving antipsychotics serotonergic drugs, psychostimulants, or any other prohibited medication, and not willing to washout.

[0263] • Psychological therapies other than those planned per the protocol that are initiated or terminated within 21 days of dosing and during the duration of the study. Patients who have been receiving psychotherapy for at least 3 months before Screening can continue this psychotherapy if there is no intention to terminate it during the Screening period or at any time during the study. The initiation of new psychotherapy is not allowed during the Screening period or at any time during the study.

[0264] • 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 and predose on Day 1 should also be excluded.

[0265] • Suicide attempts and / or self-injurious behaviour within 12 months before Screening.

[0266] • Depression secondary to other severe medical conditions according to the Investigator’s opinion.

[0267] • Other personal circumstances and behaviour judged to be incompatible with establishment of rapport with the study team or safe exposure to BPL-003.

[0268] • Use of psychedelics, such as psilocybin, ayahuasca, lysergic acid diethylamide (LSD), or 3,4- Methyl-enedioxy-methamphetamine (MDMA) during the 6 months before dosing.

[0269] • Any other clinically significant psychiatric condition which, in the opinion of the Investigator, may interfere with the interpretation of the study results or constitute a health risk for the patient if he / she takes part in the study. General Medical Exclusion Criteria:

[0270] • Patients with a history of any medical condition that could make receiving a sympathomimetic drug harmful because of transient and marked increases in blood pressure (BP) and heart rate (HR). This includes, but is not limited to, atherosclerotic cardiovascular disease, obstructive coronary artery disease, myocardial infarction, hospitalization for unstable angina, stroke, hospitalization for transient ischemic attacks, known aortic or cerebral aneurysm or revascularization procedure within 12 months prior to Screening, significant valvular heart disease, hospitalization for heart failure, hospitalization for atrial or ventricular arrhythmias.

[0271] • Patients with other mild, stable chronic medical problems should be excluded if the Investigator judges the condition would significantly increase the risks related to BPL-003 administration or be likely to produce significant symptoms during the study that could interfere with study participation or be confused with side effects of the study drug.

[0272] • History of uncontrolled hypertension despite adequate therapy or any past history of a hospital admission for hypertension.

[0273] • Patients with controlled hypertension on antihypertensive therapy are excluded if repeated supine or semi-supine systolic BP > 130 mmHg or diastolic BP > 80 mmHg.

[0274] • Patients without a diagnosis of hypertension are excluded if repeated supine or semi-supine systolic BP > 140 mmHg or diastolic BP > 90 mmHg.

[0275] • Antihypertensive medication regimen adjustments during the Screening period to assess BP control is allowable, but participants must be on a stable antihypertensive regimen for at least 2 weeks before dosing. BP eligibility should be assessed at Screening and predose on Day 1 .

[0276] • The mean of triplicate values will be used to determine eligibility. Repeat measurements are permitted if values are borderline (ie within 5 mm Hg of the above ranges), or if requested by the investigator. Volunteers can be included if the repeat value is within range or still borderline, but deemed not clinically significant by the investigator.

[0277] • Uncontrolled medical conditions judged by the Investigator to significantly increase the risk of harm from BPL-003 exposure by any mechanism.

[0278] • Uncontrolled or insulin dependent diabetes.

[0279] • Seizure disorder or history of seizures (including febrile seizures).

[0280] • Any other clinically significant, neurological, 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 the patient if he / she takes part in the study.

[0281] • Abnormal and, in the opinion of the Investigator, clinically significant results on the physical examination, vital signs, electrocardiogram (ECG), or laboratory tests at Screening or Day -3.

[0282] • Positive urine drug screen for illicit drugs or drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine / methamphetamine) at Screening or Day 1 . • Intermittent use of cannabinoids before Screening is permitted if the patient does not meet the criteria for substance use disorder, as assessed using the DSM-5. A positive test for cannabinoids at Screening is not exclusionary; however, a positive test result for cannabinoids predose on Day 1 is exclusionary.

[0283] • A positive test result at Screening due to prescribed / over-the-counter opiates or barbiturates is permitted if the patient agrees to discontinue the medication at least 1 week or 5 half-lives, whichever is longer, before Day 1 . The patient must have a negative test on Day 1 , before dosing.

[0284] • Retesting is permitted for positive test result(s) if deemed false positive in the opinion of the investigator, or for reasons stated above.

[0285] • Currently receiving tramadol, opioids, antiviral medication, St. John’s Wort, MAOIs, or any other medications that may interfere with the study drug, and not willing to discontinue.

[0286] • History of intolerance to 5MeO-DMT, N,N-dimethyltryptamine (DMT), or related compounds.

[0287] • Any nasal obstruction, blockage, or symptoms of congestion, at the time of dosing, that in the Investigator’s opinion may interfere with administration of the study drug.

[0288] • Positive test for hepatitis B, hepatitis C antibodies, or HIV. However, a positive result for hepatitis C antibodies is not exclusionary if the viral load is negative.

[0289] • Female patients who are pregnant or lactating, or of childbearing potential and not willing to use adequate forms of contraception.

[0290] • Male patients who are sexually active and not willing to using adequate forms of contraception.

[0291] • Patients who have taken part in a clinical research study within the 4 weeks before Screening.

[0292] • Patients 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.

[0293] Psychedelic Psychotherapy:

[0294] Patients will receive psychological support throughout the study. During the study, patients will complete a minimum of 3 preparatory sessions and 3 integration sessions with a qualified psychedelic psychological support provider, also called the ‘lead-therapist’. A therapeutic alliance with the therapists will be established during the preparatory meetings and patients will be prepared for the BPL-003 treatment session. An assistant-therapist will participate in the final preparatory, the dosing, and the first integration sessions, Day 2 and Day 16.

[0295] The lead-therapists will be licensed psychotherapists or psychiatrists and appropriately qualified and trained.

