Method for delivering hallucinogens by inhalation and system for carrying out the method

Abstract

Methods are provided for delivering a hallucinogen, such as a tryptamine-based hallucinogen, to a patient in need thereof via inhalation. The hallucinogen is delivered in the form of an aerosol, such as a mist or dry powder. Methods are provided for treating a central nervous system (CNS) disorder or a psychological disorder via the inhalation route.

Description

[Background technology]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 362,238, filed March 31, 2022, which is incorporated herein by reference in its entirety. [Technical Field]

[0002] Methods for the delivery of hallucinogens by inhalation, as well as systems and devices for practicing those methods, are provided. 2. Description of Related Art

[0003] Both natural and synthetic hallucinogenic compounds, such as tryptamines, phenethylamines, ergolines, and other derivatives, possess a variety of valuable therapeutic properties that may be useful in treatment.

[0004] Hallucinogens are so named because of the experiential effects they have on users. The hallucinogenic experience most often acts to elevate the user's mood upon use. However, one potential psychological drawback resulting from the administration of hallucinogens as therapeutic agents is the risk of a futility experience for the patient, observed as an acute hallucinogenic crisis, commonly referred to as a "bad trip," in which the patient experiences feelings of regret or distress.

[0005] The therapeutic index of many hallucinogens is relatively narrow, therefore maximizing the therapeutic benefit of potential drug candidate molecules requires dose titration as well as fine tuning of the dose and route of administration to reduce side effects and improve safety.

[0006] The standard route of administration is most often via oral delivery, which is often complicated by metabolic conversion, resulting in both reduced efficacy and increased toxicity. For some compounds, the oral route is completely ineffective. For example, naturally occurring dimethyltryptamine (DMT) is orally inactive unless combined with an MAO inhibitor, as in the folk medicine ayahuasca.

[0007] Inhalation methods of drug administration are generally targeted at relatively common medical conditions, including asthma, pain management, or diabetes treatment. Pulmonary delivery is attractive as a route of systemic administration due to the rapid absorption due to the large surface area of ​​the alveolar region, the abundant vasculature and thin air-blood barrier, and the avoidance of first-pass metabolism. The effectiveness of aerosol therapy is highly dependent on the amount of drug that reaches the intended deposition site. The deposition pattern of the administered aerosol is primarily determined by the formulation and delivery device. Therefore, there is an unmet medical need for methods and devices for delivering hallucinogens by inhalation that can deliver the drug systemically via the pulmonary system while allowing for controlled dosage. Summary of the Invention

[0008] Accordingly, one object is to provide a method for delivering a hallucinogen or drug (including a hallucinogen-drug combination) via inhalation to a patient in need thereof.

[0009] A further object is to provide a method for delivering a hallucinogen or drug (including a hallucinogen-drug combination) via inhalation to rapidly deliver the hallucinogen to the bloodstream, bypassing first-pass metabolism.

[0010] Another object is to provide a method for treating central nervous system or psychological disorders by administering a mixture of nitrous oxide (or a noble gas, e.g., xenon and / or argon) and oxygen (or air).

[0011] A further object is to provide a method for delivering a hallucinogen by co-administering the hallucinogen with nitrous oxide (or a noble gas, e.g., xenon and / or argon) via inhalation, wherein the nitrous oxide (or noble gas) serves as a driving gas for nebulization of the hallucinogen.

[0012] A further object is to provide a medical device for the combined administration by inhalation of a hallucinogen and nitrous oxide (or a noble gas).

[0013] A further object is to provide a nitrous oxide (or noble gas) and hallucinogen delivery device that can be remotely activated and adjusted to control the dose and duration of treatment, thereby providing treatment at home under the supervision of a therapist / psychiatrist via telemedicine, thereby aiding patient compliance with medication administration and helping to prevent overdosing.

[0014] These and other objects have been met by the discovery of methods for delivering hallucinogens to a patient in need thereof, including administering hallucinogens, alone or in combination, in aerosol form by inhalation; methods for treating a central nervous system (CNS) disorder or a psychological disorder by inhalation of a hallucinogen in aerosol form; devices for delivery of a hallucinogen and nitrous oxide (or a noble gas) mixture by inhalation, including by remote activation or remote control; and methods for treating a central nervous system (CNS) disorder or a psychological disorder by inhalation of a nitrous oxide (or a noble gas) / oxygen mixture, including those having an amount of nitrous oxide (or a noble gas) of 15-25% of the total gas volume.

[0015] Accordingly, the following embodiments are disclosed in a non-limiting sense.

[0016] Embodiment 1 1. A method of delivering a hallucinogen to a patient in need thereof, comprising administering to the patient by inhalation an aerosol comprising the hallucinogen in a carrier, the hallucinogen being a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9 and R 10 are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0017] Embodiment 2 X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 2. The method of embodiment 1, wherein at least one of comprises deuterium.

[0018] Embodiment 3 X1, X2, R9, and R 10 3. The method of embodiment 1 or 2, wherein

[0019] Embodiment 4 X1, X2, Y1, Y2, R9, and R 10 4. The method of any one of embodiments 1 to 3, wherein comprises deuterium.

[0020] Embodiment 5 5. The method of any one of embodiments 1 to 4, wherein X1, X2, and R5 comprise deuterium.

[0021] Embodiment 6 X1, X2, Y1, Y2, R5, R9, and R 10 6. The method of any one of embodiments 1 to 5, wherein comprises deuterium.

[0022] Embodiment 7 The compound of formula (I) is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(5-methoxy-d3 7. The method of any one of embodiments 1 to 6, wherein the compound is at least one selected from the group consisting of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0023] Embodiment 8 Hallucinogenic drugs include 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, and 2-(5-methoxy-d 3) 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4.

[0024] Embodiment 9 The hallucinogen is a mixture of at least two compounds of formula (I), the mixture of hallucinogens being selected from the group consisting of (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, (ii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 9. The method of any one of embodiments 1 to 8, comprising one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0025] Embodiment 10 A mixture of hallucinogens comprising (i) 60 to 99% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the mixture of hallucinogens; or (ii) 1 to 40% by weight of the total weight of the mixture of hallucinogens, based on ... and (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, collectively at 0% to less than 10% by weight of the total weight of the mixture of hallucinogens.

[0026] Embodiment 11 11. The method of any one of embodiments 1 to 10, wherein the carrier is air, oxygen, or a mixture of helium and oxygen.

[0027] Embodiment 12 12. The method of embodiment 11, wherein the carrier is a mixture of helium and oxygen.

[0028] Embodiment 13 13. The method of embodiment 12, wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C.

[0029] Embodiment 14 14. The method of embodiment 12 or 13, wherein helium is present in the mixture of helium and oxygen at about 50% to 90% by volume, and oxygen is present in the mixture of helium and oxygen at about 50% to 10% by volume.

[0030] Embodiment 15 15. The method of any one of embodiments 1-14, further comprising administering a pre-treatment inhalation regimen prior to administration of the aerosol comprising the hallucinogen and carrier.

[0031] Embodiment 16 16. The method of embodiment 15, wherein the pre-treatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C.

[0032] Embodiment 17 The hallucinogen is delivered to the patient's central nervous system, thereby providing at least a 25% improvement in drug bioavailability compared to oral delivery, and at least a 25% C improvement compared to oral delivery. max Increased T by at least 50% compared to oral delivery max 17. The method of any one of embodiments 1-16, wherein the method provides a reduction in:

[0033] Embodiment 18 18. The method of any one of embodiments 1-17, wherein the aerosol is a mist.

[0034] Embodiment 19 19. The method of any one of embodiments 1-18, wherein the aerosol is prepared by nebulization of the hallucinogen.

[0035] Embodiment 20 20. The method of embodiment 19, wherein the nebulization is performed with a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer.

[0036] Embodiment 21 The method of embodiment 19 or 20, wherein the nebulization is performed using nitrous oxide as a driving gas for entrainment of the nebulized hallucinogen.

[0037] Embodiment 22 22. The method of embodiment 21, wherein the nitrous oxide is present in a concentration of 15-25% of the volume of the gas used.

[0038] Embodiment 23 23. The method of any one of embodiments 1-22, wherein the aerosol is administered for 20 to 60 minutes.

[0039] Embodiment 24 1. A method of treating a patient having a central nervous system (CNS) or psychological disorder, comprising administering to the patient via inhalation an aerosol containing a hallucinogen in a carrier, wherein the hallucinogen is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9 and R 10 are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0040] Embodiment 25 X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 25. The method of embodiment 24, wherein at least one of comprises deuterium.

[0041] Embodiment 26 X1, X2, R9, and R 10 26. The method of embodiment 24 or 25, wherein comprises deuterium.

[0042] Embodiment 27 X1, X2, Y1, Y2, R9, and R 10 27. The method of any one of embodiments 24-26, wherein comprises deuterium.

[0043] Embodiment 28 28. The method of any one of embodiments 24-27, wherein X1, X2, and R5 comprise deuterium.

[0044] Embodiment 29 X1, X2, Y1, Y2, R5, R9, and R 10 29. The method of any one of embodiments 24-28, wherein comprises deuterium.

[0045] Embodiment 30 The compound of formula (I) is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 30. The method of any one of embodiments 24 to 29, wherein the compound is at least one selected from the group consisting of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2, and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0046] Embodiment 31 Hallucinogenic drugs include 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, and 2-(5-methoxy-d3 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4; and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4.

[0047] Embodiment 32 The hallucinogen is a mixture of at least two compounds of formula (I), the mixture of hallucinogens being selected from the group consisting of (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, (ii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, 32. The method of any one of embodiments 24-31, comprising one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0048] Embodiment 33 A mixture of hallucinogens comprising (i) 60 to 99% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the mixture of hallucinogens; or (ii) 1 to 40% by weight of the total weight of the mixture of hallucinogens, based on ... and (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, collectively at 0% to less than 10% by weight of the total weight of the mixture of hallucinogens.

[0049] Embodiment 34 34. The method of any one of embodiments 24-33, wherein the carrier is air, oxygen, or a mixture of helium and oxygen.

[0050] Embodiment 35 35. The method of embodiment 34, wherein the carrier is a mixture of helium and oxygen.

[0051] Embodiment 36 36. The method of embodiment 35, wherein the mixture of helium and oxygen is heated to about 50°C to about 60°C.

[0052] Embodiment 37 37. The method of embodiment 35 or 36, wherein helium is present in the mixture of helium and oxygen at about 50% to 90% by volume, and oxygen is present in the mixture of helium and oxygen at about 50% to 10% by volume.

[0053] Embodiment 38 The method of any one of embodiments 24-37, further comprising administering a pre-treatment inhalation therapy prior to administration of the aerosol comprising the hallucinogen and carrier.

[0054] Embodiment 39 39. The method of embodiment 38, wherein the pre-treatment inhalation therapy comprises administering to the patient via inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C.

[0055] Embodiment 40 The hallucinogen is delivered to the patient's central nervous system, thereby providing at least a 25% improvement in drug bioavailability compared to oral delivery, and at least a 25% C improvement compared to oral delivery. max Increased T by at least 50% compared to oral delivery max 40. The method of any one of embodiments 24-39, wherein the method provides a reduction in:

[0056] Embodiment 41 41. The method of any one of embodiments 24-40, wherein the aerosol is a mist.

[0057] Embodiment 42 42. The method of any one of embodiments 24-41, wherein the aerosol is prepared by nebulization of the hallucinogen.

[0058] Embodiment 43 43. The method of embodiment 42, wherein the nebulization is performed with a device selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a breath-actuated nebulizer, and a vibrating mesh nebulizer.

[0059] EMBODIMENT 44 The method of embodiment 42 or 43, wherein the nebulization is performed using nitrous oxide as a driving gas for entrainment of the nebulized hallucinogen.

[0060] Embodiment 45 45. The method of embodiment 44, wherein the nitrous oxide is present in a concentration of 15-25% of the volume of the gas used.

[0061] Embodiment 46 46. ​​The method of any one of embodiments 24-45, wherein the aerosol is administered for 20 to 60 minutes.

[0062] Embodiment 47 CNS or psychological disorders include melancholic depression, atypical depression, dysthymia, anxiety disorders, obsessive-compulsive disorder, addictive disorders, alcohol use disorders, opioid use disorders, amphetamine use disorders, nicotine use disorders, cocaine use disorders, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation or attempts, bipolar I disorder, bipolar II disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, and Alzheimer's disease. , cluster headache, migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysphagia, dementia, mild neurocognitive disorder, sexual dysfunction, gambling disorder, eating disorder, anorexia nervosa, bulimia nervosa, binge eating disorder, paraphilia, pediatric disorder, conduct disorder, voyeuristic disorder, fetishistic disorder, sexual masochistic disorder, sexual sadistic disorder, and cross-dressing disorder.

[0063] Embodiment 48 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric illness is major depressive disorder (MDD).

[0064] Embodiment 49 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric disease is treatment-resistant depression (TRD).

[0065] Embodiment 50 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric illness is generalized anxiety disorder (GAD).

[0066] Embodiment 51 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric illness is generalized anxiety disorder (GAD) accompanied by depression.

[0067] Embodiment 52 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric illness is social anxiety disorder.

[0068] Embodiment 53 The method of any one of embodiments 24-47, wherein the CNS disorder or psychiatric illness is an alcohol use disorder.

[0069] EMBODIMENT 54 1. A method of delivering a hallucinogen to a patient in need thereof, comprising administering a dry powder to the patient by inhalation via a dry powder inhaler; the dry powder comprises a hallucinogen, the hallucinogen being a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9 and R 10 are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0070] Embodiment 55 The hallucinogen is a mixture of at least two compounds of formula (I), the mixture of hallucinogens being selected from the group consisting of (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; 55. The method of embodiment 54, comprising one or more of a salt, stereoisomer, solvate, or prodrug thereof, and optionally (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0071] Embodiment 56 A mixture of hallucinogens comprising (i) 60 to 99% by weight of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the mixture of hallucinogens; or (ii) 1 to 40% by weight of the total weight of the mixture of hallucinogens, based on ... and (iii) one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, collectively at 0% to less than 10% by weight of the total weight of the mixture of hallucinogens.

[0072] Embodiment 57 57. The method of any one of embodiments 54-56, wherein the dry powder comprises a particulate carrier having a hallucinogen on its surface.

[0073] Embodiment 58 58. The method of any one of embodiments 54-57, wherein the hallucinogen is releasably absorbed onto the surface of the particulate carrier, whereby, upon inhalation by the patient, the hallucinogen is released from the particulate carrier within the patient.

[0074] Embodiment 59 The use of a hallucinogen, such as a compound of formula (I), to treat a patient with a central nervous system (CNS) disorder or a psychological disorder. [Brief explanation of the drawings]

[0075] The foregoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the claims that follow. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.

[0076] [Figure 1A] Figures 1A-1B show a directed flow exposure chamber housed within a secondary containment chamber (top view, Figure 1A), and a depiction of a rat held within a restraining tube with its nose protruding from the end of the restraining tube into the exposure chamber (Figure 1B). [Figure 1B] Same as above. [Figure 2] FIG. 2 shows DMT and DMT-d10 plasma concentration-time profiles after iv administration (1 mg / kg) in rats. [Figure 3] FIG. 3 shows DMT and DMT-d10 plasma concentration-time profiles after inhalation administration (14.7 mg / kg and 15.3 mg / kg, respectively) in rats. [Figure 4] FIG. 4 shows DMT and DMT-d10 plasma concentration-time profiles after PO (oral gavage, OG) administration (10 mg / kg) in rats. [Figure 5] Figure 5 shows DMT plasma concentration-time profiles after iv, inhaled, and PO (OG) administration, dose normalized to 1 mg / kg. [Figure 6] Figure 6 shows DMT-d10 plasma concentration-time profiles after iv, inhaled, and PO (OG) administration, dose normalized to 1 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0077] The following detailed description is merely exemplary in nature and is not intended to be limiting of the compositions or methods described.

[0078] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0079] "Alkyl" refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2 carbon atoms. This term includes, by way of example, straight-chain and branched hydrocarbyl groups such as methyl (CH-), ethyl (CHCH-), n-propyl (CHCHCH-), isopropyl ((CH)CH-), n-butyl (CHCHCHCH-), isobutyl ((CH)CHCH-), sec-butyl ((CH)(CHCH)CH-), t-butyl (t-Bu) ((CH)C-), n-pentyl (CHCHCHCHCHCH-), and neopentyl ((CH)CCH-).

[0080] The term "substituted alkyl" refers to an alkyl group, as defined herein, wherein one or more carbon atoms in the alkyl chain are optionally substituted with -O-, -N-, -S-, -S(O) n -(n is 0 to 2), -NR- (R is hydrogen or alkyl), and substituted with a heteroatom such as deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO 2- Heteroaryl, and -NR ’ R’’ , where R ’ and R ’ ’ may be the same or different and have 1 to 10 substituents selected from the group consisting of hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic groups.

[0081] "Alkylene" is -O-, -NR 10 -, -NR 10 C(O), -C(O)NR 10 - refers to a divalent aliphatic hydrocarbyl group having from 1 to 6 carbon atoms, either straight or branched, including from 1 to 3 carbon atoms, optionally interrupted by one or more groups selected from, for example, methylene (-CH-), ethylene (-CHCH-), n-propylene (-CHCHCH-), iso-propylene (-CHCH(CH)-), (-C(CH)CHCH-), (-C(CH)CHC(O)-), (-C(CH)CHC(O)NH-), (-CH(CH)CH-), and the like.

[0082] "Substituted alkylene" refers to an alkylene group having 1 to 3 hydrogens replaced with a substituent, as described for carbon in the definition of "substituted" below.

[0083] The term "alkane" refers to alkyl and alkylene groups as defined herein.

[0084] The terms "alkylaminoalkyl," "alkylaminoalkenyl," and "alkylaminoalkynyl" refer to R ’ NHR ” - refers to the group R ’ is an alkyl group as defined herein, and R ” is an alkylene, alkenylene, or alkynylene group as defined herein.

[0085] The terms "alkaryl" or "aralkyl" refer to the groups -alkylene-aryl and -substituted alkylene-aryl, where alkylene, substituted alkylene, and aryl are defined herein.

[0086] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0087] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-, where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl, and substituted alkynyl are as defined herein.

[0088] The term "alkoxyamino" refers to the group --NH-alkoxy, where alkoxy is as defined herein.

[0089] The term "haloalkoxy" refers to an alkyl-O- group in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group and includes, by way of example, groups such as trifluoromethoxy.

[0090] The term "haloalkyl" refers to an alkyl group substituted as described above, in which one or more hydrogen atoms on the alkyl group have been replaced with a halo group. Examples of such groups include, but are not limited to, fluoroalkyl groups such as trifluoromethyl, difluoromethyl, trifluoroethyl, etc.

[0091] The term "alkylalkoxy" refers to the group -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0092] The term "alkylthioalkoxy" refers to -alkylene-S-alkyl groups, alkylene-S-substituted alkyl groups, substituted alkylene-S-alkyl groups, and substituted alkylene-S-substituted alkyl groups, where alkyl, substituted alkyl, alkylene, and substituted alkylene are as defined herein.

[0093] "Alkenyl" refers to a straight or branched chain hydrocarbyl group having 2 to 6 carbon atoms, e.g., 2 to 4 carbon atoms, and having at least one site of double bond unsaturation, e.g., 1 to 2. The term includes, by way of example, bivinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

[0094] The term "substituted alkenyl" refers to an alkenyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0095] "Alkynyl" refers to a straight-chain or branched monovalent hydrocarbyl group having from 2 to 6 carbon atoms, e.g., 2 to 3 carbon atoms, and having at least 1 site of triple bond unsaturation, e.g., 1 to 2. Examples of such alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CHC≡CH).

[0096] The term "substituted alkynyl" refers to an alkynyl group, as defined herein, having from 1 to 5 substituents, or from 1 to 3 substituents, selected from deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl.

[0097] "Alkynyloxy" refers to the group -O-alkynyl, where alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0098] "Acyl" includes HC(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, "C(O)-," "substituted heteroaryl-C(O)-," "heterocyclyl-C(O)-," and "substituted heterocyclyl-C(O)-" groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CHC(O).

[0099] "Acylamino" is -NR 20 C(O) alkyl group, -NR 20 C(O)-substituted alkyl group, NR 20 C(O)cycloalkyl group, -NR 20 C(O)-substituted cycloalkyl groups, -NR 20 C(O) cycloalkenyl group, -NR 20 C(O)-substituted cycloalkenyl group, -NR 20 C(O) alkenyl group, -NR 20 C(O)-substituted alkenyl group, -NR 20 C(O) alkynyl group, -NR 20 C(O)-substituted alkynyl group, -NR 20 C(O) aryl group, -NR 20 C(O) substituted aryl group, -NR 20 C(O) heteroaryl group, -NR 20 C(O)-substituted heteroaryl groups, -NR 20 C(O) heterocyclic groups, and -NR 20 C(O)-substituted heterocyclic groups, R 20is hydrogen or alkyl, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0100] "Aminocarbonyl" or the term "aminoacyl" refers to -C(O)NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 is optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0101] "Aminocarbonylamino" is -NR 21 C(O)NR 22 R 23 R refers to the group 21 , R 22 , and R 23 is independently selected from hydrogen, alkyl, aryl, or cycloalkyl, and two R groups are joined to form a heterocyclyl group.

[0102] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0103] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0104] "Aminosulfonyl" is -SO2NR 21 R 22 R refers to the group 21 and R 22 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0105] "Sulfonylamino" is -NR 21 SO2R 22 R refers to the group 21 and R 22is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; R 21 and R 22 are optionally joined together with the atoms bound to them to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0106] "Aryl" or "ar" refers to a monovalent aromatic carbocyclic group of 6 to 18 carbon atoms having a single ring (e.g., as in a phenyl group) or a ring system having multiple fused rings, which may or may not be aromatic, provided that the point of attachment is through an aromatic ring atom (examples of such aromatic ring systems include naphthyl, anthryl, and indanyl). This term includes, by way of example, phenyl and naphthyl. Unless constrained by the definition of an aryl substituent, such aryl groups may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and trihalomethyl.

