How to use trazodone to reverse the effects of 5-HT2A receptor agonists

Abstract

The present disclosure relates to the administration of trazodone or a pharmaceutically acceptable salt thereof to reverse the pharmacological effects of a 5-HT2A receptor agonist in a subject.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 383,380, filed November 11, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to the use of trazodone or a pharmaceutically acceptable salt thereof to reverse the effects, including the hallucinogenic effects, of 5-HT2A receptor agonists. [Background technology]

[0003] Mental illnesses, including depression and anxiety, take a serious toll on health and effective human functioning worldwide. While several psychotropic drug treatments are available and widely prescribed, they fail to provide relief for many people. For those who respond, mood and behavioral changes occur, but they are often slow to appear. In recent years, this persistent unmet need for improved pharmacological therapies for treating psychiatric disorders has led to the consideration of previously maligned options. Agonists of the 5-HT2A receptor, including representative drugs such as psilocybin, N,N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD), induce severe perceptual distortions in humans (also known as hallucinations or psychedelic effects). Recently, such drugs have attracted significant interest as therapeutic agents for psychiatric disorders, and substantial proof-of-concept has been demonstrated for the treatment of depression and related mood disorders, particularly in patients who do not respond to standard-of-care treatments. However, given the severe hallucinogenic effects of these compounds, their clinical use carries substantial risks, as some patients may experience anxiety or panic due to the intensity of the psychoactive effects. In some cases, particularly in the case of 5-HT2A receptor agonists (e.g., psilocybin) with a duration of action of several hours, this may lead patients to desire to terminate the experience before its natural conclusion. In addition, 5-HT2A receptor agonists have effects on the cardiovascular system, inducing vasoconstriction, elevated blood pressure, and, in rare cases, cardiovascular spasm. In rare cases, such effects have resulted in amputation or even death due to loss of peripheral circulatory function. Furthermore, the long duration of many 5-HT2A receptor agonists makes them inconvenient for use in supervised therapy sessions due to the substantial time investment required by both patients and healthcare providers (e.g., more than 4 hours in the case of psilocybin).

[0004] Therefore, a means of rapidly reversing the effects of 5-HT2A receptor agonists would be useful both for interrupting negative or dangerous treatment sessions or for shortening treatment sessions for convenience. As 5-HT2A receptor agonists become more widely adopted as psychiatric treatments in the coming years, the need for such reversal agents is expected to only increase. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Mouse Brain in Stereotaxic Coordinates, Paxinos and Franklin, 2nd ed. [Non-patent document 2] PiHKAL: A Chemical Love Story (Shulgin, 1991) Summary of the Invention

[0006] The present disclosure has found a means to address this need through the administration of trazodone. Trazodone is marketed as an antidepressant, anxiolytic, and sleep aid. Typically, oral doses of 150 mg / day or more are used to treat depression, while doses as low as 50 mg / day are used to aid sleep. Trazodone has not been used parenterally beyond exploratory studies (e.g., intravenous PK studies). The drug has a complex pharmacology, binding to several serotonin and adrenergic receptors and exhibiting primarily antagonistic effects against these targets. One of trazodone's targets is the 5-HT2A receptor, to which the compound binds with nanomolar affinity and acts as an antagonist in vitro.

[0007] Thus, the present disclosure provides methods for reversing the effects, e.g., hallucinogenic effects, of a 5-HT2A receptor agonist using trazodone. More specifically, in one embodiment, the present disclosure relates to a method for reversing or attenuating the pharmacological effects of a 5-HT2A receptor agonist after cessation of administration of the 5-HT2A receptor agonist to the subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of trazodone or a pharmaceutically acceptable salt thereof.

[0008] The objects, features and advantages will become apparent to those skilled in the art from a consideration of the following detailed description taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic representation of the timeline of the trazodone reversal experiment described in Example 1. [Figure 2] Figure 1 shows a graphical representation of the mean HTR / min recorded from eight mice per treatment condition, shown as 2-minute time bins, over a 30-minute recording period after administration of various doses of trazodone (mg / kg, SC) to mice, and 45-75 minutes after administration of vehicle or DOPR 3.2 mg / kg SC to mice, as described in Example 1. Error bars represent the standard error of the mean. (a) Mice were administered 0 mg / kg trazodone and 0 mg / kg DOPR. (b) Mice were administered 0 mg / kg trazodone and 3.2 mg / kg DOPR. (c) Mice were administered 1.0 mg / kg trazodone and 3.2 mg / kg DOPR. (d) Mice were administered 1.8 mg / kg trazodone and 3.2 mg / kg DOPR. (e) Mice were administered 3.2 mg / kg trazodone and 3.2 mg / kg DOPR. In (f), mice were administered 10.0 mg / kg of trazodone and 3.2 mg / kg of DOPR. [Figure 3]Figure 1 shows a schematic representation of the mean HTR / 10 min recorded from eight mice per treatment condition, shown as 10-minute time bins, 45-75 minutes after mice were administered vehicle or DOPR 3.2 mg / kg SC, with a 30-minute recording period after mice were administered various doses of trazodone (mg / kg, SC) as indicated, as described in Example 1. Error bars represent the standard error of the mean. [Figure 4] FIG. 1 is a graphical representation of the mean specific 5-HT2A receptor binding recorded from five mice per treatment condition, expressed as counts per minute (cpm) per mm2, measured 60 minutes after mice were dosed with vehicle or DOPR (0.32, 1, 3.2, or 32 mg / kg, SC), as described in Example 2. Error bars represent the standard error of the mean. DETAILED DESCRIPTION OF THE INVENTION

[0010] The features and other details of the present disclosure will now be described in more detail. Before further description of the present disclosure, certain terms used in the specification, examples, and appended claims are summarized here. These definitions should be read in light of the remainder of the disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] "Treating" includes any effect that results in the improvement of a condition, disease, disorder, etc., eg, alleviating, reducing, modulating, or eliminating.

[0012] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all non-toxic solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0013] As used herein, the term "pharmaceutical composition" refers to a composition comprising trazodone or a pharmaceutically acceptable salt thereof formulated together with one or more pharmaceutically acceptable carriers.

[0014] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, most preferably humans. Trazodone and / or pharmaceutically acceptable salts thereof may be administered to mammals, such as humans, but can also be administered to other mammals, such as animals requiring veterinary treatment, including domestic animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods of the present disclosure is preferably one in which treatment of a psychiatric disease or disorder is desired.

[0015] "Modulation" includes antagonism (eg, inhibition), agonism, partial antagonism and / or partial agonism.

[0016] As used herein, the term "therapeutically effective amount" refers to the amount of trazodone or a pharmaceutically acceptable salt thereof that induces the reversal of the pharmacological effect of a 5-HT2A receptor agonist in a tissue, system, or animal (e.g., a mammal or human) as desired by a subject, researcher, veterinarian, physician, or other clinician.

[0017] As used herein, the term "cessation of 5-HT2A receptor agonist" refers to the termination of administration of a 5-HT2A receptor agonist, as defined herein below. Termination may occur after administration of one dose of a 5-HT2A receptor agonist or two or more doses of a 5-HT2A receptor agonist and before administration of trazodone or a pharmaceutically acceptable salt thereof, and no additional 5-HT2A receptor agonist is administered to the patient. In other words, no additional 5-HT2A receptor agonist is administered to the patient, i.e., administration of the 5-HT2A receptor agonist is discontinued.

[0018] The term "abnormal thinking," as used herein, refers to thoughts that are clearly different from thoughts that typically occur during normal consciousness. Examples of abnormal thinking include, but are not limited to, confusion, thought loops, recurring and questionable thoughts about relationships, various decisions, sexual orientation or identity, intrusive thoughts about safety, religion, death, and strange thoughts that make no apparent sense.

