Methods and compositions comprising 5HT receptor agonist for treatment of psychological, cognitive, behavioral, and / or mood disorders

Abstract

SOLUTION: Provided herein are methods and compositions for the treatment of psychological, cognitive, behavioral, and / or mood disorders, the composition comprising a 5HT agonist (e.g. psilocybin). In certain embodiments, such compositions are administered in amounts or levels high enough to provide a therapeutic effect, but insufficient to provide an adverse effect.SELECTED DRAWING: Figure 6

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 798,998, filed January 30, 2019, and U.S. Provisional Patent Application No. 62 / 799,010, filed January 30, 2019, each of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Serotonin (5HT) receptors are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels found in the central and peripheral nervous systems. Activation of 5HT receptors can substantially affect brain function.

[0003] Many people worldwide suffer from psychological or mood disorders, including depression, anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder, among others. Many of these illnesses are thought to involve an individual's serotonin system, which involves the interaction of (A) the neurotransmitter serotonin with (B) the various subtypes of serotonin neurotransmitter receptors found in the human body.

[0004] Various compositions that modulate activity at serotonin receptors are known. Many pharmaceuticals (antidepressants, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, etc.) are commercially available. Many of the major commercially available pharmaceuticals for treating mood disorders (such as depression, obsessive-compulsive disorder, and / or anxiety disorder) target the serotonin pathway.

[0005] However, despite their popularity and commercial success, these medications are characterized by a long onset of action, severe side effects, and limited efficacy. In many cases, these drugs are harmful to users. For example, people taking prescription drugs that target serotonin have reported suicidal thoughts, sexual dysfunction, fatigue, high blood pressure, vision problems, abnormal heart rate, nausea, and weight gain.

[0006] Psilocybin (also known as 4-phosphoryloxy-N,N-dimethyltryptamine or [3-(2-trimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate) is believed to be the most abundant psychoactive compound found in "magic mushrooms." Psilocybin is also being tested as a candidate for prescription drug development to treat drug addiction, anxiety, and mood disorders. However, therapeutic applications of psilocybin have been associated with adverse side effects, including hallucinations, panic attacks, psychosis, nausea, vomiting, muscle weakness, and lack of coordination. Therefore, there is a need to develop psilocybin pharmaceutical compositions that treat disorders associated with the 5HT receptor without causing adverse side effects. Summary of the Invention

[0007] In some embodiments, methods and compositions are provided herein for treating psychological, cognitive, behavioral, and / or mood disorders. In some embodiments, the disorders described herein are treated by administering a therapeutically effective amount of a therapeutically effective agent described herein, such as a 5HT agonist (an active 5HT agonist itself (e.g., psilocin)), or a salt, solvate, metabolite, derivative, or prodrug thereof (e.g., psilocybin). In some embodiments, the therapeutic agent is administered (or present in a composition provided herein) in an amount or level (e.g., a low, therapeutically effective amount) high enough to provide a therapeutic effect, e.g., to avoid adverse effects (e.g., hallucinations or other adverse effects, such as panic attacks, psychosis, nausea, vomiting, muscle weakness, or lack of coordination). In some examples, such low-dose therapeutic agents (and / or compositions or methods provided herein) improve motivation, attention, accuracy, reaction speed, perseveration, and / or cognitive engagement. In some embodiments, such low-dose therapeutic agents (and / or compositions or methods provided herein) are used to treat behavioral and / or cognitive disorders, such as those in which motivation, attention, accuracy, reaction speed, perseveration, and / or cognitive engagement play a role. In certain embodiments, the compositions provided herein are useful for or used to treat depression, anxiety, apathy and / or low motivation, attention disorders, disorders of executive function and / or cognitive engagement, obsessive-compulsive disorder, and / or neurocognitive disorders.

[0008] Further provided herein in some embodiments is a method of managing a neurological disease or one or more symptoms thereof in a subject, the method comprising administering to said subject a pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists (e.g., psilocin), or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof (e.g., psilocybin); b) a pharmaceutically acceptable excipient; Includes.

[0009] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to the subject in an amount that does not result in adverse side effects, such as a hallucinatory experience.

[0010] Further provided herein is a method of treating symptoms of a neurological disease in a subject suffering from or susceptible to said disease, the method comprising administering to said subject a pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists (e.g., psilocin), or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof (e.g., psilocybin); b) a pharmaceutically acceptable excipient; Includes.

[0011] In certain embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to the subject in an amount that does not result in adverse side effects, such as hallucinatory experiences.

[0012] In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 0.1 mg to about 50 mg (e.g., about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, about 10 mg to about 50 mg, etc.).

[0013] In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of from about 0.1 mg to about 2 mg.

[0014] In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 1 mg to about 15 mg.

[0015] In some embodiments, the pharmaceutical composition is a low dose pharmaceutical composition.

[0016] In some embodiments, the pharmaceutical composition comprises a controlled release component.

[0017] In some embodiments, the pharmaceutical composition comprises a controlled release component and an immediate release component.

[0018] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist (e.g., psilocin), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., psilocybin), is sufficient to achieve a maximum plasma concentration (C) of the 5HT receptor agonist (e.g., psilocin), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., of the active form thereof) of 6 ng / mL or greater. max ) is provided to the subject in an amount and / or formulation that does not result in

[0019] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., psilocybin), is a therapeutically effective amount that provides a maximum plasma concentration (Cp) of the 5HT receptor agonist (e.g., psilocin), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., of the active form) of about 0.1 ng / mL or more and less than 6 ng / mL (e.g., at least 0.5 ng / mL and about 6 ng / mL, about 1 ng / mL to about 5.5 ng / mL, about 2 ng / mL to about 5 ng / mL, etc.). max ) is provided to the subject in an amount and / or formulation that results in

[0020] In some embodiments, the therapeutically effective amount of the 5HT receptor agonist (e.g., psilocin), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is sufficient to achieve a maximum plasma concentration (Cp) of the 5HT receptor agonist (e.g., psilocin), or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., of the active form thereof) of at least 0.1 ng / mL (e.g., at least 0.2 ng / mL, at least 0.3 ng / mL, at least 0.5 ng / mL, etc.) after at least 6 hours (e.g., at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, etc.). max ) is provided to the subject in an amount and / or formulation that results in

[0021] In some embodiments, the 5HT receptor agonist is a 5HT2 receptor agonist. In some embodiments, the 5HT receptor agonist is psilocybin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0022] Also disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists (e.g., psilocin), or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof (e.g., psilocybin); b) a pharmaceutically acceptable excipient; and c) (e.g., optionally) one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; Includes.

[0023] Also disclosed herein is a pharmaceutical composition, the pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists (e.g., psilocin), or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof (e.g., psilocybin); b) a pharmaceutically acceptable excipient; and c) (e.g., optionally) one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; Includes.

[0024] In some embodiments, the pharmaceutical compositions provided herein are low-dose pharmaceutical compositions. In some embodiments, after administration to an individual, the pharmaceutical compositions provided herein provide the individual with a maximum plasma concentration (C ) of a 5HT receptor agonist (e.g., psilocin) (or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, e.g., psilocybin) (e.g., the active form of the 5HT receptor agonist, regardless of administration form) of less than 6 ng / mL. max In some embodiments, the 5HT receptor agonist is psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the 5HT receptor agonist is psilocybin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0025] Also disclosed herein are pharmaceutical compositions comprising an oral dosage form, the oral dosage form comprising an immediate-release top layer and a controlled-release core. In some embodiments, the immediate-release layer comprises (i) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and (ii) one or more second pharmaceutical agents. In some embodiments, the one or more second pharmaceutical agents are stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory agents, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, or lysergic acid diethylamide. In some embodiments, the controlled-release core comprises (a) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; (b) at least one pharmaceutically acceptable excipient; and (c) optionally one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents. In some embodiments, the pharmaceutical composition is a low-dose pharmaceutical composition. In some embodiments, after administration to an individual, the pharmaceutical composition provides the individual with a maximum plasma concentration (C of the 5HT receptor agonist (or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof) (e.g., the active form of the 5HT receptor agonist, regardless of administration form) of less than 6 ng / mL. max ) results.

[0026] Various aspects of the present disclosure are set forth with particularity in the appended claims. The features and advantages of the present disclosure will be understood by reference to the following detailed description that sets forth illustrative embodiments, and the accompanying drawings, in which the principles of the disclosure are utilized. [Brief explanation of the drawings]

[0027] [Figure 1]Figure 1 shows the effects of psilocybin on locomotor activity and behavioral signs in treated rats. Graph A shows the distance traveled (measured in cm) in response to doses of 0.03–10 mg / kg psilocybin. Graph B shows the effect of psilocybin administration on 5-HT2A-related behaviors. The total number (N) of wet dog shakes (WDS) and back muscle contractions (BMC) is plotted against dose (mg / kg). The hatched area indicates the psilocybin dose that induced statistically identical WDS and BMC behaviors to vehicle. [Figure 2] Figure 1 shows the effect of psilocybin on progression ratio (PR) in treated rats. Graph A shows the number of lever presses by high- and low-responder rats before vehicle or psilocybin administration to establish a pre-test PR baseline. Graph B shows the number of lever presses by high- and low-responder rat subgroups across doses of 0.05 mg / kg, 0.1 mg / kg, and 0.2 mg / kg psilocybin. High-responder rats are defined as rats achieving the highest tertile of lever presses in the baseline test. Low-responder rats are rats achieving the lowest tertile of lever presses in the baseline test. An asterisk (*) indicates a statistically significant difference between high- and low-responder rats. [Figure 3]These graphs show the effects of psilocybin on cognition in rats using a 5-choice reaction time task (5-CSRTT) with a 5-second interval between trials. Graph A shows the cognitive enhancement (measured as %Hits for nose-pokes into the stimulus location to collect a food reward) for all rats when psilocybin 0.05 mg / kg was administered compared to vehicle and 0.1 mg / kg. An asterisk (*) indicates a statistical difference from vehicle. Graph B shows the cognitive enhancement (measured as %Correct for nose-poke accuracy) for all rats when psilocybin 0.05 mg / kg was administered compared to vehicle and 0.1 mg / kg. Graph C shows the cognitive enhancement (%Hits) for the low-performing subgroup when two different doses of psilocybin were administered. An asterisk (*) indicates a statistical difference from vehicle. Graph D shows the effect (%Correct) of administering two different doses of psilocybin to the low-performing subgroups. High performers are defined as rats completing the highest tertile of Hit or Correct nosepokes on the baseline test. Low performers are rats completing the lowest tertile of Hit or Correct nosepokes on the baseline test. [Figure 4]This figure shows the effects of psilocybin on cognition in rats, assessing premature responses (PREM) and perseverative responses (PSV) using the 5-choice reaction time task (5-CSRTT). Graph A shows the increase in PREM and PSV responses at a 5-second inter-trial interval (ITI) establishing baseline and a 10-second ITI when 24 animals were administered two doses of psilocybin (0.05 mg / kg and 0.1 mg / kg). Standard deviations are indicated by error bars. An asterisk (*) indicates a significant difference (P = 0.05) versus vehicle using a t-test. Graph B shows the effects of psilocybin on PREM and PSV in both low- and high-performing subgroups. Standard errors are indicated by error bars. An asterisk (*) indicates a significant difference (P < 0.01) versus vehicle using a t-test. High performers are defined as rats achieving the highest tertile of premature responses in the baseline test. Poor performers are rats achieving the lowest tertile of premature responding on the baseline test. [Figure 5] Figure 1 shows plasma concentrations of psilocin over time in rats administered psilocybin at various doses: 0.05 mg / kg (Cmax psilocin ~6 ± 2 ng / ml after 30 minutes), 0.1 mg / kg (Cmax psilocin ~12 ± 3 ng / ml after 30 minutes), 1 mg / kg (Cmax psilocin ~83 ± 5 ng / ml after 30 minutes), and 10 mg / kg (Cmax psilocin ~1106 ± 164 ng / ml after 30 minutes). [Figure 6]Figure 1 shows the effects of psilocybin on cognition in rats. Graph A shows the lowest performance tertile (N=8), representing inattentive and possibly depressed inattentive intermediate traits. Graph B shows the %Hit scores for inattentive rats. Graph D shows slower response speeds for inattentive rats. Similar to the PR test, the effects of psilocybin at 0.05 and 0.1 mg / kg on accuracy (%Correct and %Hit) in the 5CSRTT were strongly evident in inattentive rats compared to vehicle in graphs C and E. An asterisk (*) indicates a statistically significant difference compared to vehicle. Psilocybin at 0.05 mg / kg further improved response speeds in the inattentive cohort compared to vehicle in graph D. DETAILED DESCRIPTION OF THE INVENTION

[0028] 5HT (or serotonin) receptors 5HT (or serotonin) receptors are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels. 5HT is a contraction of 5-hydroxytryptamine, the chemical name for serotonin.

[0029] [ka]

[0030] Serotonin receptors are activated by serotonin, its natural ligand, and mediate both excitatory and inhibitory neurotransmission. Serotonin receptors regulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P. Serotonin receptors influence a variety of biological and neurological processes, including aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation.

[0031] 5HT receptors are divided into seven families of G protein-coupled receptors. 5HT1, 5HT2, and 5HT3 are the major families, while the remaining 5HT4, 5HT5, 5HT6, and 5HT7 largely act similarly to either the 5HT1 or 5HT2 receptors. 5HT receptors act in conjunction with G proteins to modify ion channels or membrane enzymes.

[0032] In some embodiments, the 5HT agonist in the formulations, compositions, methods, etc. described herein is a 5HT1 agonist.5HT1 receptor has a strong binding affinity to serotonin.Generally, when serotonin binds to 5HT1 receptor, G protein is activated, opening ion channel, allowing potassium ions to exit neuron.This generally makes neuron more negatively charged, making it more difficult to induce potential effects.That is, serotonin binding to 5HT1 receptor is an inhibitory effect.

[0033] In some preferred embodiments, the 5HT agonist in the formulations, compositions, methods, etc. described herein is a 5HT2 agonist. In certain embodiments, the 5HT2 agonist has a relatively high affinity for the 5HT2 receptor (e.g., 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, or 50-fold higher affinity for the 5HT1 receptor and / or other 5HT receptors, such as 5HT3, 5HT4, 5HT5, 5HT6, 5HT7, or a combination of all or some of them). The 5HT2 receptor has a weaker affinity for serotonin. Therefore, once the 5HT1 receptor is at least partially (or completely) saturated, serotonin prefers to bind only to the 5HT1 receptor, typically the 5HT2 receptor. Serotonin binding to the 5HT2 receptor typically activates G proteins, closing potassium channels and resulting in the buildup of potassium ions. This typically results in depolarization, making it easier for neurons to reach their excitation threshold. Therefore, serotonin typically produces excitatory effects when bound to the 5HT2 receptor.

[0034] [Table 1]

[0035] The seven serotonin receptor families contain 14 receptor subtypes distributed throughout the body as shown in the table below.

[0036] [Table 2]

[0037] 5HT2 receptor In general, 5HT2 receptors are characterized by low affinity for serotonin (and other indole alkylamines) and are coupled to the Gq / phospholipase C pathway of signal transduction. In various instances, such receptors are classified into three distinct subtypes: 5HT 2A , 5HT 2B , and 5HT 2C mediates various physiological and behavioral functions through

[0038] [Table 3]

[0039] 5HT 2A is an important excitatory serotonin receptor subtype. In some instances, non-limiting examples of physiological processes mediated by receptors include: Central nervous system - neuroexcitation, behavioral effects, learning, anxiety, and algesia Smooth muscle contraction (bronchial and gastrointestinal tract) Vasoconstriction / vasodilation ·Platelet aggregation Role in memory and learning ·Anti-inflammatory activity Hormonal (oxytocin, prolactin, ACTH, corticosterone, renin) regulation Mood regulation (depressed patients have more 5HT than normal individuals) 2A receptors, which means 5HT 2A suggests that depression is involved in the pathogenesis of depression.

[0040] In some cases, 5HT 2A Agonism of 5HT in brain regions mediating cognitive function and social interaction may facilitate the treatment or management of disorders involving cognitive function, social interaction, or their symptoms. 2A This is evident by the widespread localization of 5HT receptors. 2A Receptor-mediated disorders include, but are not limited to, schizophrenia, depression / suicide, anxiety, obsessive-compulsive disorder (OCD), bipolar disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders such as anorexia nervosa, autism, autism spectrum disorder, Asperger's syndrome, neuropsychiatric disorders, sexual disorders such as erectile dysfunction, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, metabolic diseases such as obesity and diabetes, central nervous system disorders, peripheral nervous system disorders, Alzheimer's disease, snoring, sleep apnea (obstructive sleep apnea, central sleep apnea), insomnia, sleep deprivation, restless legs syndrome, parasomnias, nightmares, night terrors, sleepwalking, hypersomnia (daytime sleepiness), narcolepsy, and pain.

