Pharmaceutical composition containing 5-methoxy-N,N-dimethyltryptamine (5-MEO-DMT)

Abstract

The present invention relates to a pharmaceutical composition or formulation of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), more particularly to an intranasal delivery device comprising a pharmaceutically acceptable salt of 5-MeO-DMT as a nasal pharmaceutical composition or formulation, and to a method of administration and treatment using the same.

Description

Technical Field

[0001] The present invention relates to a 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) pharmaceutical composition or formulation, more particularly to an active intranasal delivery device comprising a pharmaceutical composition or formulation of a pharmaceutically acceptable salt of 5-MeO-DMT, and methods of administration and treatment using the same.

Background Art

[0002] 5-methoxy-N,N-dimethyltryptamine is a pharmacologically active compound of the tryptamine class and has the following chemical formula

[0003]

Chemical Formula

[0004] as follows. 5-MeO-DMT is a naturally occurring psychoactive / psychedelic substance. Synthetic salts of 5-MeO-DMT are also known in the art; for example, Sherwood, Alexander M. et al. "Synthesis and Characterization of 5-MeO-DMT succinate for clinical use." ACS omega 5.49 (2020): 32067-32075 discloses the hydrochloride salt of 5-MeO-DMT. However, 5-MeO-DMT and its salts are not well understood, and methods of administering pharmaceutical compositions or formulations of this compound and its salts, particularly intranasal administration methods, are difficult to develop and have not been fully explored.

[0005] [[ID=3))]

[0006] )]] 5-MeO-DMT is not suitable for oral delivery, and therefore other administration methods have been investigated. Other possible methods of administration include intravenous administration and inhalation by smoking. Nasal administration, such as intranasal liquid spray formulations, is another method that provides systemic drug delivery across the blood-brain barrier, especially when oral administration is ineffective. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In the field of the art, there remains a need for improved pharmaceutical compositions or formulations containing 5-MeO-DMT and its salts, particularly nasal pharmaceutical compositions or formulations, as well as methods of administration and treatment using these pharmaceutical compositions or formulations that enable safe, non-invasive administration that can enhance patient availability and improve patient adherence to medication. [Means for solving the problem]

[0008] The nasal cavity is recognized as a promising systemic drug delivery route due to its highly vascularized capillary bed within the nasal mucosa. Surprisingly, we have discovered that delivery of 5-MeO-DMT pharmaceutical compositions or formulations by active nasal delivery devices results in a desired intranasal deposition profile, while delivery of 5-MeO-DMT pharmaceutical compositions or formulations by passive nasal delivery devices results in an undesirable intranasal deposition profile (see Example 28).

[0009] As disclosed herein, an active intranasal delivery device is provided comprising a pharmaceutical composition / formulation of 5-MeO-DMT or a pharmaceutically acceptable salt, prodrug, hydrate, ester, cocrystal or deuterated form and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the pharmaceutical composition / formulation of 5-MeO-DMT is a spray-dried formulation. In some embodiments, the pharmaceutical composition / formulation contains less than about 5% by weight of water of the formulation.

[0010] In some embodiments, at least 95% of the particles in the pharmaceutical composition / formulation are larger than 10 microns in size. In some embodiments, the pharmaceutical composition / formulation comprises methylcellulose, optionally high-viscosity methylcellulose. In some embodiments, the pharmaceutical composition / formulation comprises low-viscosity methylcellulose and high-viscosity methylcellulose. In some embodiments, the pharmaceutical composition / formulation comprises a cellulose-like / base excipient, optionally HPMC, and optionally high-viscosity HPMC. In some embodiments, the pharmaceutical composition / formulation comprises low-viscosity HPMC and high-viscosity HPMC.

[0011] In one embodiment, the ratio of low-viscosity HPMC to high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:1. In one embodiment, the ratio of low-viscosity HPMC to high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:75. In one embodiment, the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50, or 60 millipascals-seconds or more, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 50 mPa·s. In one embodiment, the low viscosity HPMC has viscosities of less than approximately 20, 15, 10, 5, and 1 millipascal-seconds, and optionally the HPMC has a hydroxypropyl content of approximately 7.0–12.0%, a methoxy content of approximately 28.0–30.0%, and a viscosity of approximately 4.8–7.2 mPa·s.

[0012] In one embodiment, the pharmaceutical composition / formulation comprises a polyol, optionally being mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and optionally being sorbitol. In one embodiment, the pharmaceutical composition / formulation comprises about 1-10% by weight, 2-5% by weight, or 3% by weight of a polyol, and optionally about 3% by weight of sorbitol, mannitol, or isomalt.

[0013] In some embodiments, the pharmaceutical composition / formulation contains a 5-MeO-DMT salt. In some embodiments, the pharmaceutical composition / formulation contains a 5-MeO-DMT benzoate. In some embodiments, the pharmaceutical composition / formulation contains a 5-MeO-DMT hydrochloride. In some embodiments, the pharmaceutical composition / formulation contains a 5-MeO-DMT hydrobromide. In some embodiments, the 5-MeO-DMT salt is amorphous. In some embodiments, the 5-MeO-DMT salt is crystalline. In one embodiment, the crystalline 5-MeO-DMT salt is characterized by one or more peaks at 17.5, 17.7, and 21.0°2θ±0.1°2θ in an XRPD diffraction pattern measured using an X-ray wavelength of 1.5406 Å, and by powder X-ray diffraction measured using an X-ray wavelength of 1.5406 Å, in an XRPD diffraction pattern, at 9.2°±0.1°, 12.2°±0.1°, 14.1°±0.1°, and 15.0°±0. The crystalline form of 5-MeO-DMT hydrochloride is selected from a form characterized by one or more peaks at 1°, 18.5°±0.1°, and 19.5°±0.1°²θ, or a form of 5-MeO-DMT hydrobromide is selected from a form characterized by one or more peaks at 14.6, 16.8, 20.8, 24.3, 24.9, and 27.5°²θ±0.1°²θ in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction.

[0014] In one embodiment, the active intranasal delivery device includes a dispenser outlet, an air exhauster for generating an airflow while the device is in operation, and at least one reservoir containing a single-dose formulation.

[0015] In one embodiment, the active intranasal delivery device includes a dispenser outlet, an air vent for generating an airflow while the device is operating, the air vent including a piston that slides between a stop position and a dispense position within an air chamber, the air chamber including a cylindrical body, and the piston sliding airtightly within the cylindrical body, and at least one reservoir containing a single-dose formulation, the reservoir including an air inlet connected to the air vent and a pharmaceutical composition / formulation outlet connected to the dispenser outlet, the air inlet being a pharmaceutical composition / formulation holder for holding the pharmaceutical composition / formulation in the reservoir until the pharmaceutical composition / formulation is dispensed. The device includes a component and at least one reservoir, the pharmaceutical composition / formulation outlet of which is closed by a closure element that is pressurized into the pharmaceutical composition / formulation outlet of the reservoir, the device further includes a mechanical opening system that cooperates with the closure element to mechanically discharge the closure element from a closed position while the device is operating, the piston of the air discharger cooperates non-airtightly with the air chamber such that, when in a stopped position, the air chamber is in communication with the atmosphere in the stopped position, the piston includes an inner lip configured to cooperate with a cylindrical surface of a cylindrical component extending into the interior of a cylindrical body, the cylindrical surface includes fluting that cooperates non-airtightly with the inner lip of the piston in the stopped position.

[0016] In one embodiment, the active intranasal delivery device is for use in a method of treating a disease or condition. In another embodiment, the active intranasal delivery device is for use in the treatment of mental health conditions, optionally depression and / or alcohol use disorder. As disclosed herein, dry powder formulations are provided which are produced by spray drying, freeze-drying or hot-melt extrusion, and the pharmaceutical composition / formulation comprises 5-MeO-DMT or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. Beneficially, spray drying, freeze-drying or hot-melt extrusion results in close mixing of the 5-MeO-DMT salt with any carrier, excipient or any other additive.

[0017] In a first embodiment, a state-stable amorphous dry powder pharmaceutical composition / formulation is provided, comprising 5-MeO-DMT HBr (hydrobrovid salt of 5-MeO-DMT) or 5-MeO-DMT HCl (hydrochloride salt of 5-MeO-DMT) and one or more pharmaceutically acceptable carriers or excipients. Beneficially, the amorphous state does not revert to the crystalline state, thus the properties of the pharmaceutical composition / formulation are well understood. In some embodiments, the pharmaceutical composition / formulation is a spray-dried formulation. In some embodiments, less than 80% of the 5-MeO-DMT is released from the pharmaceutical composition / formulation by 4 minutes at 37°C in water. In some embodiments, less than 80% of the 5-MeO-DMT is released from the pharmaceutical composition / formulation by 5, 6, 7, 8, 9, or 10 minutes at 37°C in water. In one embodiment, less than 80% of 5-MeO-DMT is released from the pharmaceutical composition / formulation in simulated nasal fluid within 5, 6, 7, 8, 9, or 10 minutes. Beneficially, 5-MeO-DMT is not released rapidly, but rather relatively slowly. Beneficially, the treated person is ingested the active substance over a period of time. In some cases, ingesting the active substance, i.e., a psychoactive substance, over a very short time interval can be quite potent.

[0018] In some embodiments, at least 95% of the particles in the pharmaceutical composition / formulation are larger than 10 microns in size. Beneficially, the pharmaceutical composition / formulation is substantially free of respiratory fine particles (undesirable particles that may enter the lungs). In some embodiments, 5-MeO-DMT HBr is non-hygroscopic. In some embodiments, the pharmaceutical composition / formulation contains less than about 5% by weight of water. In some embodiments, the pharmaceutical composition / formulation is a free-flowing formulation. Beneficially, non-hygroscopic salts are easy to handle and formulate, they tend to be free-flowing, and they are difficult to deformulate.

[0019] In some embodiments, more than 70% (w / w) of 5-MeO-DMT HBr in the pharmaceutical composition / formulation is in amorphous form. In some embodiments, the pharmaceutical composition / formulation contains at least about 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight of 5-MeO-DMT HBr. In some embodiments, more than 70% (w / w) of 5-MeO-DMT HCl in the pharmaceutical composition / formulation is in amorphous form. In some embodiments, the pharmaceutical composition / formulation contains at least about 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight of 5-MeO-DMT HCl.

[0020] In some embodiments, when administered to the nasal cavity of a target, the pharmaceutical composition / formulation exhibits a residual time. In some embodiments, the length of time the substance is present in the nasal cavity, for example, along the nasal cilia and mucous layer in the nasal cavity, is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. Beneficially, the person being treated is inoculated with the active substance over a period of time. In some cases, inoculating an active substance, i.e., a psychoactive substance, at very short time intervals can be quite potent. In some embodiments, the pharmaceutical composition / formulation comprises a cellulose-like / base excipient, optionally cellulose ether, optionally HPMC, even more optionally high viscosity HPMC, and even more optionally high viscosity HPMC. In some embodiments, the pharmaceutical composition / formulation comprises low viscosity HPMC and high viscosity HPMC. In one embodiment, the ratio of low-viscosity HPMC to high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:1. In one embodiment, the ratio of low-viscosity HPMC to high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:75. In one embodiment, the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50, or 60 millipascals-seconds or more, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 50 mPa·s. In one embodiment, the low-viscosity HPMC has a viscosity of less than approximately 20, 15, 10, 5, or 1 millipascal-seconds, and optionally the HPMC has a hydroxypropyl content of approximately 7.0–12.0%, a methoxy content of approximately 28.0–30.0%, and a viscosity of approximately 4.8–7.2 mPa·s. In one embodiment, the pharmaceutical composition / formulation comprises a polyol, optionally the polyol being mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and further optionally the polyol being sorbitol. In one embodiment, the pharmaceutical composition / formulation comprises approximately 1–10% by weight, 2–5% by weight, or 3% by weight of a polyol, and optionally approximately 3% by weight of sorbitol.

[0021] In one embodiment, the pharmaceutical composition / formulation comprises one or more of the following: chitosan, chitosan derivatives, β-cyclodextrin, Clostridium perfringens enterotoxin, zonal toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate, sodium lauryl sulfate, glycodeoxycholate, palmitic acid, palmitoleic acid, stearic acid, oleic acid, oleyl alcohol, sodium caprate, DHA, EPA, dipalmitoylphosphatidylcholine, soy lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid. In one embodiment, the pharmaceutical composition / formulation comprises one or more of the following: a mucosal adhesion enhancer, a penetration enhancer, a cationic polymer, a cyclodextrin, a tight junction modulator, an enzyme inhibitor, a surfactant, a chelating agent, and a polysaccharide.

[0022] In some embodiments, the pharmaceutical composition / formulation comprises one or more anticaking agents. In some embodiments, the pharmaceutical composition / formulation comprises one or more of the following: calcium silicate, sodium aluminosilicate, sodium ferrocyanide, potassium ferrocyanide, calcium carbonate, magnesium carbonate, silicon dioxide, tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, microcrystalline cellulose, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, sodium stearyl fumarate, or polydimethylsiloxane.

[0023] In certain embodiments, a nasal delivery device comprising a formulation is provided. In certain embodiments, the ratio of the active substance (5-MeO-DMT) in the active substance salt is greater than about 65, 70 or 80% (i.e., using a counter ion with a lower relative molecular mass). Advantageously, in a device having a small delivery chamber, a high ratio of the active substance in the salt is desirable. Similarly, the higher the ratio of the salt in the particles, the more desirable.

[0024] In certain embodiments, a method of treating depression and / or alcohol use disorder in a subject who needs to be treated for depression and / or alcohol use disorder, the method comprising the step of nasal administration to the subject of a pharmaceutical composition / formulation in an amount sufficient to treat depression and / or alcohol use disorder is provided. In certain embodiments, a method of making a formulation, comprising: (i) mixing the components of the pharmaceutical composition / formulation with a liquid to form a mixture and spray drying the mixture to form a solid; and (ii) following step (i), further drying the solid to form the pharmaceutical composition / formulation, optionally wherein the drying step is carried out at a relative humidity (RH) between 45 and 15 °C and between 85% and 65%, between 35 and 20 °C and between 80% and 70%, and further optionally at 25 °C and 75% RH.

[0025] In certain embodiments, the pharmaceutical composition / formulation comprises approximately 40-60% by weight of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 30-40% by weight of HPMC having a hydroxypropyl content of about 7.0-12.0%, a methoxy content of about 28.0-30.0%, and a viscosity of about 4.8-7.2 mPa·s, 7-15% by weight of HPMC having a hydroxypropyl content of about 7.0-12.0%, a methoxy content of about 28.0-30.0%, and a viscosity of about 50 mPa·s, and 0-5% by weight of sorbitol. In further embodiments, the pharmaceutical composition / formulation comprises approximately 40-60% by weight of 5-MeO-DMT HBr or 5-MeO-DMT HCl, 30-40% by weight of HPMC having a hydroxypropyl content of about 7.0-12.0%, a methoxy content of about 28.0-30.0%, and a viscosity of about 4.8-7.2 mPa·s, 7-15% by weight of HPMC having a hydroxypropyl content of about 7.0-12.0%, a methoxy content of about 28.0-30.0%, and a viscosity of about 50 mPa·s, and 0-5% by weight of sorbitol.

[0026] In certain embodiments, 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is in an amorphous form. In certain embodiments, the pharmaceutical composition / formulation is a stable free-flowing formulation. In certain embodiments, the pharmaceutical composition / formulation is a state-stable free-flowing formulation. In certain embodiments, the pharmaceutical composition / formulation comprises at least about 10%, 20%, 30%, 4​​​In one embodiment, the pharmaceutical composition / formulation comprises a cellulose-like / base excipient, optionally cellulose ether, optionally HPMC, optionally high-viscosity HPMC, and optionally high-viscosity HPMC. In one embodiment, the pharmaceutical composition / formulation exhibits a sustained-release profile. In one embodiment, the pharmaceutical composition / formulation comprises a cellulose-like / base excipient, optionally HPMC, optionally high-viscosity HPMC, and optionally high-viscosity HPMC, and the pharmaceutical composition / formulation exhibits a sustained-release profile. In one embodiment, the pharmaceutical composition / formulation exhibits a sustained-release profile compared to a pharmaceutical composition / formulation without a cellulose-like / base excipient. In one embodiment, the pharmaceutical composition / formulation comprises low-viscosity HPMC and high-viscosity HPMC. In one embodiment, the pharmaceutical composition / formulation exhibits a sustained-release profile.

[0028] In some embodiments, the pharmaceutical composition / formulation comprises low-viscosity HPMC and high-viscosity HPMC, and the pharmaceutical composition / formulation exhibits a sustained-release profile. In some embodiments, the ratio of low-viscosity HPMC to high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:1. In some embodiments, the ratio of low-viscosity HPMC to high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:75. In some embodiments, the ratio of low-viscosity HPMC to high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:75, and the pharmaceutical composition / formulation exhibits a sustained-release profile. In one embodiment, the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50, or 60 millipascals-seconds or more, and optionally the HPMC is Metroz 60SH50.

[0029] In one embodiment, the low-viscosity HPMC has a viscosity of less than about 20, 15, 10, 5, or 1 millipascal-seconds, and optionally the HPMC is pharmacoat 606. In one embodiment, the pharmaceutical composition / formulation comprises a polyol, optionally the polyol being mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and further optionally the polyol being sorbitol. In one embodiment, the pharmaceutical composition / formulation comprises about 1-10% by weight, 2-5% by weight, or 3% by weight of a polyol, and optionally about 3% by weight of sorbitol.

[0030] In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT hydrochloride, optionally the salt being amorphous, and optionally a state-stable amorphous form. In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT hydrobromide, optionally the salt being amorphous, and optionally a state-stable amorphous form. In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT benzoate, optionally the salt being amorphous, and optionally a state-stable amorphous form. In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT oxalate, optionally the salt being amorphous, and optionally a state-stable amorphous form. In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT phosphate, optionally the salt being amorphous, and optionally a state-stable amorphous form. In one embodiment, the pharmaceutical composition / formulation comprises 5-MeO-DMT fumarate, and optionally the salt is in an amorphous form, and further optionally in a state-stable amorphous form.

[0031] In one embodiment, the pharmaceutical composition / formulation comprises a 5-MeO-DMT salt, optionally the salt being in an amorphous form, and further optionally a state-stable amorphous form. In a further embodiment of the present invention, a nasal delivery device comprising the pharmaceutical composition or formulation described herein and / or in any aspect or embodiment of the present invention is provided. In one embodiment, the device is for single use. In one embodiment, the device comprises a single-dose formulation. In one embodiment, the pharmaceutical composition / formulation or nasal delivery device is for pharmaceutical use.

[0032] In one embodiment, the pharmaceutical composition / formulation or nasal delivery device is for use in a method of treating depression and / or alcohol use disorder. In one embodiment, the pharmaceutical composition / formulation is prepared by spray drying, and following the spray drying of the formulation, additional adjustment steps are taken to adjust the formulation. In one embodiment, the drying step is carried out at a relative humidity (RH) between 45 and 15°C and between 85% and 65%, optionally between 35 and 20°C and between 80% and 70% RH, and further optionally at 25°C and 75% RH.

[0033] In one embodiment, a dry powder formulation is provided which is prepared by a spray-drying method, and the pharmaceutical composition / formulation comprises approximately 50% by weight of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 35% by weight of HPMC606, 12% by weight of methylose 60SH50, and 3% by weight of sorbitol.

[0034] Intranasal administration of liquids is one method that results in systemic drug delivery across the blood-brain barrier. However, one of the difficulties faced by these liquid pharmaceutical compositions or formulations is their limited retention time in the nasal cavity. The mucociliary exclusion mechanism is involved in this limited retention time, and the movement of nasal cilia causes the upper gel-like mucus layer in the epithelium to move towards the nasopharynx and throat at a rate of approximately 6 mm / min. Thus, such liquid pharmaceutical compositions or formulations are rapidly removed from the nasal cavity. In addition, some 5-MeO-DMT liquid intranasal pharmaceutical compositions or formulations may have stability issues, such as discoloration and / or a decrease in desired pharmacokinetic properties.

[0035] Several attempts have been made to develop dry powder pharmaceutical compositions or formulations for nasal administration that overcome the challenges associated with liquid pharmaceutical compositions or formulations. However, these attempts have proven difficult. The first nasal dry powder pharmaceutical compositions or formulations were approved by the Food and Drug Administration in 2016 and 2019 as Onzetra (containing sumatriptan) and Baqsimi (containing glucagon), respectively. Onzetra uses a passive administration device, and Baqsimi uses an active device; therefore, research was needed to find pharmaceutical compositions / formulations and devices that work well together in each case.

[0036] In addition, some 5-MeO-DMT salts have been found to be highly soluble in water (for example, some crystalline forms of 5-MeO-DMT halide salts have solubility in water exceeding 400 mg / mL) and to have a very rapid dissolution profile. While these properties may be desirable in solid oral or intravenous pharmaceutical compositions or formulations, they are not necessarily beneficial in nasal pharmaceutical compositions or formulations of 5-MeO-DMT.

[0037] This is because 5-MeO-DMT can produce a very intense mystical experience in the subject. Therefore, in the case of highly soluble nasal drug compositions / formulations that rapidly cross the blood-brain barrier (e.g., 80% of the active drug dose in about 4 minutes), the resulting mystical experience can occur very rapidly, be extremely intense, and cause irritation, which may be anxiety-inducing for some users.

[0038] As will be further discussed below herein, the applicant has found that, beneficially, a dry powder pharmaceutical composition or formulation of 5-MeO-DMT (and the salts described herein), in particular an amorphous dry powder pharmaceutical composition or formulation thereof, addresses and / or improves upon the problems encountered in the prior art.

[0039] The applicant has found beneficial properties in preparing a dry powder pharmaceutical composition or formulation of 5-MeO-DMT, including the following factors (not necessarily listed in order of importance): amorphous (non-crystalline) form / state; medium / low solubility form; and excipients / agents that delay / delay the dissolution of the active agent across the nasal blood-brain barrier (e.g., cellulose-like / base excipients such as HMPC and (methyl)cellulose). Therefore, the applicant has attempted to increase the residence time of the active agent (5-MeO-DMT) in the nasal cavity. Other modifications have not been found to be effective and, in fact, in some cases, have decreased the residence time in the nasal cavity. Furthermore, when adapting a pharmaceutical composition / formulation to a dry powder delivery device, the proportion of the active agent in the pharmaceutical composition / formulation should be relatively high in order to maximize the proportion of the active agent in the delivery vehicle, for example, in a relatively small delivery chamber in the delivery vehicle (e.g., accommodating a volume of less than approximately 0.05 ml). (Therefore, smaller formula weight-to-ion ratios can be beneficial, as can lower proportions of any excipient / additive.) Further beneficially, the pharmaceutical composition / formulation should be state-stable, for example, it should not (re)crystallize, especially during storage. Even more beneficially, the amorphous (non-crystalline) form / state should be state-stable above room temperature, for example, it should not (re)crystallize during storage above approximately 0, 5, 10, 15, 20, 25, 30, or 35°C. Furthermore, cellulose-like / base excipients can have viscosities that meet the requirements, e.g., high, medium, or low viscosity, or mixtures of these having different viscosities (e.g., high and low viscosity). Without being constrained by theory, 5-MeO-DMT preferentially dissolves in cellulose-like / base excipients, which can slow / delay the movement of APIs (i.e., 5-MeO-DMT) across the nasal blood-brain barrier. Advantageously, the pharmaceutical composition / formulation should not contain respiratory API fine particles (e.g., those that may enter the lungs) and / or any significant amounts of any agglutination. Respiratory fine particles are particles 10 microns or less. In some embodiments, the pharmaceutical composition / formulation contains particles greater than 10 microns. In some embodiments, the pharmaceutical composition / formulation is substantially free of respiratory fine particles.In one embodiment, 75, 80, 90, 95, 98, 99, 99.5, 99.8, or 99.9% of the particles of the pharmaceutical composition / formulation are greater than 10 micrometers.

[0040] In one embodiment, the pharmaceutical composition / formulation contains particles having a median diameter of 2000 μm, 1000 μm, 500 μm, 250 μm, 100 μm, 50 μm, or less than 1 μm. In one embodiment, the particles have a median diameter of 500 μm, 250 μm, 100 μm, 50 μm, 40 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, 5 μm, 1 μm, or greater than 0.5 μm. In one embodiment, the pharmaceutical composition / formulation has a particle size distribution of d10 = 20 to 60 μm and / or d50 = 80 to 120 μm and / or d90 = 130 to 300 μm.

[0041] It is conceivable that pharmaceutical compositions / formulations may be prepared that include slow-release elements / parts and standard-release elements / parts (e.g., mixtures of amorphous and partially crystalline 5-MeO-DMT (API)), thus having an initial release of API (e.g., a lower amount), followed by a slower release of API (e.g., a higher amount). In one embodiment, the pharmaceutical composition / formulation includes crystalline API dry-blended with an SDD containing API / HPMC. Beneficially, this can result in a higher drug load in a single device.

[0042] As disclosed herein, the pharmaceutical compositions / formulations do not contain one or more pharmaceutically acceptable carriers or excipients. 5-MeO-DMT is very likely to be treated as a controlled drug by health authorities. Health authorities require the establishment of specific methods for prescribing and using this drug in patients. When taken as prescribed by a qualified physician, the controlled substance can effectively treat many conditions. However, over the past decade, a dramatic increase in the conversion, misuse, and abuse of controlled substances has been observed in many countries.

[0043] Most abused drugs directly or indirectly target the brain's reward system, which affects the body's ability to regulate movement, emotion, motivation, and satisfaction. When the reward system is overstimulated by certain controlled substances, it produces an euphoric effect, which severely reinforces the behavioral pattern of substance use, thus encouraging users to repeat the behavior. The primary route of administration is oral, but some individuals change the route of administration to increase the effect or to prevent tolerance to the substance from developing.

[0044] Alternative routes of administration, including transnasal (e.g., lithotripsy and snorting) and intravenous (e.g., dissolution and injection) methods, and smoking inhalation, often result in faster drug delivery and onset, as well as increased efficacy. Individuals using altered routes of administration face an increased risk of overdose and the development or exacerbation of substance use disorders. Substance-preventing pharmaceutical compositions or formulations offer significant personal and public health benefits by preventing inexperienced substance users from successfully ingesting substances via altered routes of administration, thereby preventing associated overdoses and intensification of substance use.

[0045] A drug abuse prevention composition or formulation limits one or more forms of such abuse by (1) interfering with the extraction of the active ingredient, (2) reducing the bioavailability of the product when modified, thereby reducing the euphoric effect, (3) preventing administration via an alternative route, or (4) reducing the attractiveness or reward of the abuse of a modified product, thereby reducing the attractiveness or drug preference quality of the controlled substance.

[0046] In one embodiment, a 5-MeO-DMT pharmaceutical composition / formulation is formulated as an anti-abuse pharmaceutical composition / formulation comprising one or more of the following types of anti-abuse techniques: (1) physical barriers: preventing chewing, crushing, cutting, grinding or pulverizing; (2) chemical barriers: resisting opioid extraction using common solvents such as water, alcohol or other organic solvents; (3) activator / antagonist combinations: preventing, reducing, or breaking the euphoria associated with tampering with the product; (4) aversion: combining substances that produce an unpleasant effect when the dosage form is tampered with before ingestion or when a higher dose is used than directed; (5) delivery systems: a specific drug release design or method of drug delivery that confers resistance to abuse, such as a depot injectable pharmaceutical composition or formulation or implant; (6) prodrugs: losing activity until converted in the gastrointestinal tract, thereby reducing the appeal of intravenous or nasal abuse; (7) combinations: a product that combines two or more of the above methods.