[0019] As used herein, the term "visual disturbances" refers to visual symptoms or perceptions, such as hallucinations, that interfere with vision resulting from administration of a 5-HT2A receptor agonist. Examples include, but are not limited to, changes in color perception, complex patterns superimposed on the visual field, altered depth perception or sense of scale where objects appear larger / smaller or closer / farther away than they actually are, trailing lights and other objects, apparent bending, stretching, or warping of objects, illusions, blurred vision, double vision, partial or complete blindness, halos, i.e., rings of light around objects, or any other symptoms that interfere with the ability to see an object.

[0020] The term "auditory disturbance" as used herein refers to auditory distortion or hallucination resulting from the administration of a 5-HT2A receptor agonist, in which the sounds perceived by the subject are distorted compared to normal perception, or the subject hears an imaginary noise that does not exist in reality at the time the subject hears the noise, but exists in the subject's mind. For example, the subject hears a roaring noise, a mechanical hum, or music, when such a noise does not exist in reality at the time the subject claims to hear the noise that is causing distress. Alternatively, the perception of real sounds may be distorted, including changes in pitch, intensity, or timbre.

[0021] As used herein, the term "perceptual disorder" refers to an alteration or distortion of normal sensory phenomena or entirely imaginary sensory phenomena perceived by a subject that are not based in reality.

[0022] As used herein, the term "psychedelic effect" collectively refers to the acute perceptual disturbances and mood and behavioral changes induced by central nervous system-acting 5-HT2A receptor agonists while they remain present in the bloodstream at pharmacologically relevant concentrations. As used herein, the term "pharmacologically relevant concentration" refers to the concentration or amount of 5-HT2A agonist present in the bloodstream that is effective to produce or maintain a psychedelic effect in a subject.

[0023] As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic salts of the amine basic groups present in trazodone, such as, for example, the amine nitrogen in the piperazine ring. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, hydrogensulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts.

[0024] As used herein, the term "about" or "approximately" refers to within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which is determined in part by the limitations of the method by which the value is measured or determined, i.e., the measurement system. For example, "about" can mean within 3 or more standard deviations, in accordance with practice in the art. Alternatively, "about" can mean within a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, e.g., within 5-fold or within 2-fold, of a value. "About" and "approximately" are used interchangeably herein.

[0025] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0026] Unless otherwise indicated, the singular includes the plural and vice versa.

[0027] Furthermore, unless expressly stated otherwise, "or" refers to an inclusive "or" rather than an exclusive "or." For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0028] Various numerical ranges are provided herein. Unless otherwise indicated, it should be understood that a range includes its endpoints. For example, if the range is 25 mg to 50 mg, all numbers between 25 and 50 mg, as well as 25 mg and 50 mg, are contemplated as being within the range.

[0029] Unless otherwise indicated, dosages of trazodone or a pharmaceutically acceptable salt thereof are provided in mg of active free base (excluding counterion mass) per approximately 70 kg human per dosage. Accordingly, the amount of trazodone or a pharmaceutically acceptable salt thereof may be adjusted accordingly if the human weighs more or less than about 70 kg.

[0030] Trazodone has the formula:

[0031] [ka]

[0032] It is a triazolopyridinone derivative having the formula:

[0033] This drug has a complex pharmacology, binding to several serotonin and adrenergic receptors and exhibiting primarily antagonistic effects at these targets. One of trazodone's targets is the 5-HT2A receptor, to which the compound binds with nanomolar affinity and acts as an antagonist in vitro. It has been approved by the FDA as an antidepressant for the treatment of major depressive disorder. Additionally, it has been marketed as an anxiolytic and sleep aid. It has also been used off-label to treat anxiety, Alzheimer's disease, substance abuse, bulimia, and fibromyalgia. It is administered orally and is available in the United States as oral tablets of trazodone hydrochloride in strengths of 50 mg, 100 mg, 150 mg, and 300 mg. Typically, oral doses of 150 mg or more are used to treat depression, while doses as low as 50 mg are used to aid sleep. Trazodone has not been used parenterally beyond exploratory studies (e.g., intravenous PK studies).

[0034] In the context of the present disclosure, the term "5-HT2A receptor agonist" is intended to mean any compound or substance that activates the 5-HT2A receptor. The agonist may be a partial or full agonist. Such 5-HT2A receptor agonists include compounds selected from the group consisting of ergolines, tryptamines, phenethylamines, or amphetamines.For example, tryptamines, which are 5-HT2A receptor agonists, include psilocybin, psilocin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MIPT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (DIPT), N,N-dipropyltryptamine (DPT), N-ethyl-N-propyltryptamine (EPT), 5-methoxy-N-methyltryptamine (MET), N-methyl-N-isopropyltryptamine (MIPT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (DIPT), N,N-dipropyltryptamine (DPT), N-ethyl-N-propyltryptamine (EPT), 5-methoxy-N-methyltryptamine (MET), N-methyl-N-isopropyltryptamine (MIPT), N-methyl-N-isopropyltryptamine (MIPT), N-methyl-N-isopropyltryptamine (N ... N,N-diallyl-N-isopropyltryptamine (5-MeO-MIPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N-methyl-N-ethyltryptamine (5-MeO-MET), 5-methoxy-N,N-diethyltryptamine (5-MeO-DET), N,N-diallyl-5-methoxytryptamine (5-MeO-DALT), 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4-HO-MIPT) ), 4-hydroxy-N,N-diisopropyltryptamine (4-HO-DIPT), 4-hydroxy-N,N-diethyltryptamine (4-HO-DET), 4-hydroxy-N,N-dipropyltryptamine (4-HO-DPT), 4-hydroxy-N-ethyl-N-propyltryptamine (4-HO-EPT), 4-acetoxy-N-methyl-N-ethyltryptamine (4-AcO-MET), 4-acetoxy-N-methyl-N-isopropyltryptamine (4-AcO-MIPT), 4-acetoxy-N,N-diisopropyltryptamine Tryptamine (4-AcO-DIPT), 4-acetoxy-N,N-diethyltryptamine (4-AcO-DET), 4-acetoxy-N,N-dipropyltryptamine (4-AcO-DPT), 4-acetoxy-N,N-ethyl-N-propyltryptamine (4-AcO-EPT), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), alpha-methyltryptamine (AMT), alpha-ethyltryptamine (AET), 5-methoxy-alpha-methyltryptamine (5-MeO-AMT), and the like.

[0035] Ergolines that are 5-HT2A receptor agonists include, but are not limited to, lysergic acid amides selected from the group consisting of lysergic acid diethylamide (LSD), lysergic acid 2,4-dimethylazetidide (LSZ), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 1-acetyl-lysergic acid diethylamide (ALD-52), 1-propionyl-lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), 1-(cyclopropylmethanoyl)-lysergic acid diethylamide (1cP-LSD), and the like.

[0036] Phenethylamines that are 5-HT2A receptor agonists include mescaline, escaline, proscaline, methallylescaline, allylescaline, 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-methylphenethylamine (2C-D), 2-(4-ethyl-2,5-dimethoxyphenyl)ethanamine (2C-E), 2-(2,5-dimethy- 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25B-NBOMe) , 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe), 2-(4-methyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25E-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25I-NBOH), 2-(4- Bromo-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25B-NBOH), 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25C-NBOH), 2-(4-methyl-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25D-NBOH), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25E-NBOH), 2-(4-cyano-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25CN-NBOH), and the like.

[0037] Amphetamines that are 5-HT2A receptor agonists include, but are not limited to, 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-propylamphetamine (DOPR), and the like.