[0041] Any suitable 5HT (e.g. 5HT 2A and the like are also utilized in any of the compositions, formulations, methods, treatments, etc. described herein. In some preferred embodiments, the 5HT agonist in the formulations, compositions, methods, etc. described herein is 5HT 2A In one embodiment, the 5HT 2A Agonists include 5HT 2A Relatively high affinity for receptors (e.g., 5HT1, and / or 5HT3, 5HT4, 5HT5, 5HT6, 5HT7, 5HT 2B , 5HT 2C , or a combination of all or some of them) 2-fold, 3-fold, 5-fold, 10-fold, 20-fold, 50-fold greater affinity for 5HT 2A The 5HT agonist increases dopamine levels in the prefrontal cortex. 2A Agonists are of the following classes of 5HT2A In a specific embodiment, the 5HT (e.g., 5HT 2A ) The receptor agonist is ergoline.

[0042] [ka]

[0043] Some examples include ergonovine, ergotamine, and their synthetic derivatives, such as the uterotonic drug methergine, the antimigraine drugs dihydroergotamine and methylsergide, hydergine (dihydroergotoxine methanesulfonate, a mixture of INN and ergoline mesylate), and bromocriptine. Some examples include the synthetic ergolines pergolide and lisuride.

[0044] In some instances, the ergoline is an ergoline derivative such as lysergic acid amide, or a peptide alkaloid such as those described below. In some instances, the ergoline is a clavine (e.g., festuclavine, fumigaclavine A, fumigaclavine B, and fumigaclavine C) and other derivatives not falling into the above categories, such as cabergoline, pergolide, and lisuride.

[0045] Lysergic acid amide Exemplary lysergic acid amides include ergine (LSA, D-lysergic acid amide), ergonovine (ergobasine), methergine (ME-277), methylsergide (UML-491), LSD (LSD), and LSH (D-lysergic acid α-hydroxyethylamide). The following table summarizes their structures and relationships.

[0046] [Table 4]

[0047] Peptide alkaloids Typical peptide alkaloids include the peptidoglycan alkaloids (ergopeptines or ergopeptides), which are ergoline derivatives containing a tripeptide structure containing proline and two other α-amino acids (attached at the same position as the amide group of lysergic acid derivatives). Examples include ergotoxine (R 2 valine)-ergocristine, ergocornine, α-ergocryptine, β-ergocryptine ergotamine (R 2 alanine)-ergotamine, ergovaline, α-ergosine, and β-ergosine.

[0048] [Table 5]

[0049] Tryptamine Tryptamine (2-(1H-indol-3-yl)ethanamine) contains an indole ring attached to an aminoethylene group. Substituted tryptamines have an indole ring (R 1 , R 2 ), ethylene chain (R 3 ), and / or amino groups (R 4 , R 5 ), or modified on the hydroxyl group, and substituted with any suitable group, collectively referred to herein as tryptamine. Examples of tryptamines include serotonin, melatonin, psilocybin, and N,N-dimethyltryptamine. In addition, the tryptamine structure may contain moieties of more complex compounds, such as LSD, ibogaine, mitragynine, yohimbine, etc.

[0050] [ka]

[0051] Non-limiting examples of naturally occurring substituted tryptamines include:

[0052] [Table 6]

[0053] Non-limiting examples of synthetic substituted tryptamines include:

[0054] [Table 7]

[0055] Phenethylamine Phenethylamines contain a phenyl ring attached to an aminoethylene group. Substituted phenethylamines are optionally substituted in any suitable manner. For example, as described below, the phenyl ring (R 1 , R 2 , R 3 , R 4 , and / or R 5 ), ethylene chain (R 6 and / or R 7 ), and / or amino groups (R 8 and / or R 9 ) is optionally modified by substitution on

[0056] [ka]

[0057] Examples of phenethylamines include, but are not limited to, those shown in the table below.

[0058] [Table 8-1]

[0059] [Table 8-2]

[0060] In some embodiments, the compositions or formulations described herein comprise an antidepressant. Similarly, in some embodiments, the methods of treatment provided herein include administering an antidepressant, such as using a formulation or composition described herein. In some instances, antidepressants are classified into three families: monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs). SSRIs generally work by reducing serotonin reuptake by presynaptic neurons. This allows more serotonin to remain in the synaptic cleft for a longer period of time, compensating for the smaller amounts of serotonin. SSRIs generally have fewer side effects than MAOIs or tricyclic antidepressants. Notably, SSRIs generally only block the serotonin reuptake pump, unlike tricyclic antidepressants, which also block the norepinephrine reuptake pump. However, SSRIs generally affect norepinephrine indirectly, as norepinephrine levels are closely related to serotonin levels. When serotonin levels increase, norepinephrine levels also automatically increase.

[0061] Non-limiting examples of selective serotonin reuptake inhibitors include fluoxetine (PROZAC®), citalopram (CELEXA®), fluvoxamine (LUVOX®), sertraline (ZOLOFT®), and paroxetine (PAXIL®).

[0062] In some embodiments herein, the pharmaceutical composition described comprises 5HT receptor agonist, or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug.This kind of drug is collectively referred to herein as 5HT receptor agonist drug.In some examples, the pharmaceutical composition or preparation of 5HT receptor agonist, or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug has enhanced bioavailability and effect, can be administered in smaller amounts, has reduced cytotoxicity and / or reduced side effects.

[0063] Treatment method Provided herein are methods for managing disorders or diseases and treating symptoms of disorders or diseases, the methods comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, which improve dosage and administration, thereby enhancing bioavailability and efficacy in a subject.

[0064] Further provided herein are methods for managing a neurological disease or a symptom thereof in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and a pharmaceutically acceptable excipient.

[0065] Further provided herein is a method for treating symptoms of a neurological disease in a subject suffering from a neurological disease, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and a pharmaceutically acceptable excipient.

[0066] Further provided herein is a method for treating symptoms of a neurological disease in a subject susceptible to the disease, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and a pharmaceutically acceptable excipient.

[0067] Further provided herein are methods for managing neurological disorders or diseases, the methods comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof. Further provided herein are methods for treating symptoms of neurological disorders or diseases, the methods comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof.

[0068] Further provided herein are methods for managing a neurological disease or a symptom thereof in a subject, the methods comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of one or more 5HT2 receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and a pharmaceutically acceptable excipient.

[0069] Further provided herein is a method wherein the 5HT receptor agonist is a 5HT2 receptor agonist. Further provided herein is a method wherein the 5HT2 receptor agonist is a 5HT2A receptor agonist, a 5HT2B receptor agonist, and / or a 5HT2C receptor agonist.

[0070] In some embodiments, any suitable dose of the 5HT receptor agonist may be administered to an individual, for example, from about 0.1 mg to about 10 mg, or from about 10 mg to about 50 mg. In certain embodiments, the 5HT receptor agonist is administered in a dosage form that releases at least a portion of the active ingredient over at least 12 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or any other suitable or desirable period.

[0071] Further provided herein is a method in which the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 0.1 mg to about 50 mg (e.g., about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, about 10 mg to about 50 mg, etc.). Further provided herein is a method in which the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 10 mg. Further provided herein is a method in which the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 20 mg. Further provided herein is a method in which the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 30 mg. Further provided herein is a method wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 40 mg. Further provided herein is a method wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 50 mg.

[0072] Further provided herein is a method of providing to the subject a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, in an amount that does not result in adverse side effects, such as hallucinatory experiences.

[0073] Further provided herein is a therapeutically effective amount of the 5HT receptor agonist (e.g., psilocybin), or a pharmaceutically acceptable salt, solvate, metabolite (e.g., psilocin, an active metabolite of psilocybin), derivative, or prodrug thereof, that achieves a maximum plasma concentration (C) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.1 ng / mL or more and less than 6 ng / mL (e.g., at least 0.5 ng / mL and less than 6 ng / mL, about 1 ng / mL to about 5.5 ng / mL, about 2 ng / mL to about 5 ng / mL, etc.). max The method provides a method for administering to a subject an amount and / or formulation that results in:

[0074] In some embodiments, the methods provided herein include providing a 5HT receptor agonist (e.g., in a sufficient dose and suitable formulation) to provide a minimum therapeutic concentration of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof), for at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, etc.

[0075] In various embodiments herein, 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug is administered at any suitable frequency.In some examples, administration is carried out every day, every other day, about twice a week, at least three times a week (for example, 5 days on and 2 days off), or any suitable schedule.

[0076] Further disclosed herein, in some embodiments, is a method for managing a neurological disease or one or more symptoms thereof in a subject, the method comprising the step of administering to the subject a pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; and b) a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of the 5HT receptor agonist, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, is provided to the subject in an amount that does not result in adverse side effects, such as hallucinatory experiences.

[0077] Further disclosed herein, in some embodiments, is a method of treating symptoms of a neurological disease in a subject suffering from or susceptible to such a disease, the method comprising the step of administering to the subject a pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; and b) a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of the 5HT receptor agonist, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, is provided to the subject in an amount that does not result in adverse side effects, such as hallucinatory experiences.

[0078] In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 0.1 mg to about 50 mg (e.g., about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, about 10 mg to about 50 mg, etc.). In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 0.1 mg to about 2 mg. In some embodiments, the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 1 mg to about 15 mg. In some embodiments, the pharmaceutical composition is a low-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a controlled-release component. In some embodiments, the pharmaceutical composition comprises a controlled-release component and an immediate-release component.

[0079] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is an amount that provides a maximum plasma concentration (C) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of 6 ng / mL or greater. max In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that does not result in a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.1 ng / mL or more and less than 6 ng / mL (e.g., at least 0.5 ng / mL and less than 6 ng / mL, about 1 ng / mL to about 5.5 ng / mL, about 2 ng / mL to about 5 ng / mL, etc.). maxIn some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that results in a plasma concentration of the HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of at least 0.1 ng / mL (e.g., at least 0.2 ng / mL, at least 0.3 ng / mL, at least 0.5 ng / mL, etc.) after at least 6 hours (e.g., at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, etc.).

[0080] In some embodiments, said 5HT receptor agonist is 5HT2 receptor agonist.In some embodiments, said 5HT receptor agonist is psilocybin or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug.In some embodiments, said 5HT receptor agonist is psilocin or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug.

[0081] In some embodiments, the pharmaceutical composition further comprises one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents. In some embodiments, the pharmaceutical composition is an oral, buccal, nasal, or inhaled formulation. In some embodiments, the pharmaceutical composition is in the form of a spray, aerosol, mist, nebulae, ointment, cream, gel, paste, salve, solution, suspension, tincture, patch, and atomized vapor.

[0082] In some embodiments, the pharmaceutical composition further comprises an effective amount of a second agent. In some embodiments, the second agent is a vasodilator or vasoconstrictor. In some embodiments, the vasoconstrictor is epinephrine, phenylephrine, methoxamine, norepinephrine, zolmitriptan, tetrahydrozaline, naphazoline, or a combination thereof. In some embodiments, the second agent is a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, lysergic acid diethylamide, or a combination thereof. In some embodiments, the second agent is a 5HT receptor antagonist. In some embodiments, the second agent is an antipsychotic drug. In some embodiments, the antipsychotic drug is olanzapine, clozapine, risperidone, paliperidone, aripiprazole, quetiapine, iloperidone, ziprasidone, asenapine, lurasidone, sertindole, amisulpride, clotiapine, mosapramine, perospirone, sulpiride, zotepine, haloperidol, benperidol, loxapine, molindone, pimozide, thioridazine, mesoridazine, thiothixene, chlorprothixene, fluphenazine, trifluoperazine, chlorpromazine, perphenazine, prochlorperazine, droperidol, and zuclopenthixol. In some embodiments, the second drug is a norepinephrine modulator, an alpha adrenergic agonist (e.g., clonidine), a beta adrenergic antagonist (e.g., propranolol), or any combination thereof. In some embodiments, the second agent is administered simultaneously, sequentially, or alternating with the pharmaceutical composition. In some embodiments, the second agent is administered simultaneously, sequentially, or alternating with the pharmaceutical composition.

[0083] In some embodiments, the pharmaceutical composition is administered first, and the second agent is administered at least once, followed by subsequent administration of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is administered first, and the second agent is administered more than once, followed by subsequent administration of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is administered to a subject no more frequently than once per day (e.g., no more frequently than once every two days, no more frequently than once every three days, no more frequently than twice per week, no more frequently than once per week, no more than once every two weeks, etc.). In some embodiments, the pharmaceutical composition is administered to a subject once per day, every other day, three times per week, twice per week, once per week, every other week, two weeks per month, three weeks per month, once per month, twice per month, or three times per month. In some embodiments, the pharmaceutical composition is administered about once per day. In some embodiments, the pharmaceutical composition is administered about every other day. In some embodiments, the pharmaceutical composition is administered about once per week. In some embodiments, the pharmaceutical composition is administered about once per week. In some embodiments, the pharmaceutical composition is administered about once every two weeks or more. In some embodiments, the pharmaceutical composition is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, or 3 years.

[0084] In some embodiments, the neurological condition is a neurological disorder. In some embodiments, the neurological condition is a neurocognitive disorder. In some embodiments, the symptoms of the neurological condition are somatic, behavioral, emotional, psychiatric, or a combination thereof. In some embodiments, the neurological condition is an addictive disorder. In some embodiments, the addictive disorder is alcoholism, substance abuse, smoking, or obesity. In some embodiments, the neurological condition is an eating disorder or a hearing disorder. In some embodiments, the neurological condition is pain (e.g., chronic pain). In some embodiments, the neurological condition is depression, bipolar disorder, anxiety disorder, social phobia, post-traumatic stress disorder (PTSD), panic disorder, phobia, schizophrenia, psychopathy, or antisocial personality disorder. In some embodiments, the neurological condition is an impulsive disorder. In some embodiments, the impulsive disorder is attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Tourette's syndrome, or autism. In some embodiments, the neurological condition is an obsessive-compulsive disorder. In some embodiments, the obsessive-compulsive disorder is obsessive-compulsive disorder (OCD), gambling, or abnormal sexual behavior. In some embodiments, the neurological condition is a personality disorder. In some embodiments, the personality disorder is conduct disorder, antisocial personality, or aggressive behavior.

[0085] Oral formulation In some embodiments, this paper describes the compositions and preparations that comprise the active ingredient of 5HT receptor agonist.In some embodiments, the preparations that comprise 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug have enhanced bioavailability and effect, can be administered in smaller amounts, have reduced cytotoxicity and reduced side effects.

[0086] In some embodiments, the composition or formulation is an oral formulation.In some instances, the oral formulation of 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug has enhanced bioavailability and efficacy, can be administered in smaller amounts, has reduced cytotoxicity and reduced side effects.

[0087] In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a suspending agent, a disintegrant, a lubricant, and combinations thereof.

[0088] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a filler. In some embodiments, the amount of filler is about 10% to about 20% by weight. In some embodiments, the amount of filler is about 10% to about 40% by weight. In some embodiments, the amount of filler is about 20% to about 40% by weight. In some embodiments, the amount of filler is about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, or about 24% w / w. w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, or about 40% w / w.

[0089] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a binder. In some embodiments, the amount of binder is about 5% to about 15% by weight. In some embodiments, the amount of binder is about 5% to about 25% by weight. In some embodiments, the amount of binder is about 15% to about 25% by weight. In some embodiments, the amount of binder is about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, or about 25% w / w.

[0090] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a suspending agent. In some embodiments, the amount of the suspending agent is about 2% to about 3% by weight. In some embodiments, the amount of the suspending agent is about 2% to about 4% by weight. In some embodiments, the amount of the suspending agent is about 1% to about 5% by weight. In some embodiments, the amount of suspending agent is about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4.1% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4 % w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, or about 5% w / w.

[0091] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a disintegrant. In some embodiments, the amount of disintegrant is about 2% to about 3% by weight. In some embodiments, the amount of disintegrant is about 2% to about 4% by weight. In some embodiments, the amount of disintegrant is about 1% to about 5% by weight. In some embodiments, the amount of disintegrant is about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4.1% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4. w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, or about 5% w / w.

[0092] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a lubricant. In some embodiments, the amount of lubricant is about 2% to about 3% by weight. In some embodiments, the amount of lubricant is about 2% to about 4% by weight. In some embodiments, the amount of lubricant is about 1% to about 5% by weight. In some embodiments, the amount of lubricant is about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4.1% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4 w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, or about 5% w / w.

[0093] In some embodiments, the composition or formulation (e.g., oral composition or formulation) includes a surfactant. In some embodiments, the amount of surfactant is about 0.1% to about 2% by weight. In some embodiments, the amount of surfactant is about 0.1% to about 5% by weight. In some embodiments, the amount of surfactant is about 1% to about 15% by weight. In some embodiments, the amount of surfactant is about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, or about 2.9% w / w. w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.