[0047] For example, certain 5-MeO-DMT pharmaceutical compositions or formulations described herein, in the form of spray-dried dispersions of 5-MeO-DMT in combination with one or more pharmaceutically acceptable excipients, are beneficial not only for the advantageous properties of the dispersion described herein but also for the fact that the dispersion provides protection against abuse. The closely mixed nature of the dispersion provides a barrier to the easy extraction of the active pharmaceutical component.

[0048] In one embodiment, a 5-MeO-DMT pharmaceutical composition / formulation described herein is provided, wherein the pharmaceutical composition / formulation contains a polyol, and the pharmaceutical composition / formulation exhibits a significant reduction in mucosal irritation when administered intranasally, orally, sublabially, or sublingually, compared to a pharmaceutical composition / formulation that does not contain a polyol.

[0049] In one embodiment, a method is provided for reducing mucosal irritation in a subject by intranasal, oropharyngeal, sublabial or sublingual administration of 5-MeO-DMT, the method comprising the step of preparing 5-MeO-DMT in a pharmaceutical composition / formulation described herein, wherein the pharmaceutical composition / formulation comprises a polyol. In one embodiment, a 5-MeO-DMT pharmaceutical composition / formulation described herein is provided, comprising 5-MeO-DMT as a saccharinate salt, and exhibiting a strong reduction in mucosal irritation when administered intranasally, oropharyngeal, sublabial or sublingually, compared to a pharmaceutical composition / formulation in the form of 5-MeO-DMT free base or alternative salt.

[0050] In one embodiment, a method is provided for reducing mucosal irritation in a subject by intranasal, oropharyngeal, sublabial or sublingual administration of 5-MeO-DMT, the method comprising the step of preparing 5-MeO-DMT in a pharmaceutical composition / formulation described herein, wherein the pharmaceutical composition / formulation contains 5-MeO-DMT as a saccharinate salt. In one embodiment, a pharmaceutical composition / formulation containing 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided, which is described herein and / or prepared as described herein, having a nasal residence time of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes or more.

[0051] In one embodiment, the pharmaceutical composition / formulation comprises a salt of 5-MeO-DMT. In one embodiment, the pharmaceutical composition / formulation comprises a crystalline salt of 5-MeO-DMT. In one embodiment, a crystalline form of 5-MeO-DMT hydrobromide is provided. In one embodiment, a crystalline form of 5-MeO-DMT hydrobromide is provided, characterized in an XRPD diffraction pattern measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction by one or more peaks at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°2θ±0.1°2θ. In one embodiment, a crystalline form of 5-MeO-DMT phosphate is provided, characterized in an XRPD diffraction pattern measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction by one or more peaks at 12.9, 20.4 and 23.1°2θ±0.1°2θ. In one embodiment, a crystalline form of 5-MeO-DMT fumarate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by powder X-ray diffraction, by one or more peaks at 13.0, 16.3, and 22.1°2θ±0.1°2θ. In another embodiment, a crystalline form of 5-MeO-DMT oxalate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 13.0, 19.9, and 26.0°2θ±0.1°2θ. In another embodiment, a crystalline form of 5-MeO-DMT tarlate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 18.3, 18.6, and 20.7°2θ±0.1°2θ. In one embodiment, a crystalline form of 5-MeO-DMT benzenesulfonate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction, by one or more peaks at 9.5, 21.2, and 23.6°2θ±0.1°2θ.In one embodiment, a crystalline form of 5-MeO-DMT tosylate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by powder X-ray diffraction, by one or more peaks at 19.3, 23.6, and 24.1°2θ±0.1°2θ. In another embodiment, a crystalline form of 5-MeO-DMT glycolate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 20.2, 21.1, and 23.4°2θ±0.1°2θ. In another embodiment, a crystalline form of 5-MeO-DMT ketoglutarate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 14.4, 18.2, and 20.9°2θ±0.1°2θ. In one embodiment, a crystalline form of 5-MeO-DMT malerate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by powder X-ray diffraction, by one or more peaks at 18.3, 18.7, and 18.9°2θ±0.1°2θ. In another embodiment, a crystalline form of 5-MeO-DMT saccharinate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 8.7, 15.2, and 20.9°2θ±0.1°2θ. In one embodiment, a crystalline form of 5-MeO-DMT hydrochloride is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction, by one or more peaks 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°²θ. In another embodiment, a crystalline form of 5-MeO-DMT benzoate is provided, characterized in an XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å, by one or more peaks at 17.5, 17.7, and 21.0°²θ±0.1°²θ. [Modes for carrying out the invention]

[0052] In one embodiment, a dry powder pharmaceutical composition / formulation is provided comprising 5-MeO-DMT or a pharmaceutically acceptable salt thereof and polyvinylpyrrolidone (PVP). As disclosed herein, a method for producing a pharmaceutical composition / formulation of 5-MeO-DMT is provided, comprising the steps of: generating droplets by atomizing a liquid mixture containing 5-MeO-DMT; drying the droplets by contact with a high-temperature gas; optionally, separating the dried product from a drying medium; and preparing the dried product.

[0053] In one embodiment, the conditioning step includes exposing the dried product to a relative humidity (RH) between 15 and 45°C and between 65% and 85%, optionally between 20 and 35°C and between 70 and 80% RH, and optionally between 25°C and 75% RH.

[0054] In one embodiment, the adjustment step is performed over a period of one day to several weeks. In another embodiment, the adjustment step is performed over a period of one day to one week. In yet another embodiment, the adjustment step is performed over a period of one day to three days. In yet another embodiment, the adjustment step is performed over a period of less than one day.

[0055] In one embodiment, a pharmaceutical composition / formulation described earlier or later is provided. In one embodiment, the pharmaceutical composition / formulation is manufactured by spray drying, freeze-drying and / or hot-melt extrusion.

[0056] Unless otherwise specified, all powder X-ray diffraction (XRPD) maps were generated using an X-ray wavelength of 1.5406 Å, and all modulated differential scanning calorimetry (DSC) thermograms were generated at a heating rate of 2°C / min.

[0057] The applicant has found beneficial that, in order to slow the dissolution rate and thereby increase the residence time in the nasal cavity, the dry powder pharmaceutical composition / formulation should optionally contain one or more suitable excipients.

[0058] Hydroxypropyl methylcellulose (HPMC) or hypromellose refers to soluble methylcellulose ether and is approved as an inert ingredient. Without being constrained by theory, HPMC is thought to act as a viscosity enhancer, delaying / slowing down mucociliary exclusion. HPMC polymers for creating hydrophilic matrix systems are available in a variety of viscosity grades ranging from 4,000 to 100,000 mPa·s. Polymer chain length, size, and degree of branching determine the viscosity of the polymer in solution.

[0059] HPMC of different grades (having viscosities lower than those mentioned above) are also available according to their particle size distribution, viscosity, molecular weight, and substitution of methoxy and hydroxypropyl groups.

[0060] For the purposes of this application, high-viscosity HPMC is generally considered to have a viscosity grade of 20 mPa·s or higher. For the purposes of this application, low-viscosity HPMC is generally considered to have a viscosity grade of less than 20 mPa·s.

[0061] HPMC2910 has an average content of 29% methoxy groups and 10% hydroxypropoxy groups (hence the nomenclature 2910). Pharmacoat is a trademark for low-viscosity HPMC2910, and Pharmacoat 606 (marketed in the UK as of June 1, 2023) has a viscosity of 6 mPa·s. Metroze is a trademark for high-viscosity HPMC2910 and is methylcellulose. Metroze 60SH50 606 (marketed in the UK as of June 1, 2023) has a viscosity of 50 mPa·s. Dry blending Dry blending of cellulose-based excipients such as HPMC2910 with APIs at high concentrations of up to approximately 95% wt:wt (excipient to 5-MeO-DMT) in the blend (giving a solid dispersion matrix) beneficially slowed the dissolution and release rate of the API compared to unblended formulations.

[0062] When preparing dry blends, care must be taken to ensure blend homogeneity, and monitoring for any aggregation / agglomeration may be necessary. Furthermore, the properties of the blend must be evaluated to ensure that its physical characteristics are compatible with the delivery device and scale-up. For example, if the resulting blend tends to accumulate static charge, it may be difficult to fill the delivery device without loss.

[0063] The applicant has also found that closely mixed pharmaceutical compositions / formulations of APIs and excipients also provide beneficial properties. Closely mixed pharmaceutical compositions / formulations (e.g., spray drying, freeze-drying, and / or hot-melt extrusion using one or more suitable pharmaceutical excipients or carriers) are discussed further below. These techniques are best known for producing amorphous solid dispersions with improved bioavailability and increased solubility. In the case of the present invention, this does not appear to be beneficial on the surface due to the intense mystical experience associated with APIs. Typically, such dispersions contain API filling amounts of approximately 20% wt:wt or less (e.g., 5-MeO-DMT relative to the excipient). Lyophilized pharmaceutical composition or formulation Amorphous 5-MeO-DMT salt pharmaceutical compositions or formulations were prepared via a lyophilization process. It should be noted that in some cases, these have low glass transition temperatures. Therefore, conversion to the crystalline form may occur rapidly. Solubility tests using lyophilized amorphous 5-MeO-DMT benzoate showed a nearly instantaneous dissolution rate, which is applicable if this rate is a desirable property. Hot melt pharmaceutical composition or formulation Hot melt extrusion can be used to produce 5-MeO-DMT pharmaceutical compositions or formulations according to the present invention and / or any embodiment thereof. Hot melt extrusion involves processing polymer materials above their glass transition temperature (Tg) to produce a thermoplastic binder and / or molecular-level mixing of the polymer and active compound. spray dried dispersion Spray drying typically involves injecting a liquid pharmaceutical composition / formulation of material into a chamber and bringing it into contact with a drying fluid that simultaneously flows through the chamber. The injected wet material, in the form of droplets, comes into contact with the stream of drying fluid, causing the liquid to become part of the drying fluid stream from the droplets, producing a spray-dried product and a drying fluid effluent. The spray-dried product is discharged from the drying chamber, and the drying fluid effluent is similarly discharged from the drying chamber.

[0064] Advantageously, and unexpectedly, the applicant found that spray-dried dispersions of 5-MeO-DMT yielded products with lower / reduced dissolution rates. This was unexpected, as spray-dried dispersions are generally developed to improve the solubility of poorly soluble products. The prediction was that the small particles produced by spray drying would have a larger surface area, thus allowing them to dissolve more easily in the body.

[0065] However, there are limitations to the amount of product that can be administered into the nasal cavity via medical devices, typically less than 50 mg (approximately 0.05 ml in volume). In the case of 5-MeO-DMT dry powder pharmaceutical compositions or formulations, a single dose of up to 20 mg or more than API may be required, which may require, for example, an API filler of 50% wt:wt, a filler that is not typically seen in spray-dried solid dispersions.

[0066] More specific spray-drying pharmaceutical compositions or formulations are considered below. 5-MeO-DMT benzoate | Spray-dried powder pharmaceutical composition / formulation A spray-dried powder pharmaceutical composition or formulation containing an excipient and a benzoate salt of 5-MeO-DMT was prepared, which has dry particles of a size suitable for nasal administration and, surprisingly, has a reduced dissolution rate compared to the amorphous form of the 5-MeO-DMT salt. Respiratory particles, i.e., particles that can penetrate beyond the terminal bronchioles into the gas exchange area of ​​the lungs, are undesirable because they can induce bronchoconstriction, for example, in asthma. In addition, uncontrolled recrystallization over time within the spray-dried dispersion particles can lead to particle aggregation.

[0067] With respect to this benzoate salt, the applicant found that storage at 2-8°C and protection from moisture prevents recrystallization and aggregation. In this case, it was found that a post-spray drying step at 25°C / 75%RH (a step to prepare the spray-dried dispersion particles) produces stable crystalline spray-dried dispersion particles that are free of breathable API fines and show little aggregation.

[0068] It has also been discovered that by reducing the amount of benzoate salt packed (e.g., up to approximately 20% wt:wt of API packed) to prepare a spray-dried dispersion, an amorphous dispersion is produced in which the presence of crystalline benzoate salt is not indicated. In one embodiment, a dry powder pharmaceutical composition / formulation is provided of this 5-MeO-DMT salt and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition / formulation is an amorphous dry powder formulation. In one embodiment, the pharmaceutical composition / formulation is prepared by spray drying. In one embodiment, the pharmaceutical composition / formulation is prepared by freeze-drying. In one embodiment, the pharmaceutical composition / formulation is prepared by hot-melt extrusion. 5-MeO-DMT oxalate | Spray-dried powder formulation A spray-dried powder pharmaceutical composition / formulation of 5-MeO-DMT oxalate (50% API filled) and an excipient was prepared, yielding partially crystalline particles (see Example 2). Without being constrained by theory, it is thought that reducing the API content (as was the case with benzoate salts) may produce amorphous dispersions in which the presence of crystalline salts is not indicated.

[0069] In one embodiment, a dry powder pharmaceutical composition / formulation is provided, comprising the 5-MeO-DMT salt and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition / formulation is an amorphous dry powder formulation. In one embodiment, the pharmaceutical composition / formulation is prepared by spray drying. In one embodiment, the pharmaceutical composition / formulation is prepared by freeze-drying. In one embodiment, the pharmaceutical composition / formulation is prepared by hot-melt extrusion. 5-MeO-DMT Hydrobromide | Spray-dried powder formulation A spray-dried powder pharmaceutical composition / formulation was prepared using 5-MeO-DMT hydrobromide (50% API filled) and an excipient. Surprisingly, this pharmaceutical composition / formulation was found to be a stable amorphous dispersion without the need for any additional drying steps after spray drying. The pharmaceutical composition / formulation was also conditioned stable when stored in a temperature range of 2–8°C or higher.

[0070] In one embodiment, a dry powder pharmaceutical composition / formulation is provided, comprising the 5-MeO-DMT salt and one or more pharmaceutically acceptable carriers or excipients. In one embodiment, the pharmaceutical composition / formulation is an amorphous dry powder formulation. In one embodiment, the pharmaceutical composition / formulation is produced by spray drying. In one embodiment, the pharmaceutical composition / formulation is produced by freeze-drying. In one embodiment, the pharmaceutical composition / formulation is produced by hot-melt extrusion. In one embodiment, the pharmaceutical composition / formulation is non-hygroscopic. Sustained-release pharmaceutical compositions or formulations of 5-MeO-DMT salts Recent clinical trials conducted by the applicant have confirmed the desirability of sustained-release pharmaceutical compositions / formulations of 5-MeO-DMT (or its salts) suitable for intranasal administration. Surprisingly, the applicant has found that the use of higher viscosity excipients in spray-dried dispersions, as described previously or hereafter, can suitably widen the release window of API 5-MeO-DMT.

[0071] Higher viscosity HPMCs, such as HPMC Metholose 60SH50, are typically unsuitable for spray drying due to the high viscosity solutions produced as feedstock. Unexpectedly, it has been found that spray drying 5-MeO-DMT in combination with a mixture of high-viscosity HPMC and lower-viscosity HPMC (such as pharmacoat 606) produces spray-dried dispersion droplets that slow down the dissolution of APIs from pharmaceutical compositions / formulations.

[0072] Various ratios of high-viscosity HPMC to low-viscosity HPMC have been investigated, and it has been found that the dissolution rate of the API does not differ significantly between a 50:50 high:low HPMC ratio and a 25:75 high:low HPMC ratio. Overall, pharmaceutical compositions or formulations containing lower amounts of high-viscosity HPMC are more readily accepted by spray-drying processes (e.g., lower viscosity feedstocks).

[0073] It should be noted that the yield of the product obtained using a single HPMC was higher than that of the product obtained using a mixed HPMC product in the spray-drying process described above. Further investigations revealed, beneficially, that adding a polyol to a pharmaceutical composition / formulation containing a mixed HPMC improved the yield of the product (e.g., by approximately 18% compared to a pharmaceutical composition / formulation lacking a polyol). Beneficially and unexpectedly, the addition of a polyol did not have any effect on the dissolution rate of the API in the formulation.

[0074] In some embodiments, additives such as polyols or surfactants are added to the pharmaceutical composition / formulation before spray drying. In some embodiments, the pharmaceutical composition / formulation contains two (or more) different HPMCs. In some embodiments, the pharmaceutical composition / formulation contains two (or more) different HPMCs, which have different viscosities. In some embodiments, the pharmaceutical composition / formulation contains two (or more) different HPMCs. In some embodiments, the pharmaceutical composition / formulation contains two (or more) different HPMCs, which have different viscosities, and the net viscosity of the mixture is sprayable. In some embodiments, the pharmaceutical composition / formulation contains two (or more) different HPMCs, which have different viscosities, and the net viscosity of the mixture is sprayable, and at least one of the HPMCs is not suitable for spray drying on its own.

[0075] In one embodiment, a sustained-release dry powder pharmaceutical composition / formulation of 5-MeO-DMT is provided, comprising a mixture of high-viscosity HPMC and low-viscosity HPMC. In one embodiment, the sustained-release dry powder pharmaceutical composition / formulation comprises high-HPMC and low-HPMC in a 1:1 ratio. In one embodiment, the ratio is 1:2 high-HPMC to low-HPMC. In one embodiment, the ratio is 1:3 high-HPMC to low-HPMC.

[0076] In one embodiment, the pharmaceutical composition / formulation further comprises a polyol (e.g., an organic compound containing, for example, 4 to 12 carbon atoms and multiple hydroxyl groups (-OH)). Optionally, it contains 4 to 6 carbon atoms. Some of these include polyethers, polyesters, polycarbonates, and acrylic polyols. Polyether polyols can be further subdivided and classified as polyethylene oxide or polyethylene glycol (PEG), polypropylene glycol (PPG), and polytetrahydrofuran, i.e., PTMEG. These have 2, 3, and 4 carbon atoms per oxygen atom in the repeating unit, respectively. Polycaprolactone polyols are also available. The polyols may be bio-based and therefore renewable.

[0077] In one embodiment, the polyol is selected from mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt. In one embodiment, the polyol is sorbitol. In one embodiment, the pharmaceutical composition / formulation contains 3% sorbitol. In one embodiment, the sustained-release dry powder pharmaceutical composition / formulation is prepared by spray drying. In one embodiment, the preparation method includes a step of adding a polyol, such as sorbitol or mannitol, or a combination of both (e.g., isomalt). Low crystalline content spray dried dispersion Beneficially, the applicant found that reducing the relative amount of 5-MeO-DMT salt in spray-dried dispersion pharmaceutical compositions / formulations resulted in a reduction in the crystalline salt content (and therefore an overall increase in the amorphous content present in the dispersion). The level of crystalline content was determined using a DSC method with a higher-than-usual heating rate, and the crystalline content was comparable to that of low-viscosity HPMC pharmaceutical compositions or formulations. Surprisingly, the increase in amorphous API content in these pharmaceutical compositions or formulations resulted in a reduction in the dissolution rate of the formulations. This is contrary to the predicted result that amorphous solid dispersions are manufactured with the aim of enhancing the solubility and dissolution of formulations.

[0078] In one embodiment, the dry powder pharmaceutical composition / formulation has a moisture content of less than about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, and about 10% by weight of the formulation. Non-hygroscopic 5-MeO-DMT hydrobromide In one embodiment, the pharmaceutical composition / formulation is nonhygroscopic. Surprisingly, the hydrobromide salt of 5-MeO-DMT has been found to be nonhygroscopic. Hygroscopicity is the phenomenon of attracting and retaining water molecules from the surrounding environment, either through adsorption or absorption. Pharmaceuticals that capture less than 0.2% of moisture at 80% RH are considered nonhygroscopic. Pharmaceuticals that capture between 0.2% and 2.0% of moisture at 80% RH are considered slightly hygroscopic. Pharmaceuticals that capture between 2.0% and 15.0% of moisture at 80% RH are considered moderately hygroscopic. Pharmaceuticals that capture more than 15.0% of moisture at 80% RH are considered highly hygroscopic. Hygroscopic substances are difficult to handle, and expensive and cumbersome measures must be taken to ensure they are not exposed to moisture during processing and formulation. When exposed to moisture, hygroscopic substances can absorb water and be converted into hydrated forms. This presents several disadvantages. Firstly, hydrated forms may have disadvantages such as lower bioavailability and lower solubility compared to anhydrous forms. Secondly, batch-to-batch variability in the amount of hydrated substance relative to anhydrous substance may not meet the standards set by drug regulatory authorities. Thirdly, processes such as grinding may cause the drug substance to adhere to manufacturing equipment, which can further lead to processing delays, increased worker involvement, increased costs, increased maintenance, and decreased product yield. Fourthly, in addition to the problems caused by the introduction of moisture during the processing of these hygroscopic substances, the potential for moisture absorption during storage and handling adversely affects the solubility of the drug substance. Thus, the shelf life of the product may be significantly reduced, and / or packaging costs may be significantly increased. Beneficially, the non-hygroscopic properties of 5-MeO-DMT hydrobromide further make it a good salt form for dry powder formulations. Intranasal delivery device In one embodiment, an intranasal powder dispenser device is provided having a reservoir containing at least one dose of powder comprising 5-MeO-DMT or a pharmaceutically acceptable salt thereof (which constitutes any aspect and / or embodiment of the present invention and / or encompasses any pharmaceutical composition or formulation described herein). Furthermore, embodiments may include one or more of the following: an intranasal dispenser head for insertion into the user's nostril, including a dispenser orifice; and an air vent that generates a flow of compressed air during operation of the intranasal powder dispenser device to dispense a dose of powder into the nostril via the dispenser orifice. In one embodiment, the air vent has an air chamber and a piston that slides airtightly within the air chamber to compress the air contained within the air chamber. In one embodiment, in the intranasal powder dispenser device, the pressure of the compressed air flow generated by the air vent is greater than 0.7 bar, and the volume of the air chamber is about 1700 mm³. 3 It's extra-large (equivalent to a capacity of approximately 12 x 12 x 12 mm).

[0079] In one embodiment, an intranasal powder delivery device is provided, comprising a container containing a dose of powder comprising at least particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, an intranasal delivery head, and an air discharge system that generates a flow of compressed air for delivering the dose of powder into the nostrils. In one embodiment, an air chamber is located in a skirt, and a piston compresses air by sliding in a sealed manner within the air chamber. In one embodiment, the piston is connected to an actuarial member, and before actuation, at least one destructible bridge is provided between the skirt portion and the actuarial member, each destructible bridge formed on the skirt portion and cooperating with radial projections formed on the actuarial member. In one embodiment, each radial projection has an axially extended portion larger than the corresponding destructible bridge and forms axially inclined portions that are inclined on both sides.

[0080] In one embodiment, the device is an Aptar device (UDS-Unidose Solid) commercially available in the UK as of June 1, 2023. The dry powder devices described in WO21005308, WO22123128, WO22171969, and WO22208014 are incorporated herein by reference. In one embodiment, the counterion (anion) of the 5-MeO-DMT salt is a benzoate, hydrobromide, hydrochloride, phosphate, fumarate, oxalate, tartrate, benzenesulfonate, tosylate, glycolate, ketoglutarate, malate, saccharinate, or succinate salt.

[0081] In some embodiments, the pharmaceutical composition / formulation may comprise two salts of 5-MeO-DMT, where the second salt of the 5-MeO-DMT salt is a benzoate, hydrobromide, hydrochloride, phosphate, fumarate, oxalate, tartrate, benzenesulfonate, tosylate, glycolate, ketoglutarate, malate, saccharinate, or succinate salt. The type of salt may be selected by the physician or compounder to suit the requirements of the patient being treated and the specific circumstances or physical requirements of the pharmaceutical composition / formulation required. In some embodiments, one or both salts may be in an amorphous (non-crystalline) state. In some embodiments, one or both salts may be in a state-stable amorphous (non-crystalline) state.

[0082] In some embodiments, the 5-MeO-DMT salt (one or both) is a 5-MeO-DMT benzoate. Advantageously, the benzoate salt exhibits good irritation tolerance, particularly compared to the well-known chloride salts, and has a good stability profile. In some embodiments, the 5-MeO-DMT benzoate is non-crystalline. In some embodiments, the crystalline 5-MeO-DMT benzoate is characterized by one or more peaks at 2θ values ​​of 17.5°±0.1°, 17.7°±0.1°, and 21.0°±0.1° in a powder X-ray diffraction (XRPD) diffraction pattern using an X-ray wavelength of 1.5406 Å. In some embodiments, the 5-MeO-DMT salt (one or both) is a 5-MeO-DMT hydrobromide, and the pharmaceutical composition / formulation contains substantially the same dosage of active 5-MeO-DMT cations. Advantageously, the hydrobromide salt is substantially non-hygroscopic.

[0083] It should be recognized that different salts of 5-MeO-DMT have different formula weights. For example, hydrochloride, hydrobromide, and benzoate have formula weights of approximately 254.8 g / mol, 299.2 g / mol, and 340.4 g / mol, respectively, while the free base of 5-MeO-DMT has a formula weight of 218.3 g / mol. Therefore, this is the amount of substance required to obtain 1 mole of the active agent. Thus, for example, in the case of salts, the dosage can be the equivalent amount of free base delivered when the salt is ingested. Therefore, a dosage of 100 mg of 5-MeO-DMT is equivalent to 117 mg of hydrochloride salt (i.e., both yield the same molar amount of active substance). The reason the required mass of salt is larger is because the formula weight of the hydrochloride salt is larger (i.e., 218.3 g / mol for the free base compared to 254.8 g / mol for the salt). Similarly, in the case of the deuterated or tritinated forms of 5-MeO-DMT (which are also considered to be within the scope of this invention), a slight increase in mass can be expected due to the increase in the formula weight of these isotopic compounds. Unless otherwise specified, the mass (mg) of 5-MeO-DMT refers to the mass of the benzoate salt (and therefore the equivalent molar amount of the 5-MeO-DMT active agent). Accordingly, with respect to other salts mentioned herein, the appropriate mass of the other salts can be adjusted accordingly using the ratio of their formula weights. The masses of these salts are usually rounded up or down to suit the requirements. This rounding may be rounded to the nearest integer, two-digit, four-digit, or ten-digit of the milligram (mg). For example, the division of a composite dose is typically made to an integer, and therefore 3.5 and 6.5 mg (total 10 mg) can be formulated into 3 and 7 mg, respectively.

[0084] In one embodiment, the pharmaceutical composition / formulation comprises a hydrochloride, phosphate, fumarate, oxalate, tartrate, benzenesulfonate, tosylate, glycolate, ketoglutarate, malate, saccharinate, or succinate salt of 5-MeO-DMT. In another embodiment, the pharmaceutical composition / formulation does not contain a crystalline form of a hydrochloride, phosphate, fumarate, oxalate, tartrate, benzenesulfonate, tosylate, glycolate, ketoglutarate, malate, saccharinate, or succinate salt of 5-MeO-DMT.

[0085] In some embodiments, 5-MeO-DMT is administered as a free base. In some embodiments, 5-MeO-DMT is administered as a salt. In some embodiments, 5-MeO-DMT is not administered as a crystalline salt. In some embodiments, 5-MeO-DMT is not administered as a polymorphic salt. In some embodiments, 5-MeO-DMT is not administered as a polymorph of a 5-MeO-DMT salt. In some embodiments, 5-MeO-DMT is administered as a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt. In some embodiments, 5-MeO-DMT is administered as a benzoate salt. In some embodiments, 5-MeO-DMT is administered as a hydrochloride salt. In some embodiments, 5-MeO-DMT is administered as a hydrobromide salt. In one embodiment, the 5-MeO-DMT salt is administered in an amorphous form. In another embodiment, the 5-MeO-DMT salt is not administered in a crystalline form.

[0086] In some embodiments, 5-MeO-DMT is not administered as a crystalline form of the benzoate salt. The crystalline form of the benzoate salt is disclosed in WO2021250434 and is incorporated herein by reference. The crystalline form of the hydrochloride salt is also disclosed in WO2021250434 and is incorporated herein by reference. In some embodiments, the crystalline 5-MeO-DMT hydrochloride is characterized by peaks at 2θ values ​​of 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° in a powder X-ray diffraction (XRPD) diffraction pattern measured using an X-ray wavelength of 1.5406 Å.