[0038] As used herein, the term "pharmacological effect" refers to an acute behavioral, sensory, or physiological effect of a 5-HT2A agonist that occurs while the drug is still present in the bloodstream at a concentration sufficient to induce agonism at the 5-HT2A receptor (i.e., a pharmacologically relevant concentration). For example, a patient administered a 5-HT2A receptor agonist may experience effects including, but not limited to, visual, auditory, or other sensory disturbances, abnormal thoughts, including suicidal thoughts, anxiety, insomnia, vasoconstriction, elevated blood pressure, or other cardiovascular effects, blurred vision, abnormal heart rate, or nausea. The duration of these effects necessarily depends on the pharmacokinetic half-life of the particular 5-HT2A agonist and the dose administered to the subject. In the context of this disclosure, the term "pharmacological effect" does not refer to behavioral effects that persist beyond the pharmacokinetic elimination of the drug, such as antidepressant effects or mood changes that may last for weeks or months after a single dose of a 5-HT2A receptor agonist.

[0039] One advantage of trazodone and its pharmaceutically acceptable salts is that they are antagonists of both the 5-HT2A receptor and the alpha-1 adrenergic receptor. Alpha-1 receptor antagonism leads to vasodilation and hypotension, which, in combination with the direct reversal effect of trazodone's 5-HT2A receptor antagonism, act in concert to reverse the vasoconstrictor and hypertensive effects of 5-HT2A receptor agonists. Without wishing to be bound, it is believed that these two antagonist properties exhibited by trazodone and its pharmaceutically acceptable salts make them more effective than other 5-HT2A receptor antagonists in reversing the vasoconstrictor and hypertensive effects of 5-HT2A receptor agonists, because other, more selective 5-HT2A receptor antagonists lack this secondary mechanism.

[0040] Trazodone or a pharmaceutically acceptable salt thereof, such as the hydrochloride salt, is administered to patients (animals and humans) in need of such treatment in a dosage that attenuates or reverses the acute pharmacological effects of the 5-HT2A receptor agonist. It will be understood that the required dosage will vary from patient to patient, taking into account a variety of factors, including, but not limited to, the route of administration, the dosage of the 5-HT2A receptor agonist, the severity of the adverse effects of the 5-HT2A receptor agonist, the nature of the adverse effects of the 5-HT2A receptor agonist, the age, sex, and condition of the patient, any concomitant medications or special diets followed by the patient, and other factors recognized by those skilled in the art, and that the appropriate dosage is ultimately at the discretion of the attending physician. To treat patients suffering from the adverse effects of 5-HT2A receptor agonists, trazodone or a pharmaceutically acceptable salt thereof may be administered orally, subcutaneously, intravenously, intramuscularly, by inhalation spray, by vaporization, intranasally, sublingually, bucally, or rectally in a dosage unit formulation containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration may include subcutaneous, intravenous, or intramuscular injection or infusion techniques. When rapid reversal of the effects of 5-HT2A receptor agonists is desired, administration routes that provide rapid absorption and distribution throughout the body and central nervous system, such as intravenous, intramuscular, or intranasal routes, are preferred.

[0041] Treatment with trazodone is initiated at any time after administration of the 5-HT2A receptor agonist when the clinician or subject desires to terminate the pharmacological effects of the 5-HT2A receptor agonist. Treatment may continue for as long or as short a period as desired. The composition may be administered, for example, one to four or more times per day. A suitable treatment period may last, for example, a single dose or several hours, or one or two days, but typically no more than three days. However, the time frame may vary on a case-by-case basis depending on the effectiveness of the treatment, the dose of trazodone administered, and the dose and half-life of the 5-HT2A receptor agonist to be reversed. Initially, a lower dose, for example, 50 mg or less, may be administered, and such administration may be repeated several times per day. Alternatively, as described herein below, a higher dose, for example, a dose greater than 50 mg, may be administered to the subject. In one embodiment, trazodone or a pharmaceutically acceptable salt thereof needs to be administered only once. However, if insufficient reversal of the psychedelic effects of the 5-HT2A receptor agonist is achieved or they reoccur at a later time point after cessation of administration of trazodone or a pharmaceutically acceptable salt thereof, a second or third dose may be administered, as necessary, to increase or reestablish the reversal. The treatment period may be terminated when the desired result, e.g., reduction and / or cessation of the adverse effects of the 5-HT2A receptor agonist, is achieved. In some embodiments, the treatment regimen may be continued for a short period thereafter, e.g., about 1 to about 3 days, to avoid the possibility of recurrence of symptoms or the adverse effects of the 5-HT2A receptor agonist. The treatment regimen may include a correction phase in which a therapeutically effective dose sufficient to provide rapid symptomatic relief is administered, followed by a maintenance phase in which a lower dose sufficient to prevent symptom recurrence is administered. While suitable maintenance doses are likely to be found in the lower portion of the dosage ranges provided herein, correction and maintenance doses can be readily established for individual subjects by those skilled in the art without undue experimentation based on the disclosure herein. Maintenance doses may be used to maintain remission in subjects whose symptoms have previously been controlled by other means, including treatment with other pharmacological agents.

[0042] In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at the doses set forth hereinabove and below. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 5 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 10 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 15 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 20 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 25 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 30 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 40 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 50 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 75 mg / day. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a subject in one or more doses at a dose of about 100 mg / day.

[0043] In some embodiments, patients may start with a low dose, for example, about 10 mg or less, and if additional doses are required, the dose is gradually increased.In some embodiments, patients may start with a high dose, for example, about 100 mg, and if additional doses are required, the dose is decreased.In one embodiment, the maximum daily dose is about 150 mg or less.

[0044] In some embodiments, the dosage of trazodone or a pharmaceutically acceptable salt thereof, for example, when administered orally or subcutaneously, may range from about 10 mg to about 100 mg per about 70 kg human per dose, and in other embodiments, from about 10 mg to about 50 mg per about 70 kg human per dose. In some embodiments, the dosage is greater than or equal to about 10 mg per about 70 kg human per dose, but less than or equal to 100 mg per 70 kg human, while in other embodiments, the dosage may range from about 10 mg to about 50 mg per about 70 kg human per dose. For a human weighing approximately 70 kg, the dosage of trazodone or a pharmaceutically acceptable salt thereof is: 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, or any value therebetween.

[0045] In some embodiments, the dosage of trazodone or a pharmaceutically acceptable salt thereof may range from about 5 mg to about 100 mg per about 70 kg human for each administration, for example, when administered intravenously or intramuscularly. In some embodiments, the dosage may range from about 10 mg to about 50 mg per about 70 kg human for each administration of trazodone or a pharmaceutically acceptable salt thereof, while in other embodiments, it may range from about 5 mg to about 50 mg per about 70 kg human for each administration. For a human weighing approximately 70 kg, the dosage of trazodone or a pharmaceutically acceptable salt thereof is: 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, The amount may be 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, or any value therebetween.

[0046] In some embodiments, the dosage of trazodone or a pharmaceutically acceptable salt thereof may range from about 5 mg to about 50 mg per about 70 kg human for each administration, for example, when administered intranasally. In some embodiments, the dosage may range from about 5 mg to about 25 mg per about 70 kg human for each administration of trazodone or a pharmaceutically acceptable salt thereof. For an approximately 70 kg human, the dosage of trazodone or a pharmaceutically acceptable salt thereof may be 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, or any value therebetween, for each administration.

[0047] It should be understood that trazodone can induce drowsiness or sedation, especially at high doses, for example, at doses greater than about 50 mg. Therefore, if the clinician's goal is to attenuate or reverse the psychedelic effects of 5-HT2A receptor agonists in a subject without inducing sedation, the smallest possible dose of trazodone necessary to achieve the desired degree of attenuation or reversal should be used. However, it should also be understood that in some cases, it may be desirable to induce drowsiness or sedation, especially when the subject is highly aroused or suffers from insomnia due to the effects of 5-HT2A receptor agonists.