[0107] "Aryloxy" refers to the group --O-aryl, where aryl is as defined herein and includes, for example, phenoxy, naphthoxy, etc., and includes optionally substituted aryl groups, also as defined herein.

[0108] "Amino" refers to the group NH2.

[0109] The term "substituted amino" refers to the group -NRR, where if at least one R is not hydrogen, then each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl.

[0110] The term "azido" refers to the group -N3.

[0111] "Carboxyl", "carboxy" or "carboxylate" refers to -CO2H or salts thereof.

[0112] "Carboxyl-ester" or "carboxy-ester", or the term "carboxyalkyl" or "carboxylalkyl" refers to a -C(O)O-alkyl group, a -C(O)O-substituted alkyl group, a -C(O)O-alkenyl group, a -C(O)O-substituted alkenyl group, a -C(O)O-alkynyl group, a -C(O)O-substituted alkynyl group, a -C(O)Oaryl group, a -C(O)O-substituted aryl group, a -C(O)O-cycloalkyl group, a -C(O)O-substituted cycloalkyl group, a -C(O)O-cycloalkenyl

[0033] This refers to the groups, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0113] "(Carboxyl-ester)oxy" or "carbonate" refers to an -OC(O)O-alkyl group, an -OC(O)O-substituted alkyl group, an -OC(O)O-alkenyl group, an -OC(O)O-substituted alkenyl group, an -OC(O)O-alkynyl group, an -OC(O)O-substituted alkynyl group, an -OC(O)O-aryl group, an -OC(O)O-substituted aryl group, an -OC(O)O-cycloalkyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-cycloalkenyl group, an -OC(O)O-substituted cycloalkyl group, an -OC(O)O-substituted cycloalkenyl ... refers to a cycloalkenyl group, an -OC(O)O-heteroaryl group, an -OC(O)O-substituted heteroaryl group, an -OC(O)O-heterocyclic group, and an -OC(O)O-substituted heterocyclic group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0114] "Cyano" or "nitrile" refers to the group --CN.

[0115] "Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like. Such cycloalkyl groups include, for example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl.

[0116] The term "substituted cycloalkyl" includes but is not limited to deuterium, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It refers to a cycloalkyl group having 1 to 5 substituents, or 1 to 3 substituents, selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0117] "Cycloalkenyl" refers to a non-aromatic cyclic alkyl group of from 3 to 10 carbon atoms having single or multiple rings and at least one double bond, eg, 1 to 2 double bonds.

[0118] The term "substituted cycloalkenyl" includes but is not limited to deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO2- It refers to a cycloalkenyl group having 1 to 5 substituents selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl, or 1 to 3 substituents.

[0119] "Cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having single or multiple rings and at least one triple bond.

[0120] "Cycloalkoxy" refers to -O-cycloalkyl.

[0121] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0122] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0123] "Hydroxy" or "hydroxyl" refers to the group --OH.

[0124] "Heteroaryl" refers to an aromatic group of 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl, imidazolyl, or furyl) or multiple condensed rings within the ring system (e.g., in groups such as indolizinyl, quinolinyl, benzofuran, benzimidazolyl, or benzothienyl), provided that at least one ring within the ring system is aromatic and the point of attachment is through an aromatic ring atom. In some embodiments, the nitrogen and / or sulfur ring atoms of a heteroaryl group are optionally oxidized to provide N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless constrained by the definition of a heteroaryl substituent, such heteroaryl groups may be acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamido, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.

[0125] The term "heteroaralkyl" refers to the group alkylene-heteroaryl, where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0126] "Heteroaryloxy" refers to -O-heteroaryl.

[0127] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to saturated or unsaturated groups having a single ring or multiple fused rings, including fused bridges and spiro ring systems, and having 3 to 20 ring atoms, including 1 to 10 heteroatoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen; in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided the point of attachment is through a non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, -S(O)-, or -SO2- moiety.

[0128] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine. These include benzo[b]thiophene, ...

[0129] Unless otherwise constrained by the definition of a heterocyclic substituent, such heterocyclic groups may include deuterium, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted alkyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO 2- Alkyl, -SO 2- It may be optionally substituted with 1 to 5 substituents, or 1 to 3 substituents selected from substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0130] "Heterocyclyloxy" refers to the group --O-heterocyclyl.

[0131] The term "heterocyclylthio" refers to the group heterocyclic -S-.

[0132] The term "heterocyclene" refers to a diradical group formed from a heterocycle, as defined herein.

[0133] The term "hydroxyamino" refers to the group --NHOH.

[0134] "Nitro" refers to the NO2 group.

[0135] "Oxo" refers to the (=O) atom.

[0136] "Sulfonyl" refers to an SO2 alkyl group, an SO2-substituted alkyl group, or a SO 2- Alkenyl group, SO2-substituted alkenyl group, SO 2- Cycloalkyl groups, SO2-substituted cycloalkyl groups, SO 2- Cycloalkenyl groups, SO2-substituted cycloalkenyl groups, SO 2- Aryl groups, SO2-substituted aryl groups, SO 2- Heteroaryl groups, SO2-substituted heteroaryl groups, SO 2- Sulfonyl refers to heterocyclic and SO-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-.

[0137] "Sulfonyloxy" refers to an OSO2 alkyl group, an OSO2-substituted alkyl group, or an OSO 2- Alkenyl group, OSO2-substituted alkenyl group, OSO2- Cycloalkyl groups, OSO2-substituted cycloalkyl groups, OSO 2- Cycloalkenyl group, OSO2-substituted cycloalkenyl group, OSO 2- Aryl group, OSO2-substituted aryl group, OSO 2- Heteroaryl groups, OSO2-substituted heteroaryl groups, OSO 2- refers to heterocyclic groups, and OSO2-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0138] The term "aminocarbonyloxy" refers to the group -OC(O)NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic, where alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

[0139] "Thiol" refers to the group --SH.

[0140] The term "thioxo" or "thioketo" refers to the atom (=S).

[0141] The term "alkylthio" or "thioalkoxy" refers to an -S-alkyl group, where alkyl is as defined herein. In some embodiments, sulfur may be oxidized to -S(O)-. Sulfoxides can exist as one or more stereoisomers.

[0142] The term "substituted thioalkoxy" refers to an --S-substituted alkyl group.

[0143] The term "thioaryloxy" refers to an aryl-S- group, where aryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0144] The term "thioheteroaryloxy" refers to the group --S-heteroaryl, where heteroaryl is as defined herein, including an optionally substituted aryl group, as defined herein.

[0145] The term "thioheterocyclooxy" refers to the group -S-heterocyclyl, where heterocyclyl is as defined herein, including optionally substituted heterocyclyl groups, as defined herein.

[0146] Further to the disclosure herein, when used to modify a particular group or radical, the term "substituted" can also mean that one or more hydrogen atoms of the particular group or radical are each, independently of one another, replaced with the same or different substituents as defined below.

[0147] In addition to the groups disclosed for each individual term herein, substituents (such as ═O, ═NR, etc.) to replace one or more hydrogens on a saturated carbon atom in the specified group or radical are also included. 70 , =N-OR 70 , =N2, or =S) is a deuterium, -R 60 , halo, =O, -OR 70 , -SR 70 , -NR 80 R 80 , trihalomethyl, -CN, -OCN, SCN, NO, NO2, =N2, -N3, -SO2R 70 , -SO2O - M + , -SO2OR 70 , -OSO2R 70 , OSO2O - M + , OSO2OR 70 , P(O)(O - )2(M + )2, P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R70 , -C(NR 70 )R 70 , -C(O)O - M + , -C(O)OR 70 , -C(S)OR 70 ,-C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OM + , -OC(O)OR 70 ,-OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 ,-NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 , and -NR 70 C(NR 70 )NR 80 R 80 where R 60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; and each R 70 are independently hydrogen or R 60 and each R 80 are independent, R 70 or alternatively two R 80’together with the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl, which optionally contains 1 to 4 additional heteroatoms, which may be the same or different, selected from the group consisting of O, N, and S, wherein N may have —H or C1-C3 alkyl substitution; and each M + is a counter ion with a net single positive charge. + are independently, e.g., K + , Na + , Li + Alkaline ions such as + N(R 60 )4, or ammonium ions such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript 0.5 means that one of the counterions of such divalent alkaline earth ions is the ionized form of the compounds of the present disclosure, and the other typical counterion, such as chloride, or a doubly ionized compound disclosed herein, can serve as the counterion of such divalent alkaline earth ion, or a doubly ionized compound disclosed herein can serve as the counterion of such divalent alkaline earth ion.) A specific example is -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-1-yl and N-morpholinyl.

[0148] Further to the disclosure herein, substituents for hydrogen on unsaturated carbon atoms of "substituted" alkene, alkyne, aryl, and heteroaryl groups include deuterium, -R, unless otherwise specified. 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -NR 80 R 80, trihalomethyl, -CF3, -CN, OCN, SCN, NO, NO2, N3, SO2R 70 , SO3 - M + , SO3R 70 , OSO2R 70 , OSO3 - M + , -OSO3R 70 , -PO3 2 (M + )2, P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , N.R. 70 C(O)R 70 , N.R. 70 C(S)R 70 , N.R. 70 CO2 - M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 where R 60 , R70 , R 80 and M + is as previously defined, except that in the case of a substituted alkene or alkyne, the substituent may be -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0149] In addition to the groups disclosed for each individual term herein, the substituents for the hydrogen on the nitrogen atom of a "substituted" heteroalkyl group and a cycloheteroalkyl group are, unless otherwise specified, -R 60 , -OM + , -OR 70 , -SR 70 , -SM + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2OM + , -S(O)2OR 70 , -OS(O)2R 70 ,-OS(O)2OM + , -OS(O)2OR 70 , -P(O)(O)2(M + )2, -P(O)(OR 70 )OM + , -P(O)(OR 70 )(OR 70 ), C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -C(O)OR 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )NR 80 R 80 , -OC(O)R 70 , -OC(S)R 70 , -OC(O)OR 70 , -OC(S)OR 70 , -NR 70 C(O)R70 , -NR 70 C(S)R 70 , -NR 70 C(O)OR 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)NR 80 R 80 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )NR 80 R 80 where R 60 , R 70 , R 80 and M + is as previously defined.

[0150] Further to the disclosure herein, in some embodiments, a substituted group has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0151] Unless otherwise specified, it is understood that polymers defined herein are not intended to encompass any of the above-defined substituents, achieved by defining the substituent to have further substituents thereon (e.g., a substituted aryl having a substituted aryl group as a substituent itself substituted with a substituted aryl group, which in turn is substituted with a substituted aryl group, etc.). In such cases, the maximum number of such substitutions is three. For example, the sequential substitution of substituted aryl groups specifically contemplated herein is limited to substituted aryl-(substituted aryl)-substituted aryl. However, for example, a substituent defined as a polyether may have more than three sequential substitutions, e.g., -O-(CHCHO). n It may contain -H, where n can be 1, 2, 3, or more.

[0152] Unless otherwise indicated, naming of substituents not expressly defined herein is accomplished by naming the terminal portion of the functional group followed by the adjacent functional group toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-OC(O)-.

[0153] For any of the groups disclosed herein that contain one or more substituents, it is of course understood that such groups do not include any substitutions or substitution patterns that are sterically infeasible and / or synthetically impractical. Furthermore, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0154] When a substituent or group is described as "containing deuterium," it is to be understood that the substituent or group itself can be deuterium, or the substituent or group can contain at least one deuterium substitution in its chemical structure. For example, if the substituent "-R" is defined as "containing deuterium," it is to be understood that -R can be -D (-deuterium), or a group such as -CD consistent with the other requirements set forth for -R.

[0155] As used herein, the term "fat" refers to a compound having a long-chain (linear) hydrophobic moiety composed of hydrogen and 4 to 26 carbon atoms, and may be fully saturated or partially unsaturated.

[0156] The phrases "pharmaceutically acceptable," "physiologically acceptable," and the like are used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. When referring to salts, the phrases "pharmaceutically acceptable salt," "physiologically acceptable salt," and the like mean salts that are acceptable for administration to a patient, such as a mammal (salts having counterions that have acceptable mammalian safety for a given administration regimen). As is well known in the art, such salts can be derived from pharmaceutically acceptable inorganic or organic bases such as sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and, where the molecule contains a basic functional group, from addition salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, sulfamate, phosphates, nitrates, perchlorates, and the like, as well as from addition salts with organic acids such as formates, tartrates, besylates, mesylates, acetates, maleates, oxalates, fumarates, benzoates, salicylates, succinates, oxalates, glycolates, hemixalates, hemifumarates, propionates, stearates, lactates, citrates, ascorbates, pamoates, hydroxymaleates, phenylacetates, glutamates, 2-acetoxybenzoates, tosylates, ethanedisulfonates, isethionates, and the like.

[0157] The term "salt thereof" refers to a compound formed when the proton of an acid is replaced by a cation, such as a metal cation or an organic cation. Where applicable, the salt is a pharmaceutically acceptable salt, but this is not required for salts of intermediate compounds that are not intended for administration to patients. For example, salts of the present compounds include those in which the compound is protonated with an inorganic or organic acid to form a cation, and has a conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0158] "Solvate" refers to a physical association of a compound or salt of the present disclosure with one or more solvent molecules, whether organic, inorganic, or a mixture of both. This physical association includes hydrogen bonding. In certain instances, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvate can exist in an ordered and / or irregular arrangement. A solvate may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. When the solvent is water, the solvate formed is a hydrate (e.g., monohydrate, dihydrate, etc.). Thus, exemplary solvates include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc. Methods of solvation are generally known in the art.

[0159] "Stereoisomer" and "stereoisomers" refer to compounds that have the same atomic connectivity but different atomic arrangements in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. All forms of the compounds, such as racemates and optically pure stereoisomers, are contemplated herein. Chemical formulas and compounds that have at least one stereocenter but are drawn without reference to stereochemistry are intended to include both the racemate and the individual stereoisomers, such as R- and / or S-stereoisomers, and each permutation of those diastereomers as long as such diastereomers are geometrically feasible.

[0160] A "crystalline" solid is a type of solid whose fundamental three-dimensional structure contains a highly regular pattern of atoms or molecules forming a crystal lattice with long-range order, and therefore exhibits sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern. In some instances, a crystalline solid may exist in different crystalline forms known as "polymorphs," which have the same chemical composition but differ in the packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs can be characterized by, for example, the solubility, dissolution rate, bioavailability, chemical and physical stability, flowability, and compressibility of a compound. In the process of preparing polymorphs, further refinement can also be achieved in terms of overall physical or optical purity. As used herein, the term "non-crystalline" refers to a solid material that does not have substantial long-range order in the position of its molecules; the molecules are arranged randomly, such that there is effectively no well-defined arrangement, e.g., no molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions, and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have substantially sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halo) appear in its XRPD pattern. Broad peaks are characteristic of amorphous solids. Thus, a "non-crystalline" subject compound / material is a compound / material characterized as having substantially no crystallinity, e.g., less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, or 0%, i.e., at least 90%, at least 92%, at least 94%, at least 96%, at least 98%, or 100% amorphous, as determined by XRPD. For example, in some embodiments, percent crystallinity can be determined by measuring the intensity of one or more peaks in an XRPD diffractogram compared to a reference peak, which may be a known standard or internal standard.For example, other characterization techniques such as differential scanning calorimetry (DSC) analysis, Fourier transform infrared spectroscopy (FTIR), and other quantitative methods, including quantitative methods that provide the above percentages in terms of weight percent, may be used to determine the percent amorphous or crystalline of a subject compound / substance.

[0161] When referring to X-ray powder diffraction (XRPD) patterns of materials of the present disclosure, the phrase "characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from" should be understood to include those materials characterized as having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more (including all) of the recited characteristic XRPD diffraction peaks. Furthermore, this phrase is intended to be open to the inclusion of other XRPD diffraction peaks not recited. Unless otherwise stated, XRPD analysis was performed on an X-ray powder diffractometer using a CuKα radiation source (wavelength=1.54060 Å).

[0162] "Tautomer" refers to alternative forms of molecules that differ only in the electronic bonding of atoms and / or in the position of protons, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. One of ordinary skill in the art will recognize that other tautomeric ring atom configurations are possible. For example, compounds containing acid and base groups in the same molecule shown in neutral form may exist in zwitterionic form, as in amino acid / ammonium carboxylate tautomers. Thus, compounds of the present disclosure shown containing both amino phosphate and dihydrogen phosphate functionality in neutral form may exist in zwitterionic form as ammonium monohydrogen phosphate zwitterions.

[0163] "Prodrug" is meant to refer to a compound that can be converted into the biologically active compound described herein under physiological conditions or by solvation. Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. For example, prodrugs such as esters, phosphate esters, etc. may be inactive when administered to a subject, but are converted into active compounds in vivo, for example, by hydrolysis to free carboxylic acid or free hydroxyl groups. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. As used herein, prodrugs of active compounds can be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to form a free hydroxyl, amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively.Examples of prodrugs include, but are not limited to, derivatives of amine functional groups in active compounds, such as esters (e.g., acetates, formates, benzoates, etc.), carbonates, carbamates, and dihydrogen phosphate derivatives of alcohols or amides (e.g., acetamides, formamides, benzamides, etc.), carbamates, etc.

[0164] It will be understood that the compounds herein may exist in different salt, solvate, and stereoisomeric forms, and the present disclosure is intended to include all permutations of salts, solvates, and stereoisomers, for example, solvates of pharmaceutically acceptable salts of the stereoisomers of the subject compounds.

[0165] A "vapor" is a solid substance in the gas phase at a temperature below its critical temperature, meaning that the vapor can be condensed to a liquid by increasing its pressure without decreasing the temperature.

[0166] As used herein, an "aerosol" is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, xenon, argon, and other gases, and mixtures thereof). As used herein, a "mist" is a subset of aerosol, distinct from vapor, and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The liquid droplets of an aerosol or mist may contain a drug moiety dissolved in an aqueous liquid, an organic solvent, or a mixture thereof. The gas phase of an aerosol or mist may contain air, oxygen, helium, or other gases, such as nitrous oxide, xenon, and / or argon, including mixtures thereof. A mist does not contain solid particles. The aerosols and mists of the present disclosure can be generated by any suitable method and device, examples of which are described herein, for example, through the use of an inhaler or nebulizer.

[0167] As used herein, the term "composition" is equivalent to the term "formulation."

[0168] As used herein, the term " inhalation session " describes the administration event that a subject inhales a given dose of drug, regardless of the number of breaths required to inhale a given dose.For example, a subject prescribed to take 10 mg of drug twice a day will perform two inhalation sessions, and each inhalation session will provide 10 mg of drug.The duration and number of breaths of each inhalation session will depend on factors such as the inhalation device used, the amount of drug inhaled per breath, the drug concentration of the dosage form, and the breathing pattern of the subject.

[0169] As used herein, the term "treating" or "treatment" refers to treating or curing a disease or medical condition in a patient, e.g., a mammal (especially a human), including ameliorating a disease or medical condition, e.g., causing elimination or regression of the disease or medical condition in a patient; inhibiting a disease or medical condition, e.g., by slowing or arresting the onset of the disease or medical condition in a patient; or alleviating the symptoms of a disease or medical condition in a patient. Treatment may provide a therapeutic benefit, such as eradication or amelioration of one or more of the underlying symptoms, physiological or psychological symptoms associated with a disease or disorder, such that an improvement is observed in the patient, despite the fact that the patient may still be affected by the condition. In some embodiments, treatment may refer to prophylaxis, i.e., preventing the occurrence of a disease or medical condition or otherwise delaying the onset of a disease or medical condition in a patient.

[0170] A "patient" or "subject," as used interchangeably herein, may be any mammal, including, for example, a human. The patient or subject may have the condition to be treated or may be susceptible to the condition to be treated.

[0171] The term "administration schedule" refers to a plan that chronologically shows the type, amount, duration, and procedure of drug treatment, including the dosage, administration method, administration order, and administration date of each drug. The designated administration date is determined before the start of drug administration. Administration continues by repeating a series of administration schedules, each of which is considered a "course." A "continuous" administration schedule means daily administration without interruption during a treatment course. If the administration schedule follows an "intermittent" administration schedule, days of administration may be followed by "rest days" or days of non-administration of the drug during the course. A "drug holiday" indicates that the drug is not administered according to a predetermined administration schedule. For example, after receiving several courses of treatment, a subject may be prescribed a regulated drug holiday as part of the administration schedule, for example, before resuming active treatment.

[0172] All diseases and disorders listed herein may be defined as set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published by the American Psychiatric Association, or the International Classification of Diseases (ICD), published by the World Health Organization.

[0173] In some embodiments, the present disclosure provides a method of delivering a hallucinogen to a patient in need thereof, comprising administering the hallucinogen dissolved in an aerosol, e.g., a mist, via inhalation. In some embodiments, the aerosol is generated without the application of external heat (this does not exclude a slight temperature increase caused by the formation of the aerosol itself, such as by a vibrating mesh or other nebulizer, although such a slight temperature increase can often be offset by vaporization of the agent, resulting in cooling of the composition).