[0094] In some embodiments, the amount of surfactant is about 0.5% to about 5% by weight. In some embodiments, the amount of surfactant is about 0.5% by weight. In some embodiments, the amount of surfactant is about 1% by weight. In some embodiments, the amount of surfactant is about 2% by weight. In some embodiments, the amount of surfactant is about 3% by weight. In some embodiments, the amount of surfactant is about 4% by weight. In some embodiments, the amount of surfactant is about 7% to about 15% by weight. In some embodiments, the amount of surfactant is about 0.5% to about 2% by weight.

[0095] Bilayer formulation In some embodiments, the composition or formulation is or comprises a bilayer formulation (e.g., oral dosage form). In some examples, a bilayer formulation comprising a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, has enhanced bioavailability and efficacy, can be administered in smaller doses, has reduced cytotoxicity, and / or has reduced side effects.

[0096] In some embodiments, the bilayer formulation is an oral dosage form comprising a (e.g., immediate-release or controlled-release) top layer or coating and a controlled-release core, wherein at least one of (i) the top layer or coating or (ii) the controlled-release core comprises a 5HT (e.g., 5HT2) receptor agonist. In certain examples, both the (e.g., immediate-release or controlled-release) top layer or coating and the controlled-release core comprise a 5HT (e.g., 5HT2) receptor agonist, and the 5HT receptor agonists in the core and coating are the same or different. Additional agents, such as any of the additional agents described herein (e.g., stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory drugs, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, 5HT receptor antagonists, or any combination thereof), are contemplated in either or both of (i) the top layer or coating and (ii) the core.

[0097] Controlled-release coated formulations In some embodiments, at least one (e.g., controlled-release) coating (e.g., at least partially or completely) surrounds the oral dosage form core. In certain embodiments, the controlled-release coating is a stable, controlled-release monolithic coating formed by a process comprising coating the core with a coating composition to form a coated core with an intermediate coating, and curing the coated core to form a stable, controlled-release coating. In at least one embodiment, the coating composition comprises an aqueous dispersion of a neutral ester copolymer free of any functional groups, a polyglycol having a melting point of at least 55°C, and one or more second pharmaceutically acceptable excipients. In some examples, the curing step is performed at a temperature at least equal to or greater than the melting point of the polyglycol. In at least one embodiment, the stable controlled-release coating comprises a neutral ester copolymer free of any functional groups, a polyglycol having a melting point of at least 55°C, and one or more second pharmaceutically acceptable excipients.

[0098] In some embodiments, the coating composition (e.g., utilized to form the coating) comprises an aqueous dispersion of a neutral ester copolymer that does not contain any functional groups. In some embodiments, the aqueous dispersion of a neutral ester copolymer that does not contain any functional groups is a copolymer dispersion of ethyl acrylate and methyl methacrylate. Non-limiting examples of ethyl acrylate and methyl methacrylate copolymer dispersions include a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g., Eudragit® NE30D), a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g., Eudragit® NE40D), Eudragit® NM30D, Kollicoat® EMM30D, and combinations thereof. In at least one embodiment, the neutral ester copolymer that does not contain any functional groups used in the controlled-release coating composition is Eudragit® NE30D, Eudragit® NE40D, or a mixture thereof. The neutral ester copolymer free of any functional groups may be present in an amount of about 1% to about 35% by weight of the coating composition, in some embodiments, depending on the therapeutically active agent used and the controlled-release characteristics desired. In some embodiments, the neutral ester copolymer free of any functional groups is present in an amount of about 20% to about 99.5% by weight of the dry weight of the coating. In other embodiments, the neutral ester copolymer free of any functional groups is present in an amount of about 25% to about 60% by weight of the dry weight of the coating. In still other embodiments, the neutral ester copolymer free of any functional groups is present in an amount of about 37% to about 50% by weight of the dry weight of the coating. In some embodiments, the neutral ester copolymer free of any functional groups is present in an amount of about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, and about 49% by weight of the dry weight of the coating.In some embodiments, the neutral ester copolymer free of any functional groups is present in the coating composition in an amount of about 0.4% to about 39.8% by weight of the dry weight of the tablet. In other embodiments, it is present in an amount of about 0.8% to about 24% by weight of the dry weight of the tablet. In some other embodiments, the neutral ester copolymer free of any functional groups is present in an amount of about 2% to about 5.5% by weight of the dry weight of the tablet, such as about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, or about 3.4% by weight. , about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5 wt%, about 5.1 wt%, about 5.2 wt%, about 5.3 wt%, about 5.4 wt% of the coating composition.

[0099] In some embodiments, the controlled-release dosage form does not expand in a dimensionally unrestricted manner after imbibing water. In certain embodiments, the controlled-release dosage form may expand in a dimensionally unrestricted manner after imbibing water. In certain embodiments, the controlled-release coating limits the expansion of the dosage form after imbibing water.

[0100] In some embodiments, the coating composition comprises a polyglycol, such as one having a melting point of at least about 55°C. In some embodiments, the polyglycol having a melting point of at least about 55°C is a polyethylene glycol having an average molecular weight ranging from about 4,000 to about 35,000 daltons. Non-limiting examples of polyglycols having a melting point of at least about 55°C include polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or mixtures thereof. In some embodiments, the polyethylene glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, and mixtures thereof. In at least one embodiment, the polyglycol used in the coating composition is polyethylene glycol 8000. The polyglycol may be present in an amount of from about 0.1% to about 10% by weight of the coating composition, in some embodiments. In some embodiments, the polyglycol is present in an amount of about 0.5% to about 28% by weight of the dry weight of the coating, hi other embodiments, the polyglycol is present in an amount of about 4% to about 17% by weight of the dry weight of the coating.In yet other embodiments, the polyglycol is present in an amount of about 7.2% to about 15.2% by weight of the dry weight of the coating, e.g., about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%. Weight%, about 9% by weight, about 9.1% by weight, about 9.2% by weight, about 9.3% by weight, about 9.4% by weight, about 9.5% by weight, about 9.6% by weight, about 9.7% by weight, about 9.8% by weight, about 9.9% by weight, about 10% by weight, about 1 0.1% by weight, approximately 10.2% by weight, approximately 10.3% by weight, approximately 10.4% by weight, approximately 10.5% by weight, approximately 10.6% by weight, approximately 10.7% by weight, approximately 10.8% by weight, approximately 10.9% by weight, approximately 11% by weight, approximately 11.1% by weight Amount%, about 11.2% by weight, about 11.3% by weight, about 11.4% by weight, about 11.5% by weight, about 11.6% by weight, about 11.7% by weight, about 11.8% by weight, about 11.9% by weight, about 12% by weight, about 12.1% by weight, Approximately 12.2% by weight, approximately 12.3% by weight, approximately 12.4% by weight, approximately 12.5% ​​by weight, approximately 12.6% by weight, approximately 12.7% by weight, approximately 12.8% by weight, approximately 12.9% by weight, approximately 13% by weight, approximately 13.1% by weight, approximately 13 In some embodiments, the polyglycol is present in the coating composition in an amount of about 0.1% to about 11.2% by weight of the tablet dry weight. In other embodiments, the polyglycol is present in the coating composition in an amount of about 0.1% to about 8% by weight of the tablet dry weight.In still other embodiments, the polyglycol is present in the coating composition in an amount of about 0.2% to about 2.8% by weight of the dry weight of the tablet, e.g., about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, and about 2.7%. Other suitable polyglycol derivatives having a melting point of at least about 55°C may be, but are not limited to, poloxamer 188, poloxamer 338, poloxamer 407, polyethylene oxide, polyoxyethylene alkyl ether, polyoxyethylene stearate, and mixtures thereof.

[0101] In addition to the copolymer and polyglycol, the coating composition may optionally contain one or more other pharmaceutically acceptable excipients. These excipients may include, but are not limited to, anti-tacking agents, emulsifiers, anti-foaming agents, hydrophilic agents, flavor enhancers, colorants, sweeteners, and any combination thereof. In some embodiments, the excipients may affect the properties of the coating in multiple ways; therefore, many substances used in coating formulations may be described as multifunctional. Those skilled in the art will know, based on their technical knowledge, which pharmaceutically acceptable excipients are suitable for the desired controlled-release coating composition.

[0102] In some embodiments, a hydrophilic agent is included in the compositions, formulations, cores, or coatings described herein, such as to promote wetting of the coating upon contact with gastrointestinal fluids. Non-limiting examples of such hydrophilic agents include hydrophilic water-soluble polymers such as hydroxypropyl methylcellulose (HPMC) (e.g., Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyvinylpyrrolidone (Povidone® or Kollidon®), polyvinyl alcohol, polyethylene oxide, copolymers of vinylpyrrolidone and vinyl acetate (Kollidon® VA64), copolymers of polyethylene glycol and polyvinyl alcohol (Kollicoat® IR), copolymers thereof, and combinations thereof. In at least one embodiment, the hydrophilic agent used in the coating composition is HPMC. In some embodiments, the hydrophilic agent comprises a pH-dependent polymer, non-limiting examples of which include cellulose acetate phthalate (e.g., Aquacoat® CPD), cellulose acetate trimellitate, poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., Eudragit® L30D-55), Kollicoat® MAE 30 D, poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., Eudragit® L100-55), Kollicoat® MAE 30 DP, Eudragit® FS 30D, Hypromellose Acetate Succinate LF, MF, HF grades (e.g., AQOAT®), polyvinyl acetate phthalate, and mixtures thereof. When a hydrophilic agent is included in the coating composition, it is present in any suitable amount, in some embodiments, from about 0.1% to about 10% by weight of the coating composition. In other embodiments, the hydrophobic agent is present in an amount of from about 0.1% to about 5%, and in other embodiments, from about 0.1% to about 3% by weight of the coating composition. In some embodiments, the hydrophobic agent is present in an amount of from greater than about 0% to about 35% by weight of the dry weight of the coating. In other embodiments, the hydrophobic agent is present in an amount of from about 8% to about 30% by weight of the dry weight of the coating.In yet other embodiments, the hydrophobic agent is present in an amount of about 12% to about 26% by weight of the coating dry weight, e.g., about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, and about 25% by weight. In some embodiments, the hydrophobic agent is present in the coating formulation in an amount of about 0% to about 14% by weight of the tablet dry weight. In other embodiments, the hydrophobic agent is present in an amount of about 0.2% to about 6% by weight of the tablet dry weight. In still other embodiments, it is present in an amount of about 0.8% to about 2.5% by weight of the dry weight of the tablet, e.g., about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, and about 2.4%.

[0103] In some instances, the tackiness of the polymeric film is important for coating the dosage form and for subsequent curing steps (post-coating heat treatment). In some instances, during coating with either cellulose or acrylic polymers, unwanted and sometimes irreversible agglomeration of some granules, beads, or, in the worst case, the entire lot, can occur, especially at high product processing temperatures. Therefore, in some embodiments, it is desirable to add an anti-tacking agent to the coating formulation. Optional anti-tacking agents include, but are not limited to, adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, Sterotex, glyceryl monostearate, talc (e.g., Talc 400), sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof. In at least one embodiment, talc (e.g., Talc 400) is used as the anti-tacking agent. In some instances, talc also functions as a wetting agent. In some embodiments, a mixture of anti-tacking agents is utilized. Any suitable amount of anti-tacking agent may be utilized in the coating composition, such as from about 1% to about 15% by weight of the coating dispersion, and in some embodiments, from about 1% to about 7% by weight. In some embodiments, the anti-tacking agent is present in an amount of greater than about 0% to about 50% by weight of the dry weight of the coating. In other embodiments, the anti-tacking agent is present in an amount of from about 2% to about 40% by weight of the dry weight of the coating. In still other embodiments, the anti-tacking agent is present in an amount of from about 10% to about 30% by weight of the dry weight of the coating, such as about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, and about 29% by weight. In some embodiments, the anti-tacking agent is present in the coating formulation in an amount of about 0% to about 20% by weight of the dry weight of the tablet, and in other embodiments, in an amount of about 0% to about 12% by weight of the dry weight of the tablet.In still other embodiments, the dry weight of the tablet is about 0.6% to about 7% by weight, for example, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 3.6% by weight, or about 3.7% by weight. 7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, and about 6.9% by weight.

[0104] In some embodiments, the compositions, formulations, cores, or coatings described herein include an anti-foaming agent, such as, but not limited to, silicone oil, simethicone (e.g., simethicone emulsion), and mixtures thereof. In at least one embodiment, the anti-foaming agent is simethicone. When present, the anti-foaming agent is utilized in a suitable amount, such as up to about 0.5% by weight of the coating composition, and in other embodiments, from about 0.1% to about 0.4% by weight of the coating composition. In some embodiments, the anti-foaming agent is present in an amount of greater than about 0% to about 3% by weight of the dry weight of the coating. In other embodiments, the anti-foaming agent is present in an amount of from about 0.4% to about 2% by weight of the dry weight of the coating. In still other embodiments, the anti-foaming agent is present in an amount of from about 0.8% to about 1.5% by weight of the dry weight of the coating, such as about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, and about 1.4%. In some embodiments, the anti-foaming agent is present in the coating formulation in an amount of about 0% to about 1.2% by weight of the dry weight of the tablet. In other embodiments, it is present in an amount of about 0% to about 0.8% by weight of the dry weight of the tablet. In still other embodiments, it is present in an amount of about 0% to about 0.2% by weight of the dry weight of the tablet, such as about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and about 0.19% by weight of the dry weight of the tablet.

[0105] In some embodiments, an emulsifier (also called an emulgent) is included in the compositions, formulations, cores, or coatings described herein to facilitate the actual emulsification during coating manufacture and / or to stabilize the emulsion during the product's shelf life. In some examples, suitable emulsifiers include naturally occurring materials and their semi-synthetic derivatives, such as polysaccharides, glycerol esters, cellulose ethers, sorbitan esters, and polysorbates, but are not limited to these. Mixtures are possible. In at least one embodiment, the emulsifier used is polysorbate 80 (polyoxyethylene sorbitan monooleate) (e.g., Tween® 80). When present, the emulsifier may be present in an amount of greater than 0% to about 0.5% by weight of the coating composition in some embodiments. In at least one embodiment, the emulsifier is present in an amount of about 0.1% to about 0.3% by weight of the coating composition. In some embodiments, the emulsifier is present in an amount of greater than 0% to about 2% by weight of the dry weight of the coating. In other embodiments, the emulsifier is present in an amount of about 0.1% to about 1% by weight of the dry weight of the coating. In still other embodiments, the emulsifier is present in an amount of about 0.25% to about 0.75% by weight of the dry weight of the coating, e.g., about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, and about 0.70% by weight. In some embodiments, the emulsifier is present in the coating formulation in an amount of greater than about 0% to about 0.8% by weight of the dry weight of the tablet. In other embodiments, the emulsifier is present in an amount of greater than about 0% to about 0.4% by weight of the dry weight of the tablet. In still other embodiments, it is present in an amount of greater than about 0% to about 0.2% by weight of the dry weight of the tablet, e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and about 0.19% by weight.

[0106] In some embodiments, colorants are utilized in the coatings described herein. In some instances, the colorant is a water-insoluble dye (pigment). In some instances, pigments offer advantages over water-soluble dyes in that they are chemically stable to light, provide good opacity and coverage, and tend to optimize the impermeability to water vapor of a given film. Examples of suitable colorants include, but are not limited to, iron oxide pigments, titanium dioxide, and aluminum lakes. Mixtures are possible. In at least one embodiment, the pigment or colorant used is titanium dioxide. When present, the pigment or colorant may be present in an amount of from about 0.1% to about 10% by weight of the coating composition in some embodiments. In at least one embodiment, the colorant is present in an amount of from about 0.1% to about 5% by weight of the coating composition. In at least one embodiment, the colorant is present in an amount of from about 0.1% to about 2% by weight of the coating composition. In some embodiments, the colorant is present in an amount of from about 0% to about 20% by weight of the dry weight of the coating. In other embodiments, the colorant is present in an amount of greater than about 0% to about 10% by weight of the dry weight of the coating, or from about 2.2% to about 6.2% by weight of the dry weight of the coating, such as about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, or about 3.9% by weight. , about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, about 5 wt%, about 5.1 wt%, about 5.2 wt%, about 5.3 wt%, about 5.4 wt%, about 5.5 wt%, about 5.6 wt%, about 5.7 wt%, about 5.8 wt%, about 5.9 wt%, about 6 wt%, and about 6.1 wt%. In some embodiments, the colorant is present in the coating formulation in an amount of greater than about 0 wt% to about 8 wt% of the dry weight of the tablet. In other embodiments, the colorant is present in an amount of greater than about 0 wt% to about 5 wt% of the dry weight of the tablet.In still other embodiments, it is present in an amount of greater than about 0% to about 1% by weight of the dry weight of the tablet, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, and about 0.9%.