[0296] The assistant-therapists will be licensed health practitioners or have a bachelor’s degree and equivalent experience in psychedelic trials, certified psychedelic therapy training, or counselling in a healthcare setting, adding up to a minimum of 1 year of full time (2000 h).

[0297] Exploratory Endpoints: • change from baseline (Day -3) in MADRS on Days 2, 8, 16 (Part 2 only), 22 (Part 2 only), 29, 57 and 85

[0298] • percentage (%) of responders (defined as 50% reduction in MADRS total score compared to baseline (Day -3) on Days 2, 8, 16 (Part 2 only), 22 (Part 2 only), 29, 57 and 85

[0299] • percentage (%) of patients in remission (defined as MADRS total score <10) on Days 2, 8, 16 (Part 2 only), 22 (Part 2 only), 29, 57 and 85

[0300] • the percentage (%) of patients experiencing a “complete mystical experience”, as assessed by the Mystical Experience Questionnaire (MEQ30)

[0301] • description of the BPL-003 subjective experience data (from the qualitative interview)

[0302] • change from baseline (Day -3) in, Facial Expression Recognition Task (FERT), CGI-S and Patient Global Impression of Change (PGIC) on Days 2, 8, 16 (Part 2 only), 22 (Part 2 only), 29, 57 and 85

[0303] • change from baseline (Day -3) in QIDS-SR-16 on Days 8, 16 (Part 2 only), 22 (Part 2 only), 29, 57 and 85

[0304] • psychological Insight Scale (PIS) at Days 2, 8, 16 (Part 2 only), 22 (Part 2 only), and 29

[0305] • change from baseline (Day -3) in Sheehan Disability Scale (SDS) and Snaith-Hamilton Pleasure Scale (SHAPS) on Days 29, 57 and 85

[0306] • correlation of the change in FERT and the MADRS assessment at Days 8, 16 (Part 2 only), 22 (Part 2 only), and 29

[0307] • the effects of BPL-003 as determined by the MEQ30 and Ego Dissolution Inventory (EDI)

[0308] • the correlation of the occurrence of a “complete mystical experience” and “ego dissolution” measured by the MEQ30 and EDI with the MADRS improvement

[0309] • post BPL-003 treatment Delayed Psychedelic After Effects Scale (DEPAS) scores on Days 2, 16 (Part 2 only), 29, 57 and 85

[0310] • measuring the frequency, emotional valence and functional impact of any re-activation events in the study through the Reactivation Questionnaire (ReAQ)

[0311] • the plasma levels and PK of 5-MeO-DMT and its metabolites (e.g. bufotenine, 5- methoxyindolacetic acid [5-MIAA], and 5-MeO-DMT-N-Oxide)

[0312] • the impact of cytochrome P2D6 (CYP2D6) predicted phenotype on selected PD variables

[0313] • change from baseline in plasma levels of BDNF

[0314] Ego Dissolution Inventory

[0315] The Ego Dissolution Inventory (EDI), is an 8-item self-report scale designed to measure egodissolution.

[0316] 5-Level EuroQol 5-Dimension

[0317] 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.

[0318] Qualitative Interview

[0319] 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.

[0320] Optional Semi-Structured Interview & Psychological Change Measures

[0321] 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.

[0322] Montgomery-Asberg Depression Rating Scale (MADRS)

[0323] 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.

[0324] Clinical Global Impression of Severity

[0325] 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.

[0326] Patient Global Impression of Change

[0327] 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.

[0328] Readiness for discharge questionnaire

[0329] 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.

[0330] 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.

[0331] (1) The patient is fully responsive, aware of their surroundings, and reacts adequately

[0332] (2) The acute psychedelic effects of the drug have completely subsided

[0333] (3) The patient is fully orientated (name, location, time)

[0334] (4) Blood pressure and pulse rate have returned to normal or only slightly elevated levels

[0335] (5) The breathing frequency and body temperature are normal

[0336] (6) The patient has a stable gate and normal muscle coordination and can walk safely (7) Potential side effects are mild to moderate in intensity and do not need to be medically monitored

[0337] (8) The patient has no acute suicidal ideations or suicidal intentions

[0338] (9) Possible distress or feelings of being overwhelmed have sufficiently subsided to a degree that the patient themselves feel safe to be discharged

[0339] 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.

[0340] (10) In the opinion of the assessor, the patient is now safe to be discharged.

[0341] Results

[0342] Interim results are presented herein from the phase Ila clinical trial to evaluate the safety and tolerability of a two dose treatment of BPL-003 (5-MeO-DMT benzoate) in patients with treatmentresistant depression (TRD).

[0343] 12 patients received 2 doses, given 2 weeks apart (on Day 1 and Day 15), with an 8mg freebase equivalent of BPL-003 given on Day 1 and a 12mg freebase equivalent of BPL-003 given 2 weeks later on Day 15.

[0344] The Table shows the MADRS score results from this interim data.

[0345] Table 2: MADRS scores over 85 days for 12 patients who received 8 mg and 12 mg doses of BPL-003 two weeks apart.

[0346] The mean MADRS score at baseline (Day -3) was 28.6. The mean MADRS score 1 week (at Day 8) after the first dose was 15.7. This represents a change from baseline of 43.9%. The mean MADRS score 1 week (at Day 22) after the second dose was 9.6. This represents a change from baseline of 66.1 %. A second dose resulted in an increased change from baseline of 6.1 on the MADRS score. At Day 8 (1 week after the first dose), 3 / 12 (25%) of patients had a total MADRS score of less than 10. At Day 22 (1 week after the second dose), 8 / 12 patients (66.7%) of patients had a total MADRS score of less than 10. At Day 8 (1 week after the first dose), 5 / 12 (41 .7%) of patients had a total MADRS score of less than 50% the baseline value. At Day 22 (1 week after the second dose), 9 / 12 patients (75%) of patients had a total MADRS score of less than 50% the baseline value.

[0347] Figure 2 shows a comparison of the change from baseline in the MADRS score for the two dose results described above against a single 8mg BPL-003 dose administered in a Phase 2b trial in patients with TRD (NCT05870540) from the Applicant.