[0087] In some embodiments, the salt anion is an arylcarboxylate. In some embodiments, the arylcarboxylate is substituted with 1 to 3 R groups. In some embodiments, one or more R groups are independently alkynyl, carbonyl, aldehyde, haloformyl, alkyl, halide, hydroxy, alkoxy, carbonate ester, carboxylate, carboxyl, carboalkoxy, methoxy, hydroperoxy, peroxy, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, methylenedioxy, orthocarbonate ester, carboxylic acid anhydride, carboxyamide, secondary, tertiary or quaternary amine, primary or secondary ketimine, primary or secondary amine Ludimine, imide, azide, azo, cyanate, isocyanate, nitrate, nitrile, isonitrile, nitrosooxy, nitro, nitroso, oxime, pyridyl, carbamate, sulfhydryl, sulfide, disulfide, sulfinyl, sulfonyl, sulfino, sulfo, thiocyanate, isothiocyanate, carbonothioyl, carbothioic acid S-acid, carbothioic acid O-acid, thioester, thionoester, carbodithioic acid, carbodithio, phosphino, phosphono, phosphate, borono, boronate, borino, or borinate. In some embodiments, one or more R groups are independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, or C1-C6 alkynyl, each of which may be substituted with 1-3 R groups as previously described.

[0088] In one embodiment, a pharmaceutical composition / formulation comprising 5-MeO-DMT and 5-MeO-DMT with one or more pharmaceutically acceptable carriers or excipients is intended for use in one or more methods of treating mental disorders, particularly treatment-resistant depression, major depressive disorder, persistent depressive disorder, alcohol use disorder, anxiety disorders, post-traumatic stress disorder (PTSD), body dysmorphic disorder, obsessive-compulsive disorder, eating disorders, and psychoactive substance abuse.

[0089] In one embodiment, the disease or condition is a condition caused by a dysfunction of the central nervous system, a condition caused by a dysfunction of the peripheral nervous system, a condition in which sleep regulation is effective (such as insomnia), a condition in which analgesics are effective (such as chronic pain), migraine, trigeminal autonomic headache (such as short-acting persistent hemineurotic headache attacks with conjunctival congestion and lacrimation (SUNCT), and short-acting persistent hemineurotic headache attacks with cephalic autonomic symptoms (SUNA)), a condition in which neurodevelopment is effective (such as stroke, traumatic brain injury, Parkinson's disease, dementia), or a condition in which anti-inflammatory treatment is effective. Any condition, depression, treatment-resistant depression, anxiety, substance use disorder, addiction disorder, gambling disorder, eating disorder, obsessive-compulsive disorder, or body dysmorphic disorder, and optionally, any condition is SUNCT and / or SUNA, alcohol-related disorders 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, inhalation-related disorders, benzodiazepine abuse or dependence-related disorders, opioid-related disorders, tobacco addiction, alcohol abuse and / or addiction.

[0090] Where used herein, “clinical response” and / or “clinically significant reduction” and / or “clinically significant response” include, but are not limited to, improvements in rating scales such as the Clinical Global Impression-Severity Scale (CGI-S), Patient Global Impression-Severity Scale (PGI-S), Clinical Global Impression-Improvement Scale (CGI-I), or Patient Global Impression-Improvement Scale (PGI-I), and but are not limited to endpoints such as the Montgomery-Earsberg Depression / Major Depressive Disorder Rating Scale (MADRS) or the 17-item Hamilton Depression / Major Depressive Disorder Rating Scale (HAM-D) in the case of depression / major depressive disorder and persistent depressive disorder, anxiety symptoms, for example, anxiety symptoms measured by the Beck Anxiety Rating Scale (BAI), Hamilton Anxiety Scale (HAM-A), or State-Trait Anxiety Rating Scale (STAI) in the case of anxiety disorders, and the Post-Traumatic Stress Disorder Diagnostic Interview Scale in the case of post-traumatic stress disorder. Further suicidal tendency rating scales include the CAPS, the modified Yale-Brown obsessive-compulsive scale for body dysmorphic disorder (BDD-YBOCS) in cases of body dysmorphic disorder, the Yale-Brown obsessive-compulsive scale for obsessive-compulsive disorder (YBOCS), weight gain in cases of anorexia nervosa, frequency of hyperappetite episodes in cases of bulimia nervosa, frequency of binge eating episodes in cases of bulimia nervosa, duration of withdrawal or reduction of substance use in psychoactive substance abuse, and the Columbia Suicidal Severity Rating Scale (C-SSRS) or the MADRS suicidal thoughts item or the modified Clinical Global Impression-Severity (CGI-SS-R) scale for suicidal ideation (the CGI-SS-R is derived from the CGI-S and scored as follows: 0 = normal, no suicidal tendency, 1 = suspected suicidal tendency, 2 = mild suicidal tendency, 3 = moderate suicidal tendency, 4 = significant suicidal tendency, 5 = severe suicidal tendency, 6 = extreme suicidal tendency). When evaluating clinical response at an earlier time after drug administration (e.g., 2 hours) based on endpoints developed for longer recall periods, reasonable modifications to such endpoints (e.g., changing the MADRS recall period to 2 hours and carrying over sleep items recorded at baseline before drug administration) may be applied.

[0091] The severity of a condition and changes in severity can be assessed using the Clinical Global Impressions (CGI) scale, which provides criteria for evaluating symptom severity, treatment response, and treatment efficacy. The CGI scale was developed to enable a simple, standalone assessment of a patient's overall functioning from a clinician's perspective before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0092] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Considering your overall clinical experience with this particular population, how mentally ill is the patient at this moment?" It is rated on a 7-point scale: 1 = Normal, not ill at all; 2 = Borderline mental illness; 3 = Mild illness; 4 = Moderate illness; 5 = Marked illness; 6 = Severe illness; 7 = Most severe illness. The CGI-S can be used to assess treatment success by comparing pre- and post-treatment scores.

[0093] Clinical response can be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1. Preferably, the CGI-S is reduced by at least 2 and / or to a score of 0. It is particularly preferable that the CGI-S is reduced by at least 3 and / or to a score of 0. Alternatively, treatment success can be assessed using the CGI-Improved (CGI-I), which is similarly simpler in format. After treatment, the clinician compares the patient's overall clinical condition to that before treatment (the so-called baseline value). Similarly, in this case, a single question is rated on the following 7-point scale: "Compared to the patient's condition at the start of the project [before the start of drug treatment], the patient's condition is as follows: 1 = greatly improved since the start of treatment; 2 = greatly improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worsened; 6 = greatly worsened; 7 = greatly worsened since the start of treatment." The Patient Global Impression Scale (PGI), also known as the Subject Global Impression Scale (SGI), is the counterpart to the Clinical Global Impression Scale (CGI). The PGI consists of one patient-adapted item based on the CGI. The PGI can measure disease severity (PGI-S) or disease improvement (PGI-I). The individual items and subcombinations of individual items of the scales described in this invention can be used to assess aspects of specific diseases.

[0094] Numerous scales have been proposed to assess the severity of one or more conditions or disorders, such as mental or neurological disorders. Such scales are based on tests that can be self-administered or completed by a clinician / physician. Scales that can be used in accordance with the present invention include those known in the art for the diagnosis and / or monitoring of one or more conditions or disorders, such as mental or neurological disorders, which are discussed in more detail herein. The outcome of the treatment is assessed by using one or more indicators or scales at one or more point in time after the completion of the course of treatment.

[0095] The assessment may be performed after the full mystical experience has subsided. A suitable time for the initial assessment is generally about 2-3 hours after the last dose. The initial assessment can generally be performed, for example, about 2 or 3 hours after the last dose. However, the assessment of the effect on sleep disturbances, for example, can be performed early on the day following the treatment (i.e., day 1), so that the treated patient / subject has had the opportunity to sleep for at least one night.

[0096] Therefore, an evaluation on day 1 or on day 1 means an evaluation on the day following administration. Evaluations can be made at any time after 12 hours following the last dose, and optionally at any event after one night following the last dose but before 36 hours following the last dose. Evaluations can be made approximately 24 hours later. An evaluation on day 7 or on day 7 means an evaluation on day 7 after administration (the day of administration is day 0). Similar definitions apply to other evaluation points measured on each day.

[0097] When assessing clinical response at an earlier time after drug administration (e.g., 1, 2, or 3 hours) based on endpoints developed for longer recall periods (e.g., typically 7 days in the case of MADRS), or when doing so using one of the scales for assessing the severity of one or more conditions or disorders, such as psychiatric or neurological disorders, reasonable modifications to such endpoints (e.g., changing the MADRS recall period to 1, 2, or 3 hours and carrying over sleep items recorded at baseline before drug administration) may be applied. The same applies to any other scales applied herein unless the recall period is specifically indicated. The considerations outlined apply to earlier time points because, on the one hand, the influence of the patient's pre-treatment condition on any score recorded after treatment to assess clinical response should be kept as low as possible, and on the other hand, sleep items cannot be assessed 1, 2, or 3 hours after drug administration. At later time points, for example from day 1 onward, typically, all items of the relevant scales assessing clinical response can be assessed using a fitted recall period, if necessary, so that no pre-treatment scores need to be carried over.

[0098] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing sleep depth. Non-REM and REM sleep alternate during each of the 4-5 cycles of normal human sleep each night. During the early part of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, especially during the first sleep cycle. As the night progresses, non-REM sleep becomes lighter, and more of each cycle is allocated to REM sleep.

[0099] Normal, healthy sleep consists of the different stages outlined above, progressing in a continuous and tightly regulated sequence throughout the night. When this strict regulation is disrupted, sleep disorders occur. A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether it is sudden or occurs against the background of one or more medical conditions, such as a mental or neurological disorder. Sleep disorders affect a person's ability to function properly while awake.

[0100] Common forms of sleep disorders include difficulty in starting and maintaining sleep (insomnia), difficulty with excessive somnolence (hypersomnia), difficulty with the sleep-wake schedule (circadian rhythm disorders), dysfunction associated with sleep, sleep phase, or incomplete wakefulness (parasomnias), disorders characterized by respiratory disturbance (sleep-related breathing disorder), and disorders characterized by abnormal movements during sleep (sleep-related movement disorder). Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have difficulty falling asleep, frequently wake up during the night, have difficulty falling asleep, wake up too early in the morning, have poor sleep quality, and / or have at least one daytime problem resulting from sleep deprivation, such as fatigue, drowsiness, mood disturbances, difficulty concentrating, or accidents at work or while driving.

[0101] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleepwalking is also a symptom seen in patients / subjects with hypersomnia. Sleepwalking is difficulty transitioning from sleep to wakefulness. Individuals experiencing sleepwalking report confusion, disorientation, slow awakening, and repeated falls back asleep.

[0102] Circadian rhythm disorders are characterized by chronic or recurrent sleep disorders resulting from changes in an individual's internal circadian rhythm, or from a mismatch between an individual's circadian rhythm and their desired or required work or social schedule. This dyssynchronicity can be transient or persistent. The following clinical presentation combines elements of both insomnia and hypersomnia. Sleep duration is usually shortened and disrupted, performance during desired states of wakefulness is impaired, and temporary attempts to return to a regular sleep schedule are unsuccessful.

[0103] Parasomnias refer to a range of sleep disorders characterized by unusual behavioral or physiological activities (such as sleepwalking or nightmares) experienced by humans before falling asleep, during sleep, or during the wakefulness period between sleep and wakefulness. They vary considerably in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0104] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordination between the respiratory muscles and the brain (the control center). One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals to control breathing, for example, based on an underlying medical condition. Central sleep apnea has potentially serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow leads to intermittent hypoxia, which in turn leads to sleep fragmentation resulting in micro-awakenings or waking. As a result, this can lead to excessive daytime sleepiness.

[0105] In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements disrupt sleep or its onset. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Inadequate sleep quantity or quality can lead to personality changes, exacerbating pre-existing psychoses and potentially triggering the onset of new psychoses. Sleep disorders can impair cognitive function and lead to memory impairment. Individuals deprived of sleep may experience difficulty making decisions, irritability, impaired performance, and slowed reaction times. Sleep deprivation can negatively impact quality of life by contributing to the development of obesity, diabetes, and heart disease.

[0106] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered primary treatments. If unsuccessful, treatment may also involve pharmacotherapy or psychotherapy. Not all available treatments are successful for all patients / subjects, may have side effects, and / or may require treatment over long time intervals to achieve the effects of the associated treatment. In patients / subjects with sleep disorders associated with one or more conditions or disorders, such as psychiatric or neurological disorders, known treatments for psychiatric or neurological disorders do not necessarily improve the sleep disorder.

[0107] For example, sleep disorders are often associated with mental disorders such as depression. However, treating depression does not necessarily improve accompanying sleep disorders. While most antidepressants have been found to affect sleep mechanisms, some classes of antidepressants improve sleep, while others may cause sleep disorders. Sleep can be assessed by measuring parameters such as sleep duration, sleep mechanisms, sleep latency, and the number and duration of awakenings during the night. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency determination, or by self-report criteria (questionnaires).

[0108] Polysomnography is a technique that requires patients / subjects to be monitored overnight in a specialized clinic. Various functions, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen saturation, body position and movement, snoring, and heart rate, are measured throughout the night. Another quantitative measurement is actigraphy. Actimetry sensors are worn to measure motor activity, which is continuously recorded and used to assess the sleep-wake cycle. This technique allows patients / subjects to continue their normal daily activities while the required data is recorded in a natural sleep environment.

[0109] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective criterion for determining how long it takes for a person to fall asleep over multiple test naps. An average sleep latency of approximately 10 minutes is considered normal, while less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). An accompanying analysis of brain activity can aid in the further diagnosis of sleep disorders.

[0110] The sleep rating questionnaire captures assessments of sleep quality components such as perceived sleep depth, difficulty waking, and post-sleep rest, in addition to other factors that may influence sleep quality, such as comorbidities and medication use. Assessment of quantitative aspects of sleep experience is important because sleep complaints often persist despite normal values ​​on quantitative sleep assessment criteria. The questionnaire not only facilitates a rapid and accurate assessment of complex clinical problems but may also be helpful in tracking patient progression.

[0111] Various indicators of sleep quality are publicly known. The following indicators include examples of questionnaires for assessing sleep overall, and in particular, questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias. However, the present invention is not limited to the use of specific indicators or questionnaires.

[0112] Some questionnaires rely on a recall period (recall window) of several days or even several weeks. While this may be appropriate for diagnosing sleep disorders, it is not necessarily appropriate for assessing treatment effects, particularly the onset of rapid post-treatment effects. In some cases of questionnaires, the recall period may be modified so that the resulting score reflects the time since treatment. Questionnaires specifically discussed herein for assessing the effects of treatment on sleep in patients / subjects suffering from specific conditions rely on a recall period that does not begin earlier than the point at which a complete sleep experience diminished after the last dose. To meet this criterion, the commonly applied recall period is modified if necessary.

[0113] Sleep quality can generally be assessed using, for example, the Sleep-50 questionnaire. The SLEEP-50 questionnaire consists of 50 items designed to screen for a variety of sleep disorders in the general population. The scale has nine subscales, which reflect the most common sleep-related disorders and complaints, as well as some of the factors needed for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorders, sleepwalking, nightmares, factors influencing sleep, and the impact of sleep complaints on daily sleep functioning. For each item, respondents are presented with a scale ranging from 1 ("never") to 4 ("very often") and are asked to indicate the degree to which a descriptive statement fits their experience over the previous month or another appropriate recall window.

[0114] To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the respondent must also meet at least three or four cutoffs ("fairly frequent" or "very frequent," respectively) on subscales that assess the impact of sleep disorders on daily functioning.

[0115] Treatment success can be indicated by (i) a decrease in the score, preferably by a decrease to below the cutoff value. A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other measurement methods include the Insomnia Severity Index, the Espie Sleep Disorders Questionnaire, and the Patient / Subject Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0116] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and impairment. The PSQI is a self-assessment questionnaire consisting of 19 questions. Respondents are asked to indicate how frequently they experienced a particular sleep disturbance over the past month or another appropriate recall window. The 19 self-assessment questions evaluate a wide range of factors related to sleep quality, including sleep duration and latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are categorized into seven component scores: (1) Patient / Subjective Sleep Quality; (2) Sleep Latency; (3) Sleep Duration; (4) Habitual Sleep Efficiency; (5) Sleep Disorders; (6) Use of Sleeping Pills; and (7) Daytime Functional Impairment. Each component is assigned a score from 0 to 3. A higher score indicates a more severe sleep disorder.

[0117] Next, the seven element scores are totaled to obtain a single overall score ranging from 0 to 21, where "0" indicates no difficulty and "21" indicates severe difficulty in all areas. An overall score cutoff of 5 distinguishes poor sleepers from good sleepers. An overall score > 5 indicates that the patient / subject has severe difficulty in at least two areas or moderate difficulty in more than three areas. When the outcome of the treatment is assessed using the PSQI, treatment success can be indicated by (i) a decrease in the score, preferably by a decrease to 5 or less.

[0118] The Insomnia Severity Index (ISI) is a short questionnaire that assesses the patient's / subjective sleep quality, the severity of symptoms, the patient's / subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how the respondent perceives their insomnia as more noticeable than others, and the overall level of distress caused by the sleep problem. Individual responses can be scored from 0 (=none) to 4 (=very), with higher total scores corresponding to more severe insomnia. A total score of 0-7 indicates "no clinically significant insomnia," 8-14 means "subthreshold insomnia," 15-21 means "clinical insomnia (moderate severity)," and 22-28 means "clinical insomnia (severe)." The recall window is two weeks. Another appropriate recall window may be used. Treatment success can be indicated by (i) a reduction in the score, for example, by >7 points, especially by >8 points, and preferably by (ii) a reduction to below the cutoff value for clinically significant insomnia.

[0119] The Espie Sleep Disorders Questionnaire (SDQ) assesses a patient's subjective experience of insomnia. For ratings of restlessness / agitation, mental hyperactivity, insomnia outcomes, and lack of ease of falling asleep, the SDQ is particularly relevant to beliefs about the origin of sleep problems. Respondents use a 5-point scale to indicate how frequently a particular descriptive statement about insomnia reflects their experience. A score of 1 means "never applies," while a score of 5 means "very frequently applies." Higher scores indicate a greater belief in dysfunction regarding the causes and correlators of insomnia.

[0120] Treatment success can be indicated by a decrease in the score. The Patient Reported Outcomes Information System (PROMIS)® sleep disorder measurement tool is a universal assessment criterion for evaluating sleep disorders. The measurement tool is available in a long form and four different short forms (e.g., 4, 6, and 8 items) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulties related to falling asleep and staying asleep over a 7-day period. Each item in the assessment criterion is rated on a 5-point scale. The raw scores for the items are summed up to obtain a total raw score. The total raw score is then converted to a standardized T-score using a conversion sheet. Treatment success can be indicated by a decrease in the T-score.

[0121] Hypersomnia or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale. The Epworth Sleepiness Scale (ESS) assesses general daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations representing relatively inactive periods, such as an afternoon nap or sitting in a stationary car in traffic. Respondents rate their likelihood of falling asleep using a scale of 0 to 3 (0 meaning "never dozing off," and 3 meaning "likely to be dozing off"). Scoring ranges from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness. Treatment success can be indicated by (i) a reduction in score, preferably by (ii) a reduction to 10 or less.

[0122] The Stanford Sleepiness Scale is a patient / subjective sleepiness assessment criterion that evaluates sleepiness at a specific point in time. The single-item scale asks respondents to select one of seven descriptive statements that best describe their current perceived level of sleepiness. A scale from 1 (= feeling active and energetic; mentally sharp; fully awake) to 7 (= barely drowsy; falling asleep immediately; unable to stay awake) is used to assess the level of sleepiness. Treatment success can be indicated by a decrease in score. Parasomnias can be assessed by the Paris Disorders of Awakening Severity Scale (PADSS). The Paris Disorders of Awakening Severity Scale (PADSS) is a self-assessment scale that enumerates parasomnia behaviors, assesses the frequency of behaviors, and includes an assessment of outcomes. Treatment success can be indicated by (i) a decrease in score, preferably (ii) a decrease below a cutoff value.

[0123] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire. Furthermore, an appropriate recall period can be selected. Treatment success can be indicated by a decrease in score. A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire asks respondents to indicate, using a Likert scale, how severely the disorder affected them over the course of the past week. The questions can be divided into one of two categories: disorder symptoms (nature, intensity, and frequency) and their effects (sleep problems, impairment in daily functioning, and mood changes). Each of the 10 questions asks respondents to rate their RLS experience on a scale of 0-4, where 4 represents the most severe and frequent symptoms and 0 represents the lowest. The total score can range from 0 to 40. As a simple scale with good psychometric quality, the measurement can be suitable for a variety of investigative and clinical purposes, including screening and evaluation of treatment outcomes. Treatment response can be evaluated by a decrease in the score.

[0124] Bipolar disorder (BD) has various facets and is characterized by a variety of symptoms. The primary psychopathology is depression, and a diagnosis of major depressive disorder (MDD) can be initially made based on the symptoms experienced by patients / individuals experiencing depressive episodes. However, BD has several features that distinguish it from the latter, even during depressive episodes.

[0125] Of particular interest here are the symptoms that are more strongly associated with BD than with other mental disorders, because symptoms are the metrics by which the treatment of the patient / subject is evaluated. Although many symptoms can span multiple disorders, many studies have identified several symptoms that are strongly presented in BD patients / subjects: sleep disturbances, psychomotor delay (decreased energy and vitality and lack of motivation), negative thinking (feelings of worthlessness, helplessness and despair, guilt), anxiety, cognitive impairment (difficulty concentrating and memory), and social withdrawal or social alienation / affective aversion or detachment (anehedonia, affective aversion and flattening of affect). Characteristic symptoms further include suicidal ideation. Even further, characteristic symptoms include mixed symptoms (psychotic symptoms, irritability, instability, increased impulsivity, increased speech, agitation).

[0126] Clinical assessment tools, such as the Bipolar Depression Rating Scale (BDRS), have been developed and validated for use in BD, taking these symptoms into consideration. The BDRS is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated for clinical use by trained raters. Based on a clinical interview, the BDRS items rate the severity of depressive and / or mixed symptoms expressed by the patient / subject in the present and over the past few days. If there is a discrepancy between current and past symptoms, the rating should reflect the current symptoms. The scale consists of 20 questions, with a maximum possible score of 60. A higher score indicates greater severity.

[0127] The questions address depressed mood, sleep disturbances, appetite disturbances, reduced social engagement, decreased energy and vitality, decreased motivation, difficulty concentrating and remembering, anxiety, anhedonia, flattening of emotions, feelings of worthlessness, feelings of helplessness and despair, suicidal ideation, feelings of guilt, psychotic symptoms, irritability, instability, increased motor impulses, increased speech, and agitation. Each of these aspects is assessed and assigned a score of 0, 1, 2, or 3.

[0128] Depressed mood is scored as follows: 0 (no self-reported and / or acknowledged depression evidenced by gloom, sadness, pessimism, despair, and helplessness); 1 (mild) (short or transient depression or mild depressed mood); 2 (moderate) (not always present but clearly present, other emotions expressed, or depression of moderate intensity); and 3 (severe) (prominent or continuous depressed mood of marked intensity).

[0129] Sleep disorders (sleep dysregulation) are assessed based on changes in total sleep duration over a 24-hour cycle, assessed independently of the influence of external factors. This can take the form of insomnia (decreased total sleep duration) or hypersomnia (increased total sleep duration, including daytime sleep). Insomnia is assessed using a scale of 0 (no decrease in total sleep duration), 1 (mild; up to 2 hours reduction), 2 (moderate; 2-4 hours reduction), and 3 (severe; over 4 hours reduction).

[0130] Alternative ratings for excessive sleep include scores of 0 (no increase in total sleep time, including daytime sleep), 1 (mild; less than 2 hours or normal amount, but non-recovering), 2 (moderate; 2-4 hours), and 3 (severe; more than 4 hours).

[0131] Disorders of appetite are assessed based on changes in appetite and food consumption, which are assessed independently of the influence of external factors. This can take the form of loss of appetite or increase in appetite. Assessments for loss of appetite include scores of 0 (no change in appetite or food consumption), 1 (mild; no change in food intake, but the person is forced to eat or reports a loss of taste for food), 2 (moderate; some decrease in food intake), and 3 (significant decrease in food intake, difficulty eating). Alternative assessments for increase in appetite include scores of 0 (no change in appetite or food consumption), 1 (mild; no change in food intake, but increased hunger), 2 (moderate; some increase in food intake, e.g., binge eating), and 3 (significant increase in food intake or craving).

[0132] Reduced social engagement is scored as follows: 0 for no patient / subjective report of reduced social and interpersonal engagement or interaction; 1 (mild) for slight reduction in social engagement with no impairment in social or interpersonal functioning; 2 (moderate) for obvious reduction in social engagement with some functional sequelae, e.g., avoidance of some social engagement or conversation; and 3 (severe) for marked reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusal to answer the phone or meet with friends or family.

[0133] Reduced energy and vitality are scored as follows: 0 (no reduction in force, impulse, or goal-directed behavior), 1 (mild) (able to engage in normal activities but with increased effort), 2 (moderate) (significant reduction in energy leading to a decrease in some role-specific activities), and 3 (severe) (e.g., leaden paralysis or cessation of almost all role-specific activities) (e.g., excessive sleeping, avoiding answering the phone, poor personal hygiene).

[0134] Reduced motivation is scored as follows: 0 for no patient / subjective reduction in impulse, motivation, and resulting goal-oriented activities; 1 (mild) for slight reduction in motivation with no impairment of function; 2 (moderate) for reduced motivation or impulse with significant reduction in volitional activity or requiring considerable effort to maintain normal levels of functioning; and 3 (severe) for reduced motivation or impulse with noticeable reduction in goal-oriented behavior or functioning.

[0135] Concentration and memory impairments are scored as follows: 0 (no patient / subjective reports of reduced attention, concentration, or memory and resulting functional impairment); 1 (mild) (some impairment of attention, concentration, or memory with no functional impairment); 2 (moderate) (marked impairment of attention, concentration, or memory with some functional impairment); and 3 (severe) (noticeable impairment of concentration or memory with marked functional impairment (e.g., inability to read or watch TV).

[0136] Anxiety is scored as 0 (no subjective reduction in the patient's ability to experience pleasure in normal activities), 1 (mild; transient worry or tension about trivial matters), 2 (moderate; marked anxiety, tension, or worry, or some accompanying physical characteristics), or 3 (severe; marked continuous anxiety, tension, or worry that interferes with normal activities, or panic attacks), if there are no subjective reports from the patient of worry, tension, and / or physical anxiety symptoms such as tremor, palpitations, dizziness, lightheadedness, tingling, sweating, shortness of breath, restlessness, or diarrhea. Affective flattening is scored as follows: 0 for no patient / subjective awareness of a reduction in the intensity or range of sensations or emotions; 1 (mild) for a slight contraction of the range of emotions or a transient reduction in the range or intensity of emotions; 2 (moderate) for a marked contraction of the range or intensity of emotions where some emotions are retained, e.g., inability to cry; and 3 (severe) for a prominent and widespread contraction of the range of emotions or inability to experience normal emotions.

[0137] Feelings of worthlessness (also simply referred to as worthlessness) are scored as follows: 0 (no patient / subjective awareness or thoughts of reduced self-worth or self-esteem), 1 (mild; slight decrease in awareness of self-esteem), 2 (moderate; some thoughts of worthlessness and decreased self-esteem), and 3 (severe; prominent, widespread, or persistent feelings of worthlessness, e.g., feeling that others would be better off without you and being unable to perceive positive attribution).