[0174] Hallucinogens include 5-HT agonists, including partial and full agonists. 2AHallucinogens may be receptor agonists. Hallucinogens include: i) phenethylamine derivatives, including, but not limited to, 3,4-methylenedioxymethamphetamine (MDMA); 2C-X phenethylamines, such as 2,5-dimethoxy-4-bromophenethylamine (2C-B), (4-chloro-2,5-dimethoxyphenethyl)amine (2C-C), 2,5-dimethoxy-4-methylphenethylamine (2C-D); 3,4-methylenedioxy-N-ethylamphetamine; 1,3-Benzodioxolyl-N-methylbutanamine (MBDB); 3,4,5-trimethoxyamphetamine (TMA), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,3,5-trimethoxyamphetamine (TMA-4), 2,3,6-trimethoxyamphetamine (TMA-5), and 2,4,6-trimethoxyamphetamine (TMA-6). trimethoxyamphetamines (TMA), such as toxamphetamine (TMA-6); trimethoxyphenethylamines, such as 3,4,5-trimethoxyphenethylamine (mescaline) and isomescaline (2,3,4-trimethoxyphenethylamine); 2,5-dimethoxy-4-methylamphetamine (DOM); 2,5-dimethoxy-4-ethylamphetamine (DOET); 1-(2,5-dimethoxyphenyl)-2-aminopropane; 2,5-dimethoxy-4-iodoamphetamine (DOI), including (R)-DOI; 4-chloro-2,5-dimethoxyamphetamine (DOC); 4-bromo-2,5-dimethoxyamphetamine (DOB); 4-bromo-2,5-dimethoxymethamphetamine (MDOB); and 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (2C-BCB);or deuterated analogs thereof, as well as pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, (ii) psilocybin (3-[2-(dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate) and derivatives thereof, such as, but not limited to, psilocin (4-hydroxy-N,N-dimethyltryptamine), N-desmethyl-psilocybin (3-[2-(methylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate), 4-HO-NMT (4-hydroxy-N-methyltryptamine), norbaeocystin ([3-(2-aminoethyl)-1H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, 3-[2-(N,N,N-trimethylamino)ethyl]-1H-indol-4-yl Tryptamine derivatives, including dihydrogen phosphate salts, and 4-hydroxyTMT salts (salts of 4-hydroxy-N,N,N-trimethyltryptamine); N,N-dimethyltryptamine (DMT, also referred to herein as 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine); 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT); 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT); ibogaine (tryptamine complex); or deuterated analogs thereof, such as 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d; 10 ), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ), psilocin-d 10(3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol), N,N-bis(methyl-d3)-2-(5-methyl-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4, N,N-bis(methyl-d3)-2-(5-(methyl-d3)-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4, and the like, as well as pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof; (iii) The hallucinogen may be any desired agent that provides a hallucinogenic effect, including, but not limited to, lysergamide, e.g., lysergic acid diethylamide (LSD) and its derivatives, e.g., LA-SS-Az ("LSZ" or (2S,4S)-1-[[(8β)-9,10-didehydro-6-(methyl)ergolin-8-yl]carbonyl]-2,4-dimethylazetidine); or deuterated analogs thereof, as well as pharmaceutically acceptable salts, solvates, or stereoisomers thereof; any combination thereof.

[0175] In some embodiments, the hallucinogen is a compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), and Formula (VI-b) described herein, any exemplary compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, or a combination thereof. In some embodiments, the hallucinogen can be delivered as an aerosol, such as a mist, with a carrier such as air, oxygen, or a mixture of helium and oxygen. In some embodiments, the carrier can be a mixture of helium and oxygen heated to about 50°C to about 60°C.

[0176] In some embodiments, the hallucinogen is N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 4-hydroxy-N,N-dimethyltryptamine (psilocin), DMT-d 10 (2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), 5-MeO-DMT-d 10 (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), and 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (psilocin-d 10 ), or one or more pharmaceutically acceptable salts or solvates thereof.

[0177] In some embodiments, the hallucinogen is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0178] In some embodiments, the hallucinogen is 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0179] In some embodiments, the hallucinogen is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0180] In some embodiments, the hallucinogen comprises deuterated tryptamine. In some embodiments, the hallucinogen comprises 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d 4( DMT-d 10), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is 3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol (psilocin-d 10 ), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is N,N-bis(methyl-d3)-2-(5-methyl-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the hallucinogen is N,N-bis(methyl-d3)-2-(5-(methyl-d3)-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt or solvate thereof.

[0181] In some embodiments, the hallucinogen can be psilocybin or a derivative thereof, hi some embodiments, the hallucinogen is psilocin, or a pharmaceutically acceptable salt or solvate thereof.

[0182] Additionally, hallucinogens can be delivered systemically to a patient's central nervous system by inhalation. Air, oxygen, or a mixture of helium and oxygen can be heated to about 55°C to about 56°C. When a mixture of helium and oxygen is used as a carrier, helium can be present in the oxygen and helium mixture at about 50%, 60%, 70%, 80%, or 90% by volume, and oxygen can be present in the mixture at about 50%, 40%, 30%, 20%, or 10% by volume.

[0183] The method can further include administering a pre-treatment inhalation therapy to the patient prior to administration of the hallucinogen-containing aerosol. The pre-treatment can include administering to the patient by inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C (e.g., about 90, 100, 110, or 120°C).

[0184] The method includes (i) administering to the patient by inhalation a mixture of helium and oxygen heated to about 90°C to about 120°C (e.g., about 90, 100, 110, or 120°C), followed by (ii) administering to the patient by inhalation an aerosol containing a mixture of helium and oxygen heated to about 50°C to about 60°C (e.g., about 50, 52, 53, 56, 58, or 60°C) and a hallucinogen, followed by repeating steps (i) and (ii). Steps (i) and (ii) may be repeated 1, 2, 3, 4, 5, or more times.

[0185] In some embodiments, there is provided a method of treating a central nervous system (CNS) or psychological disorder comprising administering a hallucinogen in the form of an aerosol, such as a mist, by inhalation.

[0186] The hallucinogen can be delivered as an aerosol with a carrier such as, for example, air, oxygen, a mixture of helium and oxygen, a mixture of nitrous oxide (or a noble gas, e.g., xenon and / or argon) with oxygen or air, or another gas or gas mixture. The helium and oxygen mixture can be heated to about 50°C to about 60°C (e.g., about 50, 52, 53, 56, 58, or 60°C) prior to administering the aerosol containing the hallucinogen to the patient.

[0187] Examples of central nervous system or psychological disorders include melancholic depression, atypical depression, dysthymia, anxiety disorders, obsessive-compulsive disorder, addictions (drug addiction, tobacco addiction, opioid addiction), alcoholism, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation or suicide attempts, bipolar disorder and related disorders, generalized anxiety disorder (GAD), social anxiety disorder, anorexia nervosa, bulimia nervosa, Alzheimer's disease, and cluster headache. The disorder may be pain or migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset dysphagia, dementia, mild neurocognitive disorders, sexual dysfunction, gambling disorder, eating disorders such as anorexia nervosa, bulimia nervosa, binge eating disorder, and sexual perversions such as, for example, childhood sexual disorders, conduct disorders, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and cross-dressing disorder, or any other disorder described herein.

[0188] In some embodiments, the hallucinogen is delivered to the patient's central nervous system by inhalation, resulting in at least a 25% (e.g., at least about 25, 30, 35, 40, 45, 50% or more) improvement in bioavailability of the drug compared to oral delivery, or a C max at least a 25% (e.g., at least about 25, 30, 35, 40, 45, 50% or more) increase in T compared to oral delivery max at least a 50% (eg, at least a 50, 60, 70, 80% or more) reduction in, or a combination thereof, is obtained.

[0189] For example, the good aqueous solubility of most hallucinogens, including DMT (salt form), makes inhalation of aerosols, such as mists, a possible route of administration. However, inhalation of mists is primarily used for local rather than systemic delivery of drugs and faces multiple challenges related to inconsistent and incomplete dose delivery, variability in breathing patterns, dose deposition in the upper respiratory tract, etc. Provided herein are methods for inhalation administration of mists of hallucinogens.

[0190] hallucinogenic drugs

[0191] Therapeutic agents of the present disclosure may include any desired hallucinogen. As used herein, the term "psychedelic," "hallucinogenic compound," "psychedelic agent," or "psychedelic drug" refers to a compound that stimulates the production of serotonin 5-HT 2A The present invention encompasses multiple compounds, including pharmaceutically acceptable stereoisomers, salts, and solvates thereof, including receptor agonists (e.g., lyseric acid diethylamide (LSD)), empathogens (i.e., serotonin (5-HT)-releasing agents, e.g., 3,4-methylenediamine dimethicone metabonitrile deagonistrin (MDMA)), and dissociative anesthetics (i.e., N-methyl-D-aspartate (NMDA) receptor agonists; e.g., nitrous oxide, xenon, argon, ketamine, and dextromethorphan). Most hallucinogens fall into the following groups: tryptamines (also referred to herein as tryptamine derivatives), phenethylamines (also referred to herein as phenethylamine derivatives), or lysergamides. All of these drugs release serotonin 5-HT receptors, which modulate the activity of key circuits in the brain involved in sensory perception and cognition. 2AActivates receptors. Tryptamine derivatives include those described herein, such as 5-methoxy-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-dimethyltryptamine (5-OH-DMT), dimethyltryptamine (DMT), or derivatives thereof, such as deuterated analogs. 5-OH-DMT is also known as bufotenine. 5-MeO-DMT is a prodrug that produces bufotenine upon demethylation. DMT, also known as N,N-dimethyltryptamine, is the primary active ingredient in ayahuasca. Other hallucinogens are discussed below.

[0192] Derivatives include any compound made from a hallucinogen, such as one of the hallucinogens described herein, for example, by replacing an atom in the hallucinogen with another atom or group of atoms, rearranging two or more atoms in the hallucinogen, ionizing the hallucinogen, or forming a salt of one of the hallucinogens.

[0193] Unless expressly indicated to the contrary, the term "derivative" does not imply that the derivative is necessarily synthesized using the parent compound as a starting material or intermediate, although in some cases the derivative may be synthesized from the parent compound. In some embodiments, derivatives of hallucinogens have therapeutic activity.

[0194] As used herein, "5-HT 2A"Receptor agonist" refers to a compound that increases the activity of the 5-hydroxytryptamine 2A receptor, which is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family. Examples of such agonists include, but are not limited to, the phenethylamine derivatives, tryptamine derivatives, and / or lysergamides described herein, such as psilocybin and its derivatives (e.g., psilocin, N-desmethyl-psilocybin, 4-HO-NMT, norbeocystin, 3-[2-(N,N,N-trimethylamino)ethyl]-1H-indol-4-yl). dihydrogen phosphate salt, and 4-hydroxy TMT salt), DOI (±)-1-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (95% R enantiomer) (substituted amphetamine); LA-SS-Az ("LSZ" or (2S,4S)-1-[[(8β)-9,10-didehydro-6-(methyl)ergolin-8-yl]carbonyl]-2,4-dimethylazetidine) (tryptamine complex) );2C-BCB(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine;3,4,5-trimethoxyphenethylamine (mescaline);ibogaine;N,N-dimethyltryptamine (DMT);5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT);5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT);2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 );2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8);2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10);2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2(5-MeO-DMT-d5);2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4(5-MeO-DMT-d 13 ); Psilocin-d 10 (3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol); N,N-bis(methyl-d3)-2-(5-methyl-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4, N,N-bis(methyl-d3)-2-(5-(methyl-d3)-1H-indol-3-yl)ethan-1-amine-1,1,2,2-d4; Formula (I), Formula (II) described herein , compounds of Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), and Formula (VI-b); any exemplary compound described herein; and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof; or combinations thereof.

[0195] In some embodiments, the hallucinogen is a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9 and R 10 are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0196] X1 and X2 can be the same or different. In some embodiments, X1 and X2 are the same. In some embodiments, X1 and X2 are hydrogen. In some embodiments, X1 and X2 are deuterium. In some embodiments, X1 and X2 are different. In some embodiments, X1 is hydrogen or deuterium, and X2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, X2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X2 is a substituted C1-C6 alkyl. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, or -CFH. 2、 In some embodiments, one of X1 and X2 is deuterium and the other is hydrogen. In some embodiments, one or more of X1 and X2 is a substituted or unsubstituted C3-C 10In some embodiments, one or more of X and X is an unsubstituted C-C 10 In some embodiments, one or more of X and X are substituted C-C alkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 It is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, X1 and / or X2 are unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0197] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0198] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is substituted C1-C6 alkyl. When R2 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is substituted or unsubstituted C3-C6 alkyl. 10 In some embodiments, R2 is an unsubstituted C3-C 10 In some embodiments, R2 is a substituted C3-C6 alkyl group, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10 In some embodiments, R2 is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0199] R4 and R5 can be the same or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxy. In some embodiments, R4 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R4 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc.

[0200] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxy. In some embodiments, R5 is an unsubstituted C 1-R5 is a C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R5 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is a substituted alkoxy. When R5 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may include one or more substituents. For example, if the alkoxy group is a C alkoxy group (i.e., a methoxy group), the substituted C alkoxy group may be -OCDH, -OCD, H, -OCD, -OCFH, -OCF, H, -OCF, etc.

[0201] R6 and R7 can be the same or different. R6 and R7 can independently be hydrogen, deuterium, or halogen, such as -Br, -F, -Cl, or -I.

[0202] R9 and R 10 can be the same or different. In some embodiments, R and R 10 In some embodiments, R and R 10 is hydrogen. In some embodiments, R and R 10 In some embodiments, R is hydrogen and R 10 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R9 and / or R 10is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R9 and / or R 10 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R9 and / or R 10 is a substituted or unsubstituted C3-C 10 In some embodiments, R and / or R are cycloalkyl. 10 is unsubstituted C3-C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R and / or R 10 is substituted C3-C 10 Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R and / or R 10 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0203] In some embodiments, the hallucinogen is a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R 10 In some embodiments, any one or more of X, X, Y, Y, R, R, R, R, and R optionally contain deuterium. 10 In some embodiments, at least one of X, X, Y, Y, R, R, and R 10In some embodiments, at least one of X, X, Y, Y, R, and R 10 At least one of X, X, R, and R comprises deuterium. 10 In some embodiments, X, X, Y, Y, R, and R 10 In some embodiments, X1, X2, and R5 comprise deuterium. In some embodiments, X1, X2, Y1, Y2, R5, R9, and R 10 contains deuterium.

[0204] In some embodiments, the hallucinogen is a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are independently selected from the group consisting of hydrogen and deuterium; R is [ka] and; R2 is selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R4 and R5 are independently selected from hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy, and unsubstituted or substituted phosphoryloxy; R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R9, R 10 and R 11are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.

[0205] Y1 and Y2 can be the same or different. In some embodiments, Y1 and Y2 are the same. In some embodiments, Y1 and Y2 are hydrogen. In some embodiments, Y1 and Y2 are deuterium. In some embodiments, Y1 and Y2 are different. In some embodiments, one of Y1 and Y2 is deuterium and the other is hydrogen.

[0206] In some embodiments, R2 is deuterium. In some embodiments, R2 is hydrogen. In some embodiments, R2 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. In some embodiments, R2 is substituted C1-C6 alkyl. When R2 is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R2 is substituted or unsubstituted C3-C6 alkyl. 10 In some embodiments, R2 is an unsubstituted C3-C 10 In some embodiments, R2 is a substituted C3-C6 alkyl group, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. 10In some embodiments, R2 is cycloalkyl. Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R2 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0207] R4 and R5 can be the same or different. In some embodiments, R4 is deuterium. In some embodiments, R4 is hydrogen. In some embodiments, R4 is hydroxy. In some embodiments, R4 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R4 is substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R4 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R4 is a substituted alkoxy. When R4 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may contain one or more substituents. For example, when the alkoxy group is a C1 alkoxy group (i.e., a methoxy group), the substituted C1 alkoxy group may be -OCDH2, -OCD2H, -OCD3, -OCFH2, -OCF2H, -OCF3, etc. In some embodiments, R4 is an unsubstituted phosphoryloxy group (i.e., -OP(O)(OH)2 or its deprotonated form). In some embodiments, R4 is a substituted phosphoryloxy group in which one or more of the hydrogen atoms in -OP(O)(OH)2 is replaced with a substituent such as unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, or other substituents described herein.When both hydrogen atoms in -OP(O)(OH)2 are replaced with substituents, the substituents may be the same or different.

[0208] In some embodiments, R5 is deuterium. In some embodiments, R5 is hydrogen. In some embodiments, R5 is hydroxy. In some embodiments, R5 is an unsubstituted C 1-R5 is a C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R5 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R5 is an unsubstituted alkoxy group, examples of which include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentoxy, neopentoxy, and hexoxy. In some embodiments, R5 is a substituted alkoxy. When R5 is a substituted alkoxy, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The alkoxy group may include one or more substituents. For example, if the alkoxy group is a C alkoxy group (i.e., a methoxy group), the substituted C alkoxy group may be -OCDH, -OCD, H, -OCD, -OCFH, -OCF, H, or the like. In some embodiments, R is an unsubstituted phosphoryloxy group (i.e., -OP(O)(OH) or its deprotonated form). In some embodiments, R is a substituted phosphoryloxy group in which one or more of the hydrogen atoms in -OP(O)(OH) is replaced with a substituent such as an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted alkynyl, an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, an unsubstituted or substituted heteroaryl, or another substituent described herein. When both hydrogen atoms in -OP(O)(OH) are replaced with substituents, the substituents may be the same or different.

[0209] R6 and R7 can be the same or different. R6 and R7 can independently be hydrogen, deuterium, or halogen, such as -Br, -F, -Cl, or -I.

[0210] In some embodiments, R is [ka] R9 and R 10 can be the same or different. In some embodiments, R and R 10 In some embodiments, R and R 10 is hydrogen. In some embodiments, R and R 10 In some embodiments, R is hydrogen and R 10 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, R9 and / or R 10 is unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R9 and / or R 10 is a substituted C1-C6 alkyl. The alkyl group may contain one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH 2、 In some embodiments, R and / or R 10 is a substituted or unsubstituted C3-C 10 In some embodiments, R and / or R are cycloalkyl. 10 is unsubstituted C3-C 10 cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R and / or R 10 is substituted C3-C 10Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R and / or R 10 is unsubstituted or substituted alkenyl, for example, unsubstituted or substituted allyl.

[0211] In some embodiments, R is [ka] R9 and R 10 are described above. R9, R 10 , and R 11 can be the same or different. In some embodiments, R, R 10 , and R 11 are the same. In some embodiments, R, R 10 , and R 11 In some embodiments, R, R 10 , and R 11 are the same. 11 is hydrogen. In some embodiments, R 11 is the unsubstituted C 1- C alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, R 11 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 is a substituted or unsubstituted C3-C 10 In some embodiments, R 11 is unsubstituted C3-C 10and cycloalkyl, examples of which may include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. In some embodiments, R 11 is substituted C3-C 10 Preferred substituents include, but are not limited to, alkyl, deuterium, halogen (e.g., fluorine), hydroxyl, or polar substituents such as polyether substituents. The cycloalkyl group may contain one or more substituents. In some embodiments, R 11 is unsubstituted or substituted alkenyl, e.g., unsubstituted or substituted allyl. In some embodiments, R is a quaternary ammonium cation (where R, R 10 , and R 11 In some embodiments, R is a protonated ammonium cation, where R, R 10 , and R 11wherein one, two, or three are hydrogen. Examples of acids that may be used to prepare the pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthyl 2-sulfonic acid, benzoic ... toluene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, gallataric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycerin, Cholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g. For example, they include, but are not limited to, DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid, thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0212] In some embodiments, the hallucinogen is a compound of Formula (II-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, R 10 , and R 11 is as defined above for formula (II).

[0213] In some embodiments, the hallucinogen is a compound of Formula (II-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, and R 10 is as defined above for formula (II).

[0214] In some embodiments, the hallucinogen is a compound of Formula (II-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, R9, R 10 , and R 11 is as defined above for formula (II).

[0215] In some embodiments, the hallucinogen is a compound of Formula (II-d), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X1 and X2 are deuterium; Y1 and Y2 are hydrogen; R is [ka] and R2, R4, R5, R6, R7, and R 11 is as defined above for formula (II).

[0216] In some embodiments, the hallucinogen is: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0217] In some embodiments, the hallucinogen is: [ka] [ka] [ka] [ka] [ka] or at least one compound selected from the group consisting of a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0218] In some embodiments, the hallucinogen is a compound of Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), and / or Formula (II-d), wherein R 2、 At least one of R4, R5, R6, and R7 contains deuterium.

[0219] In some embodiments, R6 and / or R7 of the compounds described herein, e.g., compounds of Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), and Formula (II-d), are halogen.

[0220] In some embodiments, R4 and / or R5 of the compounds described herein, e.g., compounds of Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), and Formula (II-d), contain deuterium.

[0221] In some embodiments, X1, X2, Y1, Y2, R9, and R 10 In some embodiments, the hallucinogen is [ka] or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0222] In some embodiments, the hallucinogen is a compound of formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen and deuterium; R 2 and R 3 are independently hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6 alkyl, and -OR a selected from the group consisting of: R 4 and R 5 are independently hydrogen, deuterium, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a or R 4 and R 5 together with the atom to which they are attached optionally form an unsubstituted or substituted heterocycloalkyl or an unsubstituted or substituted heteroaryl; R 6 and R 7 are independently selected from the group consisting of hydrogen and unsubstituted or substituted C1-C6 alkyl; and Each Ra are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0223] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0224] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. 1and X 2 In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0225] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a is.

[0226] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 3is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 3 -OR a is.

[0227] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -SnPr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0228] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen, e.g., —Br, —F, —Cl, or —I. In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 5 -ORa In some embodiments, R 5 -SR a In some embodiments, R 5 is hydrogen, -OMe, or -OCD. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -OMe. In some embodiments, R 5 is -OCD3. In some embodiments, R 5 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms. 4 is -OCH3, -OCD3, -Br, -SCH3, -SCH2CH3, or -SCH2CH2CH3, and / or R 5 is hydrogen, -OMe, or -OCD3.