[0348] Figure 3 shows a comparison of the change from baseline in the MADRS score for the two dose results described above against a single 10mg BPL-003 dose administered in Part 1 (as described in Example 1).

[0349] The above results provide evidence that a subject who receives an 8 mg dose of BPL-003 followed by an additional 12 mg dose two weeks thereafter experiences a greater change in the MADRS parameters than a single dose cohort receiving either 8 mg or 10 mg of BPL-003. Accordingly, the individual parameters of the MADRS may be changed, and a subject may experience a benefit in any of the MADRS measures following the doses. In some embodiments, the administering results in a decrease in reported sadness in the subject. In some embodiments, the administering results in a decrease in apparent sadness in the subject. In some embodiments, the administering results in a decrease in inner tension in the subject. In some embodiments, the administering results in an increase of the quality of sleep in the subject. In some embodiments, the administering results in an increase of appetite in the subject. In some embodiments, the administering results in a decrease in concentration difficulties in the subject. In some embodiments, the administering results in a decrease in lassitude in the subject. In some embodiments, the administering results in a decrease in the inability to feel in the subject. In some embodiments, the administering results in a decrease in pessimistic thoughts in the subject. In some embodiments, the administering results in a decrease in suicidal thoughts in the subject.

[0350] In some embodiments, the subject is suffering from inner tension, disrupted sleep, concentration difficulties, lassitude, an inability to feel, reduced appetite, pessimistic thoughts, or suicidal thoughts. In some embodiments, the subject is suffering from inner tension. In some embodiments, the subject is suffering from disrupted sleep. In some embodiments, the subject is suffering from concentration difficulties. In some embodiments, the subject is suffering from lassitude. In some embodiments, the subject is suffering from an inability to feel. In some embodiments, the subject is suffering from pessimistic thoughts. In some embodiments, the subject is suffering from suicidal thoughts.

[0351] In some embodiments, the subject is diagnosed as having inner tension, sleep disturbances, concentration difficulties, suicidal ideation, or reduced appetite. In some embodiments, the subject is diagnosed as having inner tension. In some embodiments, the subject is diagnosed as having sleep disturbances. In some embodiments, the subject is diagnosed as having concentration difficulties. In some embodiments, the subject is diagnosed as having suicidal ideation. In some embodiments, the subject is diagnosed as having reduced appetite. Example 3: X-Ray Powder Diffraction (XRPD) of 5-MeO-DMT benzoate

[0352] The XRPD pattern of 5-MeO-DMT benzoate salt was acquired before and following particle size reduction with a mortar and pestle. This reduced the intensity of dominant diffractions and revealed that the XRPD pattern of the benzoate salt was prone to preferred orientation prior to particle size reduction, which is a function of the habit and particle size of the material. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 ,0°20±O.1 °20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.3°20. In an embodiment, there is provided crystalline 5- MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.2°20 as measured by x-ray powder diffraction using an x- ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7 and 21 .0°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1 °20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 17.5, 17.7, 21.0 and 25.3°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 1 1.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1 °20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 1 1.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 1 1.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 1 1.5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5, 14.5, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1.5406 A. In an embodiment, there is provided crystalline 5- MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.5, 17.5,

[0353] 17.7, 18.5, 21.0, 22.7, 24.7 and 25.3°20±O.3°20 as measured by x-ray powder diffraction using an x- ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5, 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21 .0,

[0354] 22.7, 24.7, 25.3 and 3O.5°20±O.1 °20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5, 14.5, 16.3, 16.5, 17.5, 17.7,

[0355] 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20. In an embodiment, there is provided crystalline 5- MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11.5, 14.5, 16.3, 16.5,

[0356] 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5,

[0357] 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.1 °20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5,

[0358] 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.2°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A. In an embodiment, there is provided crystalline 5-MeO-DMT benzoate, characterised by peaks in an XRPD diffractogram at 9.0, 11 .5,

[0359] 14.5, 16.3, 16.5, 17.5, 17.7, 18.5, 21.0, 22.7, 24.7, 25.3 and 3O.5°20±O.3°20 as measured by x-ray powder diffraction using an x-ray wavelength of 1 .5406 A.

[0360] Example 4: Targeted Nasal Delivery

[0361] The nasal cavity is recognised as a promising systemic drug delivery route due to the highly vascularised capillary bed within the nasal mucosa. There is therefore a need for formulations or compositions as described herein with an optimised particle size distribution which show turbinate deposition. There is also a need for delivery devices which can selectively deliver a formulation or composition as described herein to the nasal turbinates, for the uses as described herein.

[0362] Materials

[0363] 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) Benzoate, Hydroxypropyl methylcellulose (HPMC) ((Pharmacoat 606 - substitution 2910, viscosity 6 cP) ShinEtsu Chemical, Japan), HPLC grade 99% ethanol, HPLC grade 99% methanol, HPLC grade water, Glycerol and Brij-35 (Fisher Scientific, United Kingdom). Ultrapure water 18.2 MQ (Veolia Elga Lab Water system, in house) Active devices (UDSp, Aptar Pharma, France).

[0364] Preparation of 5-MeO-DMT Spray Dried Dispersion (5-MeO-DMT SDD)

[0365] Feed solution was prepared at 50% w / w 5-MeO-DMT Benzoate loading (32.1% 5-MeO-DMT). Both polymers were dissolved in water under ambient stirring overnight. D-sorbitol and 5-MeO-DMT Benzoate were added to solution and dissolved under ambient stirring, producing a clear, lightly straw-coloured solution. Feed solution was spray dried using the ProCepT 4M8-Trix Spray Dryer fitted with a 25 kHz Ultrasonic nozzle (ProCepT, Belgium), according to the spray drying parameters outlined in Table 3 below. Formulation was filled and assembled into UDSp devices at 37.4 ± 1 .9 mg fill weight, under reduced humidity, when required for analysis.