[0138] Feelings of helplessness and despair (also simply referred to as helplessness and despair) are characterized by a patient's / subjective awareness of pessimism or depression about the future, a lack of ability to cope, or a feeling of being out of control. If this is absent, the score is 0. For occasional mild feelings of not being able to cope as usual, or pessimism, the score is 1 (mild); if the patient / subject frequently feels they have marked feelings of helplessness or despair, which are sometimes elevated; and if there are prominent, widespread feelings of pessimism, helplessness, or despair, the score is 3 (severe).

[0139] Suicidal ideation is scored as follows: 0 for thoughts or feelings that life is not worthwhile; related to thoughts of death or suicide; no such thoughts; 1 (mild) for thoughts that life is not worthwhile or meaningless; 2 (moderate) for thoughts of dying or death but without active suicidal thoughts or plans; and 3 (severe) for thoughts or plans of suicide. Feelings of guilt (also simply referred to as guilt) are scored as follows: 0 for no patient / subjective awareness of self-blame, failure or regret for real or imagined past mistakes; 1 (mild) for a slight decrease in self-esteem or an increase in self-criticism; 2 (moderate) for prominent thoughts of failure, self-criticism, lack of coping ability, or rumination about past failures and their impact on others that may be perceived as excessive; and 3 (severe) for prominent, widespread, or persistent guilt, such as feelings that one deserves punishment; or not clearly perceived as excessive.

[0140] Psychotic symptoms are scored as follows: 0 for the absence of a dominant idea, delusion, or hallucination; 1 (mild) for a mild dominant idea, e.g., self-criticism or pessimism with no apparent effect on behavior; 2 (moderate) for a prominent dominant idea with an apparent effect on behavior, e.g., strong feelings of guilt or an obvious thought that others would be better off without you; and 3 (severe) for an obvious psychotic symptom, e.g., delusion or hallucination.

[0141] Irritability is scored as follows: 0 for no reported patient / subjective irritability, tantrums, anger, verbal or physical outbursts; 1 (mild) for slight patient / subjective irritability that could not be overtly present; 2 (moderate) for verbal dissatisfaction and irritability that is clearly present in the interview; and 3 (severe) for reports of physical outbursts, e.g., throwing / breaking objects, or noticeable verbal outbursts. Instability is scored as follows: 0 for no reported mood instability or mood swings. Instability is scored as follows: 1 (mild) for patient / subjective reports of a slight increase in mood instability; 2 (moderate) for clearly present and moderately intense mood instability; and 3 (severe) for noticeable and prominent mood instability, frequent or dramatic mood swings.

[0142] Increased motor impulse relates to the patient's / subjective reports and objective evidence of increased motor impulse and motor activity. Increased motor impulse is scored as follows: 0 for normal motor impulse, 1 (mild) for slight increase in impulse not observed in the interview, 2 (moderate) for a clear and observed increase in energy and impulse, and 3 (severe) for a noticeable or continuous increase in impulse. Increased speech relates to a observed increase in the rate or volume of speech, or observed distracting thoughts. This item is scored as follows: 0 for no such observation, 1 (mild) for a slight increase in the rate or volume of speech, 2 (moderate) for racing thoughts, or if the patient / subject is noticeably more talkative and clearly distracted, or somewhat rambling, where this does not interfere with the interview, and 3 (severity) for distracting thoughts that interfere with the interview.

[0143] Agitation is scored as follows: 0 for no noticeable agitation or agitation, 1 for slight agitation (mild), 2 for a clear increase in the level of agitation (moderate), and 3 for noticeable agitation, e.g., almost constant pacing or clenching of the hands (severe). While higher scores on the BDRS scale indicate more severe illness, there is no generally accepted limit to when a patient / subject is considered to have moderate or severe illness. The BDRS score ranges used herein to indicate the severity of depressive episodes in patients / subjects with bipolar disorder are: 13–18 for “mild illness”, 19–23 for “moderate illness”, 24–36 for “noticeable illness”, 37–39 for “severe illness”, and 37–39 for “extreme illness”. * The value is 40. Various other scales are also useful for assessing disease severity and the clinical outcomes of treatment.

[0144] Anxiety is sometimes defined as “a worried anticipation of future danger or misfortune accompanied by feelings of discomfort or physical symptoms of tension.” Anxiety is perceived only by the patient / subjectively as a threat and is often characterized by intense, excessive, and persistent worry and fear about a situation accompanied by muscle tension, restlessness, fatigue, inability to calm breathing, abdominal pressure, nausea, and difficulty concentrating.

[0145] In anxiety disorders or other mental or neurological disorders associated with anxiety, feelings of anxiety are difficult to suppress and interfere with daily activities. Anxiety is a fundamental feature of anxiety disorders, including separation anxiety disorder, specific phobias, social anxiety disorder (sociophobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance / drug-induced anxiety disorders. Anxiety is also associated with several other mental and neurological disorders. Anxiety is also associated with sleep disorders.

[0146] Several rating scales for assessing anxiety are publicly known in the art, and anxiety symptoms are further assessed as part of various rating scales used to assess mental and neurological disorders. The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. The scale is clinician / physician-administered. The scale has 14 items, which can be divided into a group of psychiatric items (1-6 and 14) that measure mental agitation and mental distress in particular, and a group of physical items (items 7-13) that measure physical complaints in particular related to anxiety. Each item is rated by the interviewer on the following scale: 0=none, 1=mild, 2=moderate, 3=severe, 4=very severe. The total score is obtained by summing up the 14 items. The total score range is 0-56. A higher score indicates greater anxiety. A score of ≤7 indicates minimal anxiety, scores of 8-14 indicate mild anxiety, scores of 15-23 indicate moderate anxiety, and scores ≥24 indicate severe anxiety.

[0147] The Beck Anxiety Rating Scale (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on physical symptoms. These items are rated on a 4-point Likert scale ranging from 0 (none at all) to 3 (severe: I can barely bear it). The total score ranges from 0 to 63. As used herein, subthreshold anxiety specifically means that a patient / subject has a Hamilton Rating Scale (HAM-A) score of at least 9 but less than 18 for anxiety and / or a Beck Anxiety Rating Scale (BAI) score of at least 11 but less than 16. Its individual aspects, such as negative thoughts or feelings of worthlessness, helplessness, and despair, as well as guilt, can be assessed by different measurement means, such as questionnaires or scales.

[0148] Questionnaires assess the mental state of a patient / subject based on observations made by the patient / subject themselves, their caregiver, or the clinician / physician administering the questionnaire. Questionnaires used to assess whether a patient / subject has a particular mental or neurological disorder may include items related to negative thinking. Measurement tools for assessing relevant aspects of negative thinking include, for example, the Shame and Guilt State Scale (SSGS), the Extended Positive and Negative Affect Schedule (PANAS-X), or the Hope State Scale (SHS).

[0149] The Shame and Guilt State Scale (SSGS) is a self-assessment scale for instantaneous (state) feelings of shame and experiences of guilt. The SSGS includes two subscales: shame and guilt. The shame subscale includes items 1, 3, 5, 7, and 9. The guilt subscale includes items 2, 4, 6, 8, and 10. All items are scored in a positive direction and rated on a 5-point Likert scale. The SSGS includes several descriptive statements that the patient / subject may or may not use to describe how they are feeling at that moment. Higher scores indicate a stronger feeling of shame or guilt. The Positive and Negative Affect Schedule Extension (PANAS-X) is an extended version of the 60-item PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, cheerfulness, confidence, attentiveness, and calmness. Therefore, the PANAS-X yields mood measurements at two different levels. The basic negative emotion scales are fear, hostility, guilt, and sadness, while the guilt scale includes the following six items: I feel guilty, I am ashamed, I deserve blame, I am angry at myself, I feel self-loathing, and I am dissatisfied with myself. Each response is to be scored as follows: 1 = very little or none, 2 = a little, 3 = moderate, 4 = a lot, or 5 = extremely. However, researchers facing tighter time constraints may select and evaluate only the scales most relevant to their research.

[0150] More intense feelings of guilt are reflected by higher scores on the guilt scale. The PANAS-X is easy and manageable to administer. Most patients / subjects complete the entire 60-item schedule in under 10 minutes. The scale consists of several words and phrases that describe different sensations and feelings. While the scale should indicate how much a patient / subject has felt this way over the past few weeks, feature scores on the PANAS-X scale have been found to be stable over time, such as between "now," "today," and "the past few days," and shorter, appropriate recall periods may be applied.

[0151] The Hopefulness State Scale (SHS) has three agency and three path items in which respondents describe how they feel "right now." The agency subscale score is derived by summing items 2, 4, and 6, which relate to the perceived ability to reach desired goals using one's own path, and the path subscale score is derived by summing items 1, 3, and 5, which relate to the thinking used to identify possible ways of achieving goals. The total Hopefulness State Scale score is derived by summing the three agency and three path items. Scores can range from a minimum of 6 to a maximum of 48, with higher scores on this scale reflecting a higher sense of hope. Negative thinking or its aspects are also reflected in other scales such as HAM-D, MADRS, BPRS, or BDRS, and their relevant items can usually be applied to assess negative thinking or its aspects.

[0152] Cognition includes the skills required to think, remember, pay attention, and solve problems. A loss or decline in these skills leads to cognitive impairment, a term used herein to refer to a defect or impairment in any domain of cognition. Cognitive impairment may be one of the manifestations of an underlying condition in a patient.

[0153] The DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition. Cognitive impairment can affect one or more of these domains. In fact, cognitive abilities are highly interconnected, and it is not unusual for more than one domain to be affected. For example, the complex attention domain has subdomains of sustained attention (commonly referred to as “concentration” or “focusing power”), divided attention, selective attention, and processing speed.

[0154] Therefore, complex attention clearly involves aspects essential to executive function as well as various cognitive tasks such as learning and memory. Cognitive control or executive function is essentially about attention. Furthermore, perception and decision-making are greatly influenced by attentional capacity. Consequently, attention is tested not only in isolation but also by, for example, cognitive control tasks / executive function. If attention is impaired, other types of cognitive abilities may also be impaired. A stimulus must be present before language can be understood, visual-spatial relationships can be perceived, information can be recalled, or a problem can be solved.

[0155] In this specification, cognitive impairment, a term meaning an acquired condition and therefore representing a decline from a previously acquired level of function, can be associated with a variety of processes. In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, can be maintained during aging and may even improve over time. However, even in the absence of any pathological conditions, aging leads to a decline in abilities such as abstract thinking, reasoning, and decision-making. These deteriorations lead to underlying age-related deficits in processing speed, attention, memory, and executive function that indicate cognitive aging.

[0156] Independent of normal aging, cognitive impairment may be associated with one or more conditions or disorders, such as mental or neurological disorders or certain other medical conditions. Mental or neurological disorders that lead to or are associated with cognitive impairment include disorders characterized by: depressive episodes, e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), such as bipolar I and bipolar II disorders; anxiety disorders, e.g., separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / drug-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder (PTSD). ); Pain disorders, e.g., chronic pain, fibromyalgia, and migraines; mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorder (SUD); mental disorders, e.g., schizophrenia; Huntington's disease; Parkinson's disease; dementia, e.g., Alzheimer's dementia (AD), Parkinson's disease dementia (PDD), Lewy body dementia, vascular dementia, frontotemporal dementia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, e.g., schizophrenic personality disorder and borderline personality disorder; chronic fatigue syndrome; one or more conditions or disorders such as mental or neurological disorders associated with HIV, traumatic brain injury, or post-COVID conditions. Cognitive impairment may also occur in patients / subjects suffering from sleep disorders, e.g., insomnia.

[0157] Cognitive impairment can also occur in disorders that exhibit symptoms characteristic of neurocognitive disorders, which cause clinically significant distress or impairment in functioning in social, occupational, or other important areas, but do not meet all the criteria for any etiologically related disorder. Cognitive impairment can also take the form of neurocognitive disorder. Mild neurocognitive disorder, also called mild cognitive impairment, is characterized by a slight decline in cognitive ability from previous levels of performance in one or more cognitive domains. The affected patient / subject can still maintain independence and perform daily tasks. However, the patient / subject usually functions at a sub-best level. Daily tasks require more effort because compensatory measures are needed to maintain independence. In major neurocognitive disorder, a marked decline in cognitive ability from previous levels of performance is observed in one or more cognitive domains. The cognitive deficit interferes with independence in daily activities.

[0158] Cognitive impairment can be assessed through questionnaires or neuropsychological assessments. Questionnaires assess the mental state of the patient / subject based on observations made by the patient / subject themselves, their caregiver, or the clinician / physician administering the questionnaire. Questionnaires used to assess whether a patient / subject suffers from a particular mental or neurological disorder may include items related to cognitive function. Neuropsychological assessment is a process in which a person's cognitive, psychological / emotional, and behavioral functions are comprehensively evaluated. At the core of neuropsychological assessment is the administration of neuropsychological tests for the formal assessment of cognitive function.

[0159] Performance in these tests is compared to levels appropriate to the patient's age, educational attainment, and cultural background. The tests typically use a set of performance-based questions, also known as a neuropsychological test battery. Abilities tested include verbal processing, visuospatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory-perceptual function.

[0160] Common tests for assessing cognitive impairment include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Co®, the Screening for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB). The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It assesses various cognitive domains, including: short-term memory; visuospatial ability; executive function; attention, concentration, and working memory; language; and orientation to time and space. The possible total score is 30 points, with scores of 26 or higher considered normal, scores between 18 and 25 considered mild cognitive impairment, scores between 10 and 17 considered moderate cognitive impairment, and scores below 10 considered severe cognitive impairment.

[0161] The Mini-Mental State Examination (MMSE) is an 11-question assessment scale that tests five areas of cognitive function: orientation, immediate recall, attention and calculation, recall, and language. The highest possible score is 30. Raw scores may need to be adjusted for educational achievement and age. Four cutoff levels are used in this test to classify the severity of cognitive impairment: 24-30 means no cognitive impairment, 19-23 means mild cognitive impairment, and 10-18 means moderate cognitive impairment. * A score of 9 indicates severe cognitive impairment. Because it is used repeatedly, the MMSE is suitable for measuring changes in cognitive state. The Mini-Co® is a concise cognitive impairment screening questionnaire. It combines a three-word recall test with a clock drawing test. The clock drawing test assesses many potentially affected cognitive areas, including executive function, visuospatial ability, motor programming, and attention. One point is awarded for each of the three words accurately recalled after the clock drawing test, and two points are awarded for an accurately drawn clock. A score of <4 indicates cognitive impairment.

[0162] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a well-established screening measure for assessing cognitive performance in psychiatric patients / subjects. SCIP consists of five subscales: Verbal Learning Test – Immediate (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Verbal Learning Test – Delayed (VLT-D), and Processing Speed ​​Test (PST). There are three different test forms to facilitate test repetition, thus reducing learning effects. Subscale scores are calculated for each of the five tests, and the total score is calculated from the sum of the subscale scores. A total score below 70 indicates cognitive impairment.

[0163] Cognitive impairment can also be assessed using the MCCB (MATRICS Consensus Cognitive Battery) or one or more of its various subtests. The subtests include: Trailmaking Test, Part A (processing speed test); Simplified Assessment of Cognition in Schizophrenia, which includes the Symbol Coding subtest (processing speed); Hopkins Verbal Learning Test Revised, Immediate Recall, 3 Learning Trials Only (verbal learning); Wechsler Memory Scale, Third Edition, Spatial Span subtest (working memory (non-verbal)); Letter-Number Span Test (working memory (verbal)); Neuropsychological Assessment Battery, Maze subtest (reasoning and problem solving); Simplified Visuospatial Memory Test Revised (visual learning); Categorical Fluency Test, Name Animals (processing speed); Mayer-Salovey-Caruso Affective Intelligence Test, Management of the Affective Branch (social cognition); and Continuum Performance Test, Identical Pair Version (attention / vigilance / hyperarousal). The test battery is suitable for measuring cognitive changes. Further tests include the Verbal Recognition Memory (VRM) test, the Rapid Visual Processing (RVP) test, the Spatial Working Memory (SWM) test, and the Digit Code Substitution Test (DSST).

[0164] Postpartum depression (PPD) is a complex mixture of physical, emotional, and behavioral changes that occur in some women after childbirth. PPD is also known as perinatal major depressive disorder. According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when major depressive disorder (MDD) symptoms develop during pregnancy or within 4 weeks of delivery. The patients / subjects treated according to this invention are preferably women >4 weeks postpartum who have been diagnosed with PPD. Furthermore, the patients / subjects are postpartum * Nine months is preferable. The depressive aspect of PPD can be assessed by the HAM-D or MADRS score. The Edinburgh Postnatal Depression Scale (EPDS) can also be used.

[0165] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients / subjects with mood disorders (Montgomery, SA, & Asberg, M. (1979). The new depression scale was designed to be more sensitive to changes. The British Journal of Psychiatry 134, pp. 382). It was designed as a supplementary scale to the Hamilton Rating Scale for Depression (HAM-D), but is more sensitive to changes brought about by antidepressants and other forms of treatment. A higher MADRS score indicates more severe depression. The items examined are outward sadness, reported sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, inability to feel, pessimistic thoughts, and suicidal thoughts, each item scoring from 0 to 6. The overall score ranges from 0 to 60.

[0166] Patients / subjects may have moderate or severe PPD as indicated by a Montgomery-Earsberg Depression Rating Scale (MADRS) score of 20 or higher or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher. Patients / subjects may further have severe PPD as indicated by a Montgomery-Earsberg Depression Rating Scale (MADRS) score of 35 or higher or a Hamilton Depression Rating Scale (HAM-D) score of 27 or higher. Patients / subjects may be diagnosed with treatment-resistant PPD. Patients / subjects treated according to the present invention may have a Montgomery-Earsberg Depression Rating Scale (MADRS) score of 20 or higher or a Hamilton Depression Rating Scale (HAM-D) score of 16 or more items (17 items).

[0167] Furthermore, patients / subjects treated according to the present invention may have a MADRS score of 28 or higher or a HAM-D score of 22 or higher. Even further, patients / subjects treated according to the present invention may have a MADRS score of 35 or higher or a HAM-D score of 25 or higher. In addition to the above, PPD impairs maternal function. In particular, the first year after birth is a critical time for both mother and child. In most cases, the mother is the primary caregiver and therefore bears the majority of the roles associated with the task of caring for the infant.

[0168] Maternal functioning includes aspects of maternal ability related to interaction with the infant and maternal self-care. Because maternal functioning includes the emotional aspects of childcare, it is also important for the child's development. In fact, the quality of mother-child interaction in the first year after birth influences the infant's development. High levels of maternal functioning may correlate with positive outcomes in infant development. Furthermore, impaired functioning during the postnatal period may hinder optimal infant development.

[0169] The Birkin Index of Maternal Functioning (BIMF) is designed to measure maternal functioning in the postnatal years. The BIMF is a 20-item self-report scale of functioning. Each item is assigned a score between 0 and 6, with a maximum total score of 120. Higher scores indicate better maternal functioning. The BIMF identifies the primary functional domains of mothers during the postnatal period as self-care, infant care, mother-child interaction, maternal mental health, social support, management, and adaptation.

[0170] A BIMF score of 95 or less is considered to represent some impairment of maternal function in the BIMF, a score of 80 or less is considered to represent impairment of maternal function in the BIMF, and a score of 65 or less is considered to represent severe impairment of maternal function in the BIMF. The present invention particularly enables the improvement of maternal function in patients / subjects who have a score of 80 or less before treatment, and even in patients / subjects who have a score of 65 or less.

[0171] Symptoms such as anhedonia, emotional despondency, and emotional flattening are clustered together in BIMF as social detachment or social alienation / emotional despondency or detachment. Reduced social engagement is a further aspect associated with social detachment or social alienation / emotional despondency or detachment.

[0172] Anhedonia is a lack of ability to experience pleasure. A patient / subject does not suffer from anhedonia if, in the patient / subjectively, there is no reduction in the ability to experience pleasure in normal activities. Anhedonia is mild if it is a slight reduction in pleasure from normally enjoyable activities, moderate if it is a significant reduction in pleasure from normally enjoyable activities or some retention of pleasure from solitary activities, or severe if it is a complete lack of ability to experience pleasure.

[0173] Anhedonia includes both completion (or preference) and anticipation (or desire) components. Completion pleasure refers to pleasure "at a point in time" experienced by the patient / subject in direct involvement of an enjoyable activity, while anticipation pleasure refers to the experience of pleasure associated with a future activity. Affective flattening is characterized by the patient / subjective awareness of a reduction in the intensity or range of sensations or emotions. If the patient / subject does not perceive a reduction in the range or intensity of sensations or emotions, they do not exhibit affective flattening. Affective flattening is mild in the case of a slight contraction of the range of emotions, or a transient reduction in the range or intensity of emotions; moderate in the case of a marked contraction of the range or intensity of emotions in which some emotions are retained, e.g., in the case of an inability to cry; and severe in the case of a prominent and widespread contraction of the range of emotions or an inability to experience normal emotions.

[0174] Affective withdrawal or detachment is a lack of ability to connect with others on an emotional level, or a reluctance to do so. For example, the BPRS includes an item on affective withdrawal, characterized as a deficit in the patient / subject's ability to emotionally engage during the interview situation. According to the description of this BPRS item, there is no affective withdrawal if the person engages with the interviewer naturally for most of the time, without a lack of emotional engagement, such as occasionally being unable to respond to comments, occasionally appearing engrossed in other things, or formally laughing.

[0175] Mild emotional withdrawal occurs when there is a noticeable inability to respond to comments, a state of being engrossed in other things, or a lack of emotional engagement indicated by a lack of warmth, but the subject responds to questions. Moderate emotional withdrawal occurs when emotional contact is absent for most of the interview, and this is because the patient / subject does not think carefully about their response, cannot make eye contact, does not seem attentive when the interviewer is listening, or is likely to be engrossed in psychotic material. Moderately severe emotional withdrawal occurs when emotional contact is absent for most of the interview in addition. Severe emotional withdrawal occurs when emotional engagement is actively avoided by the patient / subject, or when the patient / subject is frequently unresponsive, responds with yes / no answers, or responds with minimal emotion. Very severe emotional withdrawal occurs when the patient / subject consistently avoids emotional engagement, is unresponsive, responds with yes / no answers, is likely to leave during the interview, or simply does not respond at all.

[0176] Reduced social engagement characterizes patient / subjective reports of reduced social and interpersonal engagement or interaction. If there are no reports of reduced social and interpersonal engagement or interaction, there is no reduction in social engagement. Slight reduction in social engagement without impairment in social or interpersonal functioning is mild; obvious reduction in social engagement with some functional sequelae, e.g., avoidance of some social engagement or conversation is moderate; noticeable reduction in social interaction or avoidance of almost all forms of social contact, e.g., refusal to answer the phone or meet with friends or family is severe.

[0177] Social withdrawal or social alienation / affective withdrawal or detachment may be associated with one or more conditions or disorders, such as mental or neurological disorders or some other medical conditions. Mental or neurological disorders that lead to or are associated with social withdrawal or social alienation / affective withdrawal or detachment include disorders characterized by: depressive episodes, e.g., major depressive disorder (MDD); bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); trauma Post-stress disorder (PTSD); pain disorders, e.g., chronic pain and fibromyalgia; mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorder (SUD); mental disorders, e.g., schizophrenia; dementia, e.g., Alzheimer's disease (AD); Lewy body dementia (DLB), vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, e.g., schizophrenic personality disorder and borderline personality disorder (BPD).

[0178] Social withdrawal or social alienation / affective withdrawal or detachment may occur in patients / subjects suffering from sleep disorders, such as insomnia. Social withdrawal or social alienation / affective withdrawal or detachment may also occur in patients / subjects suffering from medical conditions leading to associated psychiatric or neurological conditions, including traumatic brain injury (TBI).

[0179] Social withdrawal or social alienation / affective abstinence or detachment, or its individual aspects such as anhedonia, affective abstinence, and affective flattening, can be assessed by different measurement methods, such as questionnaires or scales. Questionnaires assess the mental state of the patient / subject based on observations made by the patient / subject themselves, their caregiver, or the clinician / physician administering the questionnaire. Questionnaires used to assess whether a patient / subject suffers from a particular mental or neurological disorder may include items related to social withdrawal or social alienation / affective abstinence or detachment.

[0180] The Snais-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, or the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, perceptual experiences, and interests / entertainment. Scores of 2 or less constitute a “normal” score, while “abnormal” scores are defined as 3 or greater. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Each “disagree” response is scored as 1, and each “agree” response is scored as 0. Therefore, the final score ranges from 0 to 14. SHAPS has good constructed concept validity and sufficient test-retest reliability. High internal consistency has also been reported. While SHAPS has been used to measure anhedonia in depression, it is also frequently used to assess anhedonia in other patient / control groups.

[0181] In principle, SHAPS measures the tone of pleasure using 14 hypothetically formulated items over the past few days. However, due to the hypothetical nature of the items, a shorter, appropriate recall period may also be applied to earlier assessment points. Alternatively or additionally, the Anhedonia Dimension Rating Scale (DARS), which measures the enjoyment of interest, willingness, effort, and completion across four domains—hobbies, food and drink, social activities, and perceptual experiences—can be used to assess anhedonia. The DARS contains 17 items that assess the current state of anhedonia. The DARS is rated on a 5-point Likert scale from 0 (not at all) to 4 (very much), with higher values ​​indicating less anhedonia. All items are aggregated to a total score ranging from 0 to 68. For each of the four pleasure domains—hobbies (4 items, total score 0-16), food and beverages (4 items, total score 0-16), social activities (4 items, total score 0-16), and perceptual experiences (5 items, total score 0-20)—the patient / subject is asked to provide two or three examples of their own preferences.

[0182] The Personality Rating Scale for Adults (PID-5) for DSM-5 is a 220-item self-rating personality traits scale for adults aged 18 and older. It assesses 25 personality trait facets, including anhedonia, worry, attention-seeking, coldness, dishonesty, depression, distractibility, eccentricity, emotional instability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, deceitfulness, perceptual dysregulation, persistence, affective restriction, rigid perfectionism, risk-taking, separation anxiety, obedience, suspicion, abnormal beliefs and experiences, and detachment. Each trait facet consists of 4 to 14 items.

[0183] The feature facet Anhedonia includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (items with reverse scoring are marked with the letter "R"); the feature facet Detachment includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186; and the feature facet Intimacy Avoidance includes items 89, 97R, 108, 120, 145, and 203. These three feature facets can be combined to generate a broader feature domain called Detachment. Measurement is completed by the individual before visiting a clinician / physician. Each item asks the individual to rate how well the item generally describes them. Each item related to the measurement is rated on a 4-point scale. The responses to the items are categorized as follows: 0 = very wrong or mostly wrong; 1 = sometimes wrong or somewhat wrong; 2 = sometimes or somewhat true; 3 = very true or mostly true. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, the items are reverse-coded before entering the scale score calculation.

[0184] The scores for each item within each characteristic facet should be totaled and placed into the appropriate raw facet score box. In addition, clinicians / physicians are asked to calculate and use the average score for each facet and domain. The average score will combine the total score and the scores for each domain into a 4-point scale, which will allow clinicians / physicians to consider the individual's personality dysfunction against the observed criteria. The average facet score is calculated by dividing the raw facet score by the number of items in the facet (for example, if all items in the "anhedonia" facet are rated as "sometimes or somewhat," the average facet score would be 16 / 8 = 2, indicating moderate anhedonia). The average domain score is calculated by totaling the three facet scores that primarily contribute to a particular domain, and then averaging them. For example, if the average facet scores for anhedonia, intimacy avoidance, and detachment (scales that primarily indicate detachment) are all 2, the sum of these scores would be 6, and the average domain score would be 6 / 3 = 2. A higher average score indicates greater dysfunction in a particular personality trait facet or domain. High scores on a facet or domain may indicate a significant problem area for the individual receiving care, which could justify further evaluation, intervention, and follow-up.