[0229] In some embodiments, R 4 and R 5 R, together with the atoms to which it is attached, forms a heterocycloalkyl or heteroaryl, and specifically includes a benzo[d][1,3]oxathiol group or a benzo[d][1,3]dioxole group. 4 and R 5 In embodiments where is bonded together with the atoms to which it is attached to form a heterocycloalkyl or heteroaryl (e.g., a benzo[d][1,3]oxathiol group, a benzo[d][1,3]dioxole group, etc.), the heterocycloalkyl or heteroaryl ring (e.g., an oxathiol ring, a dioxole ring, etc.) may be further substituted with substituents as defined herein, e.g., one or more halogen (e.g., fluorine) or deuterium substituents.

[0230] R 6 and R 7 can be the same or different. R 6 and R 7can independently be hydrogen, unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl), or C1-C6 alkyl substituted with one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0231] Each R a can independently be hydrogen, deuterium, unsubstituted C-C alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C-C alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3. a or -SR a Examples include, but are not limited to, -SMe, SCD 3、 SCF 3、 Examples include SEt, SnPr, SCH2CH2CF3, SCH2CH2CF2H, SCH2CH2CFH2, OMe, OCD3, OCF3, OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0232] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 At least one of the atoms contains deuterium.

[0233] In some embodiments, the hallucinogen is a compound of Formula (III-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, Z 1 and Z 2 is independently selected from the group consisting of hydrogen, deuterium, or fluorine; and X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6 , R 7 , and R a is as defined for formula (III).

[0234] Z 1 and Z 2 may be the same or different. In some embodiments, Z 1 and Z 2 are the same. In some embodiments, Z 1 and Z 2 is hydrogen. In some embodiments, Z 1 and Z 2 is deuterium. In some embodiments, Z 1 and Z 2 is fluorine. In some embodiments, Z 1 and Z 2 are different. In some embodiments, Z1 and Z 2 One of them is deuterium and the other is hydrogen.

[0235] In some embodiments, Z 1 , Z 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 6 , and R 7 At least one of the atoms contains deuterium.

[0236] In some embodiments, R 6 and R 7 are independently hydrogen, -CH3, or -OCD3.

[0237] In a preferred embodiment, the hallucinogen is at least one phenethylamine derivative selected from the group consisting of: [ka] [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0238] Hallucinogens may also include N-substituted phenethylamines (NSPs) and their derivatives.

[0239] In some embodiments, the hallucinogen is a compound of formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 2 and R 3are independently hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 2 and R 3 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; R 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of R 5 and R 6 are independently hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 5 and R 6 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl, or X 2 and W 1 taken together with the atom to which they are attached form an optionally unsubstituted or substituted heterocycloalkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 11 and R 12 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0240] In some embodiments, R 2 is deuterium. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 2 is cyano. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 2 is a substituted C1-C6 alkyl. 2When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 2 -OR a In some embodiments, R 2 -SR a is.

[0241] In some embodiments, R 3 is deuterium. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 3 is cyano. In some embodiments, R 3 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 3 is a substituted C1-C6 alkyl. 3 When R is substituted C1-C6, preferred substituents may include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 3 -OR a In some embodiments, R 3 -SR a is.

[0242] In some embodiments, R 2 and R 3 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0243] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、-SEt, -SnPr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0244] In some embodiments, R 5 is deuterium. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 5 is cyano. In some embodiments, R 5 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 5 is a substituted C1-C6 alkyl. 5 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 5 -OR a In some embodiments, R 5 -SR a In some embodiments, R 5is hydrogen, -OMe, or -OCD. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -OMe. In some embodiments, R 5 is -OCD3. In some embodiments, R 5 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0245] In some embodiments, R 6 is deuterium. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 6 is cyano. In some embodiments, R 6 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 6 is a substituted C1-C6 alkyl. 6 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 6 -OR a In some embodiments, R 6 -SR a In some embodiments, R 6 is hydrogen, -OMe, or -OCD. In some embodiments, R6 is hydrogen. In some embodiments, R 6 is -OMe. In some embodiments, R 6 is -OCD3. In some embodiments, R 6 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0246] In some embodiments, R 5 and R 6 together with the atom to which they are attached form an optionally unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0247] W 1 and W 2 may be the same or different. In some embodiments, W 1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1and W 2 One of the atoms is deuterium and the other is hydrogen.

[0248] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0249] In some embodiments, X 2 and W 1 together with the atom to which they are attached form an unsubstituted or substituted heterocycloalkyl, for example, piperidine or pyrrolidine, which may be substituted or unsubstituted.

[0250] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 is hydrogen or deuterium, and Y 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0251] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0252] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0253] In some embodiments, R 8 is deuterium. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R 8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0254] In some embodiments, R 9 is deuterium. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R 9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0255] In some embodiments, R 10 is deuterium. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0256] R 11 and R 12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11 is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0257] In some embodiments, R 12 is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12 is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0258] In some embodiments, R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0259] Each R a can independently be hydrogen, deuterium, unsubstituted C-C alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C-C alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3. aor -SR a Examples include, but are not limited to, -SMe, SCD 3、 SCF 3、 Examples include SEt, SnPr, SCH2CH2CF3, SCH2CH2CF2H, SCH2CH2CFH2, OMe, OCD3, OCF3, OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0260] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 At least one of the atoms contains deuterium.

[0261] In some embodiments, the hallucinogen is a compound of formula (IV-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, X 1 and X 2 is deuterium; and W 1 , W 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R ais as defined above for formula (IV).

[0262] In some embodiments, W 1 , W 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0263] In some embodiments, the hallucinogen is a compound of formula (IV-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, W 1 and W 2 is deuterium, and X 1 X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 ,,R 12 , and R a is as defined above for formula (IV).

[0264] In some embodiments, X 1 , X 2 , Y 1 , Y 2 , R 2 , R 3 , R 4, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 At least one of the atoms contains deuterium.

[0265] In some embodiments, the hallucinogen is a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 3 and R 6 -OR a and R 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R 9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 11 and R 12 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0266] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR aIn some embodiments, R 4 -SMe, -SCD 3、 -SCF 3、 -SEt, -SnPr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0267] W 1 and W 2 may be the same or different. In some embodiments, W 1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1 and W 2One of the atoms is deuterium and the other is hydrogen.

[0268] X 1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0269] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y1 is hydrogen or deuterium, and Y 2 is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0270] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0271] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R 8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0272] In some embodiments, R 8is deuterium. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R 8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R 8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0273] In some embodiments, R 9is deuterium. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R 9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R 9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0274] In some embodiments, R 10is deuterium. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R 10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0275] R 11 and R12 can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11 is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0276] In some embodiments, R 12 is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12 is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0277] In some embodiments, R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0278] Each R a can independently be hydrogen, deuterium, unsubstituted C-C alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C-C alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3. a or -SR a Examples include, but are not limited to, -SMe, SCD 3、 SCF 3、 Examples include SEt, SnPr, SCH2CH2CF3, SCH2CH2CF2H, SCH2CH2CFH2, OMe, OCD3, OCF3, OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0279] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0280] In some embodiments, the hallucinogen is a compound of Formula (Va), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium; R 12 is hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , and R a is as defined above for formula (V).

[0281] In some embodiments, W 1 , W 2 , X 1, X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0282] In some embodiments, the hallucinogen is a compound of Formula (Vb), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen and deuterium; R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 and R a is as defined above for formula (V).

[0283] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 3 , R 4 , R 6 , R 7 , R8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0284] In some embodiments, the hallucinogen is a compound of formula (VI), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 2 and R 5 -OR a and R 4 is hydrogen, deuterium, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and S.R. a is selected from the group consisting of W 1 and W 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; X 1 and X 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; Y 1 and Y 2 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 7 are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl; R 8 , R 9 , and R 10 are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a is selected from the group consisting of R 11 and R 12are independently hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a、 and -SR a or R 11 and R 12 optionally, together with the atom to which they are attached, form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl; and Each R a are independently selected from the group consisting of hydrogen, deuterium, and unsubstituted or substituted C1-C6 alkyl.

[0285] In some embodiments, R 4 is deuterium. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 4 is cyano. In some embodiments, R 4 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 4 is a substituted C1-C6 alkyl. 4 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 4 -OR a In some embodiments, R 4 -SR a In some embodiments, R 4 -SMe, -SCD3、 -SCF 3、 -SEt, -SnPr, -SCH2CH2CF3, -SCH2CH2CF2H, -SCH2CH2CFH2, -Me, -CD3, -CF3, -OMe, -OCD3, -OCF3, -OCH2CH2CF3, -OCH2CH2CF2H, -OCH2CH2CFH2, or -Br. 4 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0286] W 1 and W 2 may be the same or different. In some embodiments, W 1 and W 2 are the same. In some embodiments, W 1 and W 2 is hydrogen. In some embodiments, W 1 and W 2 is deuterium. In some embodiments, W 1 and W 2 are different. In some embodiments, W 1 is hydrogen or deuterium, and W 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, W 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, W 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, W 1 and W 2 One of the atoms is deuterium and the other is hydrogen.

[0287] X1 and X 2 may be the same or different. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 is hydrogen. 1 and X 2 is deuterium. 1 and X 2 are different. In some embodiments, X 1 is hydrogen or deuterium, and X 2 is substituted or unsubstituted C1-C6 alkyl. In some embodiments, X 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, X 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, X 1 and X 2 One of the atoms is deuterium and the other is hydrogen.

[0288] Y 1 and Y 2 may be the same or different. In some embodiments, Y 1 and Y 2 are the same. In some embodiments, Y 1 and Y 2 is hydrogen. In some embodiments, Y 1 and Y 2 is deuterium. In some embodiments, Y 1 and Y 2 In some embodiments, Y 1 is hydrogen or deuterium, and Y 2is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, Y 2 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, and n-propyl, preferably methyl. In some embodiments, Y 2 is a substituted C1-C6 alkyl. The alkyl group may include one or more substituents. For example, if the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, Y 1 and Y 2 One of the atoms is deuterium and the other is hydrogen.

[0289] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is deuterium. In some embodiments, R 7 is unsubstituted C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and hexyl) or C1-C6 alkyl substituted with one or more substituents such as one or more deuterium atoms (e.g., -CDH2, -CD2H, -CD3).

[0290] R 8 , R 9 , and R 10 can be the same or different. In some embodiments, R 8 , R 9 , and R 10 are the same. In some embodiments, R 8 , R 9 , and R 10 are different. In some embodiments, R 8 , R 9 , and R 10 The two are the same.

[0291] In some embodiments, R 8 is deuterium. In some embodiments, R 8is hydrogen. In some embodiments, R 8 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 8 is hydroxyl. In some embodiments, R 8 is cyano. In some embodiments, R 8 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 8 is a substituted C1-C6 alkyl. 8 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 8 -OR a In some embodiments, R 8 -SR a In some embodiments, R 8 is hydrogen, -OMe, or -OCD. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -OMe. In some embodiments, R 8 is -OCD3. In some embodiments, R 8 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0292] In some embodiments, R 9 is deuterium. In some embodiments, R 9is hydrogen. In some embodiments, R 9 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 9 is hydroxyl. In some embodiments, R 9 is cyano. In some embodiments, R 9 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 9 is a substituted C1-C6 alkyl. 9 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 9 -OR a In some embodiments, R 9 -SR a In some embodiments, R 9 is hydrogen, -OMe, or -OCD. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 is -OMe. In some embodiments, R 9 is -OCD3. In some embodiments, R 9 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0293] In some embodiments, R 10 is deuterium. In some embodiments, R 10is hydrogen. In some embodiments, R 10 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 10 is hydroxyl. In some embodiments, R 10 is cyano. In some embodiments, R 10 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 10 is a substituted C1-C6 alkyl. 10 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 10 -OR a In some embodiments, R 10 -SR a In some embodiments, R 10 is hydrogen, -OMe, or -OCD. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is -OMe. In some embodiments, R 10 is -OCD3. In some embodiments, R 10 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0294] R 11 and R 12can be the same or different. In some embodiments, R 11 is deuterium. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 11 is hydroxyl. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 11 is a substituted C1-C6 alkyl. 11 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 11 -OR a In some embodiments, R 11 -SR a In some embodiments, R 11 is hydrogen, -OMe, or -OCD. In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is -OMe. In some embodiments, R 11 is -OCD3. In some embodiments, R 11 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0295] In some embodiments, R 12 is deuterium. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is a halogen, for example, —Br, —F, —Cl, or —I. In some embodiments, R 12 is hydroxyl. In some embodiments, R 12 is cyano. In some embodiments, R 12 is an unsubstituted C1-C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl. 12 is a substituted C1-C6 alkyl. 12 When R is substituted C1-C6, preferred substituents include, but are not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl, or polyether substituents. The alkyl group may contain one or more substituents. For example, when the alkyl group is a C1 alkyl group (i.e., a methyl group), the substituted C1 alkyl group may be -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3, etc. In some embodiments, R 12 -OR a In some embodiments, R 12 -SR a In some embodiments, R 12 is hydrogen, -OMe, or -OCD. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is -OMe. In some embodiments, R 12 is -OCD3. In some embodiments, R 12 is hydrogen, deuterium, halogen, -OR a , or -SR a and R a is a C1-C6 alkyl that is unsubstituted or substituted with one or more deuterium atoms.

[0296] In some embodiments, R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl.

[0297] Each R a can independently be hydrogen, deuterium, unsubstituted C-C alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, and hexyl), or substituted C-C alkyl, with preferred substituents including, but not limited to, deuterium, halogen (e.g., fluorine), polar substituents such as hydroxyl or polyether substituents, and the like. In some embodiments, R a is a substituted or unsubstituted C1-C6 alkyl, preferably C1-C3 alkyl, preferably substituted or unsubstituted C1 alkyl, examples of which include, but are not limited to, -CH3, -CDH2, -CD2H, -CD3, -CFH2, -CF2H, -CF3. In some embodiments, each R a is -CH3. In some embodiments, each R a is -CD3. In some embodiments, two or more R a In such a case, each R a can be the same or different. In some embodiments, each R a are the same. In some embodiments, each R a are different, for example, one R a is -CH3 and the other is -CD3. a or -SR a Examples include, but are not limited to, -SMe, -SCD 3、 SCF 3、 Examples include SEt, SnPr, SCH2CH2CF3, SCH2CH2CF2H, SCH2CH2CFH2, OMe, OCD3, OCF3, OCH2CH2CF3, -OCH2CH2CF2H, and -OCH2CH2CFH2.

[0298] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0299] In some embodiments, the hallucinogen is a compound of Formula (VI-a), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium; R 12 is hydrogen, deuterium, hydroxyl, cyano, halogen, unsubstituted or substituted C1-C6 alkyl, -OR a , and -SR a and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 and R a is as defined above for formula (VI).

[0300] In some embodiments, W 1 , W 2 , X 1 , X2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0301] In some embodiments, the hallucinogen is a compound of formula (VI-b), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof: [ka] During the ceremony, R 8 , R 9 , and R 10 are independently selected from the group consisting of hydrogen and deuterium; R 11 and R 12 together with the atom to which they are attached form an unsubstituted or substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl, and W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 and R a is as defined above for formula (VI).

[0302] In some embodiments, W 1 , W 2 , X 1 , X 2 , Y 1 , Y 2 , R 2 , R 4 , R 5 , R 7 , R8 , R 9 , R 10 , R 11 , and R 12 At least one of the atoms contains deuterium.

[0303] In some embodiments, the hallucinogen is at least one phenethylamine derivative selected from the group consisting of: [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0304] In some embodiments, the hallucinogen is a phenethylamine derivative, including but not limited to, MDMA, MDEA, MBDB, TMA, DOM, DOET, DOI, DOC; a tryptamine derivative, including but not limited to, DMT, 5-MeO-DMT, psilocybin, psilocin; a compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula III, Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), Formula (VI-b), and any exemplary compound described herein; and pharmaceutically acceptable salts, stereoisomers, and solvates thereof.

[0305] In some embodiments, the hallucinogen is N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), DMT-d 10 (2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), 5-MeO-DMT-d 10 (2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4), and psilocin-d 10(3-(2-(bis(methyl-d3)amino)ethyl-1,1,2,2-d4)-1H-indol-4-ol), or a pharmaceutically acceptable salt or solvate thereof.

[0306] In some embodiments, the hallucinogen is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0307] In some embodiments, the hallucinogen is 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0308] In some embodiments, the hallucinogen is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt or solvate thereof.

[0309] In some embodiments, the hallucinogen comprises deuterated tryptamine. In some embodiments, the hallucinogen comprises 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), or a pharmaceutically acceptable salt or solvate thereof.

[0310] In some embodiments, the hallucinogen is 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ), or a pharmaceutically acceptable salt or solvate thereof.

[0311] In some embodiments, the hallucinogen is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), or a pharmaceutically acceptable salt or solvate thereof.

[0312] In some embodiments, the hallucinogen is 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), or a pharmaceutically acceptable salt or solvate thereof.

[0313] In some embodiments, the hallucinogen is 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ), or a pharmaceutically acceptable salt or solvate thereof.

[0314] Also disclosed herein are pharmaceutically acceptable salt forms of the compounds disclosed herein as hallucinogens. The acid used to form the pharmaceutically acceptable salt may be a mono-, di-, tri-, tetra-, or may contain more acid groups. The acid group may be, for example, a carboxylic acid, sulfonic acid, phosphonic acid, or other acidic moiety containing at least one replaceable hydrogen atom.Examples of acids that may be used in the preparation of pharmaceutically acceptable (acid addition) salts disclosed herein include acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-3-sulfonic acid, naphthalene-4-sulfonic acid, naphthalene-5-sulfonic acid, naphthalene-6-sulfonic acid, naphthalene-7-sulfonic acid, naphthalene-8-sulfonic acid, naphthalene-9-sulfonic acid, naphthalene-10 ... benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, Cholic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acid (e.g. For example, they include, but are not limited to, DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid, thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and di-acids, e.g., adipic (hexanedio) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.).

[0315] In some embodiments, the salt is N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ), 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8), 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10 ), 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5), or 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) is formed.

[0316] In some embodiments, the hallucinogen is: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt of at least one compound selected from the group consisting of a stereoisomer, solvate or prodrug thereof.

[0317] In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate. In terms of providing desirable physical and pharmaceutical characteristics such as those described above, preferred pharmaceutically acceptable salts are the fumarate, benzoate, salicylate, and succinate salts of the compounds disclosed herein, with hallucinogens in the fumarate, benzoate, and salicylate salts being particularly preferred.

[0318] In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of N,N-dimethyltryptamine (DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 ) is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt. In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2 (DMT-d8). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 10) is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 (5-MeO-DMT-d5). In some embodiments, the pharmaceutically acceptable salt is a fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemixalate, or hemifumarate salt of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (5-MeO-DMT-d 13 ) fumarate, benzoate, salicylate, succinate, oxalate, glycolate, hemioxalate, or hemifumarate.

[0319] In some embodiments, the hallucinogen is a pharmaceutically acceptable salt of DMT or deuterated DMT, a crystalline solid as disclosed in PCT / EP2023 / 050702, which is incorporated herein by reference in its entirety.

[0320] In some embodiments, the pharmaceutically acceptable salt is a fumarate salt of 2-(1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT, described below). In some embodiments, the fumarate salt of DMT is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.7°, 22.5°, 23.9°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. [ka]

[0321] In some embodiments, the pharmaceutically acceptable salt is a benzoate salt of DMT. In some embodiments, the benzoate salt of DMT is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.6°, 13.5°, 15.8°, 16.1°, 17.1°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.7°, 23.8°, 24.6°, 26.9°, 29.2°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source.

[0322] In some embodiments, the pharmaceutically acceptable salt is a salicylate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.7°, 21.0°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4°, as determined by XRPD using a CuKα radiation source.

[0323] In some embodiments, the pharmaceutically acceptable salt is a succinate salt of DMT, which is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.8°, 11.7°, 14.3°, 14.7°, 17.0°, 17.4°, 19.6°, 20.6°, 22.3°, 22.6°, 22.9°, 23.1°, 23.4°, 24.9°, 25.2°, 26.3°, 26.8°, 27.3°, 27.7°, 28.8°, 29.1°, 30.9°, 31.5°, 33.8°, 34.5°, 36.5°, and 39.2°, as determined by XRPD using a CuKα radiation source.

[0324] In some embodiments, the pharmaceutically acceptable salt is an oxalate salt of DMT, which is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 11.3°, 12.3°, 15.6°, 17.7°, 19.5°, 20.0°, 20.8°, 21.4°, 22.3°, 22.7°, 24.8°, 25.7°, 26.7°, 27.9°, 28.7°, 29.5°, 31.4°, 33.0°, 35.4°, 36.5°, and 38.6°, as determined by XRPD using a CuKα radiation source.

[0325] In some embodiments, the pharmaceutically acceptable salt is a glycolate salt of DMT. In some embodiments, the glycolate salt of DMT is in the form of a crystalline solid characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 8.2°, 12.2°, 12.9°, 15.8°, 16.3°, 17.8°, 19.2°, 20.1°, 21.7°, 23.6°, 24.4°, 24.6°, 24.9°, 26.0°, 26.6°, 27.8°, 29.6°, 30.2°, 32.0°, 32.3°, 33.0°, 33.9°, and 34.6°, as determined by XRPD using a CuKα radiation source.

[0326] In some embodiments, the pharmaceutically acceptable salt is the hemi-oxalate salt of DMT, which has the following peaks as determined by XRPD using a CuKα radiation source: 8.7°, 11.5°, 13.6°, 14.2°, 15.2°, 17.4°, 17.6°, 18.0°, 19.3°, 19.6°, 20.1°, 20.6°, 21.9°, 22.1°, 22.9°, 23.2°, 23.5°, 24.5° , 25.0°, 25.5°, 26.1°, 26.4°, 27.1°, 28.4°, 28.7°, 29.8°, 30.4°, 30.7°, 31.4°, 31.8°, 33.4°, and 33.9° (2θ±0.2°).