[0366] Table 3: Target Spray Drying Parameters for 5-MeO-DMT Feed Solution

[0367] Particle Size Distribution (PSD) was determined using a Sympatec HELOS H4459 particle size analyser equipped with an R5 lens (Sympatec GmbH, Germany) in triplicate. Bulk powder was analysed using the RODOS dry powder dispersion unit at 3 bar dispersal pressure and powder from active devices (ExDevice) were manually actuated into the laser diffractor with the tip of the device positioned 3 cm from the mid-point of the laser.

[0368] The spray pattern of the plumes was measured at 40 mm and 70 mm above the tip of the active device. The spray pattern was characterized in terms of minimum diameter (Dmin), the maximum diameter (Dmax), the area of the pattern, the particle size distribution, the plume angle, and the plume width. The maximum diameter (Dmax) of the spray pattern is the widest part of the plume when measured at a particular distance from its origin. The minimum diameter (Dmin) of the spray pattern is the narrowest part of the plume when measured at a particular distance from the origin of the plume.

[0369] Methodology - summary

[0370] The Alberta Idealised Nasal Inlet (AINI) and Stage 1 collection cup of the Next Generation Impactor (NGI) was coated with a solution containing 12 g Brij-35, 20 g glycerol and 80 mL ethanol. Once dried, AINI and NGI were assembled with the addition of a pre-separator with 15 mL 50:50 (v / v) methanol:water diluent in the reservoir. The UDSp loaded with 37.4 mg formulation was positioned at either 30, 45 or 60° to the horizontal and inserted 1 cm into the nasal orifice of the AINI. A 7.5 L / min airflow was applied for 15 seconds upon actuation of the UDSp, delivering 1.875 L of air. After actuation, the configuration was disassembled and 15 mL diluent used to dissolve material on the UDSp’s exterior, deposited in the AINI and the NGI collection cup, with the addition of a secondary dilution. Analysis was performed in triplicate and analysed by HPLC, with Two-way ANOVA statistical analysis.

[0371] Methodology - detailed

[0372] Nasal deposition was measured using the Alberta Idealised Nasal Inlet (AINI) with the Copley Next Generation Impactor (NGI) from an Aptar Unidose Powder Nasal spray system (UDSp)

[0373] A) Coating of AINI and NGI collection cups

[0374] 12g Brij-35, 20g glycerol and 80 mL ethanol were mixed until dissolved to form a coating solution. Bottom of the AINI was sealed and a 20 mL coating solution was added through the vestibule while the AINI was inverted. The AINI was slowly rotated horizontally 360° clockwise and anticlockwise then rotated vertically 360° clockwise and anticlockwise. Excess coating solution was drained and the AINI was placed on its left side, back and right side for 15 minutes each. AINI was positioned upright for 30 minutes to allow any further excess coating solution to drain and for the coat to dry. 2 mL of coating solution was pipetted onto the NGI Stage 1 collection cup and rocked for 5 minutes using the NGI rocker in order to coat. Excess solution was drained and the cup was allowed to dry.

[0375] B) NGI assembly

[0376] NGI was assembled with the coated Stage 1 collection cup and uncoated collection cups for states 2-7 and micro-orifice collector. The pre-separator and throat piece were attached and a leak test was performed using the critical flow controller and high-capacity pump. The flowmeter was attached to the throat piece and the flowrate set to 7.5 L / min. The throat piece was removed and 15 mL 50:50 %v / v HPLC grade water: HPLC grade methanol (diluent) was added to the pre-separator insert cup. The AINI was then installed on the pre-separator.

[0377] C) Actuation

[0378] The UDSp containing 5-MeO-DMT was weighed to obtain a pre-actuation mass. The UDSp was then clamped into position such that the tip of the UDSp was inserted 1 cm into the vestibule of the AINI. The angle of insertion was set using an electronic protractor. The UDSp was actuated using 7.5 L / min flow rate for 15 seconds.

[0379] D) HPLC Sample collection

[0380] UDSp was then removed and weighed to obtain a post-actuation mass. The exterior of the UDSp was washed with 15 mL diluent in a glass dish and the washings were collected for HPLC analysis. AINI was disassembled and each component was thoroughly washed in separate glass dishes with 15 mL diluent. These washings were then collected for HPLC analysis. The pre-separator was removed from the NGI, the top and bottom were then covered and the pre-separator was inverted to wash the interior with the previously added 15 mL diluent. These washings were then collected for HPLC analysis. 15 mL diluent was added to the Stage 1 collection cup and the cup was rocked for 10 minutes using the NGI rocker to wash. These washings were then collected for HPLC analysis.

[0381] E) HPLC

[0382] HPLC was carried out on the samples to quantify 5-MeO-DMT content. Where necessary samples were diluted to stay within the linearity of the quantification method.

[0383] Results

[0384] Pharmacopoeia guidelines state that a nasal powder should demonstrate that deposition of the products is localised within the nasal cavity, and the current method requires that most of the particles are larger than 10 pm as determined by laser diffraction. Analysis was performed on the 5- MeO-DMT SDD with the Sympatec, and the particle size distribution shown in Figure 4. Using the ultrasonic nozzle an optimised nasal powder was achieved in which the mean particle diameter was close to the diameter recommended while maintaining minimal particles below 10 pm, passing acceptance criteria requested by the European Medicines Agency (EMA).

[0385] The AINI was used to assess the deposition profile of the 5-MeO-DMT SDD formulation with the method outlined above. The AINI consists of four components for the nasal cavity - the vestibule (nostril), turbinates, olfactory and nasopharynx - which is assembled and attached to a pre-separator. The pre-separator is incorporated to capture any deposition that would falsely land on Stage 1 due to particle bounce in the internal surfaces of the AINI. Minimal deposition was seen in the vestibule compared to commercially available nasal sprays. Minimal deposition was also seen in the lung analogue. The majority of the formulation was found in the turbinates and the olfactory region showed deposition from 5-11% - which is advantageous as it is theorised that a minimum of 0.01-1% of the oral dose is effective for nose-to-brain absorption. The results of the AINI can be seen in Figure 5.