[0048] The dose of trazodone or a pharmaceutically acceptable salt thereof can be determined by measuring the concentration of trazodone in a patient's plasma using techniques known to those skilled in the art. Using this technique, trazodone or a pharmaceutically acceptable salt thereof is administered to a patient, and the plasma concentration is measured a reasonable time after administration to determine whether the trazodone plasma concentration is within a therapeutically effective range, and maintained for about 1 to about 8 hours. In one embodiment, the plasma concentration is measured within about 5 to about 60 minutes after administration of trazodone or a pharmaceutically acceptable salt thereof. The time of plasma trazodone measurement and the desired duration for which the plasma concentration is maintained within the therapeutically effective range depend on the route of administration, the dose of trazodone, and the specific 5-HT2A receptor agonist to be reversed. For example, intravenous administration achieves peak plasma concentrations immediately, whereas oral administration does not reach peak plasma concentrations for about 1 hour. Furthermore, higher doses of trazodone maintain therapeutically effective plasma concentrations for a longer duration and may therefore be more suitable for reversing 5-HT2A receptor agonists with long half-lives. In one embodiment, the dosage administered to a patient is therapeutically effective when the plasma concentration is within the range of about 100 ng / mL to about 400 ng / mL, and in another embodiment, about 200 ng / mL to about 400 ng / mL. In one embodiment, plasma concentrations of about 100 ng / mL to about 400 ng / mL are considered to be the peak effect (C maxIn another embodiment, plasma concentrations of about 100 ng / mL to about 400 ng / mL are maintained for at least about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 24 hours. In one embodiment, dosage may be adjusted to maintain plasma concentrations in the range of about 200 ng / mL to about 400 ng / mL for at least 4 hours. For a human weighing approximately 70 kg, the dose of trazodone or a pharmaceutically acceptable salt thereof is approximately 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 19 8, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 3, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295,296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352 , 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, or any value therebetween.

[0049] In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a patient under the supervision of a healthcare provider.

[0050] In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered to a patient under the supervision of a healthcare provider in a clinic that specializes in providing psychoactive treatments. It may be administered in low doses, for example, in a dosage range of about 5 mg to 25 mg, or about 5 mg to 50 mg, or in high doses, for example, in a range of about 50 mg to about 100 mg.

[0051] In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is self-administered by the patient at home or otherwise away from the supervision of a healthcare provider.

[0052] In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is self-administered by the patient at home or otherwise away from the supervision of a healthcare provider, either in low doses, e.g., in a dosage range of about 5 mg to 25 mg, or about 5 mg to 50 mg, or in higher doses, e.g., in a range of about 50 mg to about 100 mg.

[0053] It should be understood that these dosage ranges are exemplary. Doses below or above the exemplified ranges are also contemplated and within the scope of the present disclosure. Additionally, the present specification describes a dosage range of trazodone or a pharmaceutically acceptable salt thereof that would reverse a typical dose of a 5-HT2A receptor agonist, where typical is defined as a dosage range that achieves the full psychedelic effect profile but is not an excessive dose. An excessive dose of a 5-HT2A receptor agonist may require more trazodone or a pharmaceutically acceptable salt thereof to reverse the pharmacological effect.

[0054] Another aspect of the present disclosure provides pharmaceutical compositions comprising the compounds disclosed herein formulated with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising trazodone or a pharmaceutically acceptable salt thereof formulated with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, intranasal, aerosol, or vapor administration, although the most suitable administration form in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound used. For example, the disclosed compositions may be formulated as a unit dose and / or for oral or subcutaneous administration. Such methods include combining the compounds or combinations thereof used in the present disclosure with any adjuvants. Adjuvants, also referred to as accessory ingredients, include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents. Such adjuvants are suitably selected with regard to the intended form and route of administration and in accordance with conventional pharmaceutical practice.

[0055] Exemplary pharmaceutical compositions of the present disclosure may be used in the form of pharmaceutical preparations, for example, in solid, semisolid, or liquid form, which contain one or more compounds of the present disclosure as an active ingredient, mixed with organic or inorganic carriers or excipients suitable for topical, enteral, or parenteral application. The active ingredient may be formulated with conventional non-toxic, pharmaceutically acceptable carriers for, for example, tablets, pellets, capsules, suppositories, liquids, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect against a disease process or condition. Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration or by implant. The compositions may be prepared by any method well known in the art of pharmacy.

[0056] Pharmaceutical compositions suitable for oral administration may be presented as individual dosage units, such as pills, tablets, dragees or capsules, or as powders or granules, or as solutions or suspensions. The active ingredient may also be presented as a bolus or paste. The compositions may be further processed into suppositories or enemas for rectal administration.

[0057] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical carrier, such as conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogeneous mixture of trazodone or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily divided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0058] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions containing trazodone or a pharmaceutically acceptable salt thereof are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as Glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, and high molecular weight polyethylene glycols, for example.

[0059] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface-active or dispersing agents. Molded tablets may be made by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets, as well as other solid dosage forms such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation.

[0060] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0061] Suspensions may contain, in addition to the subject composition, suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0062] Formulations for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, which are solid at room temperature but liquid at body temperature and therefore will melt in the body cavity and release the active agent(s).

[0063] Dosage forms for transdermal administration of the subject compositions include powders, sprays, including nasal sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. Trazodone or a pharmaceutically acceptable salt thereof may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0064] Ointments, pastes, creams, and gels may contain, in addition to the subject composition, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0065] Powders and sprays may contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. In addition, sprays may contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0066] Alternatively, compositions containing trazodone or a pharmaceutically acceptable salt thereof may be administered by aerosol. This can be accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing trazodone or a pharmaceutically acceptable salt thereof. Non-aqueous (e.g., fluorocarbon propellant) suspensions can also be used. Sonic nebulizers may also be used because they minimize exposure of trazodone or a pharmaceutically acceptable salt thereof to shear, which can result in degradation of the trazodone or a pharmaceutically acceptable salt thereof contained in the composition. Typically, aqueous aerosols are made by formulating an aqueous solution or suspension of trazodone or a pharmaceutically acceptable salt thereof with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0067] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise trazodone or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0068] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0069] In another aspect, the present disclosure provides an enteral pharmaceutical formulation comprising trazodone or a pharmaceutically acceptable salt thereof, an enteric material, and a pharmaceutically acceptable carrier or excipient. The enteric material refers to a polymer that is substantially insoluble in the acidic environment of the stomach and largely soluble in intestinal fluids at a specific pH. The small intestine is the portion of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the pH of the jejunum is approximately 6.5, and the pH of the distal ileum is approximately 7.5. Thus, the enteric material is not soluble up to a pH of, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials are cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac, and copal collophorium, as well as some commercially available enteric dispersions (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or readily determinable in vitro.While the foregoing is a list of possible materials, one of ordinary skill in the art having the benefit of this disclosure will recognize that this is not exhaustive and that other enteric materials exist that would also satisfy the objectives of this disclosure.

[0070] A solution comprising trazodone, or a pharmaceutically acceptable salt thereof, may be administered to a patient using an auto-injector commonly used in the art. An auto-injector is a device that completely or partially replaces the actions involved in parenteral drug delivery from a standard syringe. These actions may include removing a protective syringe cap, inserting a needle into the patient's skin, injecting the medication, removing the needle, shielding the needle, and preventing reuse of the device. Triggering may be accomplished by a number of means, such as a trigger button, applying the auto-injector to the skin, or the needle reaching its injection depth.

[0071] In some devices, the energy for delivering the fluid is provided by a spring. An auto-injector may be a disposable or single-use device that can only be used to deliver one dose of medication and must be disposed of after use. Other types of auto-injectors may be reusable. Typically, they are configured to allow the user to load and unload a standard syringe. Reusable auto-injectors may be used to perform multiple parenteral drug deliveries, while the syringe is discarded after being used and unloaded from the auto-injector. Syringes may also be packaged with additional components to provide additional functionality.