[0327] In some embodiments, the pharmaceutically acceptable salt is a hemifumarate salt of DMT, which has the following peaks as determined by XRPD using a CuKα radiation source: 8.1°, 11.3°, 12.2°, 13.3°, 14.2°, 16.2°, 17.6°, 18.3°, 18.6°, 19.5°, 19.8°, 20.0°, 20.2°, 20.9°, 21.4°, 21.9°, 22.3°, 22.7°, 23.6°, 24.4°, 25.2°, 26.2°, 27.6°, 28.2°, 29.6°, 30.2°, 31.2°, 32.2°, 33.2°, 34.2°, 35.2°, 36.2°, 37.6°, 38.2°, 39.6°, 40.0°, 41.2°, 42.2°, 43.2°, 44.2°, 45.2°, 46.2°, 47.2°, 48.2°, 49.2°, 50.2°, 51.2°, 52.2°, 53.2°, 54.2°, 55.2°, 56.2°, 57.2°, 58.2°, 59.2°, 60.2°, 61.2°, 62.2°, 63.2°, 64.2°, 65.2°, 66.2°, 67.2°, 68.2°, 69.2°, 70.2°, 71.2°, 7 , 22.9°, 23.8°, 24.5°, 25.0°, 25.2°, 26.1°, 26.4°, 26.9°, 28.4°, 28.8°, 29.5°, 29.8°, 30.9°, and 32.7° (2θ±0.2°).

[0328] In some embodiments, the pharmaceutically acceptable salt is 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 (DMT-d 10 In some embodiments, DMT-d is a fumarate salt of DMT-d 10of fumarate salt as determined by XRPD using a CuKα radiation source were 7.8°, 10.3°, 10.9°, 12.5°, 13.6°, 14.6°, 15.2°, 15.5°, 15.8°, 16.1°, 16.6°, 17.0°, 18.4°, 19.0°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.3°, 23.8°, 24.1°, 25.1°, 26.2°, 26.8°, 27. In some embodiments, DMT-d is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from: 27.9°, 28.3°, 28.9°, 29.3°, 29.6°, 29.9°, 30.6°, 31.0°, 31.3°, 32.4°, 32.9°, 33.3°, 33.6°, 34.3°, 34.9°, 35.7°, 36.1°, 37.4°, 38.0°, and 38.5°. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 7.8°, 10.3°, 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 21.3°, 21.8°, 22.5°, 23.8°, 24.1°, 25.1°, 26.2°, 33.6°, and 34.9°, as determined by XRPD using a CuKα radiation source. In some embodiments, DMT-d 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 10.9°, 13.6°, 15.8°, 16.1°, 17.0°, 18.4°, 19.7°, 19.9°, 20.6°, 23.8°, 24.1°, and 25.1°, as determined by XRPD using a CuKα radiation source. [ka]

[0329] In some embodiments, the pharmaceutically acceptable salt is DMT-d10 In some embodiments, DMT-d 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.3°, 24.6°, 25.1°, 25.3°, 25.5°, 26.9°, 28.3°, 28.9°, 29.3°, 31.4°, 31.6°, 32.0°, 32.3°, 32.8°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 11.1°, 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 21.2°, 22.8°, 23.8°, 24.6°, 26.9°, 29.3°, 32.3°, 35.1°, and 36.1°, as determined by XRPD using a CuKα radiation source. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 12.7°, 13.5°, 15.8°, 16.1°, 17.2°, 17.9°, 19.8°, 20.1°, 20.8°, 23.8°, 24.6°, 26.9°, 29.3°, and 35.1°, as determined by XRPD using a CuKα radiation source.

[0330] In some embodiments, the pharmaceutically acceptable salt is DMT-d 10 In some embodiments, DMT-d 10of salicylate as determined by XRPD using a CuKα radiation source were 9.6°, 10.5°, 11.4°, 12.3°, 13.4°, 14.2°, 14.9°, 15.6°, 16.1°, 17.1°, 18.1°, 18.7°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 22.2°, 22.6°, 23.7°, 24.6°, 25.2°, 25.6°, 26. In some embodiments, DMT-d is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from: 26.1°, 26.4°, 27.4°, 27.5°, 27.8°, 28.5°, 28.8°, 29.4°, 29.7°, 30.3°, 31.0°, 31.3°, 32.1°, 32.7°, 33.1°, 33.5°, 34.4°, and 35.0°. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern comprising at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 10.5°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.1°, 21.3°, 24.6°, 25.6°, 28.5°, 28.8°, 29.4°, 30.3°, 31.3°, 32.1°, 33.5°, and 34.4° as determined by XRPD using a CuKα radiation source. 10 is a crystalline solid form characterized by an X-ray powder diffraction pattern containing at least three characteristic peaks at diffraction angles (2θ±0.2°) selected from 9.6°, 14.9°, 17.1°, 18.1°, 19.1°, 20.1°, 20.8°, 21.3°, 24.6°, 25.6°, 28.5°, and 32.1°, as determined by XRPD using a CuKα radiation source.

[0331] Various methods and procedures for addition salt formation are known to those skilled in the art, any of which may be utilized in the present disclosure. In some embodiments, the method comprises:

[0332] (a) suspending the hallucinogen free base in a solvent or solvent mixture;

[0333] (b) contacting the hallucinogen with an acid to provide a mixture;

[0334] (c) optionally heating the mixture;

[0335] (d) optionally cooling the mixture; and

[0336] (e) isolating the salt.

[0337] The disclosed methods can use a variety of solvents, including one or more protic solvents, one or more aprotic solvents, or mixtures thereof. In some embodiments, the solvent used in the method for preparing the salt is a protic solvent. In some embodiments, the solvent used in the method for preparing the salt is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, acetone, butanone, dioxane (1,4-dioxane), water, tetrahydrofuran (THF), acetonitrile (MeCN), ether solvents (e.g., t-butyl methyl ether (TBME)), hexane, heptane, and octane, and combinations thereof. In some embodiments, the solvent is ethanol.

[0338] Suitable acids for use in preparing pharmaceutically acceptable acid addition salts may include those previously described. The acid may be an inorganic acid or an organic acid, with organic acids being preferred. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, succinic acid, oxalic acid, and glycolic acid. In some embodiments, the acid is an organic acid selected from the group consisting of fumaric acid, benzoic acid, salicylic acid, and succinic acid, with fumaric acid, benzoic acid, and salicylic acid being preferred.

[0339] In some embodiments, a stoichiometric (or superstoichiometric) amount of acid is contacted with the hallucinogen free base. In some embodiments, a substoichiometric (e.g., 0.5 molar equivalent) amount of acid is contacted with the hallucinogen free base. For example, if the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt, using a substoichiometric amount of acid may be desirable.

[0340] In some embodiments, the mixture is heated, for example, to reflux, before cooling.

[0341] In some embodiments, the mixture is cooled, causing the salt to precipitate from solution. In some embodiments, the salt precipitates from solution in a crystalline form. In some embodiments, the salt precipitates from solution in an amorphous form.

[0342] Isolation of the salt can be accomplished by a variety of well-known isolation techniques, such as filtration, decantation, etc. In some embodiments, the isolation step comprises filtering the mixture.

[0343] After isolation, additional crystallization and / or recrystallization steps may also be optionally performed, if desired, to, for example, increase purity, crystallinity, etc.

[0344] In some embodiments, the hallucinogens of the present disclosure, or any pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, are in the form of a solvate. Examples of solvate forms include, but are not limited to, hydrates, methanolates, ethanolates, isopropanolates, etc., with hydrates and ethanolates being preferred. Solvates can be formed from stoichiometric or non-stoichiometric amounts of solvent molecules. In one non-limiting example, in the case of a hydrate, the hallucinogen may be a monohydrate, a dihydrate, etc. Solvates of the compounds herein also include solution-phase forms. Thus, in some embodiments, the present disclosure provides solution-phase compositions of the hallucinogens of the present disclosure, or any pharmaceutically acceptable salts, stereoisomers, or prodrugs thereof, in a solvated form, preferably a fully solvated form. For example, pharmaceutically acceptable salt forms of hallucinogens can be prepared in solution phase, whereby the salt is pre-formed as a solid and then dissolved in a solvent (e.g., water). Alternatively, pharmaceutically acceptable salt forms of hallucinogens can be prepared in solution phase by mixing the hallucinogen (free base) with an appropriate acid in a solvent (e.g., water), thereby forming a solvated salt form in situ. If desired, these preparations can be stored for extended periods as solutions, such as in aqueous, organic solvent, or mixed organic solvent-aqueous form, without significant decomposition or physical changes, such as oiling out of solution. Solvents that can be used to form solution-phase compositions can be any one or more of the solvents described herein, such as water, ethanol, etc. In some embodiments, the solution-phase composition is an aqueous phase composition comprising a hallucinogen, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof solvated with water.

[0345] Hallucinogens may contain stereocenters. In such cases, the chemical formula / name is drawn / written without reference to stereochemistry, but the compound may exist in different stereoisomeric forms. Therefore, the present disclosure includes all possible stereoisomers, including not only racemates but also individual enantiomers (enantiomerically pure compounds), individual diastereomers (diastereomerically pure compounds), and non-racemic mixtures thereof. When compounds are desired as single enantiomers, they may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, as known in the art. Resolution of the final product, intermediate, or starting material may be carried out by any suitable method in the art.

[0346] In some embodiments, the compounds described herein, e.g., hallucinogens, are non-stereomeric. In some embodiments, the compounds described herein, e.g., hallucinogens, are racemic. In some embodiments, the compounds described herein, e.g., hallucinogens, are enantiomerically enriched (one enantiomer is present in a higher proportion), including enantiomerically pure. In some embodiments, the compounds described herein, e.g., hallucinogens, are provided as a single diastereomer. In some embodiments, the compounds described herein, e.g., hallucinogens, are provided as a mixture of diastereomers. When provided as a mixture of diastereomers, the mixture can include an equal mixture or a mixture enriched in a particular diastereomer (one diastereomer is present in a higher percentage than another).

[0347] In some embodiments, the hallucinogen is chemically pure, e.g., has greater than 90%, 92%, 94%, 96%, 97%, 98%, or 99% chemical purity by UPLC or HPLC. In some embodiments, the hallucinogen has no single impurity greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3%, or greater than 0.2% as measured by UPLC or HPLC. In some embodiments, the hallucinogen has a chemical purity greater than 97 area%, greater than 98 area%, or greater than 99 area% as measured by UPLC or HPLC. In some embodiments, the hallucinogen has no single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, greater than 0.3 area%, or greater than 0.2 area% as measured by UPLC or HPLC.

[0348] In some embodiments, 5-HT 2A The 5-HT receptor agonist and the NMDA receptor antagonist are used in combination, and in some cases are combined in a single pharmaceutical composition. 2A Receptor agonists and NMDA receptor antagonists (e.g., ketamine, nitrous oxide, memantine, amantadine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), dizocilpine (MK-801), esmethadone, and noble gases with NMDA receptor antagonist activity, such as xenon (Xe) and / or argon (Ar), have been found to enhance treatment efficacy while improving the patient experience, e.g., 5-HT 2A Receptor agonists, used in conjunction with NMDA receptor antagonists (e.g., nitrous oxide, xenon, and / or argon), can reduce or eliminate psychological disturbances such as acute hallucinogenic crises (bad trips), and unpleasant physiological and psychological side effects or other adverse events that may accompany hallucinogenic psychotherapy sessions. In some embodiments, 5-HT 2AThe receptor agonist is used in combination with nitrous oxide. In some embodiments, a noble gas (e.g., xenon and / or argon) is used together with nitrous oxide or as a substitute for nitrous oxide. Thus, any embodiment described herein using nitrous oxide may be replaced with a noble gas, such as xenon, argon, or both.

[0349] The dose of the hallucinogen can vary. Pharmaceutical compositions can include compositions containing a therapeutically effective amount of the hallucinogen. An "effective amount" or "therapeutically effective amount" is an amount of an agent sufficient to treat or ameliorate a condition, disorder, or disease. The actual amount effective for a particular application will depend, among other things, on the condition being treated, the hallucinogen being utilized, and the like. The dose and frequency (single or multiple doses) of the hallucinogen administered can vary depending on a variety of factors, including the route of administration, the subject's body size, age, sex, health, weight, body mass index, and diet, the nature and extent of symptoms of the disease being treated, the presence of other diseases or other health problems, the type of concomitant therapy, and complications from any disease or treatment regimen. Other treatment regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0350] Therapeutically effective amounts for use in humans can be determined (e.g., from animal models). For example, a dose for humans can be formulated to achieve a concentration found to be effective in animals. Dosages in humans can be adjusted by monitoring the human's response to treatment and adjusting the dose upward or downward. Determining the dose and frequency of administration of a hallucinogen is readily within the capabilities of one skilled in the medical field, taking into account the various factors discussed above.

[0351] Dosage can vary depending on the subject's requirements and the hallucinogen used.In the context of the hallucinogens presented herein, the dose administered to a subject should be sufficient to bring about a beneficial therapeutic response in the subject over time.The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects.Treatment can be initiated with a smaller dose that is less than the optimal dose of the hallucinogen.Then, the dose can be increased by small increments until the optimal effect under the circumstances is reached.

[0352] Dosage amount and interval may be adjusted individually to provide a concentration of the administered compound at a level effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual's disease state.

[0353] Administration may follow a continuous or intermittent dosing schedule. The dosing schedule may vary depending on the hallucinogen employed, the condition being treated, the route of administration, etc. For example, administration of the hallucinogen may be administered once daily (QD), or in divided doses throughout the day, such as twice daily (BID), three times daily (TID), four times daily (QID), or more. In some embodiments, administration may be administered nightly (QHS). In some embodiments, administration is administered as needed (PRN). Administration may also be administered on a weekly basis, e.g., once weekly, twice weekly, three times weekly, four times weekly, every other week, every two weeks, etc. The dosing schedule may also specify a defined number of treatments per course of treatment; for example, the hallucinogen may be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per course of treatment. Other dosing schedules may be deemed appropriate using reasonable medical judgment.

[0354] Administration can be continuous (administration 7 days a week) or intermittent, depending on, for example, the pharmacokinetics of the hallucinogen and the clearance / accumulation of the drug in a particular subject. If intermittent, the schedule can be, for example, 4 days of administration and 3 days of rest (rest days) per week, or other intermittent administration schedules deemed appropriate based on sound medical judgment. Continuous or intermittent administration continues for a particular course of treatment, typically at least a 28-day cycle (1 month), which can be repeated with or without a rest period. Longer or shorter courses, such as 14 days, 18 days, 21 days, 24 days, 35 days, 42 days, 48 ​​days, or more, or any range therebetween, can also be used. Courses can be repeated without or with a rest period, depending on the subject. Other schedules are possible depending on the presence or absence of adverse events, response to treatment, patient convenience, etc.

[0355] An effective prophylactic or therapeutic treatment regimen can be designed to be effective in treating the clinical symptoms exhibited by a particular patient without causing substantial toxicity. This regimen can involve the selection of a hallucinogen by considering factors such as the potency of the compound, relative bioavailability, patient weight, the presence and severity of adverse side effects, mode of administration, and the toxicity profile of the selected hallucinogen.

[0356] As used herein, the therapeutically or prophylactically effective fixed dose may vary depending on the various factors described above, but is typically about 1 μg to about 1000 mg or more (or any range between about 1 μg and about 1000 mg) per inhalation session, for example, about 1 μg, about 2 μg, about 5 μg, about 6 μg, about 10 μg, about 13 μg, about 15 μg, about 20 μg, about 30μg, about 40μg, about 50μg, about 60μg, about 70μg, about 80μg, about 90μg, about 100μg, about 110μg, about 120μg, about 130μg, about 140μg, about 1 50μg, about 160μg, about 170μg, about 180μg, about 190μg, about 200μg, about 210μg, about 220μg, about 230μg, about 240μg, about 250μg, about 260 μg, approximately 270μg, approximately 280μg, approximately 290μg, approximately 300μg, approximately 400μg, approximately 500μg, approximately 1.0mg, approximately 2.0mg, approximately 3.0mg, approximately 4.0mg, approximately 5.0m g, about 6.0mg, about 7.0mg, about 8.0mg, about 9.0mg, about 10.0mg, about 20.0mg, about 30.0mg, about 40.0mg, about 50.0mg, about 60.0mg, The hallucinogen is provided, e.g., via aerosol inhalation, in an amount of about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or more. In some embodiments, a subject may have one, two, three, four, five, or more inhalation sessions per day. In some embodiments, a subject may have one, two, three, four, five, or more inhalation sessions every other day, twice a week, or three times a week. In some embodiments, a subject may have one, two, three, four, five, or more inhalation sessions every other month, twice a month, three times a month, or four times a month. In some embodiments, a subject may have 1, 2, 3, 4, 5, 6, 7, 8, or more inhalation sessions per course of treatment, such as within a 28 day period.

[0357] As used herein, a dose based on a therapeutically or prophylactically effective amount can vary depending on the various factors described above, but typically, a hallucinogen is administered in an amount of about 0.00001 mg to about 10 mg per kilogram of recipient body weight, or any range therebetween, for example, about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg. The present invention provides an anti-inflammatory drug that is provided in any range of amounts between about 0.12 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, and about 10.0 mg / kg.

[0358] In some embodiments, the hallucinogen may be administered at a hallucinogenic dose, for example, about 0.1 mg / kg, about 0.15 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.35 mg / kg, about 0.4 mg / kg, about 0.45 mg / kg, about 0.5 mg / kg, up to about 5 mg / kg, about 4 mg / kg, about 3 mg / kg, about 2.5 mg / kg, about 2 mg / kg, about 1 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg. The aforementioned hallucinogenic dose is typically administered once, twice, three times, four times, five times, six times, seven times, or eight times in any one course of treatment. The course can be repeated as needed, with or without a break. Such treatment regimen can involve psychotherapy before, during, and / or after the administration of the hallucinogenic dose. These treatments can be suitable for various mental health disorders disclosed herein, including but not limited to major depressive disorder (MDD), treatment-resistant depression (TRD), anxiety disorder, and substance use disorder (e.g., alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, smoking, and cocaine use disorder).

[0359] In some embodiments, the hallucinogen may be administered in a serotonergic, but sub-hallucinogenic dose, for example, about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, up to about 0.1 mg / kg, about 0.09 mg / kg, about 0.083 mg / kg, 0.08 mg / kg, about 0.075 mg / kg, about 0.07 mg / kg, about 0.06 mg / kg, about 0.05 mg / kg, about 0.04 mg / kg, about 0.03 mg / kg, or about 0.02 mg / kg of active ingredient. Typically, the sub-psychedelic dose is administered daily for a course of treatment (e.g., one month). However, there is no limit to the number of doses in the sub-psychedelic dose, and administration can be less frequent or more frequent if deemed appropriate. Here, the dose is adjusted to provide a sub-psychedelic blood level of the hallucinogen. The course can be repeated as needed, with or without a drug holiday.

[0360] Also disclosed herein are pharmaceutical compositions comprising a hallucinogen and, optionally, another active ingredient (e.g., an NMDA receptor antagonist). Typically, the pharmaceutical composition is also formulated with other chemical components, such as, for example, a pharmaceutically acceptable excipient. One purpose of the pharmaceutical composition, in any of its embodiments, is to facilitate administration of the active ingredient disclosed herein to a subject in need thereof. In some embodiments, the hallucinogen is the only active ingredient present in the pharmaceutical composition.

[0361] The pharmaceutical composition may contain at least 0.0001 wt%, at least 0.001 wt%, at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 5 wt%, at least 10 wt%, at least 15 wt%, at least 20 wt%, at least 25 wt%, at least 30 wt%, at least 35 wt%, at least 40 wt%, at least 45 wt%, at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, at least 95 wt%, at least 99 wt%, or at least 99.9 wt% of the hallucinogen, based on the total weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, up to 65%, up to 60%, up to 55%, up to 50%, up to 45%, up to 40%, up to 35%, up to 30%, up to 25%, up to 20%, up to 15%, up to 10%, or up to 5% by weight of a hallucinogen, based on the total weight of the pharmaceutical composition. Any range between any of these recited endpoints may be used.

[0362] Pharmaceutical compositions containing hallucinogens can be prepared and administered in a variety of dosage forms. Liquid form preparations include solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid before inhalation. Solid form preparations suitable for inhalation administration, such as dry powders, are also disclosed herein. Such dosage forms can be prepared according to conventional methods known to those skilled in the pharmaceutical arts.

[0363] In embodiments where a pharmaceutical composition is formulated with a deuterated hallucinogen, e.g., a compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), or Formula (VI-b), which comprises at least one deuterium atom, the pharmaceutical composition may comprise a single isotopologue or a mixture of isotopologues of the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the subject compound of Formula (I), Formula (II), Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (III), Formula (III-a), Formula (IV), Formula (IV-a), Formula (IV-b), Formula (V), Formula (Va), Formula (Vb), Formula (VI), Formula (VI-a), or Formula (VI-b) is present in the pharmaceutical composition. The compound of formula (III), (III-a), (IV), (IV-a), (IV-b), (V), (Va), (Vb), (VI), (VI-a), or (VI-b) may be present in the pharmaceutical composition with a purity of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight, based on the total weight of the isotopologues of the compound of formula (III), (III-a), (IV), (IV-a), (IV-b), (V), (Va), (Vb), (VI), (VI-a), or (VI-b). For example, when the compound of interest is DMT-d 10 Pharmaceutical compositions formulated with may additionally contain isotopologues of the subject compounds, e.g., DMT-d9, DMT-d8, etc., as free base or salt forms, stereoisomers, solvates, or mixtures thereof. In some embodiments, the compositions are substantially free of other isotopologues of the compound in either free base or salt form, e.g., the compositions have less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or 0.5 mole percent of other isotopologues of the compound.