[0386] There is therefore provided an advantageous method for the delivery of a 5-MeO-DMT SDD. The same 5-MeO-DMT SDD was filled into the passive nasal delivery device at a loading suitable to deliver 12mg 5-MeO-DMT free base equivalent. The passive device was positioned into an adapter and drawn through the AINI / NGI with a flow rate of 30L / min to deliver either 1 L or 2L of air respectively. The nasal deposition profile produced can be seen in Figure 6. It can be readily seen that very little drug product was deposited in the desired locations of the turbinates and olfactory region.

[0387] There is therefore provided an advantageous method for the delivery of a 5-MeO-DMT wherein 5-MeO-DMT is delivered by an active nasal delivery device. In an embodiment, there is provided the use of a formulation or composition as described herein in a method of treating a patient in need thereof, wherein the formulation or composition is administered intranasally via an active delivery nasal device, as described herein, and wherein more than 30%, 40%, 50%, 60%, 70%, 80% or 90% of the formulation or composition is deposited to the turbinates and / or olfactory region of the nasal cavity. In an embodiment, the method of treating a patient in need thereof is a method of treating one or more of the conditions or diseases described herein.

[0388] In an embodiment, there is provided the use of a formulation or composition as described herein in a method of treating a patient in need thereof, wherein the formulation or composition is administered intranasally via an active delivery nasal device and wherein less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% is deposited in the lungs. In an embodiment, there is provided a nasal delivery device for delivering a formulation or composition as described herein to an olfactory region of a nasal cavity, the device comprising a formulation or composition as described herein. In an embodiment, the device is an active nasal delivery device wherein a plunger style actuator, or similar, is depressed to administer a dose. In an embodiment, the nasal delivery device is not a breath actuated delivery device. In an embodiment, the device comprises a dose volume up to 140 mm3.

[0389] In an embodiment the device is an Aptar device (UDS -Unidose Solid) as commercially available in the UK as of 1 June 2023. In an embodiment, the dry powder is administered to the subject using a dry powder device as described in U.S. Publication 2016 / 0296957, which is hereby incorporated by reference in its entirety. Dry powder devices described in U.S. Publication No. 2022 / 0362491 , International Publication No. WO 2022 / 123128, International Publication No. WO 2022 / 171969; and International Publication No. WO 2022 / 208014 are incorporated herein by reference.

[0390] In an embodiment, the nasal delivery device may be as described in any one of WO21005308; WO22123128; WO22171969; and W022208014 (the contents of which are incorporated by reference). In an embodiment, there is provided a dispenser device, optionally for dispensing a formulation or composition as described herein, the dispenser device comprising: a formulation or composition as described herein; a dispenser outlet (10); an air expeller (20) for generating a flow of air while the device is being actuated, said air expeller (20) including a piston (21) that slides in an air chamber (22) between a rest position and a dispensing position, said air chamber (22) including a cylindrical body (222) in which said piston (21) slides in airtight manner; and at least one reservoir (30) that contains a single dose of composition, said reservoir (30) including an air inlet (31) that is connected to said air expeller (20), and a composition outlet (32) that is connected to said dispenser outlet (10), said air inlet (31) including a composition retainer member (40) for retaining the composition in the reservoir (30) until the composition is dispensed, and said composition outlet (32) being closed by a closure element (50) that is force fitted in the composition outlet (32) of the reservoir (30); said device further including a mechanical opening system (61 , 62) that co-operates with said closure element (50) so as to expel it mechanically from its closed position while the device is being actuated, said mechanical opening system comprising a rod assembly (61 , 62), a first rod portion (61) being part of said air expeller (20) and sliding in said air chamber (22) during actuation of the device, and a second rod portion (62) pushed by said first rod portion (61) during actuation of the device, said rod assembly (61 , 62) cooperating at the end of the actuation stroke with said closure element (50) to expel it mechanically from its closed portion, said piston (21) of said air expeller (20), when in its rest position, co-operating in non-airtight manner with said air chamber (22), in such a manner that said air chamber (22) is in communication with the atmosphere in the rest position, said piston (21) including an inner lip (215) that slides in airtight manner on said cylindrical surface (614) during actuation of the device, and that co-operates in non-airtight manner with fluting (615) formed on said cylindrical surface (614) in the rest position to put the air chamber (22) in communication with the atmosphere in the rest position, said piston 21) co-operating in airtight manner with said cylindrical body (222) in any positions, and co-operating in non-airtight manner with said cylindrical surface (614) only in the rest position.

[0391] In an embodiment, there is provided a dispenser device, optionally for dispensing a formulation or composition as described herein, the dispenser device comprising: a formulation or composition as described herein; a dispenser outlet; an air expeller for generating a flow of air while the device is being actuated, said air expeller including a piston that slides in an air chamber between a rest position and a dispensing position, said air chamber including a cylindrical body in which said piston slides in airtight manner; and at least one reservoir that contains a single dose of composition, said reservoir including an air inlet that is connected to said air expeller, and a composition outlet that is connected to said dispenser outlet, said air inlet including a composition retainer member for retaining the composition in the reservoir until the composition is dispensed, and said composition outlet being closed by a closure element that is force fitted in the composition outlet of the reservoir; said device further including a mechanical opening system that co-operates with said closure element so as to expel said closure element mechanically from a closed position while the device is being actuated, said piston of said air expeller, when in the rest position, co-operating in non-airtight manner with said air chamber, in such a manner that said air chamber is in communication with the atmosphere in the rest position, wherein said piston includes an inner lip configured to cooperate with a cylindrical surface of a cylindrical member extending inside the cylindrical body, said cylindrical surface including fluting that co-operates in non-airtight manner with said inner lip of the piston in the rest position.