[0072] The present disclosure also provides kits for use by consumers in need of treatment with, for example, trazodone or a pharmaceutically acceptable salt thereof. Such kits include a suitable dosage form, such as those described above, and instructions describing how to use a therapeutically effective amount of such a dosage form, as described hereinabove, to attenuate or reverse the pharmacological effects of a 5-HT2A receptor agonist, e.g., the hallucinogenic effects. The instructions instruct the consumer or medical professional to administer the dosage form according to a dosing regimen known to those skilled in the art. Such kits can also be advantageously packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms (tablets, capsules, etc.). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil, the recesses having the size and shape of the tablets or capsules to be packed. The tablets or capsules are then placed in the recesses and a sheet of relatively hard material is sealed against the plastic foil on the side of the plastic foil opposite to the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying manual pressure to the recesses, thereby forming openings in the sheet at the locations of the recesses. The tablets or capsules can then be removed through said openings.

[0073] An adverse effect of 5-HT2A receptor agonists is insomnia, making sleep difficult. Furthermore, another aspect of the present disclosure is directed to a method of using trazodone or a pharmaceutically acceptable salt thereof to attenuate the residual wake-promoting effects of 5-HT2A receptor agonists, which often persist beyond the time when the agonist-induced temporary perception and thought disturbances have subsided. Users of 5-HT2A receptor agonists often report sleep difficulties that persist beyond the duration of the desired psychedelic experience. Administration of trazodone or a pharmaceutically acceptable salt thereof at the doses described above, particularly higher doses (e.g., about 50 mg to 100 mg), terminates these residual wake-promoting effects in the subject and induces sleep. More specifically, this aspect of the present disclosure is directed to a method for promoting or inducing sleep in a subject suffering from insomnia due to prior administration of a 5-HT2A receptor agonist, comprising administering to the subject a sleep-inducing therapeutically effective amount of trazodone or a pharmaceutically acceptable salt thereof at a time when the hallucinogenic or other primary pharmacological effects are subsiding. For example, trazodone is administered at the end of the psychedelic experience induced by the 5-HT2A receptor agonist, e.g., about 4 hours after administration of psilocybin or about 8 hours after administration of LSD. The administration methods, dosages, dosing regimens, and types of pharmaceutical compositions described herein above are also applicable, and the discussions thereof are incorporated by reference.

[0074] Another aspect of the present disclosure is the use of trazodone or a pharmaceutically acceptable salt thereof to reverse hyperthermia induced by serotonin-norepinephrine-dopamine releasing agents (SNDRAs), also known as triple-releasing agents (TRAs). These drugs can be used as recreational drugs to produce euphoric, entactogenic, and psychostimulant effects. Examples include 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 4-methylamphetamine, methamphetamine, α-methyltryptamine (αMT), α-ethyltryptamine (α-ET), 5-(2-aminopropyl)benzofuran (5-APB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAP ... These include, but are not limited to, (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), naphthylisopropylamine, 4,4'-dimethylaminorex (4,4'-DMAR), 5-iodo-2-aminoindan (5-IAI), 4-fluoroamphetamine (4-FA), 4-fluoromethamphetamine (4-FMA), cathinones such as mephedrone, methylone, and 3-methylmethcathinone (3-MMC), and other TRAs. TRAs, such as MDMA, especially at high doses, can induce hyperthermia in those who ingest them, putting them at risk and sometimes even fatal. Additionally, based on animal studies, hyperthermia induced by the ingestion of these drugs is believed to exacerbate the neurotoxic effects of these compounds. Treatment of subjects suffering from TRA-induced hyperthermia with trazodone or its pharmaceutically acceptable salts reduces body temperature and attenuates secondary neurotoxic effects. The modes of administration, dosages, dosing regimens, and types of pharmaceutical compositions described herein above are also applicable, the discussion of which is incorporated by reference.

[0075] The following examples further illustrate the teachings in this disclosure. [Example]

[0076] Reversal of the head twitch response (HTR) by trazodone animal These studies used male C57BL / 6 mice (approximately 7-9 weeks old). Mice were housed two per cage under standard temperature- and humidity-controlled laboratory conditions with a 12-h light / dark cycle. Mice had free access to food and water.

[0077] Drugs and drug administration Trazodone HCl and DOPR HCl were used. Both compounds were dissolved in saline vehicle at a dose volume of 10 mL / kg. For salt forms, the dose was corrected so that the administered dose represented the free base.

[0078] Behavioral testing Mice were randomly assigned to one of six treatment groups consisting of two subcutaneous injections (see Table 1) and administered according to the schedule in Figure 1. First, mice were dosed with either vehicle (saline) or DOPR (3.2 mg / kg). Forty-five minutes later, mice were dosed with vehicle (saline) or trazodone (1, 1.8, 3.2, or 10 mg / kg) and immediately placed in the test chamber for 30 minutes. Behavior was videotaped using a camera (GoPro Hero 9) mounted above the test chamber. Recorded videos were uploaded for analysis of head-shake behavior. The number of head-shake responses (HTRs) was recorded for each animal for each 2-minute bin. For each treatment group, the average number of HTRs in each 2-minute or 10-minute bin and across the entire 30-minute recording period was analyzed. The ability of trazodone to reduce DOPR-induced HTR was determined by comparing Group 2 (DOPR+vehicle) with Groups 3-6 (DOPR+trazodone).

[0079] [Table 1]

[0080] result Trazodone completely reversed HTR induced by DOPR at the maximally effective dose for HTR, even at the lowest dose tested (see Figures 2 and 3). [Example]

[0081] Occupancy of cortical 5-HT2A receptors by DOPR animal These studies used male C57BL / 6 mice, 8-12 weeks old. Mice were group-housed under standard temperature- and humidity-controlled laboratory conditions with a 12-hour light / dark cycle. Mice had free access to food and water. Animals were randomly assigned to treatment groups.

[0082] Drugs and drug administration DOPR HCl was dissolved in saline as a vehicle and administered subcutaneously using a dosage volume of 10 mL / kg body weight. The dose was calculated based on the HCl salt. MDL100,907 [methyl- 3 H] was purchased from Novandi Chemistry Ltd. Ketanserin was purchased from Tocris (UK).

[0083] Sample collection and analysis Mice were dosed with vehicle or DOPR (0.32, 1, 3.2, or 32 mg / kg, SC) and sacrificed 15 or 60 minutes after dosing (n = 5 per dose / time condition) by elevated CO2 concentration followed by cervical dislocation. Whole brains were removed, briefly rinsed with saline, and blotted dry. A coronal incision was made at the level of the optic chiasm to obtain a forebrain block containing the frontal cortex (Mouse Brain in Stereotaxic Coordinates, Paxinos and Franklin, 2nd ed.). The forebrain block was then cut at the midline, and both blocks were placed on cork discs, covered with OCT embedding matrix (KMA-0100-00A, Cell Path), flash-frozen in isopentane (cooled to -20 / -30°C), and stored at -20°C for sectioning and ex vivo autoradiography. Coronal sections containing the frontal cortex were cut (20 μm thick) using a cryostat and thaw mounted onto Superfrost plus slides, and the slides were stored at −20° C. until the day of assay.

[0084] The slides containing the brain sections were warmed to room temperature, the sections were isolated using a DAKO pen, and 0.2 nM [ 3 H]MDL100,907 (total binding) or 0.2 nM [ 3 Sections were incubated in 200 μL of assay buffer containing [H]MDL100,907 and 10 μM ketanserin (nonspecific binding) for 30 minutes at room temperature. The solution was removed from the sections by aspiration, and the slides were washed for two consecutive 5-minute periods in ice-cold wash buffer. The slides were then rinsed briefly in ice-cold distilled water to remove buffer salts and air-dried. The assay and wash buffer consisted of 50 mM Tris, pH 7.4. Binding assays were performed on two separate occasions.

[0085] The waxy residue of the DAKO pen was removed with xylene to prevent sparks in the beta imager. All dust particles were removed from the microscope slides using lint-free tissue and an air duster. Copper foil tape was attached to the free side of the microscope slide to make the slide conductive. The slides were placed in the beta imager, and the level of bound radioactivity in the sections was determined directly by counting the number of beta particles emerging from a defined area using the M3 vision program (BioSpace). Data were collected from the brain sections over a 16-hour period and expressed as counts per minute per square millimeter (cpm / mm). 2 The mean total binding (cpm / mm) for each animal was expressed as 2 ) to the mean nonspecific binding (cpm / mm 2 ) to obtain the specific binding (cpm / mm 2 ) value.