[0364] In some embodiments, any position designated as having deuterium in a compound has a minimum deuterium incorporation greater than the percentage naturally occurring in hydrogen (a natural abundance of deuterium of about 0.016 atomic %), hi some embodiments, any position designated as having deuterium in a compound has a minimum deuterium incorporation of at least 10 atomic %, at least 20 atomic %, at least 25 atomic %, at least 30 atomic %, at least 40 atomic %, at least 45 atomic %, at least 50 atomic %, at least 60 atomic %, at least 70 atomic %, at least 80 atomic %, at least 90 atomic %, at least 95 atomic %, at least 99 atomic % at the deuteration site.

[0365] In some embodiments, pharmaceutical compositions include at least two hallucinogens (referred to herein as a "hallucinogen mixture"), and may optionally further include one or more NMDA receptor antagonists when it is desirable to administer both types of active ingredients in the same dosage form.

[0366] In some embodiments, the pharmaceutical composition comprises: (i) a DMT-d 10(ii) DMT-d9, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4 or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (iii) DMT-d9, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3 or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. and optionally, (iii) a hallucinogen mixture comprising DMT-d8, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92% by weight of (i) DMT-d, based on the total weight of the hallucinogen mixture. 10, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the hallucinogen mixture comprises, in total, between 1% and 40%, 2% and 40%, 3% and 35%, 4% and 30%, 5% and 25%, 6% and 20%, 7% and 15%, 8% and 10% by weight, or any range therebetween, of one or more of (ii) DMT-d9, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture comprises, in total, one or more of (iii) DMT-d8, i.e., 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, from 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25%, or any range therebetween, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture comprises: (i) DMT-d 10or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) DMT-d9, i.e., one or more of 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0367] In some embodiments, the pharmaceutical composition comprises: (i) 5-MeO-DMT-d 10(ii) 5-MeO-DMT-d9, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. and optionally, (iii) 5-MeO-DMT-d8, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92% by weight of (i) 5-MeO-DMT-d 10, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, the hallucinogen mixture comprises, in total, between 1% and 40%, 2% and 40%, 3% and 35%, 4% and 30%, 5% and 25%, 6% and 20%, 7% and 15%, 8% and 10% by weight, or any range therebetween, of one or more of (ii) 5-MeO-DMT-d9, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture contains, in total, 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25% by weight, or any range therebetween, of one or more of (iii) 5-MeO-DMT-d8, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1-d2, 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-2,2-d2, and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2-d2, or pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture comprises: (i) 5-MeO-DMT-d 10, i.e., 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) 5-MeO-DMT-d9, i.e., one or more of 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-methoxy-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0368] In some embodiments, the pharmaceutical composition comprises: (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) 5-MeO-DMT-d 12 , i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and optionally, (iii) 5-MeO-DMT-d 11or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture comprises 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92% by weight of (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture comprises (ii) 5-MeO-DMT-d4 in a total amount of 1% to 40%, 2% to 40%, 3% to 35%, 4% to 30%, 5% to 25%, 6% to 20%, 7% to 15%, 8% to 10%, or any range therebetween, based on the total weight of the hallucinogen mixture. 12, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture contains, in total, 0% to less than 10% by weight, less than 5% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.25% by weight, or any range therebetween, of (iii) 5-MeO-DMT-d 11 In some embodiments, the hallucinogen mixture comprises one or more of: (i) 5-MeO-DMT-d 13 , i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2,2-d4, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) 5-MeO-DMT-d 12 , i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,2,2-d3 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-bis(methyl-d3)ethan-1-amine-1,1,2-d3, or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof.

[0369] In some embodiments, the pharmaceutical composition comprises one or more of: (i) 5-MeO-DMT-d5, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; (ii) 5-MeO-DMT-d4, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N- and optionally, (iii) a hallucinogen mixture comprising one or more of dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof; and optionally, (iii) 5-MeO-DMT-d3, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the hallucinogen mixture comprises, in total, 60% to 99%, 60% to 98%, 65% to 97%, 70% to 96%, 75% to 95%, 80% to 94%, 85% to 93%, 90% to 92% by weight, or any range therebetween, of (ii) 5-MeO-DMT-d5, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the hallucinogen mixture.In some embodiments, the hallucinogen mixture comprises, in total, between 1% and 40%, 2% and 40%, 3% and 35%, 4% and 30%, 5% and 25%, 6% and 20%, 7% and 15%, 8% and 10% by weight, or any range therebetween, of one or more of (ii) 5-MeO-DMT-d4, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture contains 0% to less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.25% by weight, or any range therebetween, of (iii) 5-MeO-DMT-d3, i.e., 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, based on the total weight of the hallucinogen mixture. In some embodiments, the hallucinogen mixture comprises: (i) 5-MeO-DMT-d5, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1,1-d2 and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2,2-d2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and (ii) 5-MeO-DMT-d4, i.e., one or more of 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-1-d and 2-(5-(methoxy-d3)-1H-indol-3-yl)-N,N-dimethylethan-1-amine-2-d, or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof.

[0370] In some embodiments, each of the two or more hallucinogens comprising the hallucinogen mixture is in the form of a pharmaceutically acceptable salt. In some embodiments, each of the two or more hallucinogens comprising the hallucinogen mixture is in the form of a fumarate salt. In some embodiments, each of the two or more hallucinogens comprising the hallucinogen mixture is in the form of a benzoate salt. In some embodiments, each of the two or more hallucinogens comprising the hallucinogen mixture is in the form of a salicylate salt. In some embodiments, each of the two or more hallucinogens comprising the hallucinogen mixture is in the form of a succinate salt.

[0371] Hallucinogens may be present in pharmaceutical compositions in enantiomerically pure form or as a racemic mixture. As described herein, a racemic active ingredient may contain about 50% of the R- and S-stereoisomers based on a single molar ratio of the isomers (about 48 to about 52 mole %, or about a 1:1 ratio). In some embodiments, a pharmaceutical composition may be formed by combining separately produced R- and S-stereoisomers of a compound in approximately equal molar ratios (e.g., about 48 to 52%). In some embodiments, a pharmaceutical composition may contain a mixture of separate R- and S-stereoisomers of a compound in different ratios. In some embodiments, a pharmaceutical composition contains an excess (greater than 50%) of the R-enantiomer. Suitable R / S molar ratios may be about 1.5:1, 2:1, 3:1, 4:1, 5:1, 10:1, or higher. In some embodiments, a pharmaceutical composition may contain an excess of the S-enantiomer, where the provided ratio for R / S is reversed. Other suitable amounts of R / S can also be selected. For example, the R-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. In some embodiments, the S-enantiomer can be enriched, e.g., at least about 55% to 100%, or at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, about 95%, about 98%, or 100%. Ratios between all of these exemplary embodiments, as well as larger and smaller ratios, remain within the scope of the present disclosure.

[0372] Pharmaceutical compositions may be formulated with one or more crystalline forms of a hallucinogen, including one or more crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline polymorphs. In some embodiments, the pharmaceutical composition comprises a single crystalline polymorph. Pharmaceutical compositions may be formulated with one or more amorphous forms of a hallucinogen, including one or more amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a mixture of amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a single amorphous polymorph. In some embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous polymorphs. In some embodiments, the pharmaceutical composition comprises a highly pure crystalline form of a hallucinogen. For example, a pharmaceutical composition may comprise a hallucinogen, wherein at least 90%, at least 95%, at least 99%, or at least 99.5% by weight of the hallucinogen present in the pharmaceutical composition is in crystalline form, as determined, for example, by X-ray powder diffraction and / or DSC.

[0373] A "pharmaceutically acceptable excipient" may be an excipient approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in mammals, such as humans. As used herein, the term "excipient" refers to a vehicle, diluent, adjuvant, carrier, or any other auxiliary or supplementary ingredient with which the hallucinogens of the present disclosure are formulated for administration to a mammal. Such pharmaceutically acceptable excipients may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutically acceptable excipients may also be water, saline, amino acids or peptides (e.g., leucine), sugars (e.g., lactose, trehalose, pullulan), sugar alcohols (e.g., mannitol), lipids (e.g., phospholipids), magnesium stearate, biodegradable polymers (e.g., polylactic-co-glycolic acid, chitosan, etc.), etc. The pharmaceutically acceptable excipient may include, for example, one or more gases to serve as a carrier for administration via inhalation. Additionally, adjuvants, stabilizers, thickening or viscosity-increasing agents, lubricants, flavoring or taste-masking agents, coloring agents, and other pharmaceutical additives may be included in the compositions of the present disclosure, such as those specified herein below. In some embodiments, the pharmaceutically acceptable excipient is a carrier useful for administration via inhalation. In some embodiments, the pharmaceutically acceptable excipient is an aerosol carrier as described herein.

[0374] In some embodiments, the pharmaceutical composition contains 0.1 to 99.9999 wt%, preferably 1 to 99.999 wt%, preferably 5 to 99.99 wt%, preferably 10 to 99.9 wt%, preferably 15 to 99 wt%, preferably 20 to 90 wt%, preferably 30 to 85 wt%, preferably 40 to 80 wt%, preferably 50 to 75 wt%, preferably 60 to 70 wt% of a pharmaceutically acceptable excipient, based on the total weight of the pharmaceutical composition.

[0375] Pharmaceutical compositions intended for administration by inhalation may contain one or more pharmaceutically acceptable excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers including surfactants and co-solvents, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants or cryoprotectants, thickening or viscosity-enhancing agents, pH-adjusting agents, and inert gases.

[0376] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride, Ringer's solution, isotonic glucose solution, sterile water, glucose, and lactated Ringer's solution. Non-aqueous solvents include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, coconut oil, and medium-chain triglycerides of palm seed oil. Water-miscible solvents include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0377] Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and glucose. Suitable buffering agents include, but are not limited to, acetate, phosphate, and citrate buffers. Suitable antioxidants include, but are not limited to, bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include, but are not limited to, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0378] Suitable stabilizers include, but are not limited to, organic acids (e.g., citric acid), fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ethers, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, hygroscopic polymers, glycerin, methionine, monothioglycerin, ascorbic acid, polysorbates, arginine, cyclodextrin, microcrystalline cellulose, modified cellulose (e.g., carboxymethylcellulose, sodium salt), sorbitol, and cellulose gels.

[0379] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium, silica, or silica gel, such as AEROSIL® 200 (WR Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co., Boston, Mass.); and mixtures thereof.

[0380] Suitable flavoring or taste-masking agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate, and sweetening agents such as sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0381] Suitable coloring agents include, but are not limited to, any of the certified water-soluble FD&C dyes and insoluble FD&C dyes suspended on alumina hydrate, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes by adsorption onto hydrous heavy metal oxides, resulting in an insoluble form of the dye.

[0382] Examples of suitable cryoprotectants include, but are not limited to, disaccharides such as sucrose and trehalose, glycols such as ethylene glycol, propylene glycol and glycerol, anionic polymers such as sulfobutylether-β-cyclodextrin (SBECD) and hyaluronic acid, and hydroxylated cyclodextrins.

[0383] Pharmaceutical compositions intended for administration by inhalation can be delivered as an aerosol, preferably a mist, with or without a carrier gas such as air, oxygen, mixtures of helium and oxygen, or other gases and gas mixtures, including those containing nitrous oxide, xenon, and / or argon.

[0384] Pharmaceutical compositions may also be formulated as dry powders for insufflation, alone or in combination with inert carriers such as, for example, amino acids or peptides (e.g., leucine), sugars (e.g., lactose, trehalose, pullulan), sugar alcohols (e.g., mannitol), lipids (e.g., phospholipids), magnesium stearate, and biodegradable polymers (e.g., polylactic-co-glycolic acid, chitosan, etc.).

[0385] The pharmaceutical compositions disclosed herein can be formulated for single or multiple dose administration.Single dose formulations are packaged in ampoules, vials, containers or canisters.Multiple dose parenteral formulations contain antimicrobial agents at bacteriostatic or fungistatic concentrations.

[0386] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products, which are reconstituted with a vehicle before use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0387] The pharmaceutical compositions may be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as a nebulizer that uses electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as a hydrofluoroalkane such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, 1,1,1,2-tetrafluoroethane (HFA 134A) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, perfluorinated hydrocarbons such as perflubron, and other suitable gases.

[0388] Aqueous solutions suitable for inhalation use can be prepared by dissolving the active hallucinogen in water, optionally with other water-compatible excipients / cosolvents, such as, for example, citrate buffer. Suitable stabilizers and thickeners can also be added. Aqueous emulsions suitable for inhalation use can be made by dispersing a liquid hallucinogen in water with a viscous material, such as, for example, natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents.

[0389] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers may be formulated to contain a surfactant or other suitable cosolvent, or a suitable substitute for dispersing, solubilizing, or sustaining the release of the active ingredients disclosed herein, and optionally a propellant. Such surfactants or cosolvents may include, but are not limited to, polysorbates 20, 60, and 80; Pluronic® F-68, F-84, and P-103; cyclodextrin; polyoxyl 35 castor oil; sorbitan trioleate; oleic acid; and oligolactic acid. Surfactants and cosolvents are typically used at concentrations of about 0.01% to about 2% by weight of the pharmaceutical composition. A viscosity greater than that of a simple aqueous solution may, in some cases, be desirable to reduce variability in dispensing the formulation, reduce physical separation of emulsion components of the formulation, and / or otherwise improve formulation. Such thickening or viscosity-increasing agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the above. Such agents, if desired, are typically used at a concentration of about 0.01% to about 2% by weight of the pharmaceutical composition.

[0390] The hallucinogen can also be dissolved in an organic solvent or an aqueous mixture of organic solvents. The organic solvent can be, for example, acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloromethane, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, ethanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, or xylene, and combinations thereof. The organic solvent can belong to a functional group category, such as ester solvents, ketone solvents, alcohol solvents, amide solvents, ether solvents, or hydrocarbon solvents, and each can be used.

[0391] Pharmaceutical compositions may also be formulated as dry powders for inhalation administration, e.g., via a dry powder inhaler (DPI). The hallucinogen itself can form a powder, or the powder can be formed from a pharmaceutically acceptable excipient or carrier, with the hallucinogen releasably bound to the surface of the carrier powder so that upon inhalation, moisture in the lungs releases the active ingredient from the surface, making the drug available for systemic absorption. Examples of carrier particles include, but are not limited to, amino acids or peptides (e.g., leucine), sugars (e.g., lactose, trehalose, pullulan), sugar alcohols (e.g., mannitol), lipids (e.g., phospholipids), magnesium stearate, biodegradable polymers (e.g., polylactic-co-glycolic acid, chitosan, etc.). Particular mention is made of α-lactose monohydrate.

[0392] aerosol

[0393] Devices used to deliver the therapeutic agents described herein as aerosols can be based on, for example, nebulizers, pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). Pulmonary drug delivery is a form of drug targeting, whether to the pulmonary site of action for locally acting drugs or to the site of absorption for systemically acting drugs. For the former, advantages of pulmonary delivery include relatively low doses, a potentially low incidence of systemic side effects, and, for some drugs, a rapid onset of action. For systemically acting drugs, pulmonary delivery offers the opportunity to avoid oral administration and adverse reactivity within the GI route or injection of drugs that are not well absorbed via the GI route, as well as the potential for a more favorable pharmacokinetic profile. The pulmonary epithelium is >100 m 2 It consists of an area of ​​1000 m², has an epithelial cell layer <1 micrometer thick, and is an attractive target site for systemically acting drugs.

[0394] However, delivering drugs by inhalation can be relatively complicated for two main reasons. First, the respiratory tract has evolved defense mechanisms aimed at preventing inhaled substances from entering the lungs and at removing or inactivating them after they are deposited. Second, it is necessary for patients to use an inhalation device and use it correctly. Non-compliance with inhalation treatment regimens and misuse of delivery devices are common problems. These problems pose major challenges for the pharmaceutical industry and medical professionals. The main problems in using inhalation for drug delivery are deposition of aerosolized particles in the oropharyngeal region and upper respiratory tract, and lack of coordination between device activation and inhalation due to lack of patient training.

[0395] Devices for inhaled drug delivery have two basic functions: aerosol formation and facilitation of aerosol transport to the lungs. A distinction is made between passive and active devices. Passive devices derive the energy required for aerosol formation from the inhaled airflow, i.e., from the patient, while active devices generate the aerosol independently of patient inhalation. Inhalation devices can be further classified in various ways, such as single-dose versus multi-dose, or disposable versus reusable. Multi-dose devices can offer benefits for long-term treatment, such as cost savings, portability, ease of use, and convenience. For irregular dosing and one-time use, disposable devices may be more suitable. Furthermore, aspects such as the risk of device contamination, which can act as a reservoir for microbial growth and allow for the development of antibiotic resistance, can influence the choice between multi-dose and single-dose devices.

[0396] Three main types of inhalation devices can be used for pulmonary delivery: pressurized metered dose inhalers (pMDIs), nebulizers, soft mist inhalers, and dry powder inhalers (DPIs).

[0397] pMDIs generally generate aerosol faster than the patient can inhale. Coordination between device actuation and patient inhalation is particularly difficult for children and the elderly. Some DPIs require the patient to inhale with maximum force to disperse the powder and then inhale it, which is rarely achieved without proper training. In these situations, most of the aerosol is deposited in the upper respiratory tract. With pMDIs, this problem can be addressed by providing a spacer or by designing a breath-actuated inhaler instead of a breath-regulating device.

[0398] The effectiveness of pulmonary delivery also depends on the patient's breathing pattern.High-speed inhalation is not recommended when using pMDI and nebulizer, because it generates turbulence and increases deposition due to impact on the upper respiratory tract.However, high-speed inhalation is necessary to break down drug particles for inhalation in DPI devices.

[0399] There are two main types of nebulizers: jet and ultrasonic. Each type differs in the power used to generate aerosols from liquids. Nebulizers can produce droplets ranging from 1 to 5 μm, depending on the type. Because nebulizers do not require patient coordination between inhalation and actuation, they are useful for children, the elderly, unconscious and mechanically ventilated patients, or patients unable to use pMDIs or DPIs. Compared to other aerosol devices, nebulizers have the ability to deliver larger doses, despite requiring longer administration times.

[0400] The nebulizer device can be a breath-activated, vibrating mesh nebulizer. The breath-activated jet nebulizer design is modified to allow for entrainment of air during inspiration and expulsion outside the device. The primary benefit of this approach is increased stroke rate, which in turn reduces administration time.

[0401] Breath-actuated nebulizers release aerosolized droplets only when the patient breathes in. Thus, no medication is wasted during exhalation, as is the case with conventional jet nebulizers, avoiding the dispersion of expensive or toxic medication into the surrounding environment.

[0402] A vibrating mesh nebulizer has a mesh plate that, when vibrated by a piezoelectric element, breaks the liquid into very fine droplets, increasing the volume of aerosol deposited within the alveoli. The vibrating mesh nebulizer can have an electronic indicator that indicates when the patient is breathing properly, and only then releases a dose of medication with a mass median aerodynamic diameter droplet size of 4 micrometers and minimal drug loss (approximately 1%). High-performance devices can include a vibrating mesh nebulizer coupled with adaptive aerosol delivery software that adjusts aerosol release based on the patient's breathing pattern, reducing drug loss and increasing inhaled volume. Such devices can adjust dose delivery based on the patient's last three breaths and provide feedback after dose delivery.

[0403] The compositions described herein can be delivered using a soft mist inhaler (SMI) inhalation device. An SMI is a nebulizer that disperses a solution of an active agent into fine droplets. This SMI differs from traditional nebulizers in that it does not require an external power source but is a handheld, portable device actuated by a mechanical spring. The instantaneous formation of the aerosol is comparable to that of a pMDI, requiring proper actuation-inhalation coordination. It generally takes longer for the entire aerosol to be generated (1.5 seconds vs. 0.21-0.36 seconds for an HFA-pMDI), and the aerosol is released as a slow-moving mist, allowing for relatively high lung deposition.

[0404] In some embodiments, a method for delivering a hallucinogen via aerosol inhalation is provided. Aerosols, such as mists, can be delivered using air, oxygen, and / or a mixture of oxygen and helium as carrier gases. The air, oxygen, and / or oxygen and helium mixtures can be delivered at room temperature or heated. In some embodiments, aerosols, such as mists, containing hallucinogens are delivered via inhalation using a heated helium-oxygen (heliox) mixture. Due to helium's very low viscosity, the helium-oxygen mixture produces a gas flow characterized by laminar flow, a highly desirable feature for reaching the deep lung region and reducing drug deposition in the airways, one of the major obstacles to dose delivery via inhalation. A patient can inhale a dissolved free base or salt formulation of a hallucinogen as a mist into the alveolar region of the patient's lungs. The hallucinogen or derivative can be delivered to the fluid lining of the alveolar region of the lungs and can be systemically absorbed into the patient's blood circulation. Advantageously, these formulations can be effectively delivered to the bloodstream when inhaled into the alveolar region of the lung.

[0405] Suitable devices for delivery of heated or unheated air, oxygen, or helium-oxygen mixtures include, for example, the continuous mode nebulizers Flo-Mist (Phillips) and Hope (B&B Medical Technologies), and accessories such as regulators for the Medipure™ Heliox-LCQ System (PraxAir), and control boxes for the Precision Control Flow (PraxAir). In another embodiment, the complete delivery device can be, for example, the device described in Russian Patent No. RU199823U1.