[0185] The primary aspects observed in patients / individuals with psychomotor delay are reduced energy and vitality and decreased motivation. Psychomotor delay includes slower thinking and reduced physical movement in the individual. Psychomotor dysfunction can cause a visible slowing of physical and emotional responses. Psychomotor delay may be associated with one or more conditions or disorders, such as mental or neurological disorders or some other medical conditions.

[0186] Mental or neurological disorders leading to or associated with psychomotor delay include disorders characterized by: depressive episodes, e.g., major depressive disorder (MDD); bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorder (SUD); mental disorders, e.g., schizophrenia; dementia, e.g., Alzheimer's disease (AD); Lewy body dementia (DLB); vascular dementia and Parkinson's dementia; Parkinson's disease; and chronic fatigue syndrome. Psychomotor delay may also occur in patients / subjects suffering from sleep disorders, e.g., insomnia.

[0187] Psychomotor delay can be assessed by measuring various aspects. These may include various types of drawing tasks and tests, such as the Trail Making Test (TMT), the Digit-Swap Test (DSST), or the Gibson Spiral Maze Test (GSM) and other tests known in the art. For example, in the Trail Making Test (TMT), the patient / subject must connect 25 circles in ascending order, each containing either a number (TMT A) or a combination of a number and a letter (TMT B). The task requirements are similar to those of TMT-B, except that the patient / subject must alternate between numbers and letters (e.g., 1, A, 2, B, 3, C). Thus, the test assesses processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the amount of time required to complete the task.

[0188] Another test involving motor skills is the Gibson spiral maze test (GSM), which assesses only psychomotor speed and is not influenced by cognitive ability. To complete the GSM, the patient / subject must accurately navigate the spiral maze from the starting point to the endpoint without touching the dividing lines. The digit-code substitution test (DSST) also measures psychomotor speed and consists of digit-code pairs followed by a list of digits. The patient / subject must record the corresponding code under each digit as quickly as possible. The score consists of the number of codes reported accurately out of 90. A further example of a motor test is the finger tapping test.

[0189] Therefore, while some specific tests combine measurements of both motor and cognitive aspects of psychomotor delay, others assess only the motor aspect. Speech analysis can also be a further indicator of psychomotor delay. Key scales available for assessment and measurement include the severity of psychomotor delay, the Salpêtrière Delay Rating Scale (SRRS), and the Motor Excitation and Delay Scale (MARS). The Salpêtrière Delay Rating Scale (SRRS), developed by Vidrochet, assesses cognitive and motor aspects through 15 items. The first three measure the quality of movement, particularly limb stride length and slowness, and torso, head, and neck movements. The next three items focus on speech, including language flow, tone of voice, and response length. Two items are designed to objectively measure cognitive function. These questions are based on interview conversation and measure the patient's ability to engage with a topic and speak in detail. Further items are about / subjective of the patient and assess rumination, fatigue, level of interest, perception of time, memory, and concentration. The final item on the scale relates to the overall assessment of the patient's psychomotor delay. The item is defined on a scale from 0 (no symptoms) to 4 (severe) to a total score range of 0 to 60, based on the severity of the symptoms presented.

[0190] The Motor Excitation and Delay Scale (MARS) assesses only the motor aspects. MARS is designed to assess psychomotor disorders in depressive disorders. Psychomotor disorders are categorized into five main physical categories: eyes, face, voice, limbs, and torso, with a total of 19 items on the scale. Items in the eye category include gaze direction, blink rate, gaze, and eye movements. Items related to the face category include facial expression and facial expressiveness. The voice category includes items such as volume, ambiguity, tone, and time to onset. Items under the limb category include hand, foot, and leg movements, stride length, bradykinesia, and hand tension. Torso category items include posture, bradykinesia, and axial movement. The severity of each item ranges from 1 to 4, with 4 being the most severe. Of the 19 items, 9 are related to motor excitement, and 10 assess motor delay. Delayed items include abnormal gait, torso / proximal limb bradykinesia, postural instability, and slowness of movement (i.e., limb and torso categories); lack of facial expressiveness and downcast gaze (i.e., eye and face categories); and decreased voice volume, slurred speech, delayed speech onset, and monotonous speech (i.e., voice categories). The MARS scale provides a rapid clinical assessment of motor signs.

[0191] In one embodiment, the pharmaceutical composition / formulation of the present invention is intended for use in the treatment of patients having an AES-S score of at least 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in at least a reduction of 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% in the AES-S score. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 points in the AES-S score. In one embodiment, the pharmaceutical composition / formulation of the present invention is intended for use in the treatment of patients having a MADRS score of at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% of the MADRS score.In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 points in the MADRS score. In one embodiment, the pharmaceutical composition / formulation of the present invention is for use in the treatment of patients having a GAD-7 score of at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 points. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% of the GAD-7 score. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 points of the GAD-7 score. In one embodiment, the pharmaceutical composition / formulation of the present invention is for use in the treatment of patients having a PHQ-9 score of at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 points. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% of the PHQ-9 score. In one embodiment, treatment of a patient with the pharmaceutical composition / formulation of the present invention results in a reduction of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 points of the PHQ-9 score. Pharmacokinetics The applicant funded a double-blind, randomized, phase 1, single-dose escalation trial to evaluate the safety, tolerability, and pharmacokinetic profiles of intranasal 5-MeO-DMT hydrochloride and intranasal 5-MeO-DMT benzoate in healthy subjects. The results of these trials surprisingly showed that only the benzoate salt of 5-MeO-DMT exhibited dose-proportional pharmacokinetics. For use in treatment, it is desirable for a compound to have dose-proportional pharmacokinetics, for example, to facilitate the adjustment of doses and dose regimens in patients. In one embodiment, a dose-proportional pharmacokinetic salt of 5-MeO-DMT is provided for use in the methods disclosed herein, at the option of choice. In one embodiment, the dose-proportional pharmacokinetic salt of 5-MeO-DMT is a benzoate or an HBr salt, at the option of a benzoate salt. A double-blind, randomized, phase 1, single-dose escalation study was conducted to evaluate the safety, tolerability, and pharmacokinetic profile of a liquid intranasal 5-MeO-DMT HCl (5-MeO-DMT HCl, HPMC, water for injection (WFI), and pH-adjusting sodium hydroxide solution) pharmaceutical composition / formulation in healthy subjects. The mean (+ / -SD) 5-MeO-DMT plasma logarithmic concentration-time plots are shown in Figure 1. It can be seen that 5-MeO-DMT HCl does not exhibit dose-proportional pharmacokinetics, and the mean concentration profiles shown for all 5 mg, 8 mg, 10 mg, 11 mg, and 14 mg doses are substantially similar.

[0192] A double-blind, randomized, phase 1, single-dose escalation study was conducted to evaluate the safety, tolerability, and pharmacokinetic profile of intranasal 5-MeO-DMT benzoate in healthy subjects. Mean (+ / -SD) 5-MeO-DMT plasma linear concentration-time plots and plasma logarithmic concentration-time plots are shown in Figures 2 and 3, respectively. Pharmacokinetics were shown to be approximately dose-linear. No doses exceeded the maximum exposure limit Cmax: 421 ng / mL or AUC 220 h.ng / mL as defined by prior preclinical studies in dogs. Mean (+ / -SD) 5-MeO-DMT plasma linear concentration-time plots and plasma logarithmic concentration-time plots are shown in Figures 9 and 10, respectively. The mean Cmax was 29 ng / mL for a 12 mg dose. The mean Tmax was 9.5 minutes, while the mean half-life (T1 / 2) was 21 minutes. Bufotenin, the O-demethylated metabolite of 5-MeO-DMT, was detected only at very low levels at a dose level of 6 mg after 16 minutes.

[0193] It will be understood that any reference to “5-MeO-DMT” herein means 5-MeO-DMT free base, or its pharmaceutically acceptable salts, prodrugs, hydrates, esters, cocrystals or deuterized forms, or pharmaceutical compositions / formulations containing the foregoing. definition Terms such as "a," "an," and "the" are not intended to refer only to singular entities, but also include general classes for which specific examples may be used for illustrative purposes.

[0194] As used herein, the term "approximately" refers to a value within ±10% of the stated value. As used herein, the terms “acute stress disorder” and “ASD” refer to a condition that arises in response to a stressful event or situation of an exceptionally threatening or tragic nature that can cause widespread distress in an individual (e.g., a natural or man-made disaster, combat, a major accident, witnessing the brutal death of another, or being a victim of torture, terrorism, rape, or other crime). Like PTSD, acute stress disorder is an anxiety disorder characterized by a very specific response after exposure to a traumatic event or stressor. However, the duration of acute stress disorder is shorter than that of PTSD, and therefore symptoms are present for at least one, two, or three days, but at most four, five, or six weeks. In individuals exhibiting symptoms that persist over a longer time interval, a diagnosis of PTSD may be justified.

[0195] The terms "administration" or "administering" refer to a method of administering a certain dosage of a compound or pharmaceutical composition / formulation.

[0196] "Dysthymia" or "dysthymic disorder" is defined as a chronically depressed mood that occurs for at least two years, occurring for most of the day, with more days occurring than not occurring. In children and adolescents, the mood may be more irritable than depressed, and the minimum required duration is one year. Any asymptomatic intervals during the two-year period (one year for children or adolescents) must last no more than two months. During periods of depressed mood, at least two of the following additional symptoms are present: loss of appetite or overeating, insomnia or hypersomnia, gloom or fatigue, low self-esteem, difficulty concentrating or deciding, and feelings of hopelessness. The symptoms cause clinically significant distress or impairment in social, occupational (or academic) or other important areas of functioning. A diagnosis of dysthymia is not made if the individual has had manic, mixed, or hypomanic episodes, has met the criteria for cyclothymic disorder, if depressive symptoms occur only during the course of a chronic mental disorder (e.g., schizophrenia), or if the disorder is due to the direct physiological effects of a substance or a systemic medical condition. After the first two years of dysthymic disorder, a major depressive episode may overlap with the dysthymic disorder ("double depression"). Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th edition, I 994. Diagnostic guidance for mental disorders can be found, for example, in ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), Arlington, VA.; American Psychiatric Association, 2013).

[0197] As used herein, the term “psychological support” may mean one or more of the following: therapy, psychotherapy, talk therapy, cognitive behavioral therapy (CBT), counseling, guided self-help, and / or group therapy.

[0198] As used herein, the term “Generalized Anxiety Disorder” refers to a condition characterized by excessive anxiety and worry (i.e., worrying anticipation). Typically, excessive anxiety and worry occur more frequently on days when they occur than on days when they do not, over a period of time (e.g., one, two, three, or four months or longer). Anxiety and worry may be associated with (i) restlessness, tension, or nervousness; and / or (ii) muscle tension. Anxiety and worry may be associated with (a) conspicuous avoidance of situations that may have negative consequences; (b) considerable time and effort spent preparing for situations that may have negative consequences; (c) conspicuous postponement of worry-related actions or decisions; and (d) repeated seeking of worry-related reassurance. Anxiety, worry, or physical symptoms may cause clinically significant distress or impairment in social, occupational, or other important areas of functioning in individuals with many, but not all, GAD.

[0199] As used herein, the terms “Obsessive-Compulsive Disorder,” “OCD,” and “Anxiety and Obsessive-Compulsive Spectrum Disorder” refer to a condition characterized by obsessions and / or compulsions. An obsession is a recurrent, persistent thought, impulse, or impression that is experienced at some point in the disorder as intrusive and unwanted, and which usually causes marked anxiety or distress, to which the obsessed individual attempts to ignore or suppress such thoughts, impulses, or impressions or to neutralize them by any other thought or action (i.e., by performing a compulsive act). A compulsive act is a recurrent behavior (e.g., handwashing, ordering, checking) or mental activity (e.g., praying, counting numbers, repeating words to one's mind) that a person feels compelled to perform in response to an obsession or in accordance with rules that should be strictly applied. Behaviors or mental actions are intended to prevent or reduce anxiety or distress, or to prevent some frightening event or situation, but these behaviors or mental actions are not realistically related to what they are intended to neutralize or prevent, or are clearly excessive. Typically, obsessions or compulsions cause time waste (e.g., spending more than one hour a day) or clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0200] As used herein, the term “panic disorder” refers to a condition characterized by recurrent, unexpected panic attacks. Panic disorder includes both panic disorder with agoraphobia and panic disorder without agoraphobia. Subjects having this condition may exhibit one or both of the following: (i) persistent anxiety or worry about additional panic attacks or their outcomes (e.g., losing one's mind, having a heart attack, going crazy); and / or (ii) markedly maladaptive changes in attack-related behaviors (e.g., behaviors intended to avoid having a panic attack), which may include agoraphobia avoidance.

[0201] Where used herein, terms such as “pharmacologically effective amount” and “therapeutic effective amount” refer to an amount sufficient to produce a beneficial or desired outcome, such as a clinical result, when administered to a subject, including mammals, such as humans, when used in relation to a therapeutic formulation. For example, in the context of treating depression as described herein, these terms refer to an amount of the pharmaceutical composition / formulation sufficient to produce a treatment response compared to the response obtained without administration of the formulation. The amount of a given pharmaceutical composition / formulation described herein that corresponds to such an amount may vary depending on various factors such as a given agent, formulation, route of administration, type of disease or disorder, identifying information of the subject (e.g., age, sex, weight) or the host being treated. The “effective amount” and “pharmacologically effective amount” of the pharmaceutical composition / formulation in this disclosure also include an amount that produces a beneficial or desired outcome in a subject compared to a control (e.g., a reduction in the score on the Montgomery-Earsberg Depression Rating Scale).

[0202] As used herein, the terms “Post-Traumatic Stress Disorder” and “PTSD” refer to a condition that arises as a delayed and / or prolonged response to a condition that arises as a response to a stressful event or situation (short-term or long-term) of an exceptionally threatening or tragic nature that can cause widespread distress in an individual (e.g., natural or man-made disaster, combat, serious accident, witnessing the brutal death of another, or being a victim of torture, terrorism, rape, or other crime). Predisposing factors such as personality traits (e.g., obsessive, helpless) or a history of prior neuroses may lower the threshold for the onset of the condition or exacerbate its process, but they are neither necessary nor sufficient to explain its occurrence. PTSD is a more persistent outcome of psychological trauma, less frequently occurring than the more frequently seen acute stress response. PTSD has historically been recognized as railroad accident spine, stress syndrome, artillery shock, war neurosis, traumatic war neurosis, and post-traumatic stress syndrome. Diagnostic symptoms include the initial trauma re-experiencing through relapses or nightmares; avoidance of trauma-related stimuli; and increased arousal, such as difficulty falling asleep or maintaining sleep, anger, and hyperarousal. Formal diagnostic criteria (DSM-V, DSM-IV, and / or ICD-9) require that symptoms persist for 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).The formal diagnostic criteria include: (i) intrusive symptoms associated with the traumatic event (e.g., (a) spontaneous or triggered recurrent, involuntary, and intrusive memories of the tragic traumatic event; (b) recurrent horrific dreams whose content and / or impact are related to the event; (c) dissociative reactions in which the individual feels or acts as if the traumatic event is recurring (e.g., relapses) (such reactions may occur sequentially, and the most extreme expression is a complete loss of awareness of the current environment); and (d) symbolizing or resembling an embodiment of the traumatic event. (i) intense or prolonged mental distress upon exposure to internal or external triggers, and / or (e) marked physiological responses to the traumatic event, (ii) persistent avoidance of stimuli associated with the traumatic event (e.g., (a) thoughts, feelings, or physical sensations that evoke the traumatic event, (b) activities, places, physical triggers, or time periods that evoke the traumatic event (e.g., anniversary responses), and / or (c) people, conversations, or interpersonal situations that evoke the traumatic event), iii) Cognitive and mood changes associated with the traumatic event (e.g., (a) inability to recall significant aspects of the traumatic event (typically dissociative amnesia), (b) persistent excessive pessimistic predictions about oneself, others, or the world, (c) persistent biased blame of oneself or others for the cause or outcome of the traumatic event, (d) a pervasive negative emotional state (e.g., fear, terror, anger, guilt, or shame), (e) significantly reduced interest in or participation in meaningful activities, (f) feelings of detachment or separation from others) This may include (g) a persistent lack of the capacity to experience positive emotions (e.g., a lack of the capacity to feel affection, emotional numbness), and (iv) altered arousal (i.e., hyperarousal) and responsiveness associated with the traumatic event (e.g., (a) irritability, anger, or aggressive behavior, (b) reckless or self-destructive behavior, (c) hyperarousal, (d) exaggerated startle response, (e) problems with concentration, and / or (f) sleep disturbances (e.g., difficulty falling asleep or staying asleep, or restless sleep)).Formal diagnostic criteria may include the duration of the disorder being greater than a certain time interval (e.g., one month, three months, or six months) and the disorder causing clinically significant distress or impairment in social, occupational, or other important areas of functioning. A small percentage of patients may experience a multi-year chronic course and a transition to permanent personality changes. Three main symptoms associated with PTSD are (1) “re-experiencing” the traumatic event, such as relapses, nightmares, intrusive thoughts, and recollections; (2) avoidance behaviors and emotional numbness; and (3) irritability, such as sleep disturbances, anxiety, hyperactive startle responses, hyperarousal, alert hyperarousal, irritability, and outbursts of anger.

[0203] As used herein, the terms “mental disorder” and “mental state” refer to conditions characterized by impairments in the regulation of human feelings or behavior that reflect dysfunction in the underlying mental, biological, or developmental processes of mental functioning. Mental disorders include, but are not limited to, depressive disorders (major depressive disorder, 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), intoxication (e.g., substance abuse, e.g., alcohol dependence, tobacco abuse, or drug abuse), eating disorders (e.g., anorexia nervosa, bulimia nervosa, and bulimia nervosa), and obsessive-compulsive disorder (e.g., primary impulse control disorder or obsessive-compulsive disorder). A mental disorder can be any mental state associated with one or more symptoms, such as a physical symptom (e.g., chronic pain, disproportionate anxiety to the severity of a physical complaint, pain disorder, body dysmorphia, conversion (i.e., loss of bodily function due to anxiety), hysteria, or a neurological condition of no identifiable cause) or a psychosomatic symptom (e.g., back pain, fibromyalgia, migraines, and chronic fatigue syndrome). Other mental disorders include repetitive physical attention behaviors such as tic disorders (e.g., Tourette syndrome, trichotillomania, nail biting, temporomandibular joint disorder, thumb sucking, repetitive mouth-finger behavior, lip biting, fingernail biting, eye rubbing, skin picking, or chronic motor tic disorder). In some cases, the onset of a mental disorder is associated with or characterized by prodromal symptoms such as depressed mood, decreased appetite, weight loss, increased appetite, weight gain, early insomnia, mid-stage insomnia, early awakening, hypersomnia, decreased energy, decreased interest or pleasure, self-blame, reduced concentration, indecisiveness, suicidal tendencies, psychomotor agitation, psychomotor stunting, more frequent crying, inability to cry, despair, worry / anxiety, low self-esteem, irritability, dependence, self-pity, physical complaints, decreased efficacy, helplessness, and decreased initiation of spontaneous responses.

[0204] As used herein, the terms “sociophobia” and “social anxiety disorder” refer to a condition characterized by fear or anxiety associated with one or more social situations. Individuals with this condition typically exhibit marked fear or anxiety about one or more social situations in which they are exposed to possible scrutiny by others. Examples include social interaction (e.g., having a conversation), being observed (e.g., eating or drinking), or performing in front of others (e.g., giving a speech). Typically, individuals with this condition (i) fear performing or exhibiting anxiety symptoms that are negatively perceived (i.e., humiliating, embarrassing, leading to rejection, or harming others); (ii) almost always cause imminent fear or anxiety in the social situation; (iii) avoid or tolerate the social situation, despite the intense fear or anxiety; and (iv) the fear or anxiety is not in harmony with the danger posed by the social situation. In children, fear or anxiety may be expressed in social situations by crying, tantrums, freezing, clinging, withdrawing, or refusing to speak. Fear, anxiety, and avoidance can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0205] As used herein, the terms “treat,” “treating,” or “treatment” refer to the administration of a compound or pharmaceutical composition / formulation for therapeutic purposes. Use for “treating a disorder” or “therapeutic treatment” refers to improving the condition of a patient who already has a disease by administering a treatment to alleviate the disease or one or more of its symptoms (e.g., by reducing one or more symptoms of inflammation). The term “therapeutic” includes an effect of alleviating the harmful clinical effects of a particular inflammatory process (i.e., the consequences of inflammation rather than the symptoms of inflammation). The methods of the present invention can be used as primary prevention, that is, to prevent a condition or to reduce the risk of developing a condition. Prevention refers to preventive treatment for a patient who may not have fully developed a condition or disorder but is susceptible to or at risk of developing a condition. Accordingly, in the claims and embodiments, the methods of the present invention can be used for either therapeutic or preventive purposes.

[0206] "Major depressive disorder" refers to a clinical course characterized by one or more major depressive episodes in an individual with no history of manic, mixed, or hypomanic episodes. A diagnosis of unipolar depression is not made if a manic, mixed, or hypomanic episode occurs during a course of depression, if the depression is attributable to the direct physiological effects of a substance, if the depression is attributable to the direct physiological effects of a systemic medical condition, if the depression is attributable to bereavement or other significant loss ("reactive depression"), or if the episode is better explained by schizoaffective disorder and does not co-occur with schizophrenia, schizophrenia-like disorder, delusional disorder, or psychotic disorder. If a manic, mixed, or hypomanic episode occurs, the diagnosis is changed to bipolar disorder. Depression may be associated with chronic systemic medical conditions (e.g., diabetes, myocardial infarction, carcinoma, and stroke). In general, unipolar depression is more severe than mood disorders. An essential feature of a major depressive episode is a period of at least 2 to 15 weeks in which there is a depressed mood or loss of interest or pleasure in nearly all activities. In children and adolescents, the mood may be more irritable than sad. Episodes may be monoecious or recurrent. Individuals also experience at least four additional symptoms extracted from a list including changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicide, planning, or attempts. Each symptom should be newly present or noticeably worsened compared to the person's pre-episodic state. Symptoms should persist for at least two consecutive weeks, mostly 24 hours, and the episode should involve clinically significant distress or impairment in social, occupational (or academic), or other important areas of functioning (Diagnostic and Statistical Manual of Mental Disorders (OSM IV), American Psychiatric Press, 4th edition, 1994).Diagnostic guidance for mental disorders can be found, for example, in ICD-10 (The ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, Geneva: World Health Organization, 1993) and DSM-V (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), Arlington, VA.; American Psychiatric Association, 2013).

[0207] As used herein, the term “free-flowing” refers to the ability of multiple solid particles to move continuously and uninterruptedly, similar to a fluid (for example, individual solid particles within multiple solid units do not adhere or stick to each other much), enabling airflow into the nasal cavity.

[0208] As used herein, “stable” refers to the ability of a therapeutic agent (e.g., 5-MeO-DMT) to maintain its therapeutic efficacy (e.g., all or most of its intended biological activity and / or physiological and chemical integrity) over a long period of time. A stable pharmaceutical composition or formulation exhibits physical integrity and biological activity and reduced vulnerability to chemical transformation (e.g., oxidation) before administration to a patient. A stable drug pharmaceutical composition or formulation has a shelf life of 3, 6, 12, 18, or 24 months or more at about 5°C and / or about 25°C.

[0209] As used herein, “state-stable” refers to the ability of a therapeutic agent (e.g., amorphous 5-MeO-DMT) to substantially maintain its amorphous state over extended time intervals. For example, a state-stable amorphous solid will maintain at least 75%, 85%, 90%, or 95% (w / w) of its amorphous form (i.e., resist crystallization) under storage conditions of 1, 3, 6, or 12 months at a relative humidity of 60% RH or less between 2°C and 25°C.

[0210] The term "sustained-release" refers to a drug-pharmaceutical composition / formulation that provides sustained release of a drug over an extended time interval, for example, 2 to 20 minutes or more, compared to an immediate-release drug-pharmaceutical composition / formulation, wherein the active agent formulated in the unit dosage form (e.g., 5-MeO-DMT, or a pharmaceutically acceptable salt thereof) has a elution-release profile in which at least 10 to 80% (e.g., 10 to 60%, 10 to 40%, 10 to 20%, 20 to 80%, 40 to 80%, or 60 to 80%) of the drug is released within 20 minutes of the test. Preferably, but not necessarily, sustained-release results in a substantially constant blood level of the drug over a long period that is within the therapeutic range for the disease being treated. Preferably, the sustained-release pharmaceutical composition / formulation of 5-MeO-DMT produces plasma 5-MeO-DMT levels that fall within the following concentration ranges: 5-45 ng / mL, 5-40 ng / mL, 5-35 ng / mL, 5-30 ng / mL, 5-25 ng / mL, 5-20 ng / mL, 10-50 ng / mL, 15-50 ng / mL, 20-50 ng / mL, 25-50 ng / mL, 30-50 ng / mL, 35-50 ng / mL, 40-50 ng / mL, 10-40 ng / mL, or 10-30 ng / mL.

[0211] "Immediate release" means a method of releasing an active drug (e.g., 5-MeO-DMT or a pharmaceutically acceptable salt thereof) formulated into a unit dosage form having a elution-release profile, wherein at least 80%, 85%, 90%, 95%, or 99% of the drug is released within the first two minutes of the test.

[0212] As used herein, the term “residence time” refers to the period of time a compound, such as 5-MeO-DMT, is present in the nasal cavity, for example, along the nasal cilia and mucous layer. The residence time of a compound (e.g., 5-MeO-DMT) can be formulated to have a longer residence time of at least 10, 15, 20, 25, or 30 minutes compared to immediate-release pharmaceutical compositions / formulations having residence times of less than 10, 8, 6, 5, or 2 minutes.

[0213] As used herein, the term “treatment” refers to administering a dry powder pharmaceutical composition / formulation for preventive and / or therapeutic purposes. “Preventing disease” refers to a preventive treatment for a patient who is not yet ill but is susceptible to or at risk of developing a particular disease. “Treatment” or “therapeutic treatment” refers to alleviating a disease and improving the patient’s condition by administering treatment to a patient who is already suffering from a disease (e.g., depression and alcohol use disorder). The term “treatment” also includes treating a patient to slow the progression of a disease or its symptoms. Therefore, in the claims and embodiments, treatment is an administration to a patient for either therapeutic or preventive purposes.