[0107] In some embodiments, the compositions, formulations, cores, or coatings described herein comprise a first and a second pharmaceutically acceptable excipient. In at least one embodiment, the second pharmaceutically acceptable excipient (e.g., in a controlled-release coating) comprises at least one of a neutral ester copolymer free of any functional groups (e.g., Eudragit® NE30D, Eudragit® NE40D, Eudragit® NM30D, Kollicoat® EMM30D, or a mixture thereof), HPMC (e.g., Pharmacoat® 606), talc (e.g., Talc 400), polyethylene glycol (e.g., polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or a mixture thereof), simethicone, polysorbate 80, titanium dioxide, and a mixture thereof.

[0108] In at least one embodiment, a composition, formulation, core, or coating (e.g., a stable controlled-release coating) described herein hydrates when placed in water. In at least one embodiment, a dosage form (e.g., coated with a controlled-release coating) floats in water. In at least one embodiment, the (e.g., controlled-release) dosage form, when orally administered to a patient, provides controlled release of an effective amount of active drug to at least one region of the patient's upper gastrointestinal tract (e.g., stomach).

[0109] In some embodiments, any composition, formulation, core, or coating (e.g., controlled-release coating) described herein is formed by a process that does not require the use of organic solvents. In such embodiments, the controlled-release coating composition is water-based but not solvent-based (an example dosage form coated with an water-based controlled-release coating is designated "AQ"). In some embodiments, any composition, formulation, core, or coating (e.g., controlled-release coating) described herein is formed by a process that is solvent-based (e.g., "PharmaPASS™" composition).

[0110] In various embodiments, the coating composition is applied onto the cores containing an effective amount of a therapeutically active agent by a process that includes atomizing (spraying) the coating composition (solution or suspension) onto a bed of tablet cores. Some examples of equipment suitable for film coating include ACCELA COTA® (Manesty Machines, Liverpool, UK), HI-COATER® (Freund Company, Japan), DRIACOATER™ (Driam Metallprodukt GmbH, Germany), HTF / 150™ (GS, Italy), and IDA™ (Dumoulin, France). Examples of units that function based on the fluidized bed principle include AEROMATIC™ (Fielder, Switzerland and UK) and GLATT AG™ (Switzerland). In at least one embodiment, the equipment used is ACCELA COTA®.

[0111] In some examples, the coating composition is delivered to the coating equipment from a peristaltic pump at a desired rate and sprayed onto the rotating or flowing tablet cores. The tablet cores are pre-warmed to about 30°C. During the coating process, the product temperature range is maintained between about 25°C and 35°C by adjusting the inlet and outlet air flow rates, inlet air temperature, and spray rate. A single layer of the coating composition is applied, and once spraying is complete, the coated tablet cores are dried at a low pan speed and low airflow for about 3 to about 5 minutes at a temperature between about 30°C and about 40°C. The pan is readjusted to a jog speed, and drying continues for about 12 to about 15 minutes.

[0112] In some embodiments, the coated tablet cores are placed on a tray and cured in an electric or steam oven at a temperature above the melting point of the polyethylene glycol or its derivative (post-coating heat treatment). In at least one embodiment, the curing temperature is above the melting point of the polyethylene glycol or its derivative. In at least one embodiment, the curing time is from about 2 to about 7 hours. The cured, coated tablets are then allowed to cool to about room temperature.

[0113] In other embodiments, the coated tablet cores are placed in a coating pan and cured in two stages. During the first stage, the coated tablets are cured at a first curing temperature (e.g., in some embodiments, between about 50°C and about 59°C) for a period of time (e.g., in some embodiments, between about 15 minutes and about 90 minutes, and in at least one embodiment, about 60 minutes). During the second stage, the coated tablets are cured at a second curing temperature at least equal to or greater than the melting point of the polyglycol (e.g., in some embodiments, between about 60°C and about 70°C) for an additional period of time (e.g., in some embodiments, between about 30 minutes and about 180 minutes, and in at least one embodiment, about 120 minutes). In at least one embodiment, the two-stage curing of the coated tablets reduces non-functional defects caused by the curing process in the tablets. In at least one embodiment, the two-stage curing process substantially eliminates non-functional defects caused by the curing process in the tablets. Non-functional defects that the curing process can cause in dosage forms include coating appearance defects (e.g., poor color, unevenness, and / or dull appearance), coating surface defects (e.g., coating surface roughness and / or coating wrinkles), and coating adhesion to each other and / or to the coating pan. Additionally, fewer tablet color and smoothness defects can allow for improved tablet printing.

[0114] In some embodiments, coating formulations are used to coat various 5HT receptor agonist cores and can be tailored to achieve the desired drug release profile. The length and duration of the delay are controlled by the hydration rate and coating thickness. The drug release rate after the delay is determined by the thickness and permeability of the hydrated coating. Therefore, the hydration rate and permeability of the coating can be adjusted to achieve the desired controlled-release drug profile. There is no preferred coating thickness, as the thickness depends on the drug used and the desired controlled-release profile. Other parameters that can be combined with the coating thickness include changing the concentration of certain components of the stable coating composition and / or changing the curing temperature and curing time of the coated tablet cores. Those skilled in the art will know which parameters or combinations of parameters are preferred to achieve the desired controlled-release change.

[0115] Immediate-release coated formulation In some embodiments, the compositions or formulations (e.g., oral dosage forms) provided herein include an immediate-release coating (e.g., providing immediate release of a 5HT receptor agonist). In some embodiments, the immediate-release coating includes a 5HT receptor agonist. In some embodiments, the immediate-release coating includes more than one 5HT receptor agonist. In further embodiments, the immediate-release coating includes a pharmaceutically acceptable excipient. In some embodiments, the immediate-release coating includes a 5HT receptor agonist and an additional (e.g., pharmaceutically active) agent. In other embodiments, the immediate-release coating includes an additional (e.g., pharmaceutically active) agent other than a 5HT receptor agonist. In some embodiments, the additional agent reduces, alleviates, or eliminates adverse side effects associated with administration of the 5HT receptor agonist. In some embodiments, the additional agent that reduces, alleviates, or eliminates adverse side effects associated with administration of the 5HT receptor agonist is a 5HT receptor antagonist. In some embodiments, the additional agent in the immediate-release coating is a 5HT receptor antagonist. In some embodiments, the additional agent in the immediate release coating is selected from stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory agents, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, 5HT receptor antagonists, and combinations thereof.

[0116] In some embodiments, the (for example, therapeutically) effective amount of immediate-release active agent in immediate-release form is coated on the formulation described herein.For example, in some cases, the sustained release of 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug from the formulation is due to controlled-release coating, the immediate-release layer of additional drug will be overcoated on top of the controlled-release coating.In some embodiments, the immediate-release layer of additional drug will be coated on the surface of the substrate, where 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative or prodrug is incorporated into controlled-release matrix. When a plurality of sustained-release substrates (such as multiparticulate systems including pellets, spheres, beads, etc.) containing an effective unit dose of 5HT receptor agonist, or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug, are incorporated into a hard gelatin capsule, a sufficient amount of immediate-release antihistamine or antiemetic agent can be incorporated into the capsule as powder or granules, thereby reducing side effects.Alternatively, the gelatin capsule itself can be optionally coated with an immediate-release layer of additional drug.

[0117] An immediate-release coating containing an additional agent, such as an antihistamine or antiemetic, is optionally applied to the exterior of a controlled-release tablet core (e.g., a 5HT receptor agonist as described herein) to provide a final dosage form. Such coatings can be prepared by any suitable method, for example, by mixing a compound such as promethazine with polyvinylpyrrolidone (PVP) 29 / 32 or hydroxypropylmethylcellulose (HPMC), water / isopropyl alcohol, and triethyl acetate. Such immediate-release coatings are optionally spray-coated onto the tablet core. In some examples, the immediate-release coating is applied using a press-coating process with a formulation consisting of 80% by weight of promethazine, 20% by weight of lactose, and hydroxypropylmethylcellulose type 2910.

[0118] In some embodiments, the compositions or formulations provided herein (e.g., formulations comprising an immediate-release component and a controlled-release component) are in the form of a bilayer tablet comprising a first layer and a second layer. In some embodiments, the first layer is an immediate-release layer, and / or the second layer is a controlled-release layer. The first (or upper) or immediate-release layer comprises a first active agent, such as a 5HT receptor agonist, and / or another agent, such as an agent selected from an analgesic, antitussive, antihistamine, antiemetic, and irritant. In some examples, the second or controlled-release layer comprises a second drug, such as a 5HT receptor agonist. In some embodiments, the second drug is a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, the second drug is a formulation of a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, as described herein. The bilayer tablet provides plasma concentrations within the therapeutic range of the second drug for a period of time coextensive with at least about 70% (i.e., 12 hours) of the period during which the bilayer tablet provides plasma concentrations within the therapeutic range of the first drug.

[0119] In some embodiments, a coating or layer (e.g., an immediate-release or controlled-release coating or layer) described herein comprises a stimulant, hi some embodiments, the stimulant is selected from the group consisting of aminophylline, caffeine, dyphlline, oxitriphylline, theophylline, amphetamine, benzphetamine, dextroamphetamine, diethylpropion, matindole, methamphetamine, methylphenidate, dexmethylphenidate, pemoline, sibutramine, modafinil, atomoxetine, phendimetrizine, phenteramine, adrafinil, phenylpropanolamine, pseudoephedrine, synephrine, amphetamine, flufenorex, or a combination thereof.

[0120] In some embodiments, the coating or layer (e.g., an immediate-release or controlled-release coating or layer) comprises an antiemetic agent, such as aprepitant, dronabinol, perphenazine, palonosetron, trimethobenzamide, metoclopramide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidinone, or the like. The active ingredient is selected from the group consisting of benzodiazepine, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, prochloperazine, metoclopramide, diphenhydramine, cannabis, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, propofol, or a combination thereof.

[0121] In some embodiments, the coating or layer (e.g., an immediate-release or controlled-release coating or layer) comprises an antihistamine. In some embodiments, the antihistamine is 2-(m-fluorophenyl)-histamine, chlorpheniramine, pyrilamine, terfenadine, astemizole, triprolidine, ethanolamine, carbinoxamine, diphenhydramine, doxylamine, pyrilamine, tripelennamine, hydroxyzine, fexofenadine, brompheniramine, chlorpheniramine, cyproheptadine, loratadine, cetirizine, dimaprit, impromidine, amthamine, cimetidine, ranitidine, nizatidine, famotidine, R-α-methylhistamine, imetit, impi thiazol-10, thiazol-10, thiazol-10 hydroxybenzoates ...

[0122] In some embodiments, the coating or layer (e.g., an immediate-release or controlled-release coating or layer) comprises an antidepressant. In some embodiments, the antidepressant is Abilify (aripiprazole), Adapin (doxepin), Anafranil (clomipramine), Aplenzin (bupropion), Asendin (amoxapine), Aventyl HCl (nortriptyline), Celexa (citalopram), Cymbalta (duloxetine), Desyrel (tradozone), Effexor XR (venlafaxine), Emsam (selegiline), Etrafon (perphenazine and amitriptyline), Elavil (amitriptyline), Endep (amitriptyline), Fetzima (levomilnacipran), Khedezla (desvenlafaxine), Latuda (lurasidone), Lamictal (lamotrigine), Lexapro (escitalopram), Limbitrol (amitriptyline and chlordiazepoxide), Ma rplan (isocarboxazid), Nardil (phenelzine), Norpramin (desipramine), Oleptro (tradzone), Pamelor (nortriptyline), Parnate (tranylcypromine), Paxil (paroxetine), Pexeva (paroxetine), Prozac (fluoxetine), Pristiq (desvenlafaxine), Remeron (mirtazapine), Sarafem (fluoxetine), Seroquel Selected from the group consisting of XR (quetiapine), Serzone (nefazodone), Sinequan (doxepin), Surmontil (trimipramine), Symbyax (fluoxetine and the atypical antipsychotic olanzapine), Tofranil (imipramine), Triavil (perphenazine and amitriptyline), Trintellix (vortioxetine), Viibryd (vilazodone), Vivactil (protriptyline), Wellbutrin (bupropion), Zoloft (sertraline), and Zyprexa (olanzapine).

[0123] In some embodiments, the coating or layer (e.g., an immediate-release or controlled-release coating or layer) comprises an anti-inflammatory agent, hi some embodiments, the anti-inflammatory agent is selected from the group consisting of aceclofenac, aspirin, celecoxib, diclofenac, diflunisal, etodolac, etoricoxib, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, mefenamic acid, meloxicam, montelukast, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, pranlukast, salsalate, sulindac, tenoxicam, tiaprofenic acid, tolmetin, valdecoxib, zafirlukast, and zileuton.

[0124] In some embodiments, the coating or layer (e.g., an immediate-release or controlled-release coating or layer) comprises a growth factor, hi some embodiments, the growth factor is selected from the group consisting of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), and basic fibroblast growth factor (bFGF).

[0125] In some embodiments, the coating or layer (eg, the immediate release layer) comprises a lithium compound, such as lithium carbonate, lithium citrate, or lithium orotate.

[0126] Controlled-Release Matrix Formulations In some embodiments, provided herein are controlled-release formulations or compositions (e.g., oral dosage forms such as tablets, oral dosage form cores, or oral dosage form layers). In certain embodiments, the controlled-release formulations or compositions are coated or layered with other compositions or formulations. In some examples, the controlled-release formulations or compositions are coated or layered with immediate-release and / or controlled-release coatings or layers, such as those described herein. In certain embodiments, the controlled-release compositions or formulations provided herein comprise a 5HT receptor agonist formulation comprising a controlled-release matrix and a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., about 0.1 to about 50 mg, about 10 mg to about 50 mg, about 0.1 mg to about 10 mg, about 0.2 mg to about 5 mg, about 0.1 mg to about 2 mg, or about 1 mg to about 15 mg). In some embodiments, the controlled-release and / or immediate-release coating or layer comprises a first active agent, such as a 5HT agonist, and / or another agent, such as an agent selected from an analgesic, an antitussive, an antihistamine, an antiemetic, and a stimulant. In certain embodiments, the coating (e.g., a controlled-release and / or immediate-release coating) comprises a suitable agent, such as a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, and a 5HT receptor antagonist. In some embodiments, the coating (e.g., a controlled-release and / or immediate-release coating) comprises a 5HT receptor agonist, such as those described herein, and a second agent, such as, but not limited to, a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, a 5HT receptor antagonist, or any combination thereof.

[0127] Controlled Release Matrix The active agent is released from the controlled-release matrix in any suitable manner. Two typical mechanisms for releasing an active agent from a controlled-release matrix include diffusion and / or degradation. Diffusion generally occurs when the bioactive agent is released through pores in the polymer matrix or between the polymer chains of the matrix. Typically, in a diffusion system, the bioactive agent may be dispersed throughout the matrix or localized in a reservoir within or adjacent to the matrix. In some embodiments, the controlled-release formulation utilizes a reservoir system, which generally includes a reservoir of bioactive agent, e.g., a solid drug, solution, or highly concentrated drug solution within a polymer matrix, surrounded by a controlled-release material through which the bioactive agent can diffuse. In generally, in degradable systems, the bioactive agent is released as the matrix degrades in vivo. In some instances, the bioactive agent is released by a combination of such mechanisms. In some embodiments of the controlled-release matrices described herein, release of the bioactive agent is driven by a combination of both diffusion and degradation. In certain instances, the release rate is adjusted by varying the drug to polymer ratio (e.g., higher drug concentrations tend to result in faster release rates) and / or by altering the chemical nature of the polymer matrix (e.g., including polymers with glass transition temperatures (Tg) below about 40°C or below about 0°C tends to result in faster dissolution rates than polymers with Tg above 40°C; polymers that absorb water tend to elute drug more quickly than hydrophobic polymers that do not absorb water). In some instances, these variations are controlled by the selection of materials used in the manufacturing process.

[0128] In some embodiments, the controlled-release matrix is ​​configured to release at least about 40% and up to about 60%, or at least 50% of the bioactive agent within 24 hours of administration, hi other embodiments, the controlled-release matrix is ​​configured to release at least about 80% or up to about 100%, or at least 90% of the bioactive agent within 7 days after administration.