[0406] As used herein, the term "heliox" refers to a mixture of helium gas (He) and oxygen gas (O 2) Heliox refers to a mixture of respiratory gases. In some embodiments, the heliox mixture can contain about 50%, 60%, 70%, 80%, or 90% by volume of helium in a mixture of helium and oxygen, and about 50%, 40%, 30%, 20%, or 10% by volume of oxygen in a mixture of helium and oxygen. Thus, the heliox mixture can contain helium and oxygen in ratios of 50:50, 60:40, 70:30, 80:20, or 90:10. In some embodiments, heliox can create less resistance with the airways due to increased tendency for laminar flow and reduced resistance in turbulent flow.

[0407] The use of heat in heliox mixtures can further improve drug delivery by increasing the permeability of important physical barriers for drug absorption. Heating mucosal surfaces can increase permeability by improving peripheral blood circulation and relaxing interstitial junctions as well as other mechanisms. Helium has a thermal conductivity nearly 10 times higher than oxygen and nitrogen, which can promote heat transfer more efficiently. Dry heliox mixtures can be safely used as a pretreatment step when heated up to 110°C (e.g., heated to approximately 70, 80, 90, 100, or 110°C), allowing the dry heliox mixture to more efficiently heat the mucosal surfaces of the lungs and airways.

[0408] Various types of personal inhalers can be used to deliver the therapeutic compositions described herein and are known in the art. Generally, personal inhalers are characterized by heating a solid drug or compound. Inhalers can function by directly heating a solid drug or compound to the smoldering point. Vaporization of a solid or solid concentrate can be achieved by convection during heat conduction. Convection heating of a solid concentrate involves a heating element contacting water or another liquid, which then vaporizes. The hot steam directly heats the solid or solid concentrate to smolder, releasing a vapor that is inhaled by the user. Conductive heating involves direct contact between the solid or solid concentrate and a heating element, which brings the solid to the smoldering point and releases a vapor that is inhaled by the user. Inhalers offer advantages over smoking in terms of lung injury, but the vaporized drug / active agent can be substantially degraded by the heat of vaporization.

[0409] A vapor is a solid substance in the gas phase at a temperature below its critical temperature, meaning that a vapor can be condensed into a liquid by increasing its pressure without decreasing the temperature.

[0410] As used herein, an aerosol is a suspension of fine solid particles or liquid droplets in a gas phase (e.g., air, oxygen, helium, nitrous oxide, xenon, argon, and other gases, and mixtures thereof). As used herein, a mist is a subset of aerosol that is distinct from vapor and is a dispersion of liquid droplets (liquid phase) suspended in a gas phase (e.g., air, oxygen, helium, and mixtures thereof). The mist droplets may contain hallucinogens dissolved in an aqueous liquid or organic solvent. The liquid phase of the mist droplets may contain thousands or millions of molecules. The gas phase of the mist may include air, oxygen, helium, other gases, and mixtures thereof. The mist does not contain solid particles. The mist can be generated by any suitable method, including, for example, the use of an inhaler or nebulizer.

[0411] In some embodiments, the hallucinogen is delivered via a nebulizer, which generates an aqueous droplet aerosol, such as a mist, containing the hallucinogen, optionally combined with a heated helium-oxygen mixture. In some embodiments, the hallucinogen is delivered via a nebulizer. The nebulizer generates an aerosol of aqueous droplets, such as a mist, containing the hallucinogen. The hallucinogen is combined with nitrous oxide (or a noble gas, such as xenon and / or argon), or a gas mixture containing nitrous oxide (or a noble gas), such as a nitrous oxide (or a noble gas)-air or nitrous oxide (or a noble gas)-oxygen mixture. Nitrous oxide, xenon, and / or argon (which are NMDA receptor antagonists) can enhance the effects of the hallucinogen, providing the ability to use a smaller amount of the hallucinogen to achieve a similar level of effect.

[0412] For example, a hallucinogen preparation can be placed in a liquid medium and aerosolized by a device such as a nebulizer. In some embodiments, the nebulizer can be, for example, an air compressor nebulizer, an ultrasonic nebulizer, a vibrating mesh or horn nebulizer, or a microprocessor-controlled breath-activated nebulizer. In another embodiment, the nebulizer device can be, for example, a device described in Russian Patent No. RU199823U1.

[0413] A nebulizer is a device that converts a drug, such as a hallucinogen, in solution or suspension into a fine aerosol, such as a mist, for delivery to the lungs. A nebulizer may also be referred to as a nebulizer. Nebulization refers to the process of converting a dissolved or dispersed drug into an aerosol form, such as a mist. To deliver a drug by nebulization, the drug can be dispersed in a liquid medium, such as water, ethanol, or propylene glycol, along with optional excipients. Furthermore, hallucinogens can be carried in vehicles, such as liposomes, polymers, emulsions, micelles, nanoparticles, or polyethyleneimine (PEI). Liquid drugs for nebulizers can be aqueous or viscous solutions. After applying a dispersing force (e.g., a gas jet, ultrasound, or mesh vibration), the dissolved hallucinogen is contained within droplets, which are then inhaled. The mist can include droplets containing the drug in air or another gas mixture (e.g., a mixture of helium and oxygen).

[0414] Jet nebulizers (also called air nebulizers or compressor nebulizers) use compressed gas to generate mist. In some embodiments, jet nebulizers are microprocessor-controlled, breath-activated nebulizers, also called breath-activated nebulizers. Breath-activated nebulizers do not produce mist continuously, but only when the patient inhales. Mist can be generated, for example, by passing airflow through a Venturi tube in the nebulizer bowl or cup. A Venturi tube is a system for speeding up fluid flow by compressing the fluid into a conical tube. At this limit, the fluid must increase its velocity, thereby reducing its pressure and creating a partial vacuum. Once the fluid leaves the constriction, its pressure increases again to ambient or pipe-level pressure. This can create a low-pressure region that pulls droplets from the drug solution in the nebulizer bowl through the supply tube, generating a stream of atomized droplets that then flow to the mouthpiece. As the airflow increases, particle size decreases and output increases. Due to droplets and solvent saturating the emitted gas, jet nebulizers can cool the drug solution within the nebulizer, increasing the solute concentration in the residual volume. Baffles within the nebulizer bowl or cup can be affected by larger particles, retaining them and returning them to the solution within the nebulizer bowl or cup for reparticle re-atomization. Air entrainment through the nebulizer bowl as the subject inhales can increase mist output during inspiration. Mist generation is more likely with a narrower particle size distribution, but the smaller the particle size used, the longer the nebulization time.

[0415] A commonly used unit of measure for droplet size is the mass median diameter (MMD), which is defined as the average droplet diameter by mass. This unit may also be referred to as the mass mean aerodynamic diameter, or MMAD. The MMD droplet size of a jet nebulizer can be approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 μm, or larger (or any range between approximately 1.0 and 10.0 μm), which can be smaller than that of an ultrasonic nebulizer.

[0416] Ultrasonic nebulizers generate mist using the vibration of a piezoelectric crystal, which converts an alternating current into high-frequency (approximately 1 to 3 MHz) acoustic energy. The solution is broken down into droplets on the surface, and the resulting mist is either drawn from the device by the patient's inhalation or pushed by a gas flow through the device generated by a small compressor. Ultrasonic nebulizers can include high-volume and low-volume ultrasonic nebulizers. Droplet sizes tend to be larger with ultrasonic nebulizers than with jet nebulizers. The MMD droplet size of ultrasonic nebulizers can be approximately 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0 μm, or larger (or any range between approximately 2.0 and 10.0 μm). Ultrasonic nebulizers can produce a high density mist having droplets of about 100, 150, 200, 250, 300 μm / L or more.

[0417] Mesh nebulizer devices indirectly generate mist using the vibration of a piezoelectric crystal. Mesh nebulizers include, for example, active mesh nebulizers and passive mesh nebulizers. Active mesh nebulizers use a piezoelectric element that contracts and expands with the application of an electric current, vibrating a precisely drilled mesh in contact with the drug solution to generate mist. The vibration of the piezoelectric crystal can be used to vibrate a thin metal plate with thousands of holes. One side of the plate is in contact with the liquid to be nebulized, and the vibration forces the liquid through the holes, generating a mist of small droplets. Passive mesh nebulizers generate mist using a transducer horn that induces passive vibrations in a perforated plate with tapered holes. Examples of active mesh nebulizers include the Aeroneb® (Aerogen, Galway, Ireland) and eFlow® (PARI, Starnberg, Germany), while the Microair NE-U22® (Omron, Bannockburn, IL) is a passive mesh nebulizer. Mesh nebulizers are precise and customizable. By changing the pore size of the mesh, the device can be adjusted for use with drug solutions of different viscosities, resulting in different output rates. Using this nebulization method can offer several advantages. Because droplet size can be determined by the size of the holes in the mesh (which can be customized for the application), droplet size can be extremely precise. Nebulizer meshes can be manufactured using methods such as electrodeposition, electroplating, and laser cutting to generate liquid particles in gases within the respirable range. The mesh can be made from metal alloys. Metals used in mesh manufacturing can include platinum, palladium, nickel, and stainless steel. The droplet size is approximately twice the size of the mesh holes, and therefore the mesh holes can be about 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 micrometers or larger (or any value between about 0.1 and 5.0 micrometers).Mesh generation in mesh nebulizers can vary based on the shape of the mesh, the material from which the mesh is made, and the method by which the mesh is generated. In other words, different meshes can generate different sizes of liquid particles suspended in the gas. Generally, the MMD droplet size of a mesh nebulizer can be approximately 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0 μm, or larger (or any value between approximately 1.0 and 7.0 μm).

[0418] Furthermore, droplet size can be programmable. In particular, geometric changes can be made to the nebulizer to provide a specific desired droplet size. Furthermore, droplet size can be controlled independently of droplet velocity. The volume of nebulized liquid and droplet velocity can also be precisely controlled by adjusting the frequency and amplitude of mesh vibration. Furthermore, the number of holes in the mesh and their layout on the mesh can be customized. Mesh nebulizers can be powered either electrically or by batteries.

[0419] The rate of mist output in standing cloud mL per minute (for any nebulization method described herein) can be, for example, in the range of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 mL / min or more (or any range between about 0.1 and 0.9 mL / min), and the residual volume of any type of nebulizer reservoir can be in the range of about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 mL or more (or any range between about 0.01 and 2.0 mL). Precise droplet size control can be advantageous because droplet size can be directly correlated to kinetic drug release (KDR). Precise control of KDR can be achieved through precise control of droplet size. Hallucinogens can be delivered via mist using any methodology with MMD droplet sizes of approximately 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 μm, or larger (or any range between approximately 0.5 and 10.0 μm).

[0420] In some embodiments, the hallucinogen can be delivered via a continuous positive airway pressure (CPAP) or other pressure-assisted breathing device. Pressure-assisted breathing devices push a continuous column of compressed air or other gas at a fixed, specified pressure against the face and nose of a patient wearing a mask or nose cap. As the patient's glottis opens to inhale, pressure is transmitted across the airway, helping to open it. As the patient exhales, pressure from the contracting lungs and chest wall pushes air against the continuous pressure until the two pressures equalize. At the end of exhalation, the air pressure within the airway equals the external air pressure of the machine, thereby "supporting" the airway and helping to open it, allowing for better oxygenation and airway maintenance. Pressure-assisted breathing devices can be coupled with a means for introducing mist particles into the gas flow within the breathing circuit and / or a means for ceasing the introduction of mist particles into the breathing circuit when the patient exhales. See, e.g., U.S. Pat. No. 7,267,121.

[0421] In another embodiment, the mist can be delivered by a device such as a metered dose inhaler (MDI) (also called a pressurized metered dose inhaler or pMDI), which generates an organic solvent-droplet mist containing a hallucinogen that is optionally combined with a heated helium-oxygen mixture. In some embodiments, the hallucinogen can be delivered via a metered dose inhaler MDI. The MDI device can include a canister containing the hallucinogen, as well as a propellant, a metering valve that dispenses the medication from the canister, an actuator body that receives the canister and forms an opening for oral inhalation, and an actuator stem that receives the medication from the canister and directs it out an opening in the actuator body. By moving the medication canister relative to the actuator body and actuator stem, the metering valve releases a predetermined amount of medication. In some embodiments, the hallucinogen can be dissolved in a liquid propellant mixture (which may also contain a small amount of volatile organic solvent) stored in a pressurized container of the MDI. A "metered dose" is a dose prepackaged in a single-dose inhaler or a dose automatically measured from a reservoir by a multi-dose inhaler in preparation for inhalation. MDI devices may be assisted by a spacer. An MDI spacer is a spacer that passes between the MDI and the user's mouth. The MDI spacer allows small amounts of the atomized dose droplets to settle and mix with air or other gases, thus allowing for more effective delivery of the metered dose into the user's lungs upon inhalation. The MDI spacer helps prevent the user from inhaling the metered dose directly from the MDI, which can travel at very high speeds, causing the atomized spray droplets from the MDI to hit and adhere to the back of the user's throat rather than being inhaled into the user's lungs, where the metered dose is designed to be delivered. MDI devices offer the advantage of regular dosing, which can be controlled by the drug manufacturer.

[0422] Drugs can also be delivered by dry powder inhalers (DPIs). In such DPI devices, the drug itself forms a powder, or the powder can be formed from pharmaceutically acceptable excipients or carriers, and the drug is releasably bound to the surface of the carrier powder so that, upon inhalation, moisture in the lungs releases the drug from the surface for systemic absorption. In some embodiments, hallucinogens are delivered by use of a dry powder inhaler (DPI). Depending on the hallucinogen used, the drug can be formed into the necessary powder itself or releasably bound to the surface of the carrier powder. Such carrier powders are known in the art (see, e.g., H. Hamishehkar et al., "The Role of Carrier in Dry Powder Inhaler," DOI:10.5772 / 51209 (2012)).

[0423] DPIs are typically formulated as a powder mixture of coarse carrier particles with an aerodynamic particle diameter of 1–5 μm and micronized drug particles (Iida et al., "Preparation of dry powder inhalation by surface treatment of lactose carrier particles," Chem Pharm Bull, 511150009-2363, pubmed.ncbi.nlm.nih.gov / 12520118 / 2003). Carrier particles are often used to improve the flowability of drug particles, thus improving dosing accuracy and minimizing dose variability observed with drug formulations alone, while also making them easier to handle during manufacturing operations. Carrier particles must possess several characteristics, including compatibility with the drug substance, physicochemical stability, biocompatibility, and biodegradability, as well as be inert, available, and economical. The selection of carrier particles (both content and size) is well within the capabilities of those skilled in the art. Most common carrier particles are made from lactose or other sugars, with α-lactose monohydrate being the most common lactose grade used in such particulate carrier inhalation applications. Solid dosage forms suitable for dry powder inhalation administration may be prepared according to processes known in the art, including, but not limited to, blending, co-jet milling, liposomal processes, freeze-drying, and spray-drying.

[0424] In some embodiments, any of the above delivery devices can be manufactured with sophisticated technology that allows for remote activation of drug delivery. Remote activation can be performed via a computer or mobile app. For security, the remote activation device can be password coded. This technology allows a healthcare professional to conduct a telehealth session with a patient, during which the healthcare professional remotely activates and administers the hallucinogenic drug via the desired delivery device while supervising the patient remotely during the visit.

[0425] In some embodiments, the delivery device is an inhalation delivery device for delivering a combination of nitrous oxide (or a noble gas, e.g., xenon and / or argon) and a hallucinogen via inhalation by a patient in need thereof, the delivery device comprising: an inhalation outlet portal for administering the combination of nitrous oxide (or a noble gas) and a hallucinogen to the patient; a container configured to deliver nitrous oxide gas (or a noble gas) to the inhalation outlet portal; and a device configured to generate and deliver an aerosol comprising the hallucinogen to the inhalation outlet portal. In some embodiments, the inhalation outlet portal is selected from a mouthpiece or mask that covers the patient's nose and mouth. In some embodiments, the device configured to generate and deliver the aerosol to the inhalation outlet portal is a nebulizer. In some embodiments, the nebulizer is a jet nebulizer, and the nitrous oxide gas (or a noble gas) acts as a drive gas for the jet nebulizer. In some embodiments, the device further comprises electronics configured to provide remote actuation and operational control of the inhalation delivery device described above.

[0426] In some embodiments, the device is a dual-delivery device configured to administer a hallucinogen, such as in the form of an aerosol, and simultaneously administer a controlled amount of nitrous oxide, xenon, and / or argon. Any of the aerosol delivery devices described above can be used in such a device, to which is added a source of nitrous oxide, xenon, and / or argon configured to provide a metered and controlled dose / flow rate of nitrous oxide, xenon, and / or argon through the same dispensing outlet as the aerosol delivery device. In some embodiments, the drive gas for nebulization of the hallucinogen is nitrous oxide itself, or xenon gas itself, or argon gas itself.

[0427] When a hallucinogen is co-administered with nitrous oxide (or a noble gas, such as xenon and / or argon), the nitrous oxide (or a noble gas) may be in the form of a mixture of nitrous oxide (or a noble gas) and oxygen (or air), e.g., NO (or a noble gas) and O; NO (or a noble gas) and air; NO (or a noble gas) and medical air (medical air is 78% nitrogen, 21% oxygen, and 1% other gases); NO (or a noble gas) and an N / O mixture; NO (or a noble gas) and O-enriched medical air; NO (or a noble gas) and a He / O mixture, etc. Thus, in addition to nitrous oxide (or a noble gas) and oxygen, the gas mixture may further include other gases, such as one or more of N, Ar, CO, Ne, CH, He, Kr, H, Xe, and HO (e.g., vapor). Nitrous oxide (or a noble gas) may be administered using a blending system that combines NO (or a noble gas), O, and optionally other gases from separate compressed gas cylinders into a gas mixture delivered to the patient via inhalation. Alternatively, the gas mixture containing nitrous oxide (or a noble gas) may be packaged, for example, in a pressurized tank or in a small, easy-to-use and / or portable pressurized canister or handheld device. The blending system, handheld device, and / or pressurized tank / canister may be adapted for fluid connection to an inhalation device, such as a device capable of generating a hallucinogen aerosol. Nitrous oxide (or a noble gas) itself, or a gas mixture containing nitrous oxide (or a noble gas), may be used as a carrier gas for aerosol generation (i.e., as a gas-phase component of the aerosol) or to facilitate transport of the generated aerosol to the patient's lungs. In some embodiments, NO (or a noble gas such as xenon and / or argon) is present in the gas mixture at a concentration ranging from 5 vol%, 10 vol%, 15 vol%, 20 vol%, 25 vol%, 30 vol%, 35 vol%, 40 vol%, 45 vol%, to 75 vol%, 70 vol%, 65 vol%, 60 vol%, 55 vol%, 50 vol%, based on the total volume of the gas mixture.For example, the amount of nitrous oxide (or noble gas) may be 15-25% by volume of the nitrous oxide (or noble gas) / oxygen (or air) mixture, such as about 15-20% by volume of the nitrous oxide (or noble gas) / oxygen (or air) mixture.

[0428] Advantageously, low levels of nitrous oxide, xenon, and / or argon, such as about 15-25% by volume (e.g., about 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, or less), e.g., about 15-20%, for about 90, 60, 45, 30, 15 minutes, or less, may provide good efficacy and significantly reduce the side effect profile. For example, the amount and / or severity of nausea, headache, anxiety, emotional discomfort, confusion, dizziness, and sedation may be reduced when using low levels of nitrous oxide, xenon, and / or argon (e.g., about 15-25% levels). In some embodiments, a mixture of nitrous oxide (or a noble gas such as xenon and / or argon) and oxygen (or air) is administered without the administration of a hallucinogen. In such embodiments, the mixture of nitrous oxide (or a noble gas) and oxygen (or air) contains nitrous oxide (or a noble gas) in an amount of 15-25% by volume of the total gas, e.g., 15-20% by volume of the total gas. The time for administering the gas mixture containing nitrous oxide (or a noble gas), e.g., a nitrous oxide (e.g., a noble gas) / oxygen (or air) mixture, can be any desired duration, such as 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, or any range therebetween.

[0429] In some embodiments, by co-administering a hallucinogen with nitrous oxide (or a noble gas, such as xenon and / or argon) in the form of a gas mixture containing nitrous oxide (or a noble gas) (e.g., a nitrous oxide (or a noble gas) / oxygen (or air) mixture), the amount of hallucinogen delivered can be reduced by about 2, 5, 10, 20, 30, 40, 50, 60, 70 percent or more compared to the dose delivered without nitrous oxide (or a noble gas), as described herein. A lower amount of hallucinogen may result in fewer or less severe side effects, such as acute hallucinogenic crisis (a bad trip), unpleasant physiological and psychological side effects, and psychological disturbances such as nausea, headache, anxiety, emotional discomfort, confusion, dizziness, and sedation.

[0430] Delivery of hallucinogens and mixtures of helium and oxygen

[0431] The methods disclosed herein provide for systemic delivery of hallucinogens. In particular, the hallucinogens can be delivered to the CNS of a patient. Dosages can be optimized for the metabolic and therapeutic needs of an individual patient. Harmful or undesirable side effects of high doses can be avoided by using lower doses. Methods for treating various central nervous system (CNS) diseases and other conditions are described herein. The methods can include delivering the hallucinogen to a patient in need thereof via inhalation of an aerosol containing the agent and a gas, such as air, oxygen, helium, or a mixture of helium and oxygen (i.e., a heliox mixture). In some embodiments, the air, oxygen, helium, or a mixture of helium and oxygen can be heated. The method may further include using an apparatus containing a balloon with an oxygen-helium mixture with a suppressor and a mask connected to each other by a gas or air connection tube, an additional heating element capable of heating the gas mixture up to 120°C, a nebulizer having a vibrating porous plate or mesh through which droplets of a size less than 5 microns pass, and a disinfection device.