[0214] As used herein, the term “sufficient amount” refers to an amount of a dry pharmaceutical composition / formulation sufficient to produce a beneficial or desired outcome, such as a clinical result, when administered to a subject, including, for example, a mammal, such as a human. For example, in the context of treating depression as described herein, these terms refer to an amount of a pharmaceutical composition / formulation sufficient to achieve a treatment response compared to a treatment response obtained without administration of the formulation. Such an amount of a given pharmaceutical composition / formulation described herein may vary depending on a variety of factors, such as a given drug, formulation, route of administration, type of disease or disorder, identifying information of the subject (e.g., age, sex, weight) or the host being treated. “Sufficient amount” of a pharmaceutical composition / formulation in this disclosure also includes an amount that produces a beneficial or desired outcome in the subject compared to a control (e.g., a reduction in the score on the Montgomery-Earsberg Depression Rating Scale). [Brief explanation of the drawing]

[0215] [Figure 1] Figure 1 shows the mean (+ / -SD) 5-MeO-DMTHCl plasma logarithmic concentration-time plot. [Figure 2] Figure 2 shows the mean (+ / -SD) 5-MeO-DMT benzoate plasma linear concentration-time plot. [Figure 3] Figure 3 shows the mean (+ / -SD) 5-MeO-DMT benzoate plasma logarithmic concentration-time plot. [Figure 4] Figure 4 shows the XRPD for the spray-dried dispersion (SDD) of Example 1. [Figure 5] Figure 5 shows the DSC thermogram for the SDD of Example 1. [Figure 6] Figure 6 shows the XRPD before and after dynamic water vapor sorption (DVS) for the SDD of Example 2. [Figure 7] Figure 7 shows the DVS isotherms for the SDD of Example 2. [Figure 8] Figure 8 shows the DSC thermogram for the SDD of Example 2. [Figure 9] Figure 9 shows the XRPD for the SDD of Example 3. [Figure 10] Figure 10 shows the DSC thermogram for the SDD of Example 3. [Figure 11] Figure 11 shows the XRPD for the SDD of Example 4. [Figure 12] Figure 12 shows the DSC thermogram for the SDD of Example 4. [Figure 13] Figure 13 shows the XRPD for the SDD of Example 5. [Figure 14] Figure 14 shows the XRPD for the SDD of Example 6. [Figure 15] Figure 15 shows the dissolution profile of SDD in Example 6. [Figure 16] Figure 16 shows the XRPD for the SDD of Example 7. [Figure 17] Figure 17 shows the XRPD for the SDD of Example 8. [Figure 18] Figure 18 shows the XRPD for the SDD of Example 9. [Figure 19] Figure 19 shows the XRPD for the SDD of Example 10. [Figure 20] Figure 20 shows the DSC thermogram for the SDD of Example 10. [Figure 21] Figure 21 shows the dissolution profile for SDD in Example 10. [Figure 22] Figure 22 shows the XRPD for the SDD of Example 11. [Figure 23] Figure 23 shows the DSC thermogram for the SDD of Example 11. [Figure 24] Figure 24 shows the dissolution profile for SDD in Example 11. [Figure 25] Figure 25 shows the XRPD for the SDD of Example 12. [Figure 26] Figure 26 shows the dissolution profile for SDD in Example 12. [Figure 27] Figure 27 shows the DSC thermogram for the SDD of Example 12. [Figure 28] Figure 28 shows the XRPD for the SDD of Example 13. [Figure 29] Figure 29 shows the DSC thermogram for the SDD of Example 13. [Figure 30] Figure 30 shows the dissolution profile for SDD in Example 13. [Figure 31] Figure 31 shows the XRPD of the SDD in Example 14. [Figure 32] Figure 32 shows the DSC thermogram for the SDD of Example 14. [Figure 33] Figure 33 shows the dissolution profile for SDD in Example 14. [Figure 34] Figure 34 shows the XRPD of the SDD in Example 15. [Figure 35] Figure 35 shows the DSC thermogram for the SDD of Example 15. [Figure 36] Figure 36 shows the dissolution profile for SDD in Example 15. [Figure 37] Figure 37 shows the XRPD of the freeze-dried dispersion of Example 18. [Figure 38] Figure 38 shows the DSC thermogram for the freeze-dried dispersion of Example 18. [Figure 39] Figure 39 shows the XRPD of the freeze-dried dispersion of Example 19. [Figure 40] Figure 40 shows the DSC thermogram for the freeze-dried dispersion of Example 19. [Figure 41] Figure 41 shows the XRPD of the freeze-dried dispersion of Example 20. [Figure 42] Figure 42 shows the DSC thermogram for the freeze-dried dispersion of Example 20. [Figure 43] Figure 43 shows the XRPD of the freeze-dried dispersion of Example 21. [Figure 44] Figure 44 shows the DSC thermogram for the freeze-dried dispersion of Example 21. [Figure 45] Figure 45 shows the XRPD of the freeze-dried dispersion of Example 22. [Figure 46] Figure 46 shows the DSC thermogram for the freeze-dried dispersion of Example 22. [Figure 47] Figure 47 shows the XRPD of the freeze-dried dispersion of Example 23. [Figure 48] Figure 48 shows the DSC thermogram for the freeze-dried dispersion of Example 23. [Figure 49] Figure 49 shows the XRPD diffraction patterns of the HBr pharmaceutical composition / formulation of Example 16 after storage for 1 month at T=0, T=25°C / 60%RH, and after storage for 1 month at T=2-8°C. [Figure 50] Figure 50 shows the XRPD diffraction patterns of the HCl pharmaceutical composition / formulation of Example 17 after storage for 1 month at T=0, T=25°C / 60%RH, and after storage for 1 month at T=2-8°C. [Figure 51] Figure 51 shows the XRPD diffraction patterns of the HBr pharmaceutical composition / formulation of Example 16 after storage for 2 months at T=0, T=25°C / 60%RH, and after storage for 2 months at T=2~8°C. [Figure 52] Figure 52 shows the XRPD diffraction patterns of the HCl pharmaceutical composition / formulation of Example 17 after storage for 2 months at T=0, T=25°C / 60%RH, and after storage for 2 months at T=2-8°C. [Figure 53]Figure 53 shows the particle size distribution of 5-MeO-DMT SDD as bulk material (red) and ExDevice (green). [Figure 54] Figure 54 shows the intranasal deposition profile for 5-MeO-DMT SDD delivered via an active intranasal delivery device. [Figure 55] Figure 55 shows the intranasal deposition profile for 5-MeO-DMT SDD delivered via a passive intranasal delivery device. [Figure 56] Figure 56 shows the solubility profiles of 5-MeO-DMT pharmaceutical compositions / formulations containing HPMC, isomalt, and methylcellulose. [Figure 57] Figure 57 shows the solubility profile of a 5-MeO-DMT pharmaceutical composition / formulation containing sorbitol and methylcellulose. [Examples]

[0216] Example 1: Spray drying of 5-MeO-DMT hydrobromide salt with HPMC 5-MeO-DMT hydrobromide and HPMC (Pharmacoat 606) were spray-dried in water to produce a 50% wt:wt API:excipient spray-dried dispersion (SDD). The spray-drying parameters were as follows:

[0217] [Table 1]

[0218] The generated SDD was amorphous, as indicated by powder X-ray diffraction (XRPD) analysis (Figure 4) and the absence of enthalpy of fusion when examined by differential scanning calorimetry (DSC) (Figure 5).

[0219] Example 2: Spray drying of 5-MeO-DMT oxalate salt with HPMC 5-MeO-DMT oxalate and HPMC (Pharmacoat 606) were spray-dried in water to produce 50% wt:wt API:excipient SDDs. The spray-drying parameters were as follows:

[0220] [Table 2]

[0221] The generated SDD was physically unstable amorphous SDD that underwent recrystallization at relative humidity levels above approximately 60%, as indicated by dynamic vapor deposition (DVS) analysis. XRPD analysis of the SDD before and after DVS is shown in Figure 6, where the SDD was amorphous before DVS and partially crystalline after DVS. DVS isotherms are shown in Figure 7, and DSC isotherms are shown in Figure 8.

[0222] Example 3: Spray drying of 5-MeO-DMT hydrobromide salt with PVP 5-MeO-DMT hydrobromide and polyvinylpyrrolidone (PVP) were spray-dried in water to produce 50% wt:wt API:excipient SDDs. The spray-drying parameters were as follows:

[0223] [Table 3]

[0224] The generated SDD was amorphous, as indicated by XRPD analysis (Figure 9) and the absence of enthalpy of fusion when examined by DSC (Figure 10). Example 4: Spray drying of 5-MeO-DMT benzoate salt with trehalose 5-MeO-DMT benzoate and trehalose were spray-dried in water to produce 50% wt:wt API:excipient SDD. The spray-drying parameters were as follows:

[0225] [Table 4]

[0226] The generated SDD was primarily amorphous as observed by XRPD (Figure 11), but the presence of partially crystalline material in XRPD and the enthalpy of fusion observed in DSC (Figure 12) suggests possible physical instability in the SDD.

[0227] Example 5: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture 5-MeO-DMT benzoate was spray-dried with a mixture of HPMC2910 in water to produce SDD with a 50% wt:wt API:excipient ratio. The spray-drying parameters were as follows:

[0228] [Table 5]

[0229] The method for preparing the supply solution was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC (Pharmacoat 606) and methose were added to the water while stirring and completely dissolved. Once dissolved, the required amount of API was transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray-dried.

[0230] The resulting SDD was partially crystalline (Figure 13), and furthermore, with 25% methose filling, the yield was considerably low. Example 6: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture 5-MeO-DMT benzoate was spray-dried with a mixture of HPMC2910 in water to produce SDD with a 50% wt:wt API:excipient ratio. The spray-drying parameters were as follows:

[0231] [Table 6]

[0232] The method for generating the feed solution was the same as described in Example 5. The SDD generated was partially crystalline (Figure 14), but surprisingly, the use of 12.5% total metrose filling resulted in a significant improvement in yield compared to the SDD purified in Example 5 (25% metrose).

[0233] The dissolution profile for the SDD generated can be seen in Figure 15, which shows that approximately 80% of the release occurred in about 4 minutes. Example 7: Spray Drying of 5-MeO-DMT Benzoate Salt with HPMCAS Hydroxypropylmethylcellulose acetate succinate (HPMCAS) M and 5-MeO-DMT benzoate were spray dried to generate an SDD with 50% wt:wt API:excipient. HPMCAS is produced in three substitution grades L, M, and H. The spray drying parameters were as follows.

[0234]

Table 7

[0235] The method for generating the feed solution was as follows. The required amount of acetone was weighed and placed in a 50 mL vial. The required amount of HPMC-AS was added to the acetone with stirring and completely dissolved. Once dissolved, the required amount of water was added to the solution, followed by the API, and then the vial was stirred until the API was dissolved. Once dissolved, the feed solution was immediately spray dried. <管理番号:

[0236] The SDD generated was in a stable state and was amorphous (Figure 16). Example 8: Spray Drying of 5-MeO-DMT Benzoate Salt with HPMCAS / Metrose 5-MeO-DMT benzoate with HPMCAS M and metrose 60SH50 in water was spray dried to generate an SDD with 50% wt:wt API:excipient. The spray drying parameters were as follows.

[0237] [Table 8]

[0238] The method for preparing the supply solution was as follows: The required amount of acetone was weighed and placed in a 50 mL vial. The required amount of HPMC-AS was added to the acetone while stirring and completely dissolved. Once dissolved, the required amount of water was added to the solution, followed by the HPMC, and the vial was stirred overnight until dissolved. Once dissolved, API was added and stirred, and once dissolved, the supply solution was immediately spray-dried.

[0239] The generated SDD was mainly amorphous (Figure 17), but there were some difficulties in spray drying the viscous solution containing HPMC-AS. Example 9: Spray drying of 5-MeO-DMT benzoate salt with HPMCAS / metholose 5-MeO-DMT benzoate was spray-dried with water-based HPMCAS M and metholose 60SH50 to produce SDD with a 50% wt:wt API:excipient ratio. The spray-drying parameters were as follows:

[0240] [Table 9]

[0241] The method for preparing the supply solution was as follows: The required amount of acetone was weighed and placed in a 50 mL vial. The required amount of HPMC-AS was added to the acetone while stirring and completely dissolved. Once dissolved, the required amount of water was added to the solution, followed by the HPMC, and the vial was stirred overnight until dissolved. Once dissolved, API was added and stirred, and once dissolved, the supply solution was immediately spray-dried.

[0242] The generated SDD was mainly amorphous (Figure 18), but there were some difficulties in spray drying the viscous solution containing HPMC-AS. Example 10: Spray Drying of 5-MeO-DMT Benzoate Salt with HPMC Mixture 5-MeO-DMT benzoate was spray dried with a mixture of HPMC 2910 in water to produce a 10% wt:wt API:excipient SDD. The spray drying parameters were as follows.

[0243] [Table 10]

[0244] The method of spray drying the feed solution was as follows. The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and methocel were added to the water with stirring and completely dissolved. Once dissolved, the required amount of API was transferred to the solution and dissolved. Once dissolved, the feed solution was immediately spray dried.

[0245] The SDD produced was stable and was amorphous by XRPD (Figure 19) and DSC (Figure 20). The dissolution profile of the SDD (Figure 21) showed that approximately 80% release occurred by about 10 minutes compared to about 4 minutes for the SDD of Example 6.

[0246] Example 11: Spray Drying of 5-MeO-DMT Benzoate Salt with HPMC Mixture 5-MeO-DMT benzoate was spray dried with a mixture of HPMC 2910 in water to produce a 30% wt:wt API:excipient SDD. The spray drying parameters were as follows.

[0247] [Table 11]

[0248] The method for spray-drying the supply solution was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amount of API was transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray-dried.

[0249] The generated SDD was stable and amorphous, as determined by XRPD (Figure 22) and DSC (Figure 23). The dissolution profile of the SDD (Figure 24) shows that approximately 80% release occurred by approximately 6.5 minutes, compared to approximately 4 minutes for the SDD of Example 6 and approximately 10 minutes for the SDD of Example 10.

[0250] Example 12: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture A mixture of HPMC2910 in water and a 5-MeO-DMT benzoate salt were spray-dried to produce SDD with a 50% wt:wt API:excipient ratio. The spray-drying parameters were as follows:

[0251] [Table 12]

[0252] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and methose were added to the water while stirring and completely dissolved. Once dissolved, the required amount of API was transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0253] The generated SDD was partially crystalline (Figure 25), but the dissolution profile (Figure 26) shows that approximately 80% release occurred by approximately 4.5 minutes, compared to approximately 4 minutes for the SDD of Example 6, approximately 10 minutes for the SDD of Example 10, and approximately 6.5 minutes for the SDD of Example 11.

[0254] The DSC thermogram for SDD (Figure 27) shows a small peak at approximately 140°C, indicating the presence of crystalline API. Such a peak is not observed in the corresponding HBr or HCl salt pharmaceutical composition or formulation.

[0255] Example 13: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture 5-MeO-DMT benzoate salts were spray-dried with a mixture of HPMC2910 and sorbitol in water to produce 10% wt:wt API:SDD of excipients. The spray-drying parameters were as follows:

[0256] [Table 13]

[0257] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amounts of API and sorbitol were transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0258] The generated SDD was stable and amorphous, as shown in Figures 28 and 29, and the yield was improved compared to that observed for the SDD of Example 12. The dissolution profile (Figure 30) shows that approximately 80% release occurred by approximately 10 minutes, compared to approximately 4 minutes for the SDD of Example 6, approximately 10 minutes for the SDD of Example 10, approximately 6.5 minutes for the SDD of Example 11, and approximately 4.5 minutes for the SDD of Example 12.

[0259] Example 14: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture 5-MeO-DMT benzoate salts were spray-dried with a mixture of HPMC2910 and sorbitol in water to produce 30% wt:wt API:SDD of excipients. The spray-drying parameters were as follows:

[0260] [Table 14]

[0261] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amounts of API and sorbitol were transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0262] The generated SDD was amorphous (Figure 31) and similar to that generated in Example 12, but the yield was significantly improved from 52% to 78%. The DSC thermogram is shown in Figure 32.

[0263] The dissolution profile shown in Figure 33 indicates that for the SDD of Example 14, approximately 80% release occurred within approximately 6 minutes, compared to approximately 4 minutes for the SDD of Example 6, approximately 10 minutes for the SDD of Example 10, approximately 6.5 minutes for the SDD of Example 11, approximately 4.5 minutes for the SDD of Example 12, and approximately 10 minutes for the SDD of Example 13.

[0264] By adding sorbitol, improved yields were obtained without affecting the dissolution rate or stability. Example 15: Spray drying of 5-MeO-DMT benzoate salt with HPMC mixture 5-MeO-DMT benzoate salts were spray-dried with a mixture of HPMC2910 and sorbitol in water to produce 50% wt:wt API:SDD of excipients. The spray-drying parameters were as follows:

[0265] [Table 15]

[0266] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amounts of API and sorbitol were transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0267] The generated SDD was partially crystalline (Figure 34), and the DSC thermogram and dissolution profile of this SDD can be seen in Figures 35 and 36. The dissolution profile shown in Figure 33 indicates that for the SDD of Example 15, approximately 80% release occurred within approximately 4 minutes, compared to approximately 4 minutes for the SDD of Example 6, approximately 10 minutes for the SDD of Example 10, approximately 6.5 minutes for the SDD of Example 11, approximately 4.5 minutes for the SDD of Example 12, approximately 10 minutes for the SDD of Example 13, and approximately 6 minutes for the SDD of Example 14.

[0268] Example 16: Spray drying of 5-MeO-DMT hydrobromide salt with HPMC mixture 5-MeO-DMT hydrobromide salts were spray-dried with a mixture of HPMC2910 and sorbitol in water to produce SDDs of 50% wt:wt API:excipient. The spray-drying parameters were as follows:

[0269] [Table 16]

[0270] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amounts of API and sorbitol were transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0271] Unlike Example 15, the generated SDD was stable and amorphous, and its dissolution profile was similar to that of Example 15. In addition, the yield of this SDD was higher than that of the SDD in Example 15.

[0272] Example 17: Spray drying of 5-MeO-DMT hydrochloride salt with HPMC mixture 5-MeO-DMT hydrochloride salts were spray-dried with a mixture of HPMC2910 and sorbitol in water to produce 50% wt:wt API:SDD of excipients. The spray-drying parameters were as follows:

[0273] [Table 17]

[0274] The spray drying method was as follows: The required amount of water was weighed and placed in a 50 mL vial. The required amounts of HPMC and metholose were added to the water while stirring and completely dissolved. Once dissolved, the required amounts of API and sorbitol were transferred to the solution and dissolved. Once dissolved, the supply solution was immediately spray dried.

[0275] Unlike the SDD produced in Example 15, the generated SDD was stable and amorphous. The dissolution profile was similar to that of the SDD in Example 15. Example 18: Freeze-drying of HBr salt with PVP Hydrobromide salts with PVP in water are freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0276] [Table 18]

[0277] This demonstrates that HBr in a 50% PVP mixture produces an amorphous lyophilized product. Figure 37 shows the XRPD of the lyophilized dispersion of Example 18. Figure 38 shows the DSC thermogram of the lyophilized dispersion of Example 18.

[0278] Example 19: Freeze-drying of HBr salt with lactose monohydrate The hydrobromide salt with lactose monohydrate in water is freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0279] [Table 19]

[0280] This demonstrates that HBr in a 50% packing of lactose monohydrate produces an amorphous lyophilized product. Figure 39 shows the XRPD of the lyophilized dispersion of Example 19. Figure 40 shows the DSC thermogram of the lyophilized dispersion of Example 19.

[0281] Example 20: Freeze-drying of HBr salt with trehalose Hydrobromide salts with trehalose in water are freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0282] [Table 20]

[0283] This demonstrates that HBr in trehalose at 50% packing produces an amorphous lyophilized product. Figure 41 shows the XRPD of the lyophilized dispersion of Example 20. Figure 42 shows the DSC thermogram of the lyophilized dispersion of Example 20.

[0284] Example 21: Freeze-drying of oxalate salt with trehalose The oxalate salt with trehalose in water is freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0285] [Table 21]

[0286] This demonstrates that oxalates packed at 50% in trehalose produce amorphous lyophilized products. Figure 43 shows the XRPD of the lyophilized dispersion of Example 21. Figure 44 shows the DSC thermogram of the lyophilized dispersion of Example 21.

[0287] Example 22: Freeze-drying of HBr salt with mannitol and trehalose The HBr salt with mannitol / trehalose in water is freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0288] [Table 22]

[0289] This demonstrates that HBr in a 50% mannitol / trehalose packing does not produce an amorphous lyophilized product. Figure 45 shows the XRPD of the lyophilized dispersion of Example 22. Figure 46 shows the DSC thermogram of the lyophilized dispersion of Example 22.

[0290] Example 23: Freeze-drying of mannitol and trehalose in HBr salts The HBr salt with mannitol / trehalose in water is freeze-dried to produce a 50% wt:wt API freeze-dried dispersion.

[0291] [Table 23]

[0292] This demonstrates that HBr in a 50% mannitol / trehalose packing does not produce amorphous lyophilized products. Figure 47 shows the XRPD of the lyophilized dispersion of Example 23. Figure 48 shows the DSC thermogram of the lyophilized dispersion of Example 23.

[0293] Example 24: Stable amorphous pharmaceutical composition or formulation of 5-MeO-DMT HBr and HCl The pharmaceutical compositions or formulations of 5-MeO-DMT HBr and HCl described in Examples 16 and 17 were stored for one month at (i) 25°C / 60%RH or (ii) 2–8°C. The pharmaceutical compositions or formulations contained 50% by weight of 5-MeO-DMT HBr or HCl, HPMC606:Metholose 60SH50 in a 3:1 ratio, and 3% sorbitol.

[0294] The 5-MeO-DMT HBr pharmaceutical composition / formulation remained amorphous after being stored for one month at (i) 25°C / 60%RH or (ii) 2–8°C. Figure 49 shows the XRPD diffraction patterns for the HBr pharmaceutical composition / formulation of Example 16 at T=0, after one month of storage at T=25°C / 60%RH, and after one month of storage at T=2–8°C. The XRPD showed that the pharmaceutical composition / formulation remained amorphous. Analysis by TGA, mDSC, HPLC, and scanning electron microscopy (SEM) imaging further confirmed that the pharmaceutical composition / formulation remained amorphous.

[0295] The pharmaceutical compositions / formulations of 5-MeO-DMT HCl remained amorphous after being stored for one month at (i) 25°C / 60%RH or (ii) 2–8°C. Figure 50 shows the XRPD diffraction patterns for the HCl pharmaceutical composition / formulation of Example 17 at T=0, after one month of storage at T=25°C / 60%RH, and after one month of storage at T=2–8°C. The XRPD showed that the pharmaceutical composition / formulation remained amorphous. Analysis by TGA, mDSC, HPLC, and scanning electron microscopy (SEM) imaging further confirmed that the pharmaceutical composition / formulation remained amorphous. Thus, in one embodiment, a state-stable amorphous pharmaceutical composition / formulation of 5-MeO-DMT containing 5-MeO-DMT HBr or 5-MeO-DMT HCl is provided that is suitable for storage at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months at at least 25°C / 60%RH.

[0296] In one embodiment, a stable amorphous pharmaceutical composition / formulation of 5-MeO-DMT is provided. In one embodiment, a state-stable amorphous pharmaceutical composition / formulation of 5-MeO-DMT is provided. In one embodiment, a stable amorphous pharmaceutical composition / formulation of 5-MeO-DMT is provided that is suitable for storage at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 24 months at at least 25°C / 60%RH. In one embodiment, an amorphous 5-MeO-DMT HBr formulation is provided. In one embodiment, a method for producing a stable amorphous pharmaceutical composition / formulation of 5-MeO-DMT as described herein is provided. In one embodiment, a method for producing a state-stable pharmaceutical composition / formulation of 5-MeO-DMT as described herein is provided.

[0297] Example 25: Method for determining the dissolution rate The dissolution rate of SDD was determined using a method that included the use of a UV fiber optics-based dissolution apparatus (one such suitable device being the Rainbow® Dynamic Dissolution Monitor by Pion Inc.) and a simulated intranasal fluid. The simulated intranasal fluid contained 7.45 g / L of NaCl, 1.29 g / L of KCl, 0.32 g / L of CaCl2 × 2H2O, and deionized water.

[0298] The dissolution apparatus was set up using a 2 mm probe to measure the dissolution rate. 10 mg of SDD (5 mg of API) was transferred to 5 mL of simulated intranasal fluid, heated to a constant temperature of 37°C, and stirred at 150 RPM using a cross-shaped stirring rod. Measurements were taken 130 times at 3-second intervals, then 60 times at 10-second intervals, for a total time of 16 minutes and 30 seconds. Dissolution was detected by UV absorbance.

[0299] In one embodiment, a method for determining the dissolution rate of SDD is provided. In one embodiment, the SDD is 5-MeO-DMT SDD. In one embodiment, the 5-MeO-DMT SDD may be one of those described earlier or later in this specification.

[0300] In one embodiment, probes of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 mm can be used. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of SDD can be used. In one embodiment, 1 to 100 mg of SDD can be used. In one embodiment, 1 to 100 mL of simulated intranasal fluid is used. In one embodiment, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mL of intranasal fluid is used. In one embodiment, the constant temperature used is 37°C ± 1, 2, 3, 4, or 5°C. In one embodiment, the solution is stirred at 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 RPM. In another embodiment, the solution is stirred at 50 to 200 RPM. In one embodiment, the measurement is taken 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 times at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds, and then the measurement is taken 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 times at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 seconds.

[0301] Example 26: Method for determining crystalline content A method for determining the crystalline content of hallucinogenic drug compositions or formulations has been developed. Differential scanning calorimetry (DSC) is a thermal analysis method in which the difference in the amount of heat required to increase the temperature of a sample and a reference is measured as a function of temperature. Both the sample and the reference are maintained at approximately the same temperature throughout the experiment. Differential scanning calorimetry can be used to measure some of the characteristic properties of a sample. Using this technique, it is possible to observe melting and crystallization events as well as the glass transition temperature (Tg).

[0302] The inventors have discovered that a heating rate of 10°C / min is unsuitable for determining the crystalline content in hallucinogenic pharmaceutical compositions or formulations. The enthalpy obtained from the melting of crystalline 5-MeO-DMT in the pharmaceutical composition / formulation decreased as the heating rate increased, indicating that a DSC heating rate of 10°C / min is unsuitable.

[0303] Surprisingly, heating rates exceeding 10°C / min are required to evaluate the crystalline content of hallucinogenic pharmaceutical compositions or formulations. It has been found that the optimal heating rates are 100-200°C / min, 110-190°C / min, 120-180°C / min, 130-170°C / min, or 140-160°C / min. In one embodiment, the optimal heating rate for DSC determination of the crystalline content of a hallucinogenic pharmaceutical composition / formulation is 150°C / min. In one embodiment, a method for determining the crystalline content of a 5-MeO-DMT pharmaceutical composition / formulation by DSC at 150°C / min is provided. In one embodiment, a method for determining the crystalline content of a spray-dried 5-MeO-DMT pharmaceutical composition / formulation by DSC at 150°C / min is provided.

[0304] Example 27: Further stability testing of amorphous pharmaceutical compositions or formulations of 5-MeO-DMT HBr and HCl The pharmaceutical compositions or formulations of 5-MeO-DMT HBr and HCl described in Examples 16 and 17 were stored for 2 months at (i) 25°C / 60%RH or (ii) 2–8°C. The pharmaceutical compositions or formulations contained 50% by weight of 5-MeO-DMT HBr or HCl, HPMC606:Metholose 60SH50 in a 3:1 ratio, and 3% sorbitol.

[0305] The 5-MeO-DMT HBr pharmaceutical composition / formulation remained amorphous after being stored for two months at (i) 25°C / 60%RH or (ii) 2–8°C. Figure 51 shows the XRPD diffraction patterns for the HBr pharmaceutical composition / formulation of Example 16 at T=0, after two months of storage at T=25°C / 60%RH, and after two months of storage at T=2–8°C. The XRPD showed that the pharmaceutical composition / formulation remained amorphous. Analysis by TGA, mDSC, HPLC, and scanning electron microscopy (SEM) imaging further confirmed that the pharmaceutical composition / formulation remained amorphous.

[0306] The 5-MeO-DMT HCl pharmaceutical composition / formulation remained amorphous after being stored for two months at (i) 25°C / 60%RH or (ii) 2–8°C. Figure 52 shows the XRPD diffraction patterns for the HCl pharmaceutical composition / formulation of Example 17 at T=0, after two months of storage at T=25°C / 60%RH, and after two months of storage at T=2–8°C. The XRPD showed that the pharmaceutical composition / formulation remained amorphous. Analysis by TGA, mDSC, HPLC, and scanning electron microscopy (SEM) imaging further confirmed that the pharmaceutical composition / formulation remained amorphous.