[0129] In some embodiments, the controlled-release matrix is ​​biodegradable. In some embodiments, the controlled-release matrix comprises a biodegradable polyester. Examples of biodegradable polyesters include, but are not limited to, polycaprolactone (PCL), polylactic acid (PLA), polyglycolide (PGA), and copolymers thereof, such as poly(lactic-co-glycolic acid) polymers (PLGA) and poly(glycolide-co-caprolactone) (PGC). PCL is a polymer made from stannous octoate (Stannous It refers to a biodegradable polyester prepared by ring-opening polymerization of ε-caprolactone using a catalyst such as octanoate. PCL has a melting point of approximately 60°C and degrades by hydrolysis of ester bonds under physiological conditions. PLA is a biodegradable thermoplastic polyester that can be produced by bacterial fermentation of renewable resources such as corn, starch, or sugarcane and has a melting temperature between approximately 173°C and 178°C. PGA is a biodegradable thermoplastic polyester prepared from glycolic acid by condensation polymerization or ring-opening polymerization. The melting point of PGA is approximately 225°C to 230°C. PLGA polymer refers to a biodegradable copolymer of lactic acid and glycolic acid formed by random ring-opening copolymerization of glycolic acid and lactic acid monomers. During polymerization, the monomer units are converted to esters. The lactic acid and glycolic acid are bonded together by hydroxyl bonds, resulting in an aliphatic polyester. PLGA is amorphous, with a glass transition temperature between about 40°C and 60°C. Typically, the weight-average molecular weight of PLGA copolymers is between about 1,000 Da and about 50,000 Da, or between about 5,000 Da and 25,000 Da. The ratio of lactic acid to glycolic acid may vary. Generally, increasing the amount of lactic acid causes the polymer to degrade more slowly. Increasing the amount of glycolic acid causes the polymer to degrade more rapidly. Additionally, increasing the amount of glycolic acid tends to decrease the Tg and water penetration into the polymer, resulting in more rapid compound release. Typically, the ratio of lactic acid to glycolic acid is between about 100:0 and about 25:75, between about 60:40 and 40:60, or about 50:50.Other suitable biodegradable polymers include, but are not limited to, poly(trimethylene)carbonate (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), poly(butylene succinate) (PBS). In some embodiments, the polymeric material or polymer is biostable. Examples of biostable polymers include, but are not limited to, polyurethane, silicone rubber, styrene-isobutylene-styrene block copolymers, ether-ester block copolymers (e.g., RTP1500-40D from RTP Co.), and vinyl materials, including, but not limited to, poly(ethylene-co-vinyl) acetate (PEVA). In some embodiments, the controlled-release matrix comprises an elastomeric polymeric material, including a copolymer having an elastomeric (or "soft") component and a non-elastomeric (or "hard") component. In another embodiment, the elastomeric polymeric material comprises a polymeric blend having an elastomeric component and a non-elastomeric component. In some embodiments, the compatible polymer or polymeric material is thermoplastic. As used herein, the term "thermoplastic" refers to a polymer or polymeric material that can be softened by heat, hardened by cooling, and then softened by heat repeatedly. Generally, thermoplastic materials are not crosslinked. However, in another embodiment, the compatible polymer or polymeric material may be crosslinked.

[0130] The bioactive material, if used, is incorporated into the controlled-release matrix using any of a variety of techniques known to those skilled in the art. In one embodiment, the bioactive agent is dispersed throughout the controlled-release matrix. Techniques for preparing the controlled-release matrix include, but are not limited to, melt extrusion, injection molding, or spray casting. In a typical melt extrusion process, a mixture containing a polymeric material and a bioactive agent is combined in an extruder, heated to a temperature at which the polymeric material melts, and then extruded through an orifice of the desired cross-sectional shape. The extruded material is collected under controlled conditions (e.g., speed, temperature, and humidity) to obtain a product with the desired dimensions. In one embodiment, the mass flow rate of the extrudate and the collection rate of the final extruded form may be adjusted to achieve the desired physical dimensions. For example, if the final extruded form is a film, the collection rate of the film may be increased relative to the mass flow rate of the extrudate to decrease or increase the film thickness. Because the extrudate is extruded through an orifice in a molten state, it can be stretched to its final dimensions. The extrudate is then cooled to solidify by exposure to ambient conditions, a refrigerated liquid or gas bath, or by exposure to a temperature-controlled surface such as a chilled roller. In one embodiment, a melt extrusion process is used to form a film. Alternatively, in an embodiment, a melt extrusion process is used to form pellets or beads that may then be molded into the desired film or color configuration. Some advantages of the melt extrusion process include the absence of organic solvents and high-throughput continuous production. Processing temperatures are generally sufficient to melt the polymeric material without adversely affecting the bioactivity of the bioactive agent. Processing temperatures are generally at least 80°C or about 100°C, and less than 180°C, less than 160°C, or between about 110°C and about 150°C. In some embodiments, the specific temperature depends on the melting and decomposition temperatures of the polymeric material and the bioactive agent. Furthermore, melt processing can be a continuous operation, allowing for adjustments of operating parameters and scale-up of production. In an alternative embodiment, an injection molding process is used.In a typical injection molding process, a mixture containing a polymeric material and a bioactive agent is fed into a tube, heated to a temperature sufficient to melt the polymeric material, forced into a mold cavity, and cooled to solidify into the shape of the mold cavity. The conditions (e.g., temperature and pressure) depend on the material being molded. In one embodiment, an injection molding process is used to form a film or collar. In another embodiment, a solvent casting technique is used. In a typical solvent casting process, a polymeric material and a bioactive agent are combined with a suitable solvent to form a polymeric solution that is then cast onto a substrate. The solvent is then removed, for example, by evaporation, to form a film. In one embodiment, the solvent is removed under vacuum (e.g., between about 15 Hg and about 28 Hg, depending on the volatility of the solvent). In another embodiment, the solvent is removed at an elevated temperature (e.g., between about 30°C and about 80°C). In an alternative embodiment, the polymeric solution is applied to a substrate by a spray coating process. In a spray coating process, the polymeric solution is delivered at a controlled rate by a positive displacement pump to a spray nozzle, for example, an ultrasonic spray nozzle. The spray nozzle and substrate are moved relative to one another in a controlled speed to achieve the desired coating thickness. The spray nozzle is attached to a three-axis motion control system (x, y, z) that can adjust the speed and position of the spray nozzle relative to the substrate. Additionally, if the substrate is a roll film, a roll-to-roll unwinding and rewinding device traverses underneath the spray head. The width of the coating is adjusted by moving the spray nozzle in a specific path across the width of the substrate. Additionally, the height (z) of the spray nozzle above the substrate can be increased to achieve a wider coating width. In some instances, the solvent forms a true solution with the components therein. In some instances, the bioactive agent is soluble in the solvent or forms a dispersion within the solvent.Any suitable solvent may be used, including, but not limited to, alcohols (e.g., methanol, butanol, propanol, and isopropanol), alkanes (e.g., halogenated or non-halogenated alkanes such as hexane, cyclohexane, methylene chloride, and chloroform), amides (e.g., dimethylformamide), ethers (e.g., tetrahydrofuran (THF), dioxolane, and dioxane), ketones (e.g., methyl ethyl ketone, acetone), aromatic compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate). THF and chloroform have been found to be suitable solvents due to their excellent dissolving power for various polymers and bioactive agents.

[0131] Mucoadhesive In many cases, mucoadhesive drug delivery systems interact with the mucus layer covering the mucosal epithelial surface to increase the residence time of the dosage form at the absorption site. In some examples, the compositions or formulations provided herein include a mucoadhesive, such as, but not limited to, soluble PVP, carbopol, cross-linked poly(acrylic acid) (e.g., Carbopol 974P), carbomer homopolymer, carbomer copolymer, water-swellable but water-insoluble fiber, cross-linked carboxy-functional polymer, mucoadhesive polysaccharide (e.g., hydrophilic polysaccharide gum), one or more maltodextrins, alginate, cross-linked alginate gum gel, and water-dispersible polycarboxylated vinyl polymer. In some embodiments, the mucoadhesive is carbopol. In some embodiments, the mucoadhesive is selected from, but not limited to, Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120, and sodium alginate H120L. In some embodiments, the mucoadhesive is cellulose. In certain embodiments, the mucoadhesive is carboxymethylcellulose (CMC), e.g., sodium carboxymethylcellulose (NaCMC), microcrystalline cellulose (MCC), or a combination thereof. In a non-limiting example, the mucoadhesive is a combination of MCC and CMC (e.g., Avicel® RC-591). In some embodiments, the CMC / MCC combination (e.g., Avicel® RC-591) is present in the composition in an amount of about 1 mg / mL to about 150 mg / mL, 1 mg / mL to about 75 mg / mL, or about 5 mg / mL to about 40 mg / mL. In certain embodiments, the CMC / MCC blend weight ratio is between about 1 / 99 and about 99 / 1, about 20 / 80 and about 5 / 95, or about 15 / 85 and 10 / 90. In certain embodiments, the CMC is NaCMC, and the CMC / MCC blend weight ratio is about 11 / 89.

[0132] In some embodiments, the mucoadhesive drug delivery system is a composition comprising both CMC (e.g., a CMC / MCC mixture) and maltodextrin. In certain embodiments, the residence time of the combination of CMC (e.g., a CMC / MCC mixture) and maltodextrin is increased on the affected or target surface of the mucosa (e.g., the gastrointestinal tract) when compared to a composition having a similar amount of either CMC (e.g., a CMC / MCC mixture) or maltodextrin alone.

[0133] In some embodiments, pharmaceutical compositions, formulations, and / or dosage forms of the 5HT receptor agonists disclosed herein, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, include a mucoadhesive. In some embodiments, the mucoadhesive comprises one or more maltodextrins. In various aspects, the physical properties of the maltodextrin vary, for example, depending on the dextrose equivalent of a particular maltodextrin. In some embodiments, the dextrose equivalent of a particular maltodextrin may affect the viscosity, hygroscopicity, sweetness, water retention, plasticity, solubility, and / or mucoadhesive properties of the maltodextrin. In some embodiments, the maltodextrin is selected based on the particular characteristics desired to be imparted upon administration of the pharmaceutical compositions described herein. In some embodiments, a maltodextrin is selected that enhances the mucoadhesive properties of the compositions described herein without significantly increasing the viscosity of the composition (e.g., compared to an identical composition lacking maltodextrin). In some embodiments, the oral pharmaceutical composition includes a second maltodextrin that increases the viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the second maltodextrin). In some embodiments, the second maltodextrin does not substantially affect the mucoadhesive characteristics of the pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the second maltodextrin).

[0134] In some embodiments, the mucoadhesive does not substantially increase the viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the mucoadhesive agent). In some embodiments, the mucoadhesive is selected for its mucoadhesive properties (e.g., the ability to impart mucoadhesive characteristics upon administration of the oral pharmaceutical composition).

[0135] In some embodiments, the mucoadhesive utilized in the oral pharmaceutical compositions described herein imparts increased viscosity upon administration of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the mucoadhesive). In other embodiments, the mucoadhesive does not substantially increase the viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the mucoadhesive).

[0136] In some embodiments, at least one mucoadhesive agent is selected for and used in the pharmaceutical composition such that the addition of the at least one mucoadhesive agent does not substantially increase the viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the mucoadhesive agent).

[0137] In some embodiments, at least two mucoadhesives are selected for and used in a pharmaceutical composition such that the addition of the at least two mucoadhesives does not substantially increase the viscosity of the oral pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the mucoadhesives). In some embodiments, at least one mucoadhesive increases the viscosity of the pharmaceutical composition when taken alone in the pharmaceutical composition, but does not substantially increase the viscosity of the oral pharmaceutical composition when taken with all components in the pharmaceutical composition (e.g., compared to an otherwise identical composition lacking the at least one mucoadhesive).

[0138] In some embodiments, the viscosity of the composition is at least about 2 centipoise (cP), at least about 5 cP, at least about 10 cP, at least about 20 cP, at least about 25 cP, at least about 35 cP, at least about 40 cP, at least about 50 cP, at least about 200 cP, or at least about 225 cP. In some embodiments, the viscosity of the composition is at least about 100 cP. In certain embodiments, the viscosity of the composition measured at 25° C. is from about 50 cP to about 250,000 cP, from about 50 cP to about 70,000 cP, from about 50 cP to about 25,000 cP, from about 50 cP to about 10,000 cP, from about 50 cP to about 3,000 cP, or from about 50 cP to about 2,000 cP. In one aspect, the viscosity of the composition measured at 25°C is about 25 centipoise (cP) to about 800 cP, about 50 cP to about 800 cP, or about 300 cP to about 800 cP (e.g., measured with a Brookfield viscometer). In other aspects, the viscosity of the composition may be about 100 cP to about 200 cP, about 200 cP to about 300 cP, about 250 cP to about 600 cP, or about 400 cP to about 600 cP. In certain embodiments, the viscosity of the formulation is about 30 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP (e.g., measured with a Brookfield viscometer at 25°C).

[0139] In certain embodiments, provided herein are compositions having a viscosity of at least about 2 centipoise (cP), at least about 5 cP, at least about 10 cP, at least about 20 cP, at least about 25 cP, at least about 35 cP, at least about 40 cP, at least about 50 cP, at least about 200 cP, at least about 225 cP, at least about 250 cP, at least about 300 cP, or at least about 400 cP. In some embodiments, the viscosity of the composition under these conditions is from about 50 cP to about 250,000 cP, from about 50 cP to about 70,000 cP, from about 50 cP to about 25,000 cP, from about 50 cP to about 10,000 cP, from about 50 cP to about 3,000 cP, from about 50 cP to about 2,000 cP, from about 250 cP to about 250,000 cP, from about 250 cP to about 70,000 cP, from about 250 cP to about 25,000 cP, from about 250 cP to about 10,000 cP, from about 250 cP to about 3,000 cP, or from about 250 cP to about 2,000 cP. In one aspect, the viscosity of the composition measured at 25°C is about 25 centipoise (cP) to about 800 cP, about 50 cP to about 800 cP, or about 300 cP to about 800 cP (e.g., as measured with a Brookfield viscometer). In other aspects, the viscosity of the composition under these conditions may be about 100 cP to about 200 cP, about 200 cP to about 300 cP, about 250 cP to about 600 cP, or about 400 cP to about 600 cP. In certain embodiments, the viscosity of the formulation measured under these conditions is about 30 cP, about 40 cP, about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP.

[0140] In one non-limiting example, the mucoadhesive may be at least two particulate components selected from, but not limited to, titanium dioxide, silicon dioxide, and clay. In some embodiments, when the composition is not further diluted with any liquid prior to administration, the amount of silicon dioxide is about 3% to about 15% by weight of the composition. In some embodiments, the silicon dioxide is selected from, but not limited to, fumed silicon dioxide, precipitated silicon dioxide, coacervated silicon dioxide, gel silicon dioxide, and mixtures thereof. In some embodiments, the clay is selected from, but not limited to, kaolin minerals, serpentine, smectite, illite, or mixtures thereof. In some embodiments, the clay is selected from, but not limited to, laponite, bentonite, hectorite, saponite, montmorillonite, or mixtures thereof.

[0141] In some embodiments, the mucoadhesive agent is selected in an amount sufficient to cause a pharmaceutical composition containing a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof to adhere to or remain on the mucosal surface for 5 seconds, 10 seconds, 15 seconds, 30 seconds, 45 seconds, or 1 minute after application to the mucosal surface. In certain embodiments, the mucoadhesive agent is selected in an amount sufficient to cause a pharmaceutical composition containing a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof to adhere to or remain on the mucosal surface for 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes after application to the mucosal surface. In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof that adheres to the mucosal surface for 5 seconds, 10 seconds, or 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes after administration to the mucosal surface is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight. In certain embodiments, at least 50% of the pharmaceutical composition adheres to or resides on the mucosal surface for at least 1 minute or at least 15 minutes after application to the mucosal surface.

[0142] Viscosity-enhancing excipients optionally used in the pharmaceutical compositions described herein include cross-linked poly(acrylic acid) (e.g., Carbopol 974P), glycerin, carbomer homopolymer, carbomer copolymer, acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, fucus, bentonite, carbomer, carrageenan, carbopol, cellulose, microcrystalline cellulose (MCC), carob, hornbeam, dextrose, furcellaran, gelatin, ghatti gum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, karaya gum, xanthan gum, polyethylene glycol (e.g., PEG 200-4500), tragacanth gum, ethyl cellulose, and the like. The preferred cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygeline, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose, hydroxypropylmethyl-cellulose, carboxymethyl cellulose (CMC) (e.g., sodium carboxymethyl cellulose (NaCMC)), silicon dioxide, PVP (povidone), Splenda® (dextrose, maltodextrin, and sucralose), or combinations thereof.

[0143] excipients In some embodiments, the compositions or formulations of one or more of the above-mentioned 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, further comprise an excipient. In some embodiments, the aqueous suspension of the pharmaceutical compositions disclosed herein contains pharmaceutically acceptable excipients such as suspending agents (e.g., methylcellulose), wetting agents (e.g., lecithin, lysolecithin, and / or long-chain fatty alcohols), as well as colorants, preservatives, flavoring agents, etc.

[0144] Pharmaceutical preparations for oral administration can be prepared by any suitable process, such as combining active ingredients with solid excipients, optionally grinding the resulting mixture, and then processing the mixture of granules with suitable excipients if desired to obtain tablets or dragee cores.In some examples, suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, flavoring elements, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or cellulose preparations such as PVP.If necessary, disintegrants such as cross-linked PVP, agar, or alginic acid or alginates, such as sodium alginate, can also be added.Active compounds can also be formulated as sustained-release preparations.

[0145] Pharmaceutical preparations sometimes used for oral administration include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredients in combination with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be added. All preparations for oral administration should be in dosages suitable for administration.