[0086] result The 5-HT2A receptor occupancy achieved by DOPR in mice was assessed using a selective 5-HT2A receptor antagonist tracer, [ 3 Receptor occupancy was determined ex vivo using [H]MDL100,907. 3 This resulted in a dose-dependent reduction in the amount of [H]MDL100,907 binding, indicating an increase in 5-HT2A receptor occupancy by DOPR (Figure 4). The dose of DOPR calculated to occupy 50% of 5-HT2A receptors was 2.08 mg / kg. The dose of DOPR used in the HTR experiment in Example 1 (3.2 mg / kg, SC) achieved 57% occupancy of 5-HT2A receptors at approximately the time point of HTR measurement. 5-HT2A receptor occupancy determined at other doses and time points is presented in Table 2.

[0087] [Table 2] [Example]

[0088] Measurement of plasma and brain concentrations of trazodone in mice animal These studies used male C57BL / 6 mice, 8-12 weeks old. Mice were housed four per cage under standard temperature- and humidity-controlled laboratory conditions with a 12-hour light / dark cycle. Mice had free access to food and water but were fasted 4 hours before and 2 hours after dosing. Animals were randomly assigned to treatment groups.

[0089] Drugs and drug administration Trazodone HCl was prepared using saline as a vehicle and administered subcutaneously using a dose volume of 10 mL / kg body weight. For salt forms, the dose was corrected so that the administered dose represented the free base.

[0090] Sample collection and bioanalysis Twelve mice were subcutaneously dosed with each dose level of trazodone (1, 3.2, or 10 mg / kg). At 5, 15, or 25 minutes (four animals per time point), blood samples (approximately 60 μL) were collected from the retroorbital venous plexus under mild isoflurane anesthesia (Surgivet®). Immediately after blood collection, plasma was collected by centrifugation at 4,000 rpm for 10 minutes at 4°C, and samples were stored at -70±10°C until bioanalysis. After blood collection, animals were immediately sacrificed, the abdominal vena cava was incised, and brain samples were collected from all animals. After isolation, brain samples were rinsed three times in ice-cold saline (approximately 5–10 mL of saline in a disposable Petri dish for each rinse for 5–10 seconds) and dried on absorbent paper. Brain samples were homogenized using ice-cold phosphate-buffered saline (pH 7.4). The total homogenate volume was three times the tissue mass. All homogenates were stored at -70 ± 10°C until bioanalysis. For bioanalysis, 20 μL aliquots of plasma / brain research samples or spiked plasma / brain calibration standards were added to individual pre-labeled microcentrifuge tubes, followed by 200 μL of internal standard solution (cetirizine, 50 ng / mL in acetonitrile), except for blanks, which received 200 μL of acetonitrile. Samples were vortexed for 5 minutes and then centrifuged at 4,000 rpm for 10 minutes at 4°C. After centrifugation, 200 μL of each clear supernatant was transferred to a 96-well plate and analyzed by a purpose-built LC-MS / MS method; reference samples of each analyte were used for calibration and identification.

[0091] result Trazodone concentrations were measured in the plasma and brain of mice after subcutaneous (SC) dosing at time points corresponding to those analyzed in the HTR reversal experiment (Example 1), and the results are presented in Table 3.

[0092] [Table 3] [Example]

[0093] Measurement of plasma protein binding of trazodone in mouse and human plasma method A 1 mM stock solution of trazadone was prepared in DMSO and diluted 200-fold in mouse or human plasma to obtain a final concentration of 5 μM. The final DMSO concentration was 0.5%. Rapid equilibrium dialysis (RED) was performed using a RED device containing a dialysis membrane with a molecular weight cutoff of 8,000 daltons. Each dialysis insert contains two chambers: the red chamber is for plasma, while the white chamber is for buffer.

[0094] For each dialysis insert, 200 μL aliquots of 5 μM positive control or test compound (n=2) were added separately to the plasma chamber, and 350 μL of phosphate-buffered saline (pH 7.4) was added to the buffer chamber. After sealing the RED device with adhesive film, dialysis was performed in an incubator at 37°C with shaking at 300 RPM for 4 hours. To assess recovery and stability, 50 μL aliquots of positive control and test compound were added to a 96-deep-well plate and quenched with 400 μL of acetonitrile (0 min), while control aliquots were incubated with the RED device at 37°C for 4 hours.

[0095] After dialysis, 50 μL aliquots were removed from each well (both plasma and buffer) and diluted with an equal volume of the opposite matrix (dialyzed against the other matrix) to neutralize matrix effects. Similarly, 50 μL of buffer was added to recovery and stability samples. 100 μL aliquots were subjected to LC-MS / MS analysis.

[0096] Aliquots (50 μL) of test samples were protein precipitated with 400 μL of acetonitrile containing the internal standard (glipizide) and vortexed for 5 minutes. Samples were centrifuged at 4,000 RPM for 10 minutes at 4°C, and a 100 μL aliquot of the supernatant was subjected to LC-MS / MS analysis of the parent compound using a tailored LC-MS / MS method.

[0097] result The bound and unbound fractions of trazodone in mouse and human plasma were determined using equilibrium dialysis. Trazodone was 94.4% and 90.2% bound (5.6% and 9.8% unbound) in mouse and human plasma, respectively, after a 4-hour incubation.

[0098] Description of Examples 1 to 4 The experiments described in Examples 1 and 3 were carried out to demonstrate the ability of trazodone to reverse the head shake response (HTR) in mice (a rodent correlate of its hallucinogenic effect in humans) and to establish the dose levels and exposures required to induce such a reversal effect. Furthermore, additional studies described in Examples 2 and 4 were carried out to allow extrapolation of the effective doses and exposure levels determined in rodents to humans.

[0099] First, we used 2,5-dimethoxy-4-propylamphetamine (DOPR), a representative 5-HT2A receptor agonist, to induce HTR in mice and determine the ability of multiple doses of trazodone administered after DOPR to reverse that HTR (see Example 1). The dose of DOPR (3.2 mg / kg, SC) chosen for these experiments was maximally effective in inducing HTR with this compound (higher and lower doses resulted in less HTR) and was consistent with the pharmacokinetic T after SC administration 1 hour after dosing. max ) resulting in 57% 5-HT2A receptor occupancy. In addition to inducing maximal hallucinogenic-like effects in mice, the occupancy level achieved by this dose of DOPR in mice (see Example 2) is similar to the 60-70% reported to be necessary to induce an intense psychedelic experience after psilocybin administration in humans. Thus, trazodone at exposure levels (and allometrically scaled doses for the species) capable of fully reversing the effects of selected doses of DOPR can also fully reverse the effects of fully psychedelic doses of any 5-HT2A receptor agonist in both mice and humans.

[0100] Mice were first administered DOPR (3.2 mg / kg, SC). Forty-five minutes later, mice were administered one of various doses of trazodone or vehicle (SC), and HTRs were counted by video recording over a 30-minute period after trazodone administration (45–75 minutes after DOPR administration; Figure 1). The time points for trazodone administration and HTR recording were selected so that the recording window was centered around the time of maximal DOPR 5-HT2A receptor occupancy and HTR (60 minutes after administration) and so that the speed of onset of trazodone's reversal effect could be determined. All doses of trazodone tested, including the lowest dose, were found to rapidly (within 2 minutes) and completely reverse DOPR-induced HTRs, and the reversal effect persisted for the entire duration of the 30-minute recording period (Figure 2). Furthermore, higher doses of trazodone suppressed HTRs below the baseline levels observed in vehicle-pretreated animals.