[0307] At T=3 months and T=6 months, the above pharmaceutical compositions / formulations remained amorphous. Example 28: Analysis of intranasal deposition profiles The nasal cavity is recognized as a promising systemic drug delivery route due to its highly vascularized capillary bed within the nasal mucosa. Therefore, there is a need for a pharmaceutical composition or formulation having an optimized particle size distribution that exhibits turbinate deposition, or for the pharmaceutical compositions or formulations described herein. There is also a need for a delivery device capable of selectively delivering the pharmaceutical compositions / formulations described herein to the turbinates. material 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) benzoate (as described in Example 15) was supplied by Beckley Psytech, along with hydroxypropyl methylcellulose (HPMC) ((Pharmacoat 606 - substitution degree 2910, viscosity 6 cP) Shin-Etsu Chemical Co., Ltd., Japan), HPLC-grade 99% ethanol, HPLC-grade 99% methanol, HPLC-grade water, glycerol, and Brij-35 (Fisher Scientific, United Kingdom). Ultrapure water 18.2 MΩ (Veolia Elga LabWater system, in-house), active device (UDSp, Aptar Pharma, France). Preparation of 5-MeO-DMT spray-dried dispersion (5-MeO-DMT SDD) The feed solution was prepared with 50% w / w 5-MeO-DMT benzoate (32.1% 5-MeO-DMT). Both polymers were dissolved in water overnight under ambient temperature stirring. D-sorbitol and 5-MeO-DMT benzoate were added to the solution and dissolved under ambient temperature stirring to produce a clear, pale yellow solution. The feed solution was spray-dried using a ProCepT4M8-Trix spray dryer fitted with a 25 kHz ultrasonic nozzle (ProCepT, Belgium) according to the spray drying parameters summarized in the table below. The pharmaceutical composition / formulation was loaded into a UDSp device at a fill weight of 37.4 ± 1.9 mg under low humidity and incorporated when required for analysis. Target spray drying parameters for 5-MeO-DMT supply solution

[0308] [Table 24]

[0309] Particle size analysis by laser diffraction The particle size distribution (PSD) was determined by repeating the analysis three times using a Sympatec HELOS H4459 particle size distribution analyzer (Sympatec GmbH, Germany) equipped with an R5 lens. The bulk powder was analyzed at a dispersion pressure of 3 bar using a RODOS dry powder dispersion analyzer, and the powder from the active device (ExDevice) was manually introduced into the laser diffractometer with the device tip positioned 3 cm from the midpoint of the laser. Methodology - Overview The Alberta Idealized Nasal Inlet (AINI) and the Stage 1 collection cup of the Next Generation Impactor (NGI) were coated with a solution containing 12 g of Brij-35, 20 g of glycerol, and 80 mL of ethanol. Once dry, the AINI and NGI were assembled by adding a pre-separator with 15 mL of 50:50 (v / v) methanol:water diluent in the reservoir. A UDSp filled with 37.4 mg of pharmaceutical composition / formulation was positioned at 30, 45, or 60° to the horizontal and inserted 1 cm into the nasal orifice of the AINI. When the UDSp was activated, an airflow of 7.5 L / min was applied for 15 seconds, delivering 1.875 L of air. After activation, the components were disassembled, and a second dilution was added using 15 mL of diluent to dissolve the material adhering to the outside of the UDSp and accumulated in the AINI and NGI collection cups. The analysis was repeated three times and analyzed using two-way ANOVA statistical analysis via HPLC. Methodology - Details Intranasal deposition using the Aptar single-dose powder nasal spray system (UDSp) was measured using the Alberta idealized nasal inlet (AINI) in combination with the Copley next-generation impactor (NGI). A) Coating of AINI and NGI collection cups A coating solution was prepared by mixing 12 g of Brij-35, 20 g of glycerol, and 80 mL of ethanol until dissolved. The bottom of the AINI was sealed, and 20 mL of the coating solution was added from the vestibule while the AINI was inverted. The AINI was slowly rotated 360° clockwise and counterclockwise horizontally, and then 360° clockwise and counterclockwise vertically. Excess coating solution was drained, and the AINI was left for 15 minutes with its left, back, and right sides touching the ground. The AINI was left upright for 30 minutes to drain any further excess coating solution and allow the coating to dry.

[0310] 2 mL of coating solution was pipetteed into an NGI Stage 1 collection cup and coated by agitating for 5 minutes using an NGI shaker. Excess solution was drained and the cup was dried. B) NGI Assembly The NGI was assembled with a coated Stage 1 collection cup and uncoated collection cups and micro-orifice collectors for Stages 2-7. A pre-separator and throat piece were attached, and leak tests were performed using a critical flow controller and a large-capacity pump. A flow meter was attached to the throat piece and the flow rate was set to 7.5 L / min.

[0311] The throat piece was removed, and 15 mL of 50:50% v / v HPLC-grade water:HPLC-grade methanol (diluent) was added to the pre-separator insertion cup. Then, AINI was introduced into the pre-separator. C) actuation The UDSp containing 5-MeO-DMT was weighed to obtain its pre-operation mass. The UDSp was then clamped in place so that its tip was inserted 1 cm into the vestibule of the AINI. An electronic protractor was used to set the insertion angle. The UDSp was operated for 15 seconds at a flow rate of 7.5 L / min. D) HPLC sample recovery Next, the UDSp was removed and weighed to obtain the post-operation mass. The outside of the UDSp was washed with 15 mL of diluent in a glass dish, and the washing solution was collected for HPLC analysis.

[0312] The AINI was disassembled, and each component was thoroughly washed in a separate glass dish with 15 mL of diluent. These washing solutions were then collected for HPLC analysis. The pre-separator was removed from the NGI, then the top and bottom were covered, and the pre-separator was inverted to wash the inside with 15 mL of pre-added diluent. These washes were then collected for HPLC analysis.

[0313] 15 mL of diluent was added to the Stage 1 collection cup, and the cup was washed by agitating it for 10 minutes using an NGI shaker. These washes were then collected for HPLC analysis. E) HPLC HPLC was performed on the sample to quantify the 5-MeO-DMT content. If necessary, the sample was diluted to remain within the linearity of the quantification method.

[0314] In one embodiment, the use of the above method or a similar method in a method for analyzing the intranasal deposition of one or more pharmaceutical compositions or formulations described herein is provided. In one embodiment, the use of the above method or a similar method in a method for analyzing the intranasal deposition of one or more 5-MeO-DMT pharmaceutical compositions or formulations described herein is provided. In one embodiment, the use of the above method or a similar method in a method for analyzing the intranasal deposition of one or more hallucinogenic dry powder pharmaceutical compositions or formulations or pharmaceutical compositions or formulations is provided. In one embodiment, the use of the above method or a similar method in a method for analyzing the intranasal deposition of hallucinogenic dry powder formulations is provided. In one embodiment, the use of the above coating or a similar substance in a method for analyzing the intranasal deposition of hallucinogenic pharmaceutical compositions / formulations is provided. In one embodiment, the use of the above coating or a similar substance in a method for analyzing the intranasal deposition of hallucinogenic dry powder formulations is provided. In one embodiment, the use of the above coating or a similar substance in a method for analyzing the intranasal deposition of one or more hallucinogenic dry powder pharmaceutical compositions or formulations or pharmaceutical compositions or formulations is provided. result Pharmacopoeia guidelines state that intranasal powders should demonstrate that product deposition is localized within the nasal cavity, and current methods require that most particles be greater than 10 μm, as determined by laser diffraction. Analysis of 5-MeO-DMT SDD using Sympatec revealed the particle size distribution, as shown in Figure 53. Using an ultrasonic nozzle, an optimized intranasal powder was obtained that was close to the recommended particle size while minimizing particles with an average particle size of less than 10 μm, and that met the acceptance criteria required by the EMA.

[0315] Using AINI, the deposition profiles of 5-MeO-DMT SDD pharmaceutical compositions / formulations were evaluated by the method outlined above. AINI consists of four components related to the nasal cavity: the vestibule (nostrils), turbinates, olfactory organs, and nasopharynx, which are assembled and attached to a pre-separator. The pre-separator is incorporated to capture any deposits that deviate to Stage 1 due to particle bounce off the inner surface of AINI. Minimal deposition was observed in the vestibule compared to commercially available nasal sprays. Minimal deposition was also observed in the lung analogue. The majority of the pharmaceutical compositions / formulations were found in the turbinates, and the olfactory organ region showed 5–11% deposition, which is advantageous as it is theoretically assumed that a minimum of 0.01–1% of the oral dose is effective for absorption from the nose to the brain. The AINI results can be seen in Figure 54.

[0316] Therefore, a favorable method for the delivery of 5-MeO-DMT SDD is provided. The 5-MeO-DMT SDD (as in Example 15) was filled into a passive intranasal delivery device with a load suitable for delivering 12 mg of 5MeO-DMT free base equivalent. The passive device was placed in an adapter and delivered 1 L or 2 L of air, respectively, by drawing air through the AINI / NGI at a flow rate of 30 L / min. The resulting intranasal deposition profile can be seen in Figure 55. It can be easily seen that very little drug product was deposited at the desired locations in the nasal turbinates and olfactory organ regions.

[0317] Accordingly, a method is provided for the delivery of 5-MeO-DMT SDD, wherein the SDD is delivered by an active intranasal delivery device. In one embodiment, a use is provided for the use of the pharmaceutical composition / formulation described herein in a method of treating a patient in need thereof, wherein the pharmaceutical composition / formulation is administered intranasally via an active intranasal delivery device as described herein, and more than 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the pharmaceutical composition / formulation is deposited in the turbinates and / or olfactory organ regions of the nasal cavity.

[0318] In one embodiment, a method for treating a patient in need is a method for treating one or more of the conditions or diseases described herein. In one embodiment, a use of the pharmaceutical composition / formulation described herein in a method for treating a patient in need is provided, wherein the pharmaceutical composition / formulation is administered intranasally via an active delivery intranasal device, and less than 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, or 1% is deposited in the lungs.

[0319] In one embodiment, an intranasal delivery device is provided for delivering a pharmaceutical composition / formulation described herein to the olfactory organ region of the nasal cavity, the intranasal delivery device comprising the pharmaceutical composition / formulation described herein. In one embodiment, the device is an active intranasal delivery device in which a plunger-type actuator or similar is pressed to administer a dose. In one embodiment, the intranasal delivery device is not a respiratory-operated delivery device. In one embodiment, the device is up to 140 mm 3 The dosage includes the following. In one embodiment, the intranasal delivery device may be such as those described in any one of WO21005308, WO22123128, WO22171969, and WO22208014 (the contents of which are incorporated by reference).

[0320] In one embodiment, a dispenser device for dispensing a pharmaceutical composition / formulation as described herein, optionally, wherein the dispenser device comprises the pharmaceutical composition / formulation as described herein, a dispenser outlet (10), and an air exhauster (20) for generating an airflow while the device is operating, wherein the air exhauster (20) includes a piston (21) that slides between a stop position and a dispensing position within an air chamber (22), and the air chamber (22) is located inside the piston (21). An air discharger comprising a cylindrical body (222) that slides airtightly in a section, and at least one reservoir (30) containing a single-dose formulation, wherein the reservoir (30) comprises an air inlet (31) connected to the air discharger (20) and a pharmaceutical composition / formulation outlet (32) connected to the dispenser outlet (10), the air inlet (31) comprises a pharmaceutical composition / formulation holder member (40) for holding the pharmaceutical composition / formulation in the reservoir (30) until the pharmaceutical composition / formulation is dispensed, and the pharmaceutical composition / formulation outlet (32) is connected to the reservoir - The device comprises at least one reservoir which is closed by a closing element (50) which is pressed into the pharmaceutical composition / formulation outlet (32) of (30), and the device further comprises a mechanical opening system (61, 62) which cooperates with the closing element (50) to mechanically discharge the closing element from the closed position while the device is in operation, the mechanical opening system comprising a rod assembly (61, 62), i.e., a first rod portion (61) which is part of the air discharger (20) and slides within the air chamber (22) while the device is in operation and The rod assembly (61, 62) includes a second rod portion (62) that is pushed in by a first rod portion (61), and the rod assembly (61, 62) cooperates with the closing element (50) at the end of the operating stroke to mechanically discharge the closing element from its closed position, the piston (21) of the air discharger (20) cooperates non-airtightly with the air chamber (22) such that the air chamber (22) is in communication with the atmosphere when the piston (21) is in its stopped position, and the piston (21) slides airtightly on the cylindrical surface (614) during the operation of the device.A dispenser device is provided, which includes an inner lip (215) that non-airtightly cooperates with a fluting (615) formed on the cylindrical surface (614) at the stopping position to bring the air chamber (22) into communication with the atmosphere at the stopping position, wherein the piston (21) cooperates airtightly with the cylindrical body (222) at any position and non-airtightly with the cylindrical surface (614) only at the stopping position.

[0321] In one embodiment, a dispenser device for dispensing a pharmaceutical composition / formulation as described herein, wherein the dispenser device comprises a pharmaceutical composition / formulation as described herein, a dispenser outlet, an air vent for generating an airflow while the device is operating, the air vent comprising a piston sliding between a stop position and a dispensing position within an air chamber, the air chamber comprising a cylindrical body in which the piston slides airtightly, and at least one reservoir containing a single-dose formulation, the reservoir comprising an air inlet connected to the air vent and a pharmaceutical composition / formulation outlet connected to the dispenser outlet, the air inlet from which the pharmaceutical composition / formulation is dispensed. A dispenser device is provided, comprising a pharmaceutical composition / formulation retainer member for holding a pharmaceutical composition / formulation in the reservoir, the pharmaceutical composition / formulation outlet of which is closed by a closure element pressed into the pharmaceutical composition / formulation outlet of the reservoir, the device further comprising a mechanical opening system which cooperates with the closure element to mechanically discharge the closure element from a closed position while the device is operating, the piston of the air discharger cooperates non-airtightly with the air chamber such that the air chamber is in communication with the atmosphere when in a stopped position, the piston includes an inner lip configured to cooperate with a cylindrical surface of a cylindrical member extending into the interior of a cylindrical body, the cylindrical surface includes fluting which cooperates non-airtightly with the inner lip of the piston when in a stopped position.

[0322] A method for nasal delivery to a patient of a powder pharmaceutical composition / formulation comprising a hallucinogen and one or more pharmaceutically acceptable carriers or excipients, 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 pharmaceutical composition / formulation reaches the nasal turbinates and olfactory organ regions, the hallucinogen is 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition / formulation is delivered via an intranasal powder dispenser device which may include an intranasal dispenser head for insertion into the patient's nostrils, including a dispenser orifice, and one or more air exhausters that generate a flow of compressed air to dispense a dose of the powder pharmaceutical composition / formulation into the nostrils via the dispenser orifice during operation of the intranasal powder dispenser device.

[0323] In one embodiment, a transnasal delivery system optionally comprising an active intranasal delivery device as described herein, comprising a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an active intranasal delivery device as described herein, optionally configured to deliver the particles to the turbinates and olfactory organ regions of the target nasal cavity in a single action, wherein the system has a plume geometric shape with an angle of 20 to 45 degrees and a width of 25 to 55 mm.

[0324] [Table 25]

[0325] spray pattern, D10 = 13-17, D50 = 35-60, D90 = 650-700, % < 10 μm = < 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% Particle size distribution (at 40mm), or D10 = 13-17, D50 = 24-30, D90 = 540-610, % < 10 μm = < 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% Particle size distribution (at 70mm), or D10=13~17, D50=22~27, D90=35~56,%<9μm=<0.1~10% Particle size distribution, or 0.5-5% % of particles with a size of 11.7 μm or less Configured to operate to release a powder plume containing one or more of the following: 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. A transnasal delivery system is provided.

[0326] In one embodiment, a transnasal delivery system optionally comprising an active intranasal delivery device as described herein, comprising a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an active intranasal delivery device as described herein, optionally configured to deliver the particles to the turbinates and olfactory organ regions of the target nasal cavity in a single action, wherein the system has a plume geometric shape with an angle of 20 to 45 degrees and a width of 25 to 55 mm.

[0327] [Table 26]

[0328] spray pattern, D10=13~17, D50=35~60, D90=650~700, %<10μm=<0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% particle size distribution (at 40mm), or D10=13~17, D50=24~30, D90=540~610, %<10μm=<0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% particle size distribution (at 70mm), or 0.5-5% of particles with a size of 11.7 μm or less Configured to operate to release a powder plume containing one or more of the following: 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. A transnasal delivery system is provided.

[0329] In one embodiment, a transnasal delivery system optionally comprising an active intranasal delivery device as described herein, comprising a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an active intranasal delivery device as described herein, optionally configured to deliver the particles to the turbinates and olfactory organ regions of the target nasal cavity in a single action, wherein the system has a plume geometric shape with an angle of 20 to 35 degrees and a width of 25 to 45 mm.

[0330] [Table 27]

[0331] spray pattern, D10 = 13-17, D50 = 22-27, D90 = 35-56, % < 9 μm = < 0.1-10% particle size distribution, or 0.5-5% of particles with a size of 11.7 μm or less. Configured to operate to release a powder plume containing one or more of the following: 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. A transnasal delivery system is provided.

[0332] In one embodiment, a transnasal delivery system optionally comprising an active intranasal delivery device as described herein, comprising a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an optional active intranasal delivery device as described herein configured to deliver the particles to the turbinates and olfactory organ region of the target nasal cavity in a single action, wherein the system has a plume geometric shape with an angle of 27-40 degrees and a width of 33-50 mm.

[0333] [Table 28]

[0334] spray pattern, D10=15 or 16, D50=38 or 54, D90=684 or 685, %<10μm=<0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% particle size distribution (at 40mm), or D10=15 or 16, D50=27 or 28, D90=558 or 596, %<10μm=<0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% particle size distribution (at 70mm), or D10=13~17, D50=22~27, D90=35~56, %<9μm=<0.1~10% particle size distribution, or 0.5~5% of particles with a size of 11.7μm or less Configured to operate to release a powder plume containing one or more of the following: 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. A transnasal delivery system is provided.

[0335] In one embodiment, the powder plume of 5-MeO-DMT or a pharmaceutically acceptable salt thereof has a plume geometry of an angle of 22-35 degrees and a width of 27-55 mm, or an angle of 22-33 degrees and a width of 27-42 mm, or an angle of 25-30 degrees and a width of 29-39 mm, or an angle of 26-28 degrees and a width of 32-35 mm, or an angle of 27.5 degrees. Plume geometric shapes with a width of 34.33 mm, or an angle of 24.4 degrees, a width of 30.30 mm, or an angle of 24.8 degrees, a width of 30.76 mm, or an angle of 27.4 degrees, a width of 34.13 mm, or an angle of 30.5 degrees, a width of 38.29 mm, or an angle of 39.2 degrees, a width of 50.35 mm, or an angle of 33.43 Plume geometric shapes with angles of 28 degrees and a width of 52.25 mm, or plume geometric shapes with angles of 28 degrees and a width of 34 mm, or plume geometric shapes with angles of 24 degrees and a width of 30 mm, or plume geometric shapes with angles of 425-43525 degrees and a width of 31 mm, or plume geometric shapes with angles of 27 degrees and a width of 34 mm, or plume geometric shapes with angles of 31 degrees and a width of 38 mm, or angles of 20, 21, 22, 23, 24, 25, 26, 27, It has a plume geometric shape with an angle of 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 or 46 degrees and a width of 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 or 56 mm.

[0336] In one embodiment, a powdered plume of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is

[0337] [Table 29]

[0338] or

[0339] [Table 30]

[0340] It has a spray pattern. In one embodiment, a powdered plume of 5-MeO-DMT or a pharmaceutically acceptable salt thereof is

[0341] [Table 31]

[0342] or

[0343] [Table 32]

[0344] or

[0345] [Table 33]

[0346] or

[0347] [Table 34]

[0348] It has a spray pattern. In one 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 μm = 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, %<10μm=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, %<9μm=<0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%.

[0349] In one embodiment, the percentage of particles with a size of 11.7 μm or less in the powder plume containing 5-MeO-DMT or a pharmaceutically acceptable salt thereof is 0.5-5%, 0.6-4%, 0.7-3%, 0.8-2%, and 0.9-1%. In one embodiment, active intranasal delivery has an activating force between 30 and 60 N. In one embodiment, the activating force is between 40 and 50 N. In one embodiment, the activating force is 41, 42, 43, 44, 45, 46, 47, 48, or 49 N. In one 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 80 N. In one embodiment, the actuation force is 36 N. In one embodiment, the actuation force is 37 N. In one embodiment, the actuation force is 38 N. In one embodiment, the actuation force is 39 N. In one embodiment, the operating force is 36N.

[0350] In some embodiments, a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof comprises the crystalline form of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as described herein. In some embodiments, a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof has a moisture content of <5%, <4%, <3%, <2%, or <1%. In some embodiments, 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 one embodiment, a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof has hydroxyl impurities in amounts of <5% by weight, <4% by weight, <3% by weight, <2% by weight, <1% by weight, <0.9% by weight, <0.8% by weight, <0.7% by weight, <0.6% by weight, <0.5% by weight, <0.4% by weight, <0.3% by weight, <0.2% by weight, <0.1% by weight, <0.09% by weight, <0.08% by weight, <0.07% by weight, <0.06% by weight, <0.05% by weight, <0.04% by weight, <0.03% by weight, <0.02% by weight, or <0.01% by weight.

[0351] In one embodiment, a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof contains any one impurity in amounts of <5% by weight, <4% by weight, <3% by weight, <2% by weight, <1% by weight, <0.9% by weight, <0.8% by weight, <0.7% by weight, <0.6% by weight, <0.5% by weight, <0.4% by weight, <0.3% by weight, <0.2% by weight, <0.1% by weight, <0.09% by weight, <0.08% by weight, <0.07% by weight, <0.06% by weight, <0.05% by weight, <0.04% by weight, <0.03% by weight, <0.02% by weight, or <0.01% by weight. In one embodiment, a dry powder pharmaceutical composition / formulation comprising multiple powder particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof has any impurities in amounts of <5% by weight, <4% by weight, <3% by weight, <2% by weight, <1% by weight, <0.9% by weight, <0.8% by weight, <0.7% by weight, <0.6% by weight, <0.5% by weight, <0.4% by weight, <0.3% by weight, <0.2% by weight, <0.1% by weight, <0.09% by weight, <0.08% by weight, <0.07% by weight, <0.06% by weight, <0.05% by weight, <0.04% by weight, <0.03% by weight, <0.02% by weight, or <0.01% by weight.

[0352] In one embodiment, the impurity profile is determined by RP-HPLC. In another embodiment, the percentage of particles with a size of 11.7 μm or less in the powder plume is determined by a next-generation impactor and HPLC. In another embodiment, the moisture content is determined by Karl Fischer coulometric titration. In yet another embodiment, the plume geometry is analyzed using a Proveris SprayVIEW instrument (or equivalent) in conjunction with a Proveris automated device. In yet another embodiment, the analysis is performed at a distance of 7.0 cm. In one 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 direction: 0deg, pallet: gradient, arm 1 / arm 2 (%): 20~30%, discharge time (ms): 1000, setting time (ms): 1000.

[0353] In one embodiment, the spray pattern is determined using a Proveris SprayVIEW device (or equivalent) in conjunction with a Proveris automated device. In one embodiment, the analysis is performed at two distances (4.0 cm and 7.0 cm). In one embodiment, the settings for the 7.0 cm distance are as described above, and for the 4.0 cm distance (wherein different from the settings used for 7.0 cm), the settings are as follows: orifice tip distance (cm): 4.0, camera position from horizontal (cm): 8.0, and camera height (cm): 22.

[0354] In one embodiment, the particle size distribution is determined by laser diffraction using a Malvern Mastersizer (or equivalent). In one embodiment, the settings are as follows: Instrument: Malvern Mastersizer 3000 (or equivalent) with Malvern software, Sampling and handling device: HydroMV dispersion device, Material refractive index: 1.590, Absorption refractive index: 0.001, Dispersant refractive index: 1.391 (2,2,4-trimethylpentane), Obscuration limit: 10-20%, Sonication time: External sonication for 120 seconds during sample preparation before addition to HydroMV, Stirrer speed: 3000 rpm, Measurement time: 30 seconds, Background time: 30 seconds, Dispersant: Degassed and equilibrated to ambient temperature 2,2,4-trimethylpentane (RI=1.391) and lecithin 0.05% w / w.

[0355] In one embodiment, the aerodynamic particle size distribution (DISP) is measured using Proveris Sprayview and Copley Next Generation Impactor (NGI) or equivalents that conform to USP / Ph.Eur. <601> The method is determined based on the following. In one embodiment, a standard solution is prepared based on a label claim relating to a drug product (x mg per 100 ml of diluent, where x = label claim). In one embodiment, the settings are as follows: operating acceleration: 5000 mm / s / s, operating speed: 70 mm / s, symmetry: yes, initial delay: 0 ms, retention time: 100 ms, final delay: 0 ms, stroke length: 14 mm, and one shot is fired into the NGI. The device is weighed before firing (W1) and after firing (W2) to calculate the shot weight (W3). W1 - W2 = shot weight (W3), 5 ml of test solvent is added to each NGI cup, and then placed in an NGI slow-rocking machine for 5 minutes. The expansion chamber, stopper, inlet cone, all cups and Proveris color are quantitatively washed with diluent and placed in the correct flask size to the specified volume. The assay is determined via HPLC.

[0356] In one embodiment, the particle size distribution (PSD) is determined by laser diffraction. In one embodiment, the analysis is performed at a dispersion pressure of 3 bar using a Sympatec instrument equipped with an R5 lens. The transnasal delivery system / device is fixed to a clamp stand and positioned centrally relative to the extractor, so that the tip of the device is 3 cm from the midpoint of the laser. After reference, the device is operated manually, so that the powder passes through the laser beam and a reading is taken. The reading is repeated three times using the R5 lens, and then the average is calculated.

[0357] Example 29: Further 5-MeO-DMT pharmaceutical compositions or formulations A spray-dried pharmaceutical composition / formulation was prepared with 50% 5-MeO-DMT benzoate, 34.5% HPMC606, 3% isomalt, and 12.5% ​​methylcellulose (MC) SM-100 grade. The isomalt used had the following properties: solubility: 42 g / 100 g in water at 20°C and bulk density: 0.40 g / cm³. 3 It was an aggregated spherical isomalt (galenIQ721) having [a specific characteristic].

[0358] [Table 35]

[0359] The dissolution profile shown in Figure 56 indicates that for this SDD, approximately 80% release occurred by approximately 6 minutes. In one embodiment, a 5-MeO-DMT pharmaceutical composition / formulation comprising HPMC, isomalt, and methylcellulose is provided. In one embodiment, a sustained-release pharmaceutical composition / formulation of 5-MeO-DMT is provided. A spray-dried pharmaceutical composition / formulation with 50% 5-MeO-DMT benzoate, 3% sorbitol, and 47% MC SM-25 was prepared.

[0360] [Table 36]

[0361] The dissolution profile shown in Figure 57 indicates that for this SDD, approximately 80% release occurred by approximately 6 minutes. In one embodiment, a 5-MeO-DMT pharmaceutical composition / formulation comprising methylcellulose and sorbitol is provided. In one embodiment, a sustained-release pharmaceutical composition / formulation of 5-MeO-DMT is provided.

[0362] Example 30: 5-MeO-DMT oral / pharyngeal pharmaceutical composition or formulation Oral and pharyngeal medicinal compositions or formulations of 5-MeO-DMT have been developed and are characterized as follows:

[0363] [Table 37]

[0364] The pharmaceutical compositions or formulations were evaluated using sheep nasal epithelium in in vitro nasal epithelial penetration experiments. The mean cumulative amount (μg / mL, applied dose %) and peak flow rate (μg / min) of 5-MeO-DMT delivered to the receptor solution 1 hour after application of the six pharmaceutical compositions or formulations to reconstituted oral tissue are shown below.