[0392] In an embodiment, said piston comprises one or more markings which are visible only when the piston is in the rest position and not visible when the piston is in the dispensing position. In an embodiment, a method comprising the use of the dispenser device comprises the actuation of the piston from the rest position to the dispensing position such that the one or more markings are no longer visible. In an embodiment, successful actuation of the dispensing device occurs when the one or more markings are no longer visible. In an embodiment, the one or more markings may be: one or more coloured lines, one or more coloured shapes, one or more words or written text or one or more physical features.

[0393] In an embodiment, there is provided an active nasal delivery device as described herein comprising one or more markings, said markings being visible when the active nasal delivery device is in the resting state and not visible following successful actuation of said active nasal delivery device. In an embodiment, the absence from view of said markings represents successful actuation of the active nasal delivery device. In an embodiment, the one or more markings may be as described herein.

[0394] A method of intranasally delivering a powder pharmaceutical formulation comprising a psychedelic and one or more pharmaceutically acceptable carriers or excipients, to a patient, wherein 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more or 99% or more of the formulation reaches the turbinates and olfactory region, wherein the psychedelic is 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, and the formulation is delivered via a nasal powder dispenser device which may comprise one or more of: a nasal dispenser head for inserting into a patient's nostril, the nasal dispenser head including a dispenser orifice; and an air expeller that, during actuation of the nasal powder dispenser device, generates a flow of compressed air so as to dispense a dose of the powder pharmaceutical formulation into the nostril through the dispenser orifice.

[0395] In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a spray pattern of: Table 4: Example Spray Pattern 1 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

[0396] % particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

[0397] In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 20 to 45 degrees; width: 25 to 55 mm; a spray pattern of:

[0398] Table 5: Example Spray Pattern 2 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, DOO = 540 to 610, %<10pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or

[0399] % particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

[0400] In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 20 to 35 degrees; width: 25 to 45 mm; a spray pattern of:

[0401] Table 6: Example Spray Pattern 3 a particle size distribution of: D10 = 13 to 17, D50 = 22 to 27, DOO = 35 to 56, %<9 pm = <0.1- 10%; or

[0402] % particles of equal to or less than 1 1 ,7pm size of:0.5 to 5%.

[0403] In an embodiment, there is provided an intranasal delivery system, optionally comprising an active nasal delivery device as described herein, comprising: a dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; and an active nasal delivery device, optionally as described herein, configured to deliver the particles to the turbinates and olfactory region of the nasal cavity of a subject at a single actuation; wherein the system is operably configured to emit a powder plume comprising 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, having one or more of: a plume geometry of: angle: 27 or 40 degrees; width: 33 or 50 mm; a spray pattern of:

[0404] Table 7: Example Spray Pattern 4 a particle size distribution (at 40mm) of: D10 = 15 or 16, D50 = 38 or 54, D90 = 684 or 685, %<10 pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; or a particle size distribution (at 70mm) of: D10 = 15 or 16, D50 = 27 or 28, D90 = 558 or 596, %<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, D90 = 35 to 56, %<9 pm = <0.1- 10%; or

[0405] % particles of equal to or less than 1 1 ,7pm size of: 0.5 to 5%.

[0406] In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a plume geometry of: angle: 22 to 35 degrees; width: 27 to 55 mm; or plume geometry of: angle: 22 to 33 degrees; width: 27 to 42 mm; or a plume geometry of: angle: 25 to 30 degrees; width: 29 to 39 mm; or a plume geometry of: angle: 26 to 28 degrees; width: 32 to 35 mm; or a plume geometry of: angle: 27.5 degrees; width: 34.33 mm; or a plume geometry of: angle: 24.4 degrees; width: 30.30 mm; or a plume geometry of: angle: 24.8 degrees; width: 30.76 mm; or a plume geometry of: angle: 27.4 degrees; width: 34.13 mm; or a plume geometry of: angle: 30.5 degrees; width: 38.29 mm; or a plume geometry of: angle: 39.2 degrees; width: 50.35 mm; or a plume geometry of: angle: 33.43 degrees; width: 52.25 mm; or a plume geometry of: angle: 28 degrees; width: 34 mm; or a plume geometry of: angle: 24 degrees; width: 30 mm; or a plume geometry of: angle: 25 degrees; width: 31 mm; or a plume geometry of: angle: 27 degrees; width: 34 mm; a plume geometry of: angle: 31 degrees; width: 38 mm or a plume geometry of: angle: 20, 21 , 22, 23, 24, 25,

[0407] 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45 or 46 degrees; width: 26,

[0408] 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55 or 56 mm.

[0409] In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a spray pattern of:

[0410] Table 8: Example Spray Pattern 5 or

[0411] Table 9: Example Spray Pattern 6

[0412] In an embodiment, the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has a spray pattern of:

[0413] Table 10: Example Spray Pattern 7 or Table 11 : Example Spray Pattern 8 or

[0414] Table 12: Example Spray Pattern 9 or

[0415] Table 13: Example Spray Pattern 10

[0416] In an embodiment, the particle size distribution of the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is: D10 = 15.54 or 15.05 or 15.89 or 15.31 , D50 = 26.8 or 28.21 or 38.27 or 53.92, D90 = 558.4 or 595.9 or 683.8 or 385.3, %<10 pm = 5.45 or 3.01 or 3.90 or 3.79; or D10 = 10.4 or 10.7, D50 = 21 .0 or 22.8, D90 = 38.4 or 14.9, %<10 pm = 8.65% or 8.35%; or D10 = 13, 14, 15, 16 or 17, D50 = 22, 23, 24, 25, 26 or 27, D90 = 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55 or 56, %<9 pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%.

[0417] In an embodiment, the % particles of equal to or less than 11 ,7pm size of the powder plume of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is: 0.5 to 5%, 0.6 to 4%, 0.7 to 3%, 0.8 to 2%, 0.9 to 1 %. In an embodiment, the active nasal delivery has an actuation force of between 30 and 60N. In an embodiment, the actuation force is between 40 and 50N. In an embodiment, the actuation force is 41 , 42, 43, 44, 45, 46, 47, 48 or 49N. In an embodiment, the actuation force is 20, 21 , 22, 23, 24, 25,26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79 or 80N. In an embodiment, the actuation force is 36N. In an embodiment, the actuation force is 37N. In an embodiment, the actuation force is 38N. In an embodiment, the actuation force is 39N. In an embodiment, the actuation force is 36N.