[0101] The effect was also quantified in 10-minute bins (0-10, 10-20, and 20-30 minutes after trazodone administration), which showed the same rapid and robust HTR reversal effect, even at the lowest dose (FIG. 3).

[0102] In separate PK experiments, plasma and brain concentrations of trazodone were determined at 5, 15, and 25 minutes after SC dosing, which coincided with the midpoints of the three 10-minute bins analyzed in Figure 3 (see Example 3).

[0103] Since even the lowest dose of trazodone was sufficient to maintain complete reversal of DOPR-induced HTR in the 20-30 min time bin (Figure 3), where trazodone concentrations were lowest (see Example 3), we conclude that the minimum effective plasma concentration (MEC) for reversal of the hallucinogenic effects of fully psychedelic doses of 5-HT2A receptor agonists by trazodone is approximately 369 ng / mL or less (plasma concentration 25 min after 1 mg / kg SC trazodone).

[0104] Using the above plasma MEC in mice and knowledge of the plasma pharmacokinetics of trazodone in humans, we can estimate the dose of trazodone required to reverse the hallucinogenic effects of a typical, fully psychedelic, but not excessive, dose of a 5-HT2A receptor agonist (e.g., approximately 25 mg orally of psilocybin) in humans. According to the free drug hypothesis, the pharmacological effect of a compound in vivo is mediated by the concentration of the free, unbound form of the compound. Therefore, when predicting human dosing based on the above mouse findings, it is important to take into account interspecies differences in plasma protein binding. Using equilibrium dialysis, the unbound fraction of trazodone in mouse plasma was found to be 5.6%, while in human plasma it was found to be 9.8% (see Example 4). Thus, the total plasma MEC of approximately 369 ng / mL determined in mice corresponds to a free plasma concentration of approximately 21 ng / mL (approximately 369 mg / mL * 0.056). This, in turn, corresponds to a total human plasma MEC of approximately 214 ng / mL (approximately 21 ng / mL / 0.098). Therefore, based on the data, a human dose of trazodone achieving a total plasma concentration of approximately 214 ng / mL or greater is expected to reverse the hallucinogenic effects of a typical, fully psychedelic dose of any 5-HT2A receptor agonist, as long as the plasma concentration of trazodone remains above this MEC. The concept of a "typical, fully psychedelic dose" should be understood to mean the minimum dose required to induce a psychedelic experience in a typical human subject that is subjectively reported as intense and to induce typical cognitive phenomena characteristic of the psychedelic state (e.g., visual, auditory, or other perceptual disturbances and substantial changes in thought patterns).

[0105] Examples of fully psychedelic doses of common 5-HT2A receptor agonists that are reversible at an MEC of approximately 214 ng / mL are listed in Table 4. Typical fully psychedelic dose ranges for other 5-HT2A receptor agonists can be found in PiHKAL: A Chemical Love Story (Shulgin, 1991), the contents of which are incorporated herein by reference.

[0106] [Table 4]

[0107] The human pharmacokinetic parameters of trazodone (Table 5) can be used to estimate the minimum effective dose (MED) required to achieve this MEC for reversal of 5-HT2A-induced subjective effects, including visual, auditory, and thought disturbances, by different routes of administration.

[0108] [Table 5]

[0109] By the oral route, the MED is estimated to be approximately 12 mg (approximately 214 ng / mL / approximately 17.2 ng / mL / mg). By the intravenous route, the MED is estimated to be less than 12 mg, considering that higher peak concentrations are achieved after intravenous bolus administration compared to oral administration. The peak reversal effect after oral trazodone administration is comparable to the T of trazodone. maxIt is estimated that the peak reversal effect after administration of trazodone as an intravenous bolus occurs almost instantaneously (less than 5 minutes). Administration of trazodone by other routes, such as intranasal, intramuscular, or subcutaneous, is also contemplated and achieves the same effect. Sublingual and buccal routes can also be used, but may be less desirable due to slower onset of action. For these other routes, it should be understood that the MED and rate of onset will depend on A) the PK of trazodone after administration by such route and B) the specific formulation used; therefore, doses should be selected to achieve a total plasma concentration of about 214 ng / mL or greater. The rate of onset by the intranasal and intramuscular routes is faster than that by the oral route, and should reach a peak reversal effect in about 15 to 20 minutes. A given peak magnitude of reversal (plasma C) by these routes is achieved. max The dose required to achieve this should be intermediate between the oral and intravenous routes.

[0110] Assuming that the desired degree of hallucinogenic reversal (e.g., complete reversal) is achieved after the first dose of trazodone, A) trazodone acts as a 5-HT2A receptor agonist. max A) administered after the T of the 5-HT2A receptor agonist is reversed. Assuming the half-life of the 5-HT2A receptor agonist is less than the half-life of trazodone (approximately 6-12 hours), additional doses of trazodone should not be required to maintain effective levels. max It should be understood that if the drug is administered before the initial dose, so that the plasma concentration of the agonist is still elevated, the hallucinogenic effect may reoccur if the plasma concentration of the agonist increases beyond that which can be overcome by the dose of trazodone administered. 1 / 2In the case of 5-HT2A receptor agonists with a 5-HT2A receptor antagonism greater than c), trazodone may be eliminated more rapidly than competing agonists, and thus re-administration of trazodone may be necessary to maintain reversal. Furthermore, given the competitive nature of trazodone's 5-HT2A receptor antagonism, it should be understood that reversal of exceptionally high doses of a given 5-HT2A receptor agonist (e.g., doses substantially higher than those listed in Table 4) necessarily requires higher doses of trazodone to achieve plasma concentrations above the MEC outlined above. However, in such cases, even low or moderate doses of trazodone may provide partial reversal of the psychedelic effect, which is likely to be beneficial to the subject in terms of reduced anxiety and physiological risk, even in the absence of complete reversal. Similarly, reversal of lower doses of 5-HT2A receptor agonists may require lower doses of trazodone. Finally, trazodone may be administered at any time after administration of the 5-HT2A receptor agonist, at the discretion of the subject or healthcare provider, whether to interrupt unpleasant psychological experiences reported by the subject, to attenuate dangerous cardiovascular side effects, or simply to shorten the duration of the psychedelic therapy session for convenience.

[0111] The above preferred embodiments and examples are provided to illustrate the scope and spirit of the present invention. From these embodiments and examples, other embodiments and examples will become apparent to those skilled in the art. Other embodiments and examples are within the contemplation of the present invention. Accordingly, the present invention should be limited only by the amended claims.

[0112] appendix In Table 5, various references were identified, the citations of which are provided in this appendix. Greenblatt 1987: Greenblatt et al., Clin. Pharmacol. Ther., (1987), 42, 193-200. Nilsen 1992: Nilsen et al., Pharmacology and Toxicology, (1992), 71, 150-153. Gammans, 1984: Gammans et al., Br. J. Clin. Pharmac., (1984), 18, 431-437. Bayer 1983: Bayer et al., Br. J. Clin. Pharmac., (1983), 16, 371-376. Kale, 2015: Kale et al., Clinical Trial, (2015), 1-16. Nilsen 1993: Pharmacology and Toxicology, (1993), 72, 286-289.

Claims

1. A method for reversing or attenuating the pharmacological effect of a 5-HT2A receptor agonist in a subject, comprising administering to said subject in need of such treatment a therapeutically effective amount of trazodone or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, wherein the effect to be reversed comprises visual, auditory, or other sensory impairment.

3. 10. The method of claim 1, wherein the effect reversed comprises abnormal thinking.

4. 10. The method of claim 1, wherein the effect reversed comprises vasoconstriction, elevated blood pressure, or other cardiovascular effect.

5. 10. The method of claim 1, wherein the effect to be reversed comprises nausea.

6. 10. The method of claim 1, wherein the effect to be reversed comprises insomnia.

7. 10. The method of claim 1, wherein the pharmacological effect is a hallucination.