[0146] For injection, the pharmaceutical compositions disclosed herein are optionally formulated in aqueous solutions, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or buffered saline. Such compositions may further contain one or more excipients, such as preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, etc. Methods of formulation are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa. These pharmaceutical compositions may also be formulated for transmucosal, buccal, inhalation, parenteral, transdermal, and rectal administration.

[0147] In addition to the formulations of the present disclosure, the pharmaceutical composition can optionally be formulated as depot preparation.Such long-acting formulations can be administered by implantation or transdermal delivery (for example, subcutaneous or intramuscular), intramuscular injection, or transdermal patch.For example, the pharmaceutical composition can optionally be formulated as suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil), ion exchange resin, or poorly soluble derivative, for example, poorly soluble salt.

[0148] In some embodiments, the pharmaceutical formulations include, but are not limited to, aqueous dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolve formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations (e.g., nanoparticle formulations), and mixtures of immediate release and controlled release formulations.

[0149] In some examples, the pharmaceutical formulation comprises a multiparticulate formulation. In some examples, the pharmaceutical formulation comprises a nanoparticle formulation. In some examples, the nanoparticle comprises a cyclodextrin or a lipid. Optionally, the nanoparticle comprises a solid lipid nanoparticle, a polymeric nanoparticle, a self-emulsifying nanoparticle, a liposome, a microemulsion, or a micellar solution.

[0150] In some instances, the nanoparticles comprise a core or a core and a shell, such as in core-shell nanoparticles.

[0151] In some examples, the nanoparticles are further coated with molecules to attach functional moieties, in some examples, the coating comprises chondroitin sulfate, dextran sulfate, carboxymethyldextran, alginic acid, pectin, carrageenan, fucoidan, agaropectin, porphyran, karaya gum, gellan gum, xanthan gum, hyaluronic acid, glucosamine, galactosamine, chitin (or chitosan), polyglutamic acid, polyaspartic acid, lysozyme, cytochrome C, ribonuclease, trypsinogen, chymotrypsinogen, α-chymotrypsin, polylysine, polyarginine, histone, protamine, ovalbumin, dextrin, or cyclodextrin.

[0152] Optionally, the nanoparticles have at least one dimension that is less than about 500 nm, less than 400 nm, less than 300 nm, less than 200 nm, or less than 100 nm.

[0153] In some embodiments, the pharmaceutical formulation comprises a carrier or carrier material selected based on compatibility with the compositions disclosed herein and the release profile characteristics of the desired dosage form. Pharmaceutically compatible carrier materials include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, PVP, cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose, cellulose conjugates, sugar sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and any combination thereof. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0154] In some examples, the pharmaceutical formulation further comprises a pH adjusting or buffering agent, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid, bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, trishydroxymethylaminomethane, and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride, etc. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0155] In some examples, the pharmaceutical formulation contains one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range, including salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, and suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0156] In some examples, the pharmaceutical formulation includes a binder used to hold the 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug in a cohesive mixture with the inactive ingredient. Suitable binders include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose, acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, acid polysaccharides (polysaccharide copolymers), and the like. sugars such as cellulose gum, cellulose gum, cellulose gum, cellulose gums, natural or synthetic gums such as acacia, tragacanth, gum ghatti, mucilage of isapol bark, starch, bean syrup ...

[0157] In some instances, the pharmaceutical formulation further comprises a diluent used to stabilize the 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug. This is because the diluent provides a stable environment. Salts dissolved in buffer solutions (which can also adjust or maintain pH) are used as diluents in the art, including, but not limited to, phosphate buffered saline solutions. In some instances, the diluent increases the bulk of the composition to facilitate compression or create sufficient bulk for homogeneous mixing for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®; calcium hydrogen phosphate, calcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars such as Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and any combination thereof.

[0158] In some cases, the pharmaceutical formulation includes a disintegrant or disintegrating agent that promotes the breakdown or disintegration of substances. The term "disintegrate" includes both dissolution and dispersion of the dosage form when it comes into contact with gastrointestinal fluids. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, pregelatinized starches such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, celluloses such as wood products, methyl crystalline celluloses such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable surfactants include Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked PVP, alginates such as alginic acid, salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and any combination thereof.

[0159] In some examples, the pharmaceutical formulation comprises a filler, such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and any combination thereof.

[0160] Lubricants and glidants may also be included in the pharmaceutical formulations described herein to prevent, reduce, or inhibit adhesion or friction of materials. Typical lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil, hydrogenated vegetable oils such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol such as Carbowax®, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate, colloidal silica such as Syloid®, Cab-O-Sil®, starch such as corn starch, silicone oil, surfactants, and any combination thereof.

[0161] Plasticizers include compounds used to soften microencapsulation materials or film coatings, thereby reducing their brittleness. Suitable plasticizers include PEGs such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethylcellulose, and triacetin. Plasticizers also function as dispersing or wetting agents.

[0162] Solubilizing agents include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, docusate sodium, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, PVP, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, and any combination thereof.

[0163] Stabilizers include compounds such as any antioxidant, buffer, acid, preservative, and any combination thereof.

[0164] Suspending agents include PVP, such as PVP K12, PVP K17, PVP K25, or PVP K30, vinylpyrrolidone / vinyl acetate copolymer (S630), PEG (e.g., the molecular weight of PEG is about 300 to about 6000, about 3350 to about 4000, or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose acetate stearate, polysorbate 80, hydroxyethylcellulose, sodium alginate, gums such as tragacanth gum, gum arabic, guar gum, xanthan including xanthan gum, sugars, cellulose compounds such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate 80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and any combination thereof.

[0165] Surfactants include compounds such as sodium lauryl sulfate, docusate sodium, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (BASF), and any combination thereof. Additional surfactants include polyoxyethylene fatty acid glycerides, vegetable oils (e.g., polyoxyethylene (60) hydrogenated castor oil), polyoxyethylene alkyl ethers, alkyl phenyl ethers, such as Octoxynol 10 and Octoxynol 40. Surfactants are sometimes included for purposes such as enhancing physical stability.

[0166] Viscosity enhancing agents include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, hydroxypropyl methylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

[0167] Wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween 80, Vitamin E TPGS, ammonium salts, and any combination thereof.

[0168] Antifoaming agents are chemical additives that reduce and prevent foam formation in the preparation of oral liquid formulations. The terms antifoaming agent and defoamer are often used interchangeably. Commonly used agents are insoluble oils, polydimethylsiloxanes (e.g., simethicone), other silicones, certain alcohols, stearates, and glycols. Additives are used to prevent foam formation or are added to break up already formed foam. Antifoaming agents reduce foaming in the preparation of oral liquid formulations, which can lead to coagulation of aqueous dispersions. In some embodiments, the 5HT receptor agonist compositions described herein include an antifoaming agent. In some embodiments, the antifoaming agent is simethicone.

[0169] In some embodiments, there is considerable overlap between the excipients used in the pharmaceutical compositions, formulations and dosage forms of the 5HT receptor agonists described herein or their pharmaceutically acceptable salts, solvates, metabolites, derivatives or prodrugs.Therefore, the excipients listed above are merely examples of the types of excipients that may be included in the solid dosage forms of the pharmaceutical compositions described herein, and should not be construed as being limited thereto.

[0170] Pharmaceutical formulation methods and routes of administration In some embodiments, the 5HT receptor agonists, pharmaceutical compositions, or formulations described herein are administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal routes. In some embodiments, the pharmaceutical compositions described herein comprise a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, and are formulated into any suitable dosage form, including, but not limited to, an emulsion suitable for injection, a nanosuspension suitable for injection, a water-soluble oral dispersion, a liquid, a gel, a syrup, an elixir, a slurry, a suspension, an aerosol, a controlled-release formulation, a fast-dissolve formulation, an effervescent formulation, a lyophilized formulation, a tablet, a powder, a pill, a dragee, a capsule, a delayed-release formulation, an extended-release formulation, a pulsed-release formulation, a multiparticulate formulation, or a mixed immediate- or controlled-release formulation.

[0171] In some embodiments, the oral pharmaceutical composition is a tablet (including a suspension tablet, a fast-dissolving tablet, a bite-disintegrating tablet, a rapid-disintegrating tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile-packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled-release formulation, a pulsed-release dosage form, a multiparticulate dosage form, a pellet, a granule, or an aerosol. In some embodiments, the oral pharmaceutical composition is a solid dosage form, e.g., a tablet, an effervescent tablet, or a capsule. In some embodiments, the solid dosage form is prepared by mixing particles of a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, with one or more pharmaceutical excipients to form a bulk formulation composition. When these bulk formulation compositions are referred to as homogeneous, this means that the particles of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof are uniformly dispersed throughout the composition so that the composition can be subdivided into equally effective unit dosage forms such as tablets, pills, capsules, etc. The individual unit doses may further comprise a film coating that disintegrates after ingestion or contact with diluent.

[0172] For oral administration, the pharmaceutical compositions disclosed herein are readily formulated by combining the active compounds with, in some instances, pharmaceutically acceptable carriers well known in the art. Such carriers allow the compositions disclosed herein to be formulated as tablets, including chewable tablets, pills, dragees, capsules, lozenges, hard candies, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for ingestion by the patient to be treated. Such formulations may contain pharmaceutically acceptable carriers, including solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Generally, the compositions disclosed herein will be present in oral dosage forms at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, about 30% to about 50%, about 60%, about 70%, about 80%, or about 90% by weight of the total composition, in an amount sufficient to provide the desired dosage unit.

[0173] dose In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 1 mg / ml to about 30 mg / ml. In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.1 mg / ml to about 10 mg / ml. In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.1 mg / ml, about 0.2 mg / ml, about 0.3 mg / ml, about 0.4 mg / ml, about 0.5 mg / ml, about 0.6 mg / ml, about 0.7 mg / ml, about 0.8 mg / ml, about 0.9 mg / ml, about 1 mg / ml, about 1.1 mg / ml, about 1.2 mg / ml, or about 1. 3mg / ml, about 1.4mg / ml, about 1.5mg / ml, about 1.6mg / ml, about 1.7mg / ml, about 1.8mg / ml, about 1.9mg / ml, about 2mg / ml, about 2.1mg / ml, about 2.2mg / ml, about 2.3 mg / ml, approximately 2.4 mg / ml, approximately 2.5 mg / ml, approximately 2.6 mg / ml, approximately 2.7 mg / ml, approximately 2.8 mg / ml, approximately 2.9 mg / ml, approximately 3 mg / ml, approximately 3.1 mg / ml, approximately 3.2 mg / ml, approximately 3.3 mg / ml, about 3.4mg / ml, about 3.5mg / ml, about 3.6mg / ml, about 3.7mg / ml, about 3.8mg / ml, about 3.9mg / ml, about 4mg / ml, about 4.1mg / ml, about 4.2mg / ml, about 4.3mg / ml ml, about 4.4mg / ml, about 4.5mg / ml, about 4.6mg / ml, about 4.7mg / ml, about 4.8mg / ml, about 4.9mg / ml, about 5mg / ml, about 5.1mg / ml, about 5.2mg / ml, about 5.3mg / ml , about 5.4mg / ml, about 5.5mg / ml, about 5.6mg / ml, about 5.7mg / ml, about 5.8mg / ml, about 5.9mg / ml, about 6mg / ml, about 6.1mg / ml, about 6.2mg / ml, about 6.3mg / ml, about 6.4mg / ml, about 6.5mg / ml, about 6.6mg / ml, about 6.7mg / ml, about 6.8mg / ml, about 6.9mg / ml, about 7mg / ml, about 7.1mg / ml, about 7.2mg / ml, about 7.3mg / ml, about 7.4mg / ml, about 7.5mg / ml, about 7.6mg / ml, about 7.7mg / ml, about 7.8mg / ml, about 7.9mg / ml, about 8mg / ml, about 8.1mg / ml, about 8.2mg / ml, about 8.3mg / ml, about 8.4mg / ml, about 8.5mg / ml, about 8.6mg / ml, about 8.7mg / ml, about 8.8mg / ml, about 8.9mg / ml, about 9mg / ml, about 9.1mg / ml, about 9.2mg / ml, about 9.3mg / ml, about 9.4mg / ml, about 9.5mg / ml, about 9.6mg / ml, about 9.7mg / ml, about 9.8mg / ml , about 9.9mg / ml, about 10mg / ml, about 10.1mg / ml, about 10.2mg / ml, about 10.3mg / ml, about 10.4mg / ml, about 10.5mg / ml, about 10.6mg / ml, about 10.7mg / ml, about 10.8mg / ml, about 10.9mg / ml, about 1 1mg / ml, about 11.1mg / ml, about 11.2mg / ml, about 11.3mg / ml, about 11.4mg / ml, about 11.5mg / ml, about 11.6mg / ml, about 11.7mg / ml, about 11.8mg / ml, about 11.9mg / ml, about 12mg / ml, about 12.1mg / ml, about 12.2mg / ml, about 12.3mg / ml, about 12.4mg / ml, about 12.5mg / ml, about 12.6mg / ml, about 12.7mg / ml, about 12.8mg / ml, about 12.9mg / ml, about 13mg / ml, about 13.1mg / ml, about 13.2mg / m l, about 13.3mg / ml, about 13.4mg / ml, about 13.5mg / ml, about 13.6mg / ml, about 13.7mg / ml, about 13.8mg / ml, about 13.9mg / ml, about 14mg / ml, about 14.1mg / ml, about 14.2mg / ml, about 14.3mg / ml, About 14.4 mg / ml, about 14.5 mg / ml, about 14.6 mg / ml, about 14.7 mg / ml, about 14.8 mg / ml, about 14.9 mg / ml, about 15 mg / ml, about 15.5 mg / ml, about 16 mg / ml, about 16.5 mg / ml, about 17 mg / ml, about 17.5 mg / ml, about 18 mg / ml, about 18.5 mg / ml, about 19 mg / ml, about 19.5 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 27.5 mg / ml, and about 30 mg / ml.

[0174] In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition corresponds to about 0.8 mg / ml to about 24 mg / ml of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, such as about 0.8 mg / ml, about 0.9 mg / ml, about 1 mg / ml, about 1.1 mg / ml, about 1.2 mg / ml, about 1.3 mg / ml, about 1.4 mg / ml, about 1.5 mg / ml, about 1.6 mg / ml, about 1.7 mg / ml of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. ml, about 1.8mg / ml, about 1.9mg / ml, about 2mg / ml, about 2.1mg / ml, about 2.2mg / ml, about 2.3mg / ml, about 2.4mg / ml, about 2.5mg / ml, about 2.6mg / ml, about 2.7mg / ml, about 2.8 mg / ml, approximately 2.9 mg / ml, approximately 3 mg / ml, approximately 3.1 mg / ml, approximately 3.2 mg / ml, approximately 3.3 mg / ml, approximately 3.4 mg / ml, approximately 3.5 mg / ml, approximately 3.6 mg / ml, approximately 3.7 mg / ml, approximately 3.8 mg / ml, approximately 3 .9mg / ml, about 4mg / ml, about 4.1mg / ml, about 4.2mg / ml, about 4.3mg / ml, about 4.4mg / ml, about 4.5mg / ml, about 4.6mg / ml, about 4.7mg / ml, about 4.8mg / ml, about 4.9mg / ml , about 5mg / ml, about 5.1mg / ml, about 5.2mg / ml, about 5.3mg / ml, about 5.4mg / ml, about 5.5mg / ml, about 5.6mg / ml, about 5.7mg / ml, about 5.8mg / ml, about 5.9mg / ml, about 6mg / m l, about 6.1mg / ml, about 6.2mg / ml, about 6.3mg / ml, about 6.4mg / ml, about 6.5mg / ml, about 6.6mg / ml, about 6.7mg / ml, about 6.8mg / ml, about 6.9mg / ml, about 7mg / ml, about 7.1m g / ml, about 7.2 mg / ml, about 7.3 mg / ml, about 7.4 mg / ml, about 7.5 mg / ml, about 7.6 mg / ml, about 7.7 mg / ml, about 7.8 mg / ml, about 7.9 mg / ml, about 8 mg / ml, about 8.1 mg / ml, about 8.2mg / ml, about 8.3mg / ml, about 8.4mg / ml, about 8.5mg / ml, about 8.6mg / ml, about 8.7mg / ml, about 8.8mg / ml, about 8.9mg / ml, about 9mg / ml, about 9.1mg / ml, about 9.2mg / ml, about 9. 3mg / ml, about 9.4mg / ml, about 9.5mg / ml, about 9.6mg / ml, about 9.7mg / ml, about 9.8mg / ml, about 9.9mg / ml, about 10mg / ml, about 10.1mg / ml, about 10.2mg / ml, about 10.3mg / ml, About 10.4mg / ml, about 10.5mg / ml, about 10.6mg / ml, about 10.7mg / ml, about 10.8mg / ml, about 10.9mg / ml, about 11mg / ml, about 11.1mg / ml, about 11.2mg / ml, about 11.3mg / ml, Approximately 11.4mg / ml, approximately 11.5mg / ml, approximately 11.6mg / ml, approximately 11.7mg / ml, approximately 11.8mg / ml, approximately 11.9mg / ml, approximately 12mg / ml, approximately 12.1mg / ml, approximately 12.2mg / ml, approximately 12.3mg / ml, approximately 12.4mg / ml, about 12.5mg / ml, about 12.6mg / ml, about 12.7mg / ml, about 12.8mg / ml, about 12.9mg / ml, about 13mg / ml, about 13.1mg / ml, about 13.2mg / ml, about 13.3mg / ml, about 13.4mg / ml, about 13.5mg / ml, about 13.6mg / ml, about 13.7mg / ml, about 13.8mg / ml, about 13.9mg / ml, about 14mg / ml, about 14.1mg / ml, about 14.2mg / ml, about 14.3mg / ml, about 1 This corresponds to 4.4 mg / ml, about 14.5 mg / ml, about 14.6 mg / ml, about 14.7 mg / ml, about 14.8 mg / ml, about 14.9 mg / ml, about 15 mg / ml, about 15.5 mg / ml, about 16 mg / ml, about 16.5 mg / ml, about 17 mg / ml, about 17.5 mg / ml, about 18 mg / ml, about 18.5 mg / ml, about 19 mg / ml, about 19.5 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, or about 24 mg / ml.