[0418] In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5- MeO-DMT, or a pharmaceutically acceptable salt thereof, comprises a crystalline form of 5-MeO- DMT, or a pharmaceutically acceptable salt thereof, as described herein. In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5- MeO-DMT, or a pharmaceutically acceptable salt thereof, has a moisture content of <5%, <4%, <3%, <2%, or <1%. In an embodiment, the moisture content is <2%, <1.9%, <1.8%, <1.7%, <1.6%, <1.5%, <1 .4%, <1 .3%, <1 .2% or <1.1%. In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% by weight of a hydroxyl impurity. In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5- MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% of by weight of any one impurity.

[0419] In an embodiment, the dry powder formulation comprising a plurality of powder particles of 5- MeO-DMT, or a pharmaceutically acceptable salt thereof, has <5%, <4%, <3%, <2%, <1%, <0.9%, <0.8%, <0.7%, <0.6%, <0.5%, <0.4%, <0.3%, <0.2%, <0.1%, <0.09%, <0.08%, <0.07%, <0.06%, <0.05%, <0.04%, <0.03%, <0.02% or <0.01% of by weight of any impurity. In an embodiment, the impurity profile is determined by RP-HPLC. In an embodiment, the % particles of equal to or less than 11 ,7pm size of the powder plume is determined by Next Generation Impactor and HPLC. In an embodiment, the moisture content is determined by Karl Fisher coulometric titration.

[0420] In an embodiment, the plume geometry is analysed using the Proveris SprayVIEW apparatus (or equivalent) in conjunction with the Proveris automated actuation device. In an embodiment, Analysis is performed at one distance (7.0cm). In an embodiment, the settings are as follows: Orifice tip distance (cm): 7.0, Frame rate (Hz): 500, Number of images 250, Lens aperture 2.0, Camera position from horizontal (cm): 27.0, Camera height (cm): 8.0, Laser position (cm): 5.2, Laser depth (cm): 5.3, Laser height (cm): 13.2, Actuator position (cm): 7.0, Plume orientation: 0 deg, Palette: Gradient, Arm 1 / Arm 2 (%): 20 - 30%, Evacuation time (ms): 1000, Setting time (ms): 1000. In an embodiment, the spray pattern is determined using the Proveris SprayVIEW apparatus (or equivalent) in conjunction with the Proveris automated actuation device. In an embodiment, analysis is performed at two distances (4.0cm and 7.0cm). In an embodiment, the settings are as above for the 7.0cm distance and as follows for the 4.0cm distance (where different from the settings used for 7.0cm): Orifice tip distance (cm): 4.0, Camera position from horizontal (cm): 8.0 and Camera height (cm): 22.

[0421] In an embodiment, the particle size distribution is determined by laser diffraction using a Malvern Mastersizer (or equivalent). In an embodiment, the settings are as follows: Instrument: Malvern Mastersizer 3000 with Malvern software (or equivalent), Sampling handling Unit: Hydro MV dispersion unit, Material Refractive Index: 1.590, Absorption Refractive Index: 0.001 , Dispersant Refractive Index: 1.391 (2,2,4-trimethylpentane), Obscuration Limits: 10-20%, Sonification time: Externally sonicated for 120 secs during sample preparation prior to addition to Hydro MV, Stirrer Speed: 3000 rpm, Measurement time: 30 secs, Background time: 30 secs, Dispersant: 2,2,4 - trimethylpentane (Rl=1 .391) and Lecithin 0.05% w / w, degassed and equilibrated to ambient temperature. In an embodiment, the aerodynamic particle size distribution (DISP) is determined by a method based on USP <601 >, using the Proveris Sprayview and a Copley Next Generation Impactor (NGI) or equivalent, complying with USP / Ph.Eur. In an embodiment, standard solutions are prepared based on the label claim for the drug product (xmg per 100ml diluent) where x=label claim. In an embodiment, the settings are as follows: Actuation acceleration: 5000mm / s / s, Actuation velocity: 70mm / s, Symmetric: Yes, Initial delay: 0 ms, Hold time: 100 ms, Final delay: 0 ms, Stroke length: 14 mm, One shot is fired into the NGI. Weigh the device prior to (W1) and after firing (W2) to calculate shot weight (W3). W1 - W2 = shot weight (W3), Add 5 ml of test solvent to each NGI cup then place on the NGI gentle rocker for 5 minutes. Quantitatively wash the expansion chamber, bungs, inlet cone, all cups and the Proveris collar with diluent into the correct flask size and make to volume. Assay is determined via HPLC.

[0422] In an embodiment, the particle size distribution (PSD) is determined by laser diffraction. In an embodiment, the analysis is performed using Sympatec instrumentation with R5 lens and a dispersal pressure of 3 bar. The intranasal delivery system / device is held in a clamp stand and positioned central with the extractor and so the tip of the device is 3 cm from the mid-point of the laser. After referencing, the device is manually / hand actuated so the powder passes through the laser beam, which takes a reading. Readings are performed with an R5 lens, in triplicate and then an average calculated.

Claims

CLAIMSWhat is claimed is:1 . A method of treating depression in a patient in need thereof, the method comprising administering to the patient having depression a first pharmaceutical composition and a second pharmaceutical composition, wherein:(a) the first pharmaceutical composition comprises about 8mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and the second pharmaceutical composition comprises about 12mg 5- MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients; or(b) the first pharmaceutical composition comprises about 12mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and the second pharmaceutical composition comprises about 12mg 5- MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients; wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition.

2. The method of claim 1 , wherein the second pharmaceutical composition is administered to the subject within 3 weeks of administration of the first pharmaceutical composition.

3. The method of claim 1 , wherein the second pharmaceutical composition is administered to the subject within 2 weeks of administration of the first pharmaceutical composition.