[0432] In some embodiments, the hallucinogen is delivered to the lower respiratory tract, e.g., to lung compartments such as the alveoli, alveolar ducts, and / or bronchioles. From there, the drug can enter the bloodstream and travel to the central nervous system. In some embodiments, delivering the hallucinogen to a patient in need thereof by inhalation of a mist can deliver the hallucinogen to the patient's CNS without passing through the liver. Administration via inhalation allows the gaseous drug or one dispersed in a liquid or mist to rapidly deliver the hallucinogen to the bloodstream, bypassing first-pass metabolism. First-pass metabolism, also referred to as the "first-pass effect" or "presystemic metabolism," describes drugs that enter the liver and undergo extensive biotransformation.

[0433] Some embodiments provide a therapeutic step in which a hallucinogen can be administered to a patient in need thereof by administering a mixture of helium and oxygen heated to approximately 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or higher (any range between 50°C and 60°C) and nebulized hallucinogen via inhalation. In some embodiments, the hallucinogen mist or vapor can have a particle size of about 0.1 microns to about 10 microns (e.g., about 10, 5, 4, 3, 2, 1, 0.1, or less). In some embodiments, the hallucinogen can be nebulized via a nebulizer, which produces an inhalant that is a mist with dissolved hallucinogen. In some embodiments, the nebulized hallucinogen is propelled along a patient delivery line by patient inhalation. In other embodiments, the nebulized hallucinogen is propelled along a patient delivery line by patient inhalation using a carrier gas. The carrier gas can be air, oxygen, a mixture of oxygen and helium, heated air, heated oxygen, or a mixture of heated helium and oxygen.

[0434] In other embodiments of the present disclosure, the treatment step may be preceded by a pre-treatment step, which in some embodiments may include first administering a pre-treatment inhalation therapy prior to administration of the hallucinogen mist. In some embodiments, the pre-treatment inhalation step may include (i) administering via inhalation hallucinogen-free air, oxygen, or a mixture of helium and oxygen heated to about 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, 101°C, 102°C, 103°C, 104°C, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C, 116°C, 117°C, 118°C, 119°C, 120°C, or higher (or any range between about 90°C and 120°C), followed by (ii) administering a treatment step of inhaling air, oxygen, an oxygen and helium mixture, heated air, heated oxygen, or a heated helium and oxygen mixture. Heated air, heated oxygen, or a mixture of heated helium and oxygen, in combination with the aerosolized hallucinogen, may be heated to about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or higher (or any range between about 50°C and 60°C).

[0435] In some embodiments of the present disclosure, the pre-treatment step (i) and treatment step (ii) can be repeated 0, 1, 2, 3, 4, 5, or more times. In some embodiments of the present disclosure, steps (i) and (ii) can be repeated 0, 1, 2, 3, 4, 5, or more times, followed by a treatment step, which can be repeated 0, 1, 2, 3, 4, 5, or more times. In some embodiments of the present disclosure, the treatment step can be repeated 0, 1, 2, 3, 4, 5, or more times without a pre-treatment step.

[0436] Treatment with any pretreatment can be administered once a week, twice a week, once a day, twice a day, three or more times a day, or other treatment schedules described herein. Each treatment can be for about 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, or more, or any range therebetween.

[0437] A drug delivery procedure may involve inhaling a priming non-drug, hot heliox mixture to effectively preheat the mucosal bed, followed by inhalation of the nebulized hallucinogen, again driven by the heated heliox, but at a lower temperature determined by the lower thermal tolerance to the wet versus dry inhalation gas stream. As a result, this procedure may be performed in multiple repeated cycles, with target pharmacokinetics (PK) and drug exposure controlled by drug concentration, temperature, helium-oxygen mixture flow rate, mixture composition, number and duration of cycles, time of day, and combinations of the above.

[0438] The delivery methods described herein can be used to treat certain diseases and disorders. Treating and treatment refer to methods of alleviating or preventing a condition, disorder, disease, or one or more symptoms of a condition, disorder, or disease, or a combination thereof. Treating or treatment can include partial or complete halting of the progression of a condition, disorder, or disease, or partial or complete reversal of a condition, disorder, or disease. Treatment can provide a therapeutic benefit, such as eradication or improvement of one or more physiological or psychological symptoms associated with the underlying condition, disease, or disorder, such that the patient observes improvement, despite the fact that the patient may still be affected by the condition.

[0439] Thus, provided herein are methods for treating a central nervous system (CNS) or psychological disorder comprising administering a hallucinogen of the present disclosure, such as by inhalation, a mixture of heated helium and oxygen and an nebulized hallucinogen. Treatment can alleviate one or more symptoms of the disorder.

[0440] In some embodiments, the hallucinogens may be administered to treat CNS diseases or other disorders. In some embodiments, the hallucinogens may be administered to treat depression, including, but not limited to, major depression, melancholic depression, atypical depression, or dysthymia. In some embodiments, the hallucinogens may be administered to treat psychological disorders, including anxiety disorders, obsessive-compulsive disorders, addictions (drug addiction, tobacco addiction, opioid addiction), alcoholism, depression, and anxiety (associated with a diagnosis of a chronic or life-threatening or terminal illness), obsessive-compulsive behaviors, or related symptoms.

[0441] In some embodiments, the disease or disorder is a central nervous system (CNS) disorder and / or psychological disorder, including, for example, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation or attempt, bipolar and related disorders (including, but not limited to, bipolar I disorder, bipolar II disorder, cyclothymic disorder), obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), acute hallucinatory crisis, social anxiety disorder, substance use disorder (alcohol use disorder, opioid use disorder, amphetamine use disorder, The disease or disorder may include conditions such as: Alzheimer's disease, cluster headaches and migraines, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, dementia, mild neurocognitive disorders, gambling disorders, eating disorders such as anorexia nervosa, bulimia nervosa, and binge eating disorder, as well as childhood sexual disorders, conduct disorders, voyeuristic disorder, fetishistic disorder, sexual masochism or sadism disorder, and paraphilias such as cross-dressing disorder, and obesity. In some embodiments, the disease or disorder may involve a condition of the autonomic nervous system (ANS). In some embodiments, the disease or disorder may involve a pulmonary disorder (e.g., asthma and chronic obstructive pulmonary disorder (COPD)). In some embodiments, the disease or disorder may involve a cardiovascular disorder (e.g., atherosclerosis).

[0442] In some embodiments, the methods provided herein are used to treat subjects with depressive disorders. As used herein, the term "depressive disorder" or "depression" refers to a group of disorders characterized by a persistent low mood that can affect a person's thoughts, behavior, emotions, and sense of well-being over a period of time. In some embodiments, depressive disorders disrupt a person's physical and mental function. In some embodiments, depressive disorders cause physical symptoms such as weight loss, aches and pains, headaches, cramps, or indigestion. In some embodiments, depressive disorders cause mental symptoms such as persistent sadness, hopelessness and irritability, guilt, lethargy or helplessness, loss of interest or pleasure in hobbies and activities, difficulty concentrating, difficulty remembering, or difficulty making decisions. In some embodiments, the depressive disorder is major depressive disorder (MDD), atypical depression, bipolar disorder, catatonic depression, depressive disorder due to physical illness, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, or treatment-resistant depression (TRD).

[0443] In some embodiments, the disease or disorder is major depressive disorder (MDD). As used herein, the term "major depressive disorder" refers to a condition characterized by periods of depressed mood present in most situations. Major depressive disorder is often accompanied by low self-esteem, loss of interest in usually enjoyable activities, low energy, and pain without a clear cause. In some instances, the definition of major depression is characterized by depressive symptoms lasting at least two weeks. In some instances, individuals experience periods of depression several years apart. In some instances, individuals experience depressive symptoms nearly constantly. Major depressive disorder can adversely affect an individual's personal, work, or school life, as well as sleep, eating habits, and general health. Approximately 2-7% of adults with major depressive disorder commit suicide, and up to 60% of adults who commit suicide had major depressive disorder or another related mood disorder. Dysthymia is a subtype of major depressive disorder that consists of the same cognitive and physical problems as major depressive disorder, but with less severe but longer-lasting symptoms. Examples of symptoms of major depressive disorder include, but are not limited to, feelings of sadness, fear, emptiness, or hopelessness, angry outbursts, minor irritability or frustration, loss of interest or pleasure in most or all usual activities, sleep disturbances including insomnia or hypersomnia, fatigue or lack of energy, loss of appetite, weight loss or gain, anxiety, agitation or restlessness, diminished ability to think, speak, or move, feelings of lethargy or guilt, fixation on past failures or self-blame, disturbed thinking, concentration, decision-making, and memory, frequent thoughts of death, suicidal thoughts, suicide attempts, or suicide, and unexplained physical problems such as back pain or headaches.

[0444] As used herein, the term "atypical depression" refers to a condition in which an individual exhibits a long-term pattern of signs of mood reactivity (i.e., mood brightening in response to actual or potentially positive events), significant weight gain, increased appetite, hypersomnia, a feeling of heaviness and sluggishness in the arms or legs, and / or sensitivity to interpersonal rejection that results in significant social or occupational harm. Exemplary symptoms of atypical depression include, but are not limited to, daily feelings of sadness or melancholy, loss of pleasure in previously enjoyable activities, significant changes (gain or loss) in weight or appetite, near-daily insomnia or hypersomnia, noticeable physical restlessness or exhaustion, daily fatigue or low energy, near-daily feelings of hopelessness, helplessness or excessive guilt, near-daily problems concentrating or making decisions, recurring thoughts of death or suicide, suicide attempts, or attempted suicide.

[0445] As used herein, the term "bipolar disorder" refers to a condition in which an individual experiences unusual changes in mood, energy, activity level, and ability to perform daily tasks. Individuals with bipolar disorder experience periods of abnormal agitation, changes in sleep patterns and activity levels, and abnormal behavior. These distinct periods are called "mood episodes." Mood episodes are significantly different from the person's typical mood and behavior. Examples of symptoms of mania and excessive behavior include, but are not limited to, abnormally cheerful, volatile, or irritable behavior; increased activity, energy, or irritability; exaggerated feelings of happiness and confidence; decreased need for sleep; abnormal talkativeness, racing thoughts, distractibility, and poor decision-making, such as continuous spending sprees, sexual risk-taking, or foolish investments. Examples of depressive episodes or depressed mood symptoms include, but are not limited to, melancholy, such as feelings of sadness, emptiness, despair, or fear; a significant loss of interest in or a lack of enjoyment in all or almost all activities; significant weight loss or weight gain, or decreased or increased appetite; insomnia or hypersomnia (excessive sleep or excessive sleepiness); restless or sluggish behavior; fatigue or low energy; feelings of helplessness or excessive or inappropriate guilt; impaired thinking ability or impaired concentration or indecisiveness; and thoughts of suicide or attempt. Bipolar disorders include bipolar I disorder, bipolar II disorder, and cyclothymic disorder. Bipolar I disorder is defined by a manic episode lasting at least 7 days or by severe manic symptoms requiring hospitalization. Subjects with bipolar I disorder may also experience depressive episodes, which typically last at least 2 weeks. Depressive episodes with mixed characteristics, i.e., depressive and manic symptoms may occur simultaneously, are also possible. Bipolar II disorder is characterized by a pattern of depressive and hypomanic episodes, but not the severe manic episodes typical of bipolar I disorder. Cyclothymic disorder (also called cyclothymia) is characterized by periods of hypomanic symptoms (elevated and euphoric mood) and depressive symptoms lasting at least two years.The mood swings are not sufficient in number, severity, or duration to meet full criteria for a hypomanic or depressive episode.

[0446] As used herein, the term " catatonic depression " refers to the state that individuals are silent and immobile for a long time.The example of catatonic depression symptoms includes but is not limited to: feeling sad every day, losing interest in most activities, sudden weight gain or loss, appetite change, difficulty falling asleep, difficulty getting up, restlessness, irritability, helplessness, guilt, fatigue, difficulty concentrating, difficulty thinking, difficulty making decisions, thoughts of suicide or death, and / or suicide attempt.

[0447] As used herein, the term "depressive disorder caused by a physical illness" refers to a condition in which an individual experiences depressive symptoms due to another illness. Examples of physical illnesses known to cause depressive disorders include, but are not limited to, HIV / AIDS, diabetes, arthritis, stroke, brain disorders such as Parkinson's disease, Huntington's disease, multiple sclerosis, and Alzheimer's disease, metabolic diseases (e.g., vitamin B12 deficiency), autoimmune diseases (e.g., lupus erythematosus and rheumatoid arthritis), viral or other infectious diseases (hepatitis, mononucleosis, herpes), back pain, and cancer (e.g., pancreatic cancer). In some embodiments, the disease or disorder is cancer-related depression and anxiety.

[0448] As used herein, the term "postpartum depression" refers to a condition resulting from childbirth and hormonal changes, psychological adjustment to parenthood, and / or fatigue. Although postpartum depression is often associated with women, men can suffer from postpartum depression as well. Examples of symptoms of postpartum depression include, but are not limited to, feelings of sadness, hopelessness, emptiness, or heaviness; crying more often than usual or for no apparent reason; worrying or feeling excessive anxiety; feeling moody, irritable, or restless; excessive sleepiness or being unable to sleep even when the baby is sleeping; difficulty concentrating, remembering details, or making decisions; experiencing anger or rages; losing interest in usually enjoyable activities; suffering from physical aches and pains, including frequent headaches, stomach problems, and muscle aches; overeating or eating too little; withdrawing from or avoiding friends and family; difficulty bonding or forming an emotional attachment to the baby; intermittent doubts about one's ability to care for the baby; and thoughts of harming oneself or the baby.

[0449] As used herein, the term "premenstrual dysphoric disorder" refers to a condition in which ...

Claims

1. A pharmaceutical composition comprising a hallucinogenic agent for use in pharmaceuticals, The pharmaceutical composition is administered to a patient in need by inhalation as an aerosol containing the hallucinogenic agent in a carrier, wherein the hallucinogenic agent is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 【Chemistry 1】 During the ceremony, X １ and X ２ The following are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ These are independently selected from the group consisting of hydrogen and deuterium; R ２ However, selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ and R ５ These are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R ６ and R ７ are independently selected from the group consisting of hydrogen, deuterium, and halogen; and R ９ and R １０ These are independently selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. The pharmaceutical composition wherein at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R10 contains deuterium.

2. The hallucinogenic agent is a mixture of hallucinogenic agents of at least two compounds of formula (I), wherein the mixture of hallucinogenic agents is (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ or a pharmaceutically acceptable salt, solvate or prodrug thereof, (ii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ or one or more of their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, and optionally, (iii)2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ A pharmaceutical composition for use according to claim 1, comprising, or one or more pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

3. A pharmaceutical composition comprising a hallucinogenic agent for use in the treatment of patients with central nervous system (CNS) disorders or psychological disorders, The pharmaceutical composition is administered to the patient by inhalation as an aerosol containing a hallucinogenic agent in a carrier. The hallucinogenic agent is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 【Chemistry 2】 During the ceremony, X １ and X ２ The following are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ These are independently selected from the group consisting of hydrogen and deuterium; R ２ However, selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ and R ５ These are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R ６ and R ７ These are independently selected from the group consisting of hydrogen, deuterium, and halogens; and R ９ and R １０ These are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. The pharmaceutical composition wherein at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R10 contains deuterium.

4. X １ , X ２ , R ９ , and R １０ A pharmaceutical composition for use according to claim 3, comprising deuterium.

5. X １ , X ２ , Y １ , Y ２ , R ９ , and R １０ A pharmaceutical composition for use according to claim 3, comprising deuterium.

6. X １ , X ２ , and R ５ A pharmaceutical composition for use according to claim 3, comprising deuterium.

7. X １ , X ２ , Y １ , Y ２ , R ５ , R ９ , and R １０ A pharmaceutical composition for use according to claim 3, comprising deuterium.

8. The compound of formula (I) is 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ , 2-(5-(methoxy-d ３ )-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d ２ , and 2-(5-(methoxy-d ３ )-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ A pharmaceutical composition for use according to claim 3, which is at least one selected from the group consisting of pharmaceutically acceptable salts, solvates, or prodrugs thereof.

9. The hallucinogenic agent is 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(5-methoxy-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ , 2-(5-(methoxy-d ３ )-1H-indole-3-yl)-N,N-dimethylethane-1-amine-1,1-d ２ , and 2-(5-(methoxy-d ３ )-1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ The pharmaceutical composition for use according to claim 3, comprising at least one fumarate, benzoate, salicylate, or succinate selected from the group consisting of the following.

10. The hallucinogenic agent is a mixture of hallucinogenic agents of at least two compounds of formula (I), wherein the mixture of hallucinogenic agents is (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ or a pharmaceutically acceptable salt, solvate or prodrug thereof, (ii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ or one or more of their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, and optionally, (iii)2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ A pharmaceutical composition for use according to claim 3, comprising, or one or more pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

11. The mixture of the hallucinogenic drug is (i) 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1,2,2-d ４ , or a pharmaceutically acceptable salt, solvate or prodrug thereof, (ii) in total 1 to 40% by weight of the total weight of the mixture of the hallucinogenic drug, 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1,2-d ３ , or one or more of their pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs, and (iii) in total 0% to less than 10% by weight of the total weight of the mixture of the hallucinogenic drug, 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,1-d ２ , 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ )ethane-1-amine-1,2-d ２ , or one or more of their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, for use in the pharmaceutical composition according to claim 10.

12. The pharmaceutical composition for use according to claim 3, wherein the carrier is air, oxygen, or a mixture of helium and oxygen.

13. The pharmaceutical composition for use according to claim 3, wherein the aerosol is a mist.

14. The pharmaceutical composition for use according to claim 3, wherein the aerosol is prepared by spraying the hallucinogenic agent.

15. The pharmaceutical composition for use according to claim 14, wherein the atomization is carried out using an apparatus selected from the group consisting of a jet nebulizer, an ultrasonic nebulizer, a respiratory-operated nebulizer, and a vibrating mesh nebulizer.

16. The pharmaceutical composition for use according to claim 14, wherein the atomization is carried out using nitrous oxide as a driving gas for entrainment of the hallucinogenic agent in atomized form.

17. The aforementioned CNS disorder or psychological disorder is (i) Melancholic depression, atypical depression, dysthymia, anxiety disorders, obsessive-compulsive disorder, addiction disorders, alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, cocaine use disorder, post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation or attempts, bipolar I disorder, bipolar II disorder, cyclothymic disorder, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), social anxiety disorder, A At least one selected from the group consisting of Luzheimer's disease, cluster headache, migraine, attention deficit hyperactivity disorder (ADHD), pain and neuropathic pain, aphantasia, childhood-onset fluency disorder, dementia, mild neurocognitive impairment, sexual dysfunction, gambling disorder, eating disorders, anorexia nervosa, bulimia nervosa, binge eating disorder, sexual perversion, childhood sexual disorders, behavioral disorders, voyeurism, fetishism, sexual masochism, sexual sadism, and cross-dressing disorder; (ii) The CNS disorder or mental disorder is major depressive disorder (MDD); (iii) The CNS disorder or mental disorder is treatment-resistant depression (TRD); (iv) The CNS disorder or mental disorder is generalized anxiety disorder (GAD); (v) The CNS disorder or mental disorder is generalized anxiety disorder with depression (GAD); (vi) The CNS disorder or mental disorder is social anxiety disorder; or (vii) The pharmaceutical composition for use according to any one of claims 3 to 16, wherein the CNS disorder or mental disorder is alcohol use disorder.

18. A pharmaceutical composition comprising a hallucinogenic agent for use in pharmaceuticals, The pharmaceutical composition is administered to patients in need as a dry powder by inhalation via a dry powder inhaler. The hallucinogenic agent is a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof. 【Transformation 3】 During the ceremony, X １ and X ２ The following are independently selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; Y １ and Y ２ These are independently selected from the group consisting of hydrogen and deuterium; R ２ However, selected from the group consisting of hydrogen, deuterium, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; R ４ and R ５ These are independently selected from the group consisting of hydrogen, deuterium, hydroxyl, unsubstituted or substituted alkyl, and unsubstituted or substituted alkoxy; R ６ and R ７ These are independently selected from the group consisting of hydrogen, deuterium, and halogens; and R ９ and R １０ These are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl. The pharmaceutical composition wherein at least one of X1, X2, Y1, Y2, R2, R4, R5, R6, R7, R9, and R10 contains deuterium.

19. The hallucinogenic agent is a mixture of hallucinogenic agents of at least two compounds of formula (I), wherein the mixture of hallucinogenic agents is (i) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2,2-d ４ or a pharmaceutically acceptable salt, solvate or prodrug thereof, (ii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ or one or more of their pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs, and optionally, (iii)2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ A pharmaceutical composition for use according to claim 18, comprising, or one or more pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

20. The hallucinogenic mixture contains (i) 60 to 99% by weight of 2-(1H-indole-3-yl)-N,N-bis(methyl-d) of the total weight of the hallucinogenic mixture. ３ ) Ethane-1-amine-1,1,2,2-d ４ or a pharmaceutically acceptable salt, solvate or prodrug thereof, (ii) 1 to 40% by weight of the total weight of the hallucinogenic agent mixture in total 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2,2-d ３ and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,1,2-d ３ , or one or more pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof, and (iii) 2-(1H-indole-3-yl)-N,N-bis(methyl-d) in total amounts of 0% to less than 10% by weight of the total weight of the hallucinogenic agent mixture. ３ ) Ethane-1-amine-1,1-d ２ , 2-(1H-indole-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-2,2-d ２ , and 2-(1H-indol-3-yl)-N,N-bis(methyl-d ３ ) Ethane-1-amine-1,2-d ２ A pharmaceutical composition for use according to claim 19, comprising, or one or more pharmaceutically acceptable salts, stereoisomers, solvates, or prodrugs thereof.

Images