[0175] In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.001 mg to about 20 mg. In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.005 mg to about 10 mg. In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.01 mg to about 5 mg. In some embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.05 mg to about 2.5 mg.In other embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is about 0.001 mg, about 0.005 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0. 15mg, about 0.17mg, about 0.2mg, about 0.23mg, about 0.25mg, about 0.28mg, about 0.3mg, about 0.33mg, about 0.35mg, about 0.37mg, about 0.4mg, about 0.43mg, about 0. 45mg, about 0.47mg, about 0.5mg, about 0.53mg, about 0.55mg, about 0.57mg, about 0.6mg, about 0.63mg, about 0.65mg, about 0.67mg, about 0.7mg, about 0.73mg, about 0.7 5mg, about 0.78mg, about 0.8mg, about 0.83mg, about 0.85mg, about 0.87mg, about 0.9mg, about 0.95mg, about 1mg, about 1.1mg, about 1.2mg, about 1.3mg, about 1.4mg, about 1 .5mg, about 1.6mg, about 1.7mg, about 1.8mg, about 1.9mg, about 2mg, about 2.1mg, about 2.2mg, about 2.3mg, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, This is equivalent to about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, or about 11 mg.

[0176] In other embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is less than 0.001 mg, less than 0.005 mg, less than 0.01 mg, less than 0.02 mg, less than 0.03 mg, less than 0.04 mg, less than 0.05 mg, less than 0.06 mg, less than 0.07 mg, less than 0.08 mg, less than 0.09 mg, less than 0.1 mg, less than 0.11 mg, less than 0.12 mg, less than 0.15 mg, less than 0.17 mg, less than 0.2 mg Less than g, Less than 0.23 mg, Less than 0.25 mg, Less than 0.28 mg, Less than 0.3 mg, Less than 0.33 mg, Less than 0.35 mg, Less than 0.37 mg, Less than 0.4 mg, Less than 0.43 mg, Less than 0.45 mg, Less than 0.47 mg, Less than 0.5 mg, Less than 0.53 mg, Less than 0.55 mg, Less than 0.57 mg, Less than 0.6 mg, Less than 0.63 mg, Less than 0.65 mg, Less than 0.67 mg, Less than 0.7 mg, Less than 0.73 mg, Less than 0.75 mg, Less than 0.78 mg, Less than 0.8 mg, Less than 0.83 mg Less than g, Less than 0.85 mg, Less than 0.87 mg, Less than 0.9 mg, Less than 0.95 mg, Less than 1 mg, Less than 1.1 mg, Less than 1.2 mg, Less than 1.3 mg, Less than 1.4 mg, Less than 1.5 mg, Less than 1.6 mg, Less than 1.7 mg, Less than 1.8 mg, Less than 1.9 mg, Less than 2 mg, Less than 2.1 mg, Less than 2.2 mg, Less than 2.3 mg, Less than 2.4 mg, Less than 2.5 mg, Less than 2.6 mg, Less than 2.7 mg, Less than 2.8 mg, Less than 2.9 mg, Less than 3 mg, Less than 3.1 mg, Less than 3.2 mg, 3 This corresponds to less than 0.3mg, less than 3.4mg, less than 3.5mg, less than 3.6mg, less than 3.7mg, less than 3.8mg, less than 3.9mg, less than 4mg, less than 4.1mg, less than 4.2mg, less than 4.3mg, less than 4.4mg, less than 4.5mg, less than 4.6mg, less than 4.7mg, less than 4.8mg, less than 4.9mg, less than 5mg, less than 5.1mg, less than 5.2mg, less than 5.3mg, less than 5.4mg, less than 5.5mg, less than 5.6mg, less than 5.7mg, less than 5.8mg, or less than 5.9mg.

[0177] In other embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is 0.005 mg or less, 0.01 mg or less, 0.02 mg or less, 0.03 mg or less, 0.04 mg or less, 0.05 mg or less, 0.06 mg or less, 0.07 mg or less, 0.08 mg or less, 0.09 mg or less, 0.1 mg or less, 0.11 mg or less, 0.12 mg or less, 0.15 mg or less, 0.17 mg or less, 0.2 mg or less, 0.23 mg or less, or mg or less, 0.25 mg or less, 0.28 mg or less, 0.3 mg or less, 0.33 mg or less, 0.35 mg or less, 0.37 mg or less, 0.4 mg or less, 0.43 mg or less, 0.45 mg or less, 0.47 mg or less, 0.5 mg or less, 0.53 mg or less , 0.55 mg or less, 0.57 mg or less, 0.6 mg or less, 0.63 mg or less, 0.65 mg or less, 0.67 mg or less, 0.7 mg or less, 0.73 mg or less, 0.75 mg or less, 0.78 mg or less, 0.8 mg or less, 0.83 mg or less, 0.8 5mg or less, 0.87mg or less, 0.9mg or less, 0.95mg or less, 1mg or less, 1.1mg or less, 1.2mg or less, 1.3mg or less, 1.4mg or less, 1.5mg or less, 1.6mg or less, 1.7mg or less, 1.8mg or less, 1.9mg or less , 2mg or less, 2.1mg or less, 2.2mg or less, 2.3mg or less, 2.4mg or less, 2.5mg or less, 2.6mg or less, 2.7mg or less, 2.8mg or less, 2.9mg or less, 3mg or less, 3.1mg or less, 3.2mg or less, 3.3mg or less, Equivalent to 3.4mg or less, 3.5mg or less, 3.6mg or less, 3.7mg or less, 3.8mg or less, 3.9mg or less, 4mg or less, 4.1mg or less, 4.2mg or less, 4.3mg or less, 4.4mg or less, 4.5mg or less, 4.6mg or less, 4.7mg or less, 4.8mg or less, 4.9mg or less, 5mg or less, 5.1mg or less, 5.2mg or less, 5.3mg or less, 5.4mg or less, 5.5mg or less, 5.6mg or less, 5.7mg or less, 5.8mg or less, 5.9mg or less, or 6mg or less.

[0178] In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.001 mg / kg to about 50 mg / kg. In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.005 mg / kg to about 10 mg / kg. In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.01 mg / kg to about 5 mg / kg. In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug used in the pharmaceutical composition is about 0.05 mg / kg to about 1 mg / kg. In other embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.11 mg / kg, about 0.12 mg / kg, about 0.15 mg / kg, about 0.17 mg / kg, about 0.2 mg / kg, about 0.23 mg / kg, about 0.25 mg / kg, about 0.28 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 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / g / kg, about 0.33mg / kg, about 0.35mg / kg, about 0.37mg / kg, about 0.4mg / kg, about 0.43mg / kg, about 0.45mg / kg, about 0. 47mg / kg, about 0.5mg / kg, about 0.53mg / kg, about 0.55mg / kg, about 0.57mg / kg, about 0.6mg / kg, about 0.63mg / kg, about 0 .65mg / kg, approx. 0.67mg / kg, approx. 0.7mg / kg, approx. 0.73mg / kg, approx. 0.75mg / kg, approx. 0.78mg / kg, approx. 0.8mg / kg, approx. 0.83mg / kg, about 0.85mg / kg, about 0.87mg / kg, about 0.9mg / kg, about 0.95mg / kg, about 1mg / kg, about 1.1mg / kg, about 1.2mg / kg, about 1.3mg / kg, about 1.4mg / kg, about 1.5mg / kg, about 1.6mg / kg, about 1.7mg / kg, about 1.8mg / kg, about 1.9mg / kg, about 2mg / kg, about 2.1mg / kg, about 2.2mg / kg, about 2 .3mg / kg, about 2.4mg / kg, about 2.5mg / kg, about 2.6mg / kg, about 2.7mg / kg, about 2.8mg / kg, about 2.9mg / kg, about 3mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.3mg / kg, about This corresponds to 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0179] In other embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is less than 0.001 mg / kg, less than 0.005 mg / kg, less than 0.01 mg / kg, less than 0.02 mg / kg, less than 0.03 mg / kg, less than 0.04 mg / kg, less than 0.05 mg / kg, less than 0.06 mg / kg, less than 0.07 mg / kg, less than 0.08 mg / kg, less than 0.09 mg / kg, less than 0.1 mg / kg, less than 0.11 mg / kg, less than 0.12 mg / kg, less than 0.15 mg / kg. Less than 0.17mg / kg, Less than 0.2mg / kg, Less than 0.23mg / kg, Less than 0.25mg / kg, Less than 0.28mg / kg, Less than 0.3mg / kg, Less than 0.33mg / kg, Less than 0.35mg / kg, Less than 0.37mg / kg, Less than 0.4mg / kg, Less than 0.43mg / kg, Less than 0.45mg / kg, Less than 0.47mg / kg, Less than 0.5mg / kg, Less than 0.53mg / kg, Less than 0.55mg / kg, Less than 0.57mg / kg, Less than 0.6mg / kg, Less than 0.63mg / kg, Less than 0.65mg / kg, Less than 0.67mg / kg Less than 0.7mg / kg, less than 0.73mg / kg, less than 0.75mg / kg, less than 0.78mg / kg, less than 0.8mg / kg, less than 0.83mg / kg, less than 0.85mg / kg, less than 0.87mg / kg, less than 0.9mg / kg, less than 0.95mg / kg, less than 1mg / kg, less than 1.1mg / kg, less than 1.2mg / kg, less than 1.3mg / kg, less than 1.4mg / kg, less than 1.5mg / kg, less than 1.6mg / kg, less than 1.7mg / kg, less than 1.8mg / kg, less than 1.9mg / kg, less than 2mg / kg, less than 2.1mg / kg, 2. Less than 2mg / kg, less than 2.3mg / kg, less than 2.4mg / kg, less than 2.5mg / kg, less than 2.6mg / kg, less than 2.7mg / kg, less than 2.8mg / kg, less than 2.9mg / kg, less than 3mg / kg, less than 3.1mg / kg, less than 3.2mg / kg, less than 3.3mg / kg, less than 3.4mg / kg, less than 3.5mg / kg, less than 3.6mg / kg, less than 3.7mg / kg, less than 3.8mg / kg, less than 3.9mg / kg, less than 4mg / kg, less than 4.1mg / kg, less than 4.2mg / kg, less than 4.3mg / kg, less than 4.4mg / kg, 4.This corresponds to less than 5 mg / kg, less than 4.6 mg / kg, less than 4.7 mg / kg, less than 4.8 mg / kg, less than 4.9 mg / kg, or less than 5 mg / kg.

[0180] In other embodiments, the amount of 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition is 0.005 mg / kg or less, 0.01 mg / kg or less, 0.02 mg / kg or less, 0.03 mg / kg or less, 0.04 mg / kg or less, 0.05 mg / kg or less, 0.06 mg / kg or less, 0.07 mg / kg or less, 0.08 mg / kg or less, 0.09 mg / kg or less, 0.1 mg / kg or less, 0.11 mg / kg or less, 0.12 mg / kg or less, 0.15 mg / kg or less, 0.17 mg / kg or less Below, 0.2mg / kg or less, 0.23mg / kg or less, 0.25mg / kg or less, 0.28mg / kg or less, 0.3mg / kg or less, 0.33mg / kg or less, 0.35mg / kg or less, 0.37mg / kg or less, 0.4mg / kg or less, 0.43mg / kg or less, 0.45 mg / kg or less, 0.47 mg / kg or less, 0.5 mg / kg or less, 0.53 mg / kg or less, 0.55 mg / kg or less, 0.57 mg / kg or less, 0.6 mg / kg or less, 0.63 mg / kg or less, 0.65 mg / kg or less, 0.67 mg / kg or less, 0.7 mg / kg or less , 0.73mg / kg or less, 0.75mg / kg or less, 0.78mg / kg or less, 0.8mg / kg or less, 0.83mg / kg or less, 0.85mg / kg or less, 0.87mg / kg or less, 0.9mg / kg or less, 0.95mg / kg or less, 1mg / kg or less, 1.1mg / kg 1.2 mg / kg or less, 1.3 mg / kg or less, 1.4 mg / kg or less, 1.5 mg / kg or less, 1.6 mg / kg or less, 1.7 mg / kg or less, 1.8 mg / kg or less, 1.9 mg / kg or less, 2 mg / kg or less, 2.1 mg / kg or less, 2.2 mg / kg or less, 2. 3mg / kg or less, 2.4mg / kg or less, 2.5mg / kg or less, 2.6mg / kg or less, 2.7mg / kg or less, 2.8mg / kg or less, 2.9mg / kg or less, 3mg / kg or less, 3.1mg / kg or less, 3.2mg / kg or less, 3.3mg / kg or less, 3.4mg / k g or less, 3.5 mg / kg or less, 3.6 mg / kg or less, 3.7 mg / kg or less, 3.8 mg / kg or less, 3.9 mg / kg or less, 4 mg / kg or less, 4.1 mg / kg or less, 4.2 mg / kg or less, 4.3 mg / kg or less, 4.4 mg / kg or less, 4.5 mg / kg or less, 4.This corresponds to 6mg / kg or less, 4.7mg / kg or less, 4.8mg / kg or less, 4.9mg / kg or less, 5mg / kg or less, 6mg / kg or less, 7mg / kg or less, 8mg / kg or less, 9mg / kg or less, or 10mg / kg or less.

[0181] In some embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition corresponds to about 1% w / w to about 50% w / w of the solids in the oral liquid formulation. In other embodiments, the amount of the 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof in the pharmaceutical composition corresponds to about 1% w / w, about 1.1% w / w, about 1.2% w / w, about 1.3% w / w, about 1.4% w / w, about 1.5% w / w, about 1.6% w / w, about 1.7% w / w, about 1.8% w / w, about 1.9% w / w, about 2% w / w, about 2.1% w / w, about 2.2% w / w, about 2.3% w / w, about 2.4% w / w, about 2.5% w / w, about 2.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3.0% w / w, about 3.1% w / w, about 3.2% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4.0% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 4.9% w / w, about 4 0.6% w / w, about 2.7% w / w, about 2.8% w / w, about 2.9% w / w, about 3% w / w, about 3.1% w / w, about 3.2% w / w, about 3.3% w / w, about 3.4% w / w, about 3.5% w / w, about 3.6% w / w, about 3.7% w / w, about 3.8% w / w, about 3.9% w / w, about 4% w / w, about 4.1% w / w, about 4.2% w / w, about 4.3% w / w, about 4.4% w / w, about 4.5% w / w, about 4.6% w / w, about 4.7% w / w, about 4.8% w / w, about 4.9% w / w, about 5% w / w, about 5.1% w / w, about 5.2% w / w, about 5.3% w / w, about 5.4% w / w, about 5.5% w / w, about 5.6% w / w, about 5.7% w / w, about 5.8% w / w, about 5.9% w / w, about 6% w / w, about 6.1% w / w, about 6.2% w / w, about 6.3% w / w, about 6.4% w / w, about 6.5% w / w, about 6.6% w / w, about 6.7% w / w, about 6.8% w / w, about 6.9% w / w, about 7% w / w, about 7.1% w / w, about 7.2% w / w, about 7.3% w / w, about 7.4% w / w, about 7.5% w / w, about 7.6% w / w, about 7.7% w / w, approximately 7.8% w / w, approximately 7.9% w / w, approximately 8% w / w, approximately 8.1% w / w, approximately 8.2% w / w, approximately 8.3% w / w, approximately 8.4% w / w, approximately 8.5% w / w, approximately 8.6% w / w, approximately 8.7% w / w, approximately 8.8% w / w, approximately 8.9% w / w, approximately 9% w / w, approximately 9.1% w / w, approximately 9.2% w / w, approximately 9.3% w / w, approximately 9.4% w / w, approximately 9.5% w / w, approximately 9.6% w / w, approximately 9.7% w / w, approximately 9.8% w / w, approximately 9.9% w / w, approximately 10% w / w, approximately 10.2% w / w, approximately 10.4%w / w, approximately 10.6%w / w, approximately 10.8%w / w, approximately 11%w / w, approximately 11.2%w / w, approximately 11.4%w / w, approximately 11.6%w / w, approximately 11.8%w / w, approximately 12%w / w, approximately 12.2%w / w, approximately 12.4%w / w, approximately 12.6%w / w, approximately 12.8%w / w, approximately 13%w / w, approximately 13.2%w / w, approximately 13.4%w / w, approximately 13.6%w / w, approximately 13.8%w / w, approximately 14%w / w, approximately 14.2%w / w, approximately 14.4%w / w, approximately 14.6%w / w, approximately 14.8%w / w, approximately 15%w / w, approximately 15.5%w / w, approximately 16%w / w, approximately 16.5%w / w, approximately 17%w / w, approximately 17.5%w / w, approximately 18%w / w, approximately 1 8.5% w / w, about 19% w / w, about 19.5% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34 % w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, or about 50% w / w.