4. The method of claim 1 , wherein the second pharmaceutical composition is administered to the subject within 1 week of administration of the first pharmaceutical composition.

5. The method of claim 1 , wherein the second pharmaceutical composition is administered to the subject 14 days after the administration of the first pharmaceutical composition.

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

7. The method of any one preceding claim, wherein the method further comprises the provision of psychological support to the patient.

8. The method of any one preceding claim, wherein the method further comprises the provision of psychological support to the patient, wherein the psychological support is provided:Prior to administration of the first or second pharmaceutical composition;During administration of the first or second pharmaceutical composition; and / or After administration of the first or second pharmaceutical composition.

9. The method of any one preceding claim, wherein the method further comprises the provision of psychological support to the patient, wherein the psychological support is provided for atleast 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks prior to administration of the first or second pharmaceutical composition.

10. The method of any one preceding claim, 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 first or second pharmaceutical composition.11 . The method of any one preceding claim, wherein the method further comprises the provision of at least 2 psychological support sessions over about 2 weeks prior to the administration of the first pharmaceutical composition.

12. The method of any one preceding claim, wherein the method further comprises the provision of at least 1 psychological support session following administration of the first pharmaceutical composition and prior to the administration of the second pharmaceutical composition.

13. The method of any one preceding claim, wherein the method further comprises the provision of psychological support by a psychedelic assisted therapy therapist.

14. The method of any one preceding claim, wherein the pharmaceutical compositions are administered under the supervision of one or more professionals.

15. The method of any one preceding claim, wherein the pharmaceutical compositions are administered under the supervision of one or more licensed professionals.

16. The method of any one preceding claim, wherein the pharmaceutical compositions are administered under the supervision of a cognitive behavioural therapist and a psychedelic assisted therapy therapist.

17. The method of any one preceding claim, wherein the pharmaceutical compositions are administered by the patient themselves or by a licensed professional.

18. The method of any one preceding claim, 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.

19. The method of any one preceding claim, wherein the method of treatment is a method of treatment of a patient aged 18 to 75 years.

20. The method of any one preceding claim, wherein the method of treatment is 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; 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.

21. 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.

22. 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.

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

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

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

26. 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; particleshaving 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.

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

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

29. 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.

30. 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 8mg, 9mg, 10mg, 11 mg, 12mg, 13mg or 14mg 5-MeO-DMT freebase.

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

32. 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 8mg, 9mg, 10mg, 11 mg, 12mg, 13mg or 14mg 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.

33. 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), sodiumtaurocholate, 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.

34. 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.

35. 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.

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

37. 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.

38. 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.

39. 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.

40. 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.41 . 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.

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

43. The method of any one preceding claim, wherein the method of treatment is a method of treatment of a depressive disorder, such as major depressive disorder (MDD), moderate to severe MDD, treatment-resistant MDD, major depression, melancholic depression, atypical depression or dysthymia, or difficult to treat depression.

44. The method of any one preceding claim, wherein the method of treatment is a method of treatment of depression and one or more other conditions selected from: anxiety, treatmentresistant 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.

45. The method of any one preceding claim, wherein the pharmaceutical composition is contained within, and administered from, a single use intranasal delivery device.

46. The method of 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.

47. The method of 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.

48. The method of 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.

49. The method of 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 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, D90 = 650 to700, %<10 pm = <0.1 , 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10%; ora particle size distribution (at 70mm) of: D10 = 13 to 17, D50 = 24 to 30, DOO = 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, D90 = 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%.

50. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants.

51. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the patient has been taking the one or more antidepressants for at least about 4, 5, 6, 7, 8, 9 or 10 weeks.

52. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the patient has been taking the one or more antidepressants for at least about 6 weeks.

53. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants are one or more selective serotonin reuptake inhibitors (SSRIs).

54. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants are citalopram, escitalopram, fluoxetine or sertraline.

55. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 10-40 mg daily.

56. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 40 mg daily.

57. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants,58. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is citalopram and wherein the dose of citalopram is 20 mg daily.

59. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 10-20 mg daily.

60. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 20 mg daily.

61. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is escitalopram and wherein the dose of escitalopram is 10 mg daily.

62. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 20-60 mg daily.

63. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 60 mg daily.

64. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 40 mg daily.

65. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is fluoxetine and wherein the dose of fluoxetine is 20 mg daily.

66. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 50-200 mg daily.

67. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 200 mg daily.

68. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 150 mg daily.

69. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 100 mg daily.

70. The method of any one preceding claim, wherein the method is a method of treatment of a patient wherein the patient is currently taking one or more antidepressants, wherein the one or more antidepressants is sertraline and wherein the dose of sertraline is 50 mg daily.

71. The method of any one preceding claim, wherein the treatment of depression comprises administering to the patient a 5-MeO-DMT dosing regimen, and the 5-MeO-DMT dosing regimen consists of administering(a) a first pharmaceutical composition comprising about 8mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or about 8mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and(b) a second pharmaceutical composition comprising about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients,wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition, and wherein the 5-MeO- DMT dosing regimen includes no further 5-MeO-DMT administrations to the patient for a period of at least 1 month, 2 months, or 3 months following the administration of the first pharmaceutical composition.

72. The method of any one preceding claim, wherein the treatment of depression comprises administering to the patient a 5-MeO-DMT dosing regimen, and the 5-MeO-DMT dosing regimen consists of administering(a) a first pharmaceutical composition comprising about 12mg 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT), or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients; and(b) a second pharmaceutical composition comprising about 12mg 5-MeO-DMT, or about 12mg of a freebase equivalent of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, wherein the second pharmaceutical composition is administered to the subject within 4 weeks of administration of the first pharmaceutical composition, and wherein the 5-MeO- DMT dosing regimen includes no further 5-MeO-DMT administrations to the patient for a period of at least 1 month, 2 months, or 3 months following the administration of the first pharmaceutical composition.

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