8. A method for promoting or inducing sleep in a subject who continues to suffer from insomnia following administration of a 5-HT2A receptor agonist after the primary sensory effects of the agonist have subsided, comprising administering to the subject a therapeutically effective amount of trazodone or a pharmaceutically acceptable salt thereof.

9. 9. The method of any one of claims 1 to 8, wherein the agonist of the 5-HT2A receptor to be reversed is selected from the group consisting of an ergoline, a tryptamine, a phenethylamine, or an amphetamine.

10. Tryptamines include psilocybin, psilocin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), N-methyl-N-ethyltryptamine (MET), N-methyl-N-isopropyltryptamine (MIPT), N,N-diethyltryptamine (DET), N,N-diisopropyltryptamine (DIPT), N,N-dipropyltryptamine (DPT), N-ethyl-N-propyltryptamine (EPT), 5-methoxy-N-methyl-N-isopropyltryptamine ( 5-MeO-MIPT), 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), 5-methoxy-N-methyl-N-ethyltryptamine (5-MeO-MET), 5-methoxy-N,N-diethyltryptamine (5-MeO-DET), N,N-diallyl-5-methoxytryptamine (5-MeO-DALT), 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4-HO-MIPT), 4-hydroxy-N,N-di Isopropyltryptamine (4-HO-DIPT), 4-hydroxy-N,N-diethyltryptamine (4-HO-DET), 4-hydroxy-N,N-dipropyltryptamine (4-HO-DPT), 4-hydroxy-N-ethyl-N-propyltryptamine (4-HO-EPT), 4-acetoxy-N-methyl-N-ethyltryptamine (4-AcO-MET), 4-acetoxy-N-methyl-N-isopropyltryptamine (4-AcO-MIPT), 4-acetoxy-N,N-diisopropyltryptamine (4-AcO-DIP) 10. The method of claim 9, wherein the tryptamine is selected from the group consisting of 4-acetoxy-N,N-diethyltryptamine (4-AcO-DET), 4-acetoxy-N,N-dipropyltryptamine (4-AcO-DPT), 4-acetoxy-N-ethyl-N-propyltryptamine (4-AcO-EPT), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), alpha-methyltryptamine (AMT), alpha-ethyltryptamine (AET), and 5-methoxy-alpha-methyltryptamine (5-MeO-AMT).

11. 10. The method of claim 9, wherein the ergoline is a lysergic acid amide selected from the group consisting of lysergic acid diethylamide (LSD), lysergic acid 2,4-dimethylazetidide (LSZ), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 1-acetyl-lysergic acid diethylamide (ALD-52), 1-propionyl-lysergic acid diethylamide (1P-LSD), 1-butyryl-lysergic acid diethylamide (1B-LSD), and 1-(cyclopropylmethanoyl)-lysergic acid diethylamide (1cP-LSD).

12. Phenethylamines include mescaline, escaline, proscaline, methallyl escaline, allyl escaline, 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 4-chloro-2,5-dimethoxyphenethylamine (2C-C), 4-iodo-2,5-dimethoxyphenethylamine (2C-I), 2,5-dimethoxy-4-methylphenethylamine (2C-D), 2-(4-ethyl-2,5-dimethoxyphenyl)ethanamine (2C-E), 2-(2,5-dimethoxy-4-propylphenyl)ethan-1-amine (2C- P), 2-[4-(ethylsulfanyl)-2,5-dimethoxyphenyl]ethan-1-amine (2C-T-2), 2-[2,5-dimethoxy-4-(propylsulfanyl)phenyl]ethan-1-amine (2C-T-7), 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25B-NBOMe), 2-(4-methyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe), 2-(4-methyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25E-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25I-NBOH), 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25I-NBOH), 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25B-NBOH), 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25C-NBOH), 2-(4-methyl-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25D-NBOH), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25E-NBOH), and 2-(4-cyano-2,10. The method of claim 9, wherein the compound is selected from the group consisting of 5-dimethoxyphenyl)-N-[(2-hydroxyphenyl)methyl]ethanamine (25CN-NBOH).

13. 10. The method of claim 9, wherein the amphetamine is selected from the group consisting of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-ethylamphetamine (DOET), and 2,5-dimethoxy-4-propylamphetamine (DOPR).

14. 10. The method of claim 9, wherein the 5-HT2A receptor agonist is selected from the group consisting of psilocybin, 4-AcO-DMT, psilocin, DMT, 5-MeO-DMT, LSD, mescaline, 2C-B, 2C-E, 2C-T-2, 2C-T-7, and DOM.

15. 1. A method for treating hyperthermia induced by a serotonin-norepinephrine-dopamine releasing agent, comprising administering to a subject in need thereof a therapeutically effective amount of trazodone or a pharmaceutically acceptable salt thereof.

16. Serotonin-norepinephrine-dopamine releasing agents include 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 4-methylamphetamine, methamphetamine, α-methyltryptamine (αMT), α-ethyltryptamine (α-ET), 5-(2-aminopropyl)benzofuran (5-APB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-5-yl)-N-methylpropional (1-methylpropional ...

16. The method of claim 15, wherein the active ingredient is pan-2-amine (5-MAPB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), naphthylisopropylamine, 4,4'-dimethylaminorex (4,4'-DMAR), 5-iodo-2-aminoindan (5-IAI), 4-fluoroamphetamine (4-FA), 4-fluoromethamphetamine (4-FMA), mephedrone, methylone, or 3-methylmethcathinone (3-MMC).

17. 16. The method of claim 15, wherein the serotonin-norepinephrine-dopamine releasing agent is 3,4-methylenedioxymethamphetamine.

18. 18. The method of any one of claims 1 to 17, wherein trazodone or a pharmaceutically acceptable salt thereof is administered orally.

19. 19. The method of claim 18, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 100 mg per about 70 kg human.

20. 19. The method of claim 18, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 50 mg per about 70 kg human.

21. 18. The method of any one of claims 1 to 17, wherein trazodone or a pharmaceutically acceptable salt thereof is administered intravenously.

22. 22. The method of claim 21, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 100 mg per about 70 kg human.

23. 22. The method of claim 21, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 50 mg per about 70 kg human.

24. 18. The method of any one of claims 1 to 17, wherein trazodone or a pharmaceutically acceptable salt thereof is administered intranasally.

25. 25. The method of claim 24, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 50 mg per about 70 kg human.

26. 25. The method of claim 24, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 25 mg per about 70 kg human.

27. 18. The method of any one of claims 1 to 17, wherein trazodone is administered intramuscularly.

28. 28. The method of claim 27, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 100 mg per about 70 kg human.

29. 28. The method of claim 27, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 5 mg to about 50 mg per about 70 kg human.

30. 18. The method of any one of claims 1 to 17, wherein trazodone or a pharmaceutically acceptable salt thereof is administered subcutaneously.

31. 31. The method of claim 30, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 100 mg per about 70 kg human.

32. 31. The method of claim 30, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 50 mg per about 70 kg human.

33. 33. The method of any one of claims 1 to 32, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof is sufficient to achieve a peak plasma concentration of at least 100 ng / mL.

34. 33. The method of any one of claims 1 to 32, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof is sufficient to achieve a peak plasma concentration of at least 200 ng / mL.

35. 33. The method of any one of claims 1 to 32, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof is sufficient to achieve a peak plasma concentration of about 100 ng / mL to about 400 ng / mL.

36. 33. The method of any one of claims 1 to 32, wherein the dose of trazodone or a pharmaceutically acceptable salt thereof is sufficient to maintain a plasma concentration of at least 200 ng / mL for at least 4 hours.

37. 37. The method of any one of claims 1 to 36, wherein trazodone or a pharmaceutically acceptable salt thereof is administered two or more times per day to maintain reversal of the long-acting 5-HT2A receptor agonist.

38. 38. The method of any one of claims 1 to 37, wherein the pharmaceutically acceptable salt of trazodone is trazodone hydrochloride.

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