[0365] [Table 38]

[0366] S29 delivered the most 5-MeO-DMT to the receptor solution after 1 hour (p<0.05, approximately 1.6 times more) compared to S12. S12 delivered more 5-MeO-DMT to the receptor solution (p<0.05, approximately 1.5 times more) compared to all other pharmaceutical compositions or formulations.

[0367] Regarding peak flow rate, S29 had the highest peak flow rate (p<0.05, approximately 1.8 times) among the tested pharmaceutical compositions or formulations. However, considering the applied dose percentage, S12 delivered more 5-MeO-DMT to the receptor solution as cumulative percentage (p<0.05, 2 times) and peak flow rate percentage (p<0.05, 1.8 times). Note that S29 contains almost twice as much API (4.02% w / w) compared to S01, S12, S26, and S28 (2.01% w / w).

[0368] Accordingly, in some embodiments, oropharyngeal medicinal compositions / formulations of 5-MeO-DMT or a pharmaceutically acceptable salt thereof as described herein are provided. In some embodiments, the oropharyngeal medicinal composition / formulation comprises alcohol. In some embodiments, the oropharyngeal medicinal composition / formulation comprises ethanol. In some embodiments, the oropharyngeal medicinal composition / formulation comprises a copolymer of poly(ethyl acrylate, methyl methacrylate, and chlorotrimethyl-ammonium ethyl methacrylate). In some embodiments, the oropharyngeal medicinal composition / formulation comprises Eudragit. In some embodiments, the oropharyngeal medicinal composition / formulation comprises EudragitRS100. In some embodiments, the oropharyngeal medicinal composition / formulation comprises EudragitE100. In some embodiments, the oropharyngeal medicinal composition / formulation comprises propylene glycol. In some embodiments, the oropharyngeal medicinal composition / formulation comprises hydrofluorocarbon. In some embodiments, the oropharyngeal medicinal composition / formulation comprises 1,1,1,2-tetrafluoroethane. In one embodiment, the oropharyngeal pharmaceutical composition / formulation contains APIs in amounts between 1%-30%, 1%-25%, 1%-20%, 1%-15%, 1%-10%, 1%-9%, 1%-8%, 1%-7%, 1%-6%, 1%-5%, 1%-4%, 1%-3%, and 1%-2% w / w of the whole oropharyngeal formulation. In one embodiment, the oropharyngeal pharmaceutical composition / formulation contains one or more pharmaceutically acceptable carriers or excipients, each of which is present individually in amounts between 1%-50%, 1%-40%, 1%-30%, 1%-25%, 1%-20%, 1%-15%, 1%-10%, 1%-9%, 1%-8%, 1%-7%, 1%-6%, 1%-5%, 1%-4%, 1%-3%, and 1%-2% w / w of the whole oropharyngeal formulation.

[0369] Example 31: Evaporative pharmaceutical composition or formulation of 5-MeO-DMT The inhalation route of administration allows for high bioavailability and low variability in bioavailability between patients and between re-administrations in the same patient, thus enabling high rates and high reproducibility of the supreme experience. 5-MeO-DMT aerosol can be produced by the volatilization of the drug by an evaporator device. Such a device may include a hot air generator and a detachable valve balloon from which the aerosol can be inhaled by the patient. The hot air generator can produce an adjustable temperature between approximately 40°C and approximately 210°C at an airflow rate of approximately 12 L / min. The central part of the device may be an administration capsule, and an alcoholic solution of 5-MeO-DMT in the relevant dose can be applied to the administration capsule, which can then be applied to the filling chamber of the device, where the administration capsule can be heated by hot air within the filling chamber. The administration capsule may include a small disc (called a droplet pad or liquid pad) made of densely packed stainless steel wire mesh. The bottom and lid of the administration capsule may have holes that allow airflow to pass through the administration capsule.

[0370] To prepare for administration, the patient may first be asked to perform one or two deep inhalations and complete exhalation, ending this sequence with a deep exhale. Then, holding the mouthpiece firmly against the lips, the patient can inhale a full volume of the inhalation balloon in a single inhalation, hold the breath for 10 (±2.5) seconds, and then exhale normally. After completing the inhalation procedure, the patient may be instructed to lie down.

[0371] The thermal decomposition properties of the salt forms of 5-MeO-DMT have been investigated and are summarized in the following report.

[0372] [Table 39]

[0373] Benzoate and oxalate salts were the only salt forms that underwent complete mass loss and were within a suitable temperature range. Therefore, a salt form favorable to the evaporation of 5-MeO-DMT, whether benzoate or oxalate salt, is provided. In one embodiment, the 5-MeO-DMT salt is in crystalline form.

[0374] In one embodiment, an evaporable pharmaceutical composition / formulation of 5-MeO-DMT benzoate is provided. In one embodiment, a method of treatment is provided, comprising administration of the pharmaceutical composition / formulation of 5-MeO-DMT benzoate by evaporation of the pharmaceutical composition / formulation. In one embodiment, a pharmaceutical composition / formulation comprising 5-MeO-DMT benzoate and an alcohol is provided. In one embodiment, the alcohol is ethanol. In one embodiment, a 5-MeO-DMT benzoate aerosol is provided.

[0375] In one embodiment, an evaporable pharmaceutical composition / formulation of 5-MeO-DMT oxalate is provided. In one embodiment, a method of treatment is provided, comprising administration of the pharmaceutical composition / formulation of 5-MeO-DMT oxalate by evaporation of the pharmaceutical composition / formulation. In one embodiment, a pharmaceutical composition / formulation comprising 5-MeO-DMT oxalate and an alcohol is provided. In one embodiment, the alcohol is ethanol. In one embodiment, a 5-MeO-DMT oxalate aerosol is provided.

Claims

1. An active intranasal delivery device comprising a pharmaceutical composition or preparation of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

2. Angle 20 to 45 degrees, Width 25-55mm, The plume geometric shape, Table 1 spray pattern, D10 = 13-17, D50 = 35-60, D90 = 650-700, % < 10 μm = < 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% Particle size distribution (at 40 mm), or D10 = 13-17, D50 = 24-30, D90 = 540-610, % < 10 μm = < 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10% Particle size distribution (at 70 mm), or D10=13-17, D50=22-27, D90=35-56, %<9μm=<0.1-10% Particle size distribution, or ０．５～５％ % of particles with a size of 11.7 μm or less Configured to operate to release a powder plume containing one or more of the following: 5-MeO-DMT, or a pharmaceutically acceptable salt thereof. The active intranasal delivery device according to claim 1.

3. The active intranasal delivery device according to claim 1 or 2, wherein the pharmaceutical composition or formulation of 5-MeO-DMT is a spray-dried or dry-blended dry powder pharmaceutical composition or formulation.

4. The active intranasal delivery device according to any one of claims 1 to 3, wherein the pharmaceutical composition or formulation contains a water content of less than about 5% by weight of the pharmaceutical composition or formulation.

5. The active intranasal delivery device according to any one of claims 1 to 4, wherein at least 95% of the particles of the pharmaceutical composition or formulation are larger than 10 microns in size.

6. The active intranasal delivery device according to any one of claims 1 to 5, wherein the pharmaceutical composition or formulation comprises methylcellulose, optionally high-viscosity methylcellulose.

7. The active intranasal delivery device according to any one of claims 1 to 6, wherein the pharmaceutical composition or formulation comprises low-viscosity methylcellulose and high-viscosity methylcellulose.

8. The active intranasal delivery device according to any one of claims 1 to 7, wherein the pharmaceutical composition or formulation comprises a cellulose-like / base excipient, optionally HPMC, and optionally high-viscosity HPMC.

9. The active intranasal delivery device according to claim 8, wherein the pharmaceutical composition or formulation comprises a low-viscosity HPMC and a high-viscosity HPMC.

10. The active intranasal delivery device according to claim 9, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:

1.

11. The active intranasal delivery device according to claim 9, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:

75.

12. The active intranasal delivery device according to claim 8, wherein the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50, or 60 millipascals-seconds or more, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 50 mPa·s.

13. The active intranasal delivery device according to claim 8, wherein the low viscosity HPMC has a viscosity of less than about 20, 15, 10, 5, or 1 millipascal-seconds, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 4.8 to 7.2 mPa·s.

14. The active intranasal delivery device according to any one of claims 1 to 13, wherein the pharmaceutical composition or formulation comprises a polyol, optionally the polyol being mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and optionally the polyol being sorbitol.

15. The active intranasal delivery device according to claim 14, wherein the pharmaceutical composition or formulation comprises about 1 to 10% by weight, 2 to 5% by weight, or 3% by weight of a polyol, and optionally about 3% by weight of sorbitol, mannitol, or isomalt.

16. The active intranasal delivery device according to any one of claims 1 to 15, wherein the pharmaceutical composition or formulation comprises a 5-MeO-DMT salt.

17. The active intranasal delivery device according to any one of claims 1 to 15, wherein the pharmaceutical composition or formulation comprises 5-MeO-DMT benzoate.

18. The active intranasal delivery device according to any one of claims 1 to 15, wherein the pharmaceutical composition or formulation comprises 5-MeO-DMT hydrochloride.

19. The active intranasal delivery device according to any one of claims 1 to 15, wherein the pharmaceutical composition or formulation comprises 5-MeO-DMT hydrobromide.

20. The active intranasal delivery device according to any one of claims 16 to 19, wherein the 5-MeO-DMT salt is amorphous.

21. The active intranasal delivery device according to any one of claims 16 to 19, wherein the 5-MeO-DMT salt is crystalline.

22. The crystalline 5-MeO-DMT salt is The crystalline form of 5-MeO-DMT benzoate is characterized by one or more peaks at 17.5, 17.7 and 21.0°2θ ± 0.1°2θ in the XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å. The crystalline form of 5-MeO-DMT hydrochloride, characterized by one or more peaks 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°²θ in the XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction, or The crystalline form of 5-MeO-DMT hydrobromide is characterized by one or more peaks at 14.6, 16.8, 20.8, 24.3, 24.9 and 27.5°2θ ± 0.1°2θ in the XRPD diffraction pattern, measured using an X-ray wavelength of 1.5406 Å by powder X-ray diffraction. An active intranasal delivery device according to claim 21, selected from the above.

23. An active intranasal delivery device according to any one of claims 1 to 22, comprising a dispenser outlet, an air discharger for generating an airflow while the device is in operation, and at least one reservoir containing a single dose of a pharmaceutical composition or formulation.

24. The active intranasal delivery device comprises a dispenser outlet and an air vent for generating an airflow while the device is operating, the air vent including a piston that slides between a stop position and a dispense position within an air chamber, the air chamber including a cylindrical body, and the piston sliding airtightly within the cylindrical body; and at least one reservoir containing a single dose of pharmaceutical composition or formulation, the reservoir including an air inlet connected to the air vent and a pharmaceutical composition or formulation outlet connected to the dispenser outlet, the air inlet including a pharmaceutical composition or formulation holder member for holding the pharmaceutical composition or formulation in the reservoir until the pharmaceutical composition or formulation is dispensed. An active intranasal delivery device according to any one of claims 1 to 22, comprising at least one reservoir, the formulation outlet of which is closed by a closing element pressed into the pharmaceutical composition or formulation outlet of the reservoir, the device further comprising a mechanical opening system which cooperates with the closing element to mechanically discharge the closing element from a closed position while the device is operating, the piston of the air exhauster cooperates non-airtightly with the air chamber such that the air chamber is in communication with the atmosphere when the air exhaust is in a stopped position, the piston includes an inner lip configured to cooperate with the cylindrical surface of a cylindrical member extending into the interior of the cylindrical body, the cylindrical surface includes fluting which cooperates non-airtightly with the inner lip of the piston when the air exhaust is in a stopped position.

25. Conditions caused by central nervous system dysfunction, conditions caused by peripheral nervous system dysfunction, conditions where sleep regulation is effective (such as insomnia), conditions where analgesics are effective (such as chronic pain), migraines, trigeminal autonomic headaches (such as short-acting persistent hemineurotic headache attacks with conjunctival hyperemia and lacrimation (SUNCT), and short-acting persistent hemineurotic headache attacks with cerebrovascular autonomic symptoms (SUNA)), conditions where neurodevelopmental therapy is effective (such as stroke, traumatic brain injury, Parkinson's disease, dementia), conditions where anti-inflammatory treatment is effective, depression, treatment-resistant depression, anxiety, substance use disorders, addiction disorders, gambling disorders, An active intranasal delivery device according to claim 23 for use in a method of treating a disease or condition selected from eating disorders, obsessive-compulsive disorder, or body dysmorphic disorder, wherein the condition is optionally 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, inhalation-related disorders, benzodiazepine abuse or dependence-related disorders, opioid-related disorders, tobacco addiction, alcohol abuse and / or addiction.

26. Conditions caused by central nervous system dysfunction, conditions caused by peripheral nervous system dysfunction, conditions where sleep regulation is effective (such as insomnia), conditions where analgesics are effective (such as chronic pain), migraines, trigeminal autonomic headaches (such as short-acting persistent hemineurotic headache attacks with conjunctival hyperemia and lacrimation (SUNCT), and short-acting persistent hemineurotic headache attacks with cerebrovascular autonomic symptoms (SUNA)), conditions where neurodevelopmental therapy is effective (such as stroke, traumatic brain injury, Parkinson's disease, dementia), conditions where anti-inflammatory treatment is effective, depression, treatment-resistant depression, anxiety, substance use disorders, addiction disorders, gambling disorders, An active intranasal delivery device according to claim 24 for use in a method of treating a disease or condition selected from eating disorders, obsessive-compulsive disorder, or body dysmorphic disorder, wherein the condition is optionally 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, inhalation-related disorders, benzodiazepine abuse or dependence-related disorders, opioid-related disorders, tobacco addiction, alcohol abuse and / or addiction.

27. A dry powder pharmaceutical composition or formulation prepared by spray drying, freeze-drying, or hot-melt extrusion, comprising 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

28. The pharmaceutical composition or formulation according to claim 27, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is in an amorphous (non-crystalline) form.

29. The pharmaceutical composition or formulation according to claim 27 or 28, which is a stable, free-flowing pharmaceutical composition or formulation.

30. A pharmaceutical composition or formulation according to claim 27 or 28, comprising at least about 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition or formulation according to any one of claims 27 to 30, exhibiting a sustained-release profile having optionally a nasal cavity residence time of at least 10, 15, 20, 25, or 30 minutes.

32. A pharmaceutical composition or formulation according to any one of claims 27 to 31, wherein 80% of the 5-MeO-DMT active agent exhibits a sustained-release profile in which time intervals of approximately 2 to 40, optionally 3 to 30, and optionally 4 to 15 minutes are released.

33. A pharmaceutical composition or formulation according to any one of claims 27 to 32, comprising a cellulose-like / base excipient, optionally HPMC, optionally high-viscosity HPMC, and optionally high-viscosity HPMC, exhibiting a sustained-release profile.

34. A pharmaceutical composition or formulation according to any one of claims 27 to 33, comprising a low-viscosity HPMC and a high-viscosity HPMC, and exhibiting a sustained-release profile.

35. The pharmaceutical composition or formulation according to claim 34, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:

1.

36. The pharmaceutical composition or formulation according to claim 34 or 35, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:75, and exhibits a sustained-release profile.

37. The pharmaceutical composition or formulation according to any one of claims 33 to 36, wherein the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50 or 60 millipascals-seconds or more, and optionally the HPMC is metholose 60SH50.

38. The pharmaceutical composition or formulation according to any one of claims 33 to 37, wherein the low-viscosity HPMC has a viscosity of less than about 20, 15, 10, 5, or 1 millipascal-seconds, and optionally the HPMC is pharmacoat 606.

39. A pharmaceutical composition or formulation according to any one of claims 27 to 38, comprising a polyol, wherein the polyol is optionally mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and further optionally the polyol is sorbitol.

40. A pharmaceutical composition or formulation according to any one of claims 27 to 39, comprising approximately 1 to 10% by weight, 2 to 5% by weight, or 3% by weight of a polyol, and optionally approximately 3% by weight of sorbitol.

41. A pharmaceutical composition or formulation according to any one of claims 27 to 40, comprising 5-MeO-DMT hydrochloride, wherein optionally the salt is in an amorphous form, and optionally a state-stable amorphous form.

42. A pharmaceutical composition or formulation according to any one of claims 27 to 40, comprising 5-MeO-DMT hydrobromide, wherein optionally the salt is in an amorphous form, and optionally a state-stable amorphous form.

43. A pharmaceutical composition or formulation according to any one of claims 27 to 40, comprising 5-MeO-DMT benzoate, wherein optionally the salt is in an amorphous form, and optionally a state-stable amorphous form.

44. A pharmaceutical composition or formulation according to any one of claims 27 to 40, comprising 5-MeO-DMT oxalate, wherein optionally the salt is in an amorphous form, and optionally a state-stable amorphous form.

45. An intranasal delivery device comprising a pharmaceutical composition or formulation according to any one of claims 27 to 44.

46. The intranasal delivery device according to claim 45, which is for single use.

47. The intranasal delivery device according to claim 46, comprising a single-dose pharmaceutical composition or formulation.

48. A pharmaceutical composition or formulation according to any one of claims 27 to 44 for use as a pharmaceutical, or an intranasal delivery device according to any one of claims 45 to 47.

49. A pharmaceutical composition or formulation according to any one of claims 27 to 44 or an intranasal delivery device according to any one of claims 45 to 47 for use in a method of treating depression and / or alcohol use disorder.

50. The pharmaceutical composition or formulation according to any one of claims 27 to 44, wherein the pharmaceutical composition or formulation is prepared by spray drying, and following the spray drying of the pharmaceutical composition or formulation, an additional drying step is performed to prepare the pharmaceutical composition or formulation, wherein optionally the drying step is performed at a relative humidity (RH) between 45 and 15°C and 85% and 65%, between 35 and 20°C and 80% and 70%, and optionally at 25°C and 75% RH.

51. A dried powder pharmaceutical composition or formulation prepared by spray drying, comprising approximately 50% by weight of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 35% by weight of HPMC606, 12% by weight of metholose 60SH50, and 3% by weight of sorbitol.

52. A state-stable amorphous dry powder pharmaceutical composition or formulation comprising 5-MeO-DMT HBr and one or more pharmaceutically acceptable carriers or excipients.

53. The pharmaceutical composition or formulation according to claim 52, which is a spray-dried pharmaceutical composition or formulation.

54. The pharmaceutical composition or formulation according to claim 52, which is a free-flowing pharmaceutical composition or formulation.

55. The pharmaceutical composition or formulation according to claim 52, wherein the 5-MeO-DMT HBr is non-hygroscopic.

56. The pharmaceutical composition or formulation according to claim 52, comprising a water content of less than about 5% by weight of the pharmaceutical composition or formulation.

57. The pharmaceutical composition or formulation according to claim 52, wherein more than 70% (w / w) of the 5-MeO-DMT HBr in the pharmaceutical composition or formulation is in amorphous form.

58. A pharmaceutical composition or formulation according to claim 52, comprising at least about 10% by weight, 20% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight of 5-MeO-DMT HBr.

59. The pharmaceutical composition or formulation according to claim 52, wherein at least 95% of the particles of the pharmaceutical composition or formulation are larger than 10 microns in size.

60. The pharmaceutical composition or formulation according to claim 52, wherein 80% or less of the 5-MeO-DMT is released from the pharmaceutical composition or formulation within 4 minutes at 37°C in water.

61. The pharmaceutical composition or formulation according to claim 52, wherein, when administered to the target nasal cavity, the pharmaceutical composition or formulation exhibits a residual time of at least 10, 15, 20, 25, or 30 minutes, which is the length of time the substance is present in the nasal cavity, for example, along the nasal cilia and mucous layer in the nasal cavity.

62. A pharmaceutical composition or formulation according to claim 52, comprising a cellulose-like / base excipient, optionally HPMC, optionally high-viscosity HPMC, and optionally high-viscosity HPMC.

63. A pharmaceutical composition or formulation according to claim 62, comprising low-viscosity HPMC and high-viscosity HPMC.

64. The pharmaceutical composition or formulation according to claim 63, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 1:10 to 10:1, optionally 1:4 to 4:1, and optionally 1:2 to 2:

1.

65. The pharmaceutical composition or formulation according to claim 64, wherein the ratio of the low-viscosity HPMC to the high-viscosity HPMC is 50:50, 45:55, 40:60, 35:65, 30:70, or 25:

75.

66. The pharmaceutical composition or formulation according to claim 62, wherein the high-viscosity HPMC has a viscosity of about 20, 30, 40, 50, or 60 millipascals-seconds or more, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 50 mPa·s.

67. The pharmaceutical composition or formulation according to claim 62, wherein the low viscosity HPMC has a viscosity of less than about 20, 15, 10, 5, or 1 millipascal-seconds, and optionally the HPMC has a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 4.8 to 7.2 mPa·s.

68. The pharmaceutical composition or formulation according to claim 52, comprising a polyol, wherein the polyol is optionally mannitol, xylitol, sorbitol, maltitol, erythritol, lactitol, or isomalt, and further optionally the polyol is sorbitol.

69. The pharmaceutical composition or formulation according to claim 68, comprising approximately 1 to 10% by weight, 2 to 5% by weight, or 3% by weight of a polyol, and optionally approximately 3% by weight of sorbitol.

70. An intranasal delivery device comprising the pharmaceutical composition or formulation according to claim 52.

71. A method for treating depression and / or alcohol use disorder in a subject who needs treatment for the depression and / or alcohol use disorder, comprising the step of intranasally administering to the subject a pharmaceutical composition or formulation according to claim 52 in an amount sufficient to treat the depression and / or alcohol use disorder.

72. A method for producing a pharmaceutical composition or formulation according to claim 52, comprising: (i) mixing components of the pharmaceutical composition or formulation with a liquid to form a mixture, and spray-drying the mixture to form a solid; and (ii) following step (i), further drying the solid to form the pharmaceutical composition / formulation, wherein the drying step is optionally carried out at a relative humidity (RH) between 45 and 15°C and 85% and 65%, between 35 and 20°C and 80% and 70%, and optionally at 25°C and 75%.

73. The method according to claim 72, wherein the pharmaceutical composition or formulation comprises approximately 40 to 60% by weight of 5-MeO-DMT HBr, 30 to 40% by weight of HPMC having a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 4.8 to 7.2 mPa·s, 7 to 15% by weight of HPMC having a hydroxypropyl content of about 7.0 to 12.0%, a methoxy content of about 28.0 to 30.0%, and a viscosity of about 50 mPa·s, and 0 to 5% by weight of sorbitol.

74. A dispenser device for dispensing a pharmaceutical composition or formulation according to any one of claims 51 to 69, comprising: a dispenser outlet; an air vent for generating an airflow while the device is operating, the air vent comprising a piston that slides between a stop position and a dispensing position within an air chamber, the air chamber comprising a cylindrical body in which the piston slides airtightly; and at least one reservoir comprising a single dose of the pharmaceutical composition or formulation, the reservoir comprising an air inlet connected to the air vent and an outlet connected to the dispenser outlet, the air inlet being connected to the reservoir until the pharmaceutical composition or formulation is dispensed. A dispenser device comprising a pharmaceutical composition or formulation holder member for holding a pharmaceutical composition / formulation, the outlet of the pharmaceutical composition or formulation being closed by a closure element pressurized into the outlet of the pharmaceutical composition or formulation of the reservoir, the device further comprising a mechanical opening system which cooperates with the closure element to mechanically discharge the closure element from a closed position while the device is operating, the piston of the air vent cooperates non-airtightly with the air chamber such that the air chamber is in communication with the atmosphere when the air chamber is in a stopped position, the piston includes an inner lip configured to cooperate with the cylindrical surface of a cylindrical member extending into the interior of the cylindrical body, the cylindrical surface includes fluting which cooperates non-airtightly with the inner lip of the piston when the air chamber is in a stopped position.

75. The dispenser device according to claim 74, wherein the dispenser device is for use in a method of treating a mental health condition / disorder in a subject who needs to be treated for a mental health condition / disorder, the method comprising the step of administering a pharmaceutical composition or formulation according to any one of claims 51 to 69 to the subject via the dispenser device according to claim 74 in an amount sufficient to treat the mental health condition / disorder.

76. The dispenser device according to claim 75, wherein the dispenser device is for use in a method of treating depression and / or alcohol use disorder in a subject who needs to be treated for depression and / or alcohol use disorder, the method comprising the step of administering a pharmaceutical composition or formulation according to any one of claims 51 to 69 to the subject via the dispenser device according to claim 74 in an amount sufficient to treat depression and / or alcohol use disorder.

77. An evaporative pharmaceutical composition or preparation of 5-MeO-DMT benzoate.

78. Aerosol containing 5-MeO-DMT benzoate.

79. An evaporable pharmaceutical composition or formulation of 5-MeO-DMT oxalate.

80. Aerosol containing 5-MeO-DMT oxalate.

81. Oral and pharyngeal pharmaceutical compositions or formulations comprising (i) an alcohol, optionally ethanol, and (ii) a copolymer of poly(ethyl acrylate, methyl methacrylate, and chlorotrimethyl-ammonium ethyl methacrylate).

82. (i) a 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and (ii) a lyophilized pharmaceutical composition or preparation comprising trehalose.

83. A lyophilized pharmaceutical composition or formulation according to claim 82, comprising 5-MeO-DMT oxalate.

84. A lyophilized pharmaceutical composition or formulation according to claim 82, comprising 5-MeO-DMT benzoate.

85. A lyophilized pharmaceutical composition or formulation according to claim 82, comprising 5-MeO-DMT hydrobromide.

86. A freeze-dried pharmaceutical composition or formulation according to any one of claims 82 to 85, wherein the composition is amorphous.

87. A lyophilized pharmaceutical composition or formulation according to any one of claims 82 to 86, comprising 50% 5-MeO-DMT and 50% trehalose.

88. (i) a pharmaceutically acceptable salt thereof, and (ii) a lyophilized pharmaceutical composition or preparation comprising lactose monohydrate.

89. A lyophilized pharmaceutical composition or formulation according to claim 88, comprising 5-MeO-DMT oxalate.

90. A lyophilized pharmaceutical composition or formulation according to claim 88, comprising 5-MeO-DMT benzoate.

91. A lyophilized pharmaceutical composition or formulation according to claim 88, comprising 5-MeO-DMT hydrobromide.

92. A freeze-dried pharmaceutical composition or formulation according to any one of claims 88 to 91, wherein the composition is amorphous.

93. A lyophilized pharmaceutical composition or formulation according to any one of claims 88 to 92, comprising lactose monohydrate.

94. (i) a 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and (ii) a lyophilized pharmaceutical composition or preparation comprising polyvinylpyrrolidone (PVP).

95. A lyophilized pharmaceutical composition or formulation according to claim 94, comprising 5-MeO-DMT oxalate.

96. A lyophilized pharmaceutical composition or formulation according to claim 94, comprising 5-MeO-DMT benzoate.

97. A lyophilized pharmaceutical composition or formulation according to claim 94, comprising 5-MeO-DMT hydrobromide.

98. A freeze-dried pharmaceutical composition or formulation according to any one of claims 94 to 97, wherein the composition is amorphous.

99. A lyophilized pharmaceutical composition or formulation according to any one of claims 94 to 98, comprising 50% 5-MeO-DMT and 50% PVP.

100. A freeze-dried pharmaceutical composition or formulation according to any one of claims 82 to 99, intended for use as a pharmaceutical.

101. A method for preparing a freeze-dried pharmaceutical composition or formulation according to any one of claims 82 to 99.

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