[0182] Therapeutic Uses - Disorders, Diseases, and Conditions Provided herein are methods for managing a disorder or disease, the methods comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof.

[0183] Further provided herein are methods for treating symptoms of a disorder or disease, the methods comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof.

[0184] In some embodiments, the disorder or disease is a neurological disorder or disease. In some embodiments, the disorder or disease is a neurocognitive disorder or disease. In some embodiments, the disorder or disease is a neurodegenerative disorder or disease. In some embodiments, the symptoms of the neurological disease are somatic, behavioral, emotional, psychiatric, or a combination thereof.

[0185] Provided herein are methods for managing or treating a disorder, disease, or condition, including, but not limited to, an addictive disorder, including, but not limited to, alcoholism, substance abuse, smoking, or obesity. Provided herein are methods for managing or treating a disorder, disease, or condition, including, but not limited to, an eating disorder and a hearing disorder. Provided herein are methods for managing or treating a disorder, disease, or condition, including, but not limited to, pain, such as chronic pain. Provided herein are methods for managing or treating a disorder, disease, or condition, including, but not limited to, depression, bipolar disorder, post-traumatic stress disorder (PTSD), panic disorder, phobia, schizophrenia, psychopathy, or antisocial personality disorder. Provided herein are methods for managing or treating disorders, diseases, or symptoms, including but not limited to, impulsive disorders such as attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, or autism. Provided herein are methods for managing or treating disorders, diseases, or symptoms, including but not limited to, obsessive-compulsive disorders such as obsessive-compulsive disorder (OCD), gambling, or abnormal sexual behavior. Provided herein are methods for managing or treating disorders, diseases, or symptoms, including but not limited to, personality disorders such as conduct disorder, antisocial personality, or aggressive behavior.

[0186] Further non-limiting examples of disorders, diseases, and conditions that can be managed or treated include:

[0187] Neurodevelopmental disorders, including but not limited to Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder, and Learning Disabilities.

[0188] Psychotic abnormalities such as schizophrenia spectrum disorders, including but not limited to: reality, delusions, hallucinations, and disorganized thinking and speech.

[0189] Bipolar disorder and related disorders that may involve episodes of mania (periods of excessive excitement, activity, and energy) alternating with periods of depression.

[0190] Depressive disorders, including but not limited to depression, major depression, major depressive disorder (MDD), and premenstrual dysphoric disorder (PMDD), which may involve extreme sadness and decreased interest in previously enjoyed activities.

[0191] Anxiety disorders that may involve excessive worrying about possible bad things or situations. Examples include, but are not limited to, generalized anxiety disorder (GAD), panic disorder, and phobias (irrational fears of specific things).

[0192] Obsessive-compulsive and related disorders, which may involve unwanted recurring urges, thoughts, or images (obsessions) and a sense of compulsion to perform repetitive behaviors in response to them (compulsions). Non-limiting examples include obsessive-compulsive disorder (OCD), holding disorder, extreme onychophagia, and trichotillomania.

[0193] Disorders related to trauma and insults that may develop during or after a stressful or traumatic life event. Non-limiting examples include post-traumatic stress disorder (PTSD) and acute stress disorder.

[0194] Dissociative disorders that can disrupt one's sense of self, such as, but not limited to, dissociative identity disorder and dissociative amnesia.

[0195] Somatic symptom and related disorders, which may involve distressing and disabling physical symptoms without a clear medical cause. Non-limiting examples include illness anxiety disorder, somatic symptom disorder (hypochondriasis), and factitious disorder.

[0196] Eating disorders can involve eating-related disorders such as, but not limited to, anorexia nervosa, hypeorge nervosa, and binge eating disorder.

[0197] Elimination disorders, which may involve the accidental or conscious inappropriate elimination (emission) of urine or feces, such as, but not limited to, bedwetting (enuresis).

[0198] Sleep-wake disorders, which may involve severe sleep disturbances, including but not limited to insomnia disorder, nightmare disorder, sleep apnea, and restless leg syndrome.

[0199] Disruptive, impulse control, and conduct disorders that may involve emotional and / or behavioral self-regulation, such as, but not limited to, kleptomania (repeated stealing), pyromania, and intermittent explosive disorder.

[0200] Substance-related disorders, which may involve problems related to the overuse of substances such as alcohol (alcoholism, alcoholism), tobacco products, drugs, opioids (e.g., cocaine, oxycodone, morphine), recreational drugs, and hallucinogens.

[0201] Addiction disorders, which may involve problems related to the overuse of specific behaviors or fixations, such as, but not limited to, gambling disorder.

[0202] Neurocognitive disorders that can affect the ability to think and make decisions, such as, but not limited to, traumatic brain injury (TBI) and Alzheimer's disease.

[0203] Personality disorders that may involve persistent patterns of emotional instability and unhealthy behaviors that interfere with daily life and relationships. Examples include, but are not limited to, borderline personality disorder, antisocial disorder, and narcissistic personality disorder.

[0204] Gender dysphoria, which may involve distress caused by wanting to be a different gender than one's own.

[0205] Sexual dysfunction, such as premature ejaculation, erectile dysfunction, and female orgasmic dysfunction.

[0206] Paraphilic disorders (sexual perversions, sexual deviations), which may involve sexual interest in atypical objects, situations, fantasies, behaviors, or individuals. Examples include, but are not limited to, sexual sadism disorder, voyeurism, and pedophilic disorder.

[0207] Further examples of disorders, diseases, and conditions that can be managed or treated include fragile X syndrome, Down's syndrome, migraine, cluster headache, psychiatric disorders, neurodevelopmental disorders, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, learning disabilities, schizophrenia spectrum disorders, psychotic disorders, bipolar disorder, depression, major depression, major depressive disorder (MDD), premenstrual dysphoric disorder (PMDD), suicidality, mood-related disorders, panic disorder, panic attacks, phobias, cyclophobia, and selective thrombosis. Mutism, Obsessive-Compulsive Disorder (OCD), Hoarding Disorder, Trichotillomania, Excoriation Disorder, Substance / Drug-Induced Obsessive-Compulsive Disorder, Trauma-Related Disorder, Traumatic Brain Injury (TBI), Post-Traumatic Stress Disorder (PTSD), Acute Stress Disorder, Dissociative Disorder, Dissociative Identity Disorder, Dissociative Amnesia, Anxiety Disorder, Worry Disorder, Generalized Anxiety Disorder (GAD), Social Anxiety Disorder, Separation Anxiety Disorder, Illness Anxiety Disorder, Somatic Disorder / Illness, Somatic Symptom Disorder (Hypochondriasis), Eating Disorders, Eating Disordersdisorders), anorexia nervosa, anorexia nervosa, hyperorexia nervosa, binge eating disorder, elimination disorders, enuresis, sleep disorders, insomnia, nightmare disorder, sleep apnea, central sleep apnea, narcolepsy, obstructive sleep apnea, hypopnea and sleep-related hypoventilation, restless legs syndrome, jet lag, sexual dysfunction, premature ejaculation, erectile dysfunction, female orgasmic disorder, gender identity disorder, gender dysphoria, disruptive disorder, impulse control disorder, conduct disorder, disruptive behavior disorder, impulse control disorder, oppositional defiant disorder (ODD), aggression, kleptomania, pyromania, dependency disorders, substance dependence, substance abuse, alcoholism, drug dependence, opioid dependence, cocaine addiction, gambling addiction, tobacco dependence, bulimia, other substance and behavioral addictions, obesity, cognitive impairment, memory-related disorders, These conditions include, but are not limited to, learning-related disabilities, neurocognitive disorders, Alzheimer's disease, personality disorders, narcissistic personality disorder, Asperger's syndrome, Tourette's syndrome, Huntington's disease, Parkinson's disease, Lewy body disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, muscle atrophy, prion diseases, dementia, vascular dementia, infectious causes of dementia / neurocognitive problems, dementia due to substance abuse or exposure to toxins, frontotemporal degeneration, mood disorders, delirium, aphasia, apraxia, acognition, tremors, amnesia, anterograde amnesia, retrograde amnesia, body dysmorphic disorder, reactive attachment disorder, fragile X syndrome, Down's syndrome, migraine, hemicrania, cluster headache, cardiovascular disease, inflammatory diseases, fibromyalgia, and pain.

[0208] Provided herein are methods for managing disorders or diseases or treating symptoms of disorders or diseases, comprising administering one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof. In some embodiments, the 5HT receptor agonist is a 5HT2 receptor agonist. In some embodiments, the 5HT2 receptor agonist is a 5HT2A receptor agonist, a 5HT2B receptor agonist, and / or a 5HT2C receptor agonist. In some embodiments, the 5HT receptor agonist is psilocin or psilocybin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to the subject in an amount that does not result in adverse side effects, such as hallucinatory experiences.

[0209] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is an amount that provides a maximum plasma concentration (C) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of 6 ng / mL or greater. max In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that does not result in a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.1 ng / mL or more and less than 6 ng / mL (e.g., at least 0.5 ng / mL and less than 6 ng / mL, about 1 ng / mL to about 5.5 ng / mL, about 2 ng / mL to about 5 ng / mL, etc.). maxIn some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that results in a plasma concentration of the HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of at least 0.1 ng / mL (e.g., at least 0.2 ng / mL, at least 0.3 ng / mL, at least 0.5 ng / mL, etc.) after at least 6 hours (e.g., at least 12 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 120 hours, at least 144 hours, etc.).

[0210] In some embodiments, a therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is a therapeutically effective amount that provides a maximum plasma concentration (C) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.001 ng / mL to about 10 ng / mL. max In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that does not result in a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.01 ng / mL to about 5 ng / mL. max In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is provided to a subject in an amount and / or formulation that does not result in a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 0.05 ng / mL to about 1 ng / mL. maxIn some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is about 0.001 ng / mL, about 0.005 ng / mL, about 0.01 ng / mL, about 0.02 ng / mL, about 0.03 ng / mL, about 0.04 ng / mL, about 0.05 ng / mL, about 0.06 ng / mL, about 0.07 ng / mL, about 0.08 ng / mL, about 0.09 ng / mL, about 0.1 ng / mL, about 0.11 ng / mL, about 0.12 ng / mL, about 0.15 ng / mL, about 0.17ng / mL, about 0.2ng / mL, about 0.23ng / mL, about 0.25ng / mL, about 0.28ng / mL, about 0.3ng / mL, about 0.33ng / mL, about 0.35ng / mL, about 0.37ng / mL, about 0.4ng / mL, about 0.43ng / mL, about 0 .45ng / mL, about 0.47ng / mL, about 0.5ng / mL, about 0.53ng / mL, about 0.55ng / mL, about 0.57ng / mL, about 0.6ng / mL, about 0.63ng / mL, about 0.65ng / mL, about 0.67ng / mL, about 0.7ng / mL, about 0.7 3ng / mL, approximately 0.75ng / mL, approximately 0.78ng / mL, approximately 0.8ng / mL, approximately 0.83ng / mL, approximately 0.85ng / mL, approximately 0.87ng / mL, approximately 0.9ng / mL, approximately 0.95ng / mL, approximately 1ng / mL, approximately 1.1ng / mL, approximately 1.2ng / m L, approximately 1.3ng / mL, approximately 1.4ng / mL, approximately 1.5ng / mL, approximately 1.6ng / mL, approximately 1.7ng / mL, approximately 1.8ng / mL, approximately 1.9ng / mL, approximately 2ng / mL, approximately 2.1ng / mL, approximately 2.2ng / mL, approximately 2.3ng / mL, approximately 2.4ng / mL, Approximately 2.5ng / mL, approximately 2.6ng / mL, approximately 2.7ng / mL, approximately 2.8ng / mL, approximately 2.9ng / mL, approximately 3ng / mL, approximately 3.1ng / mL, approximately 3.2ng / mL, approximately 3.3ng / mL, approximately 3.4ng / mL, approximately 3.5ng / mL, approximately 3.6ng / mL, approximately 3.7ng / mL, approximately 3.8ng / mL, approximately 3.9ng / mL, approximately 4ng / mL, approximately 4.1ng / mL, approximately 4.2ng / mL, approximately 4.3ng / mL, approximately 4.4ng / mL, approximately 4.5ng / mL, approximately 4.6ng / mL, approximately 4.7ng / mL, approximately 4.8ng / mL, approximately 4.a maximum plasma concentration (C.I.) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of about 9 ng / mL, about 5 ng / mL, about 5.1 ng / mL, about 5.2 ng / mL, about 5.3 ng / mL, about 5.4 ng / mL, about 5.5 ng / mL, about 5.6 ng / mL, about 5.7 ng / mL, about 5.8 ng / mL, about 5.9 ... or about 6 ng / mL. max ) is provided to the subject in an amount and / or formulation that does not result in

[0211] In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is less than 0.001 ng / mL, less than 0.005 ng / mL, less than 0.01 ng / mL, less than 0.02 ng / mL, less than 0.03 ng / mL, less than 0.04 ng / mL, less than 0.05 ng / mL, less than 0.06 ng / mL, less than 0.07 ng / mL, less than 0.08 ng / mL, less than 0.09 ng / mL, less than 0.1 ng / mL, less than 0.11 ng / mL, less than 0.12 ng / mL, less than 0.15 ng / mL. Less than 0.17ng / mL, less than 0.2ng / mL, less than 0.23ng / mL, less than 0.25ng / mL, less than 0.28ng / mL, less than 0.3ng / mL, less than 0.33ng / mL, less than 0.35ng / mL, less than 0.37ng / mL, less than 0.4ng / mL, less than 0.43ng / mL, less than 0.45ng / mL, less than 0.47ng / mL, less than 0.5ng / mL, less than 0.53ng / mL, less than 0.55ng / mL, less than 0.57ng / mL, less than 0.6ng / mL, less than 0.63ng / mL, less than 0.65ng / mL, less than 0.67ng / mL , less than 0.7ng / mL, less than 0.73ng / mL, less than 0.75ng / mL, less than 0.78ng / mL, less than 0.8ng / mL, less than 0.83ng / mL, less than 0.85ng / mL, less than 0.87ng / mL, less than 0.9ng / mL, less than 0.95ng / mL, less than 1ng / mL, less than 1.1ng / mL, less than 1.2ng / mL, less than 1.3ng / mL, less than 1.4ng / mL, less than 1.5ng / mL, less than 1.6ng / mL, less than 1.7ng / mL, less than 1.8ng / mL, less than 1.9ng / mL, less than 2ng / mL, less than 2.1ng / mL, 2. Less than 2ng / mL, less than 2.3ng / mL, less than 2.4ng / mL, less than 2.5ng / mL, less than 2.6ng / mL, less than 2.7ng / mL, less than 2.8ng / mL, less than 2.9ng / mL, less than 3ng / mL, less than 3.1ng / mL, less than 3.2ng / mL, less than 3.3ng / mL, less than 3.4ng / mL, less than 3.5ng / mL, less than 3.6ng / mL, less than 3.7ng / mL, less than 3.8ng / mL, less than 3.9ng / mL, less than 4ng / mL, less than 4.1ng / mL, less than 4.2ng / mL, less than 4.3ng / mL, less than 4.4ng / mL, 4.a maximum plasma concentration (C) of said 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of less than 5 ng / mL, less than 4.6 ng / mL, less than 4.7 ng / mL, less than 4.8 ng / mL, less than 4.9 ng / mL, less than 5 ng / mL, less than 5.1 ng / mL, less than 5.2 ng / mL, less than 5.3 ng / mL, less than 5.4 ng / mL, less than 5.5 ng / mL, less than 5.6 ng / mL, less than 5.7 ng / mL, less than 5.8 ng / mL, or less than 5.9 ng / mL. max ) is provided to the subject in an amount and / or formulation that does not result in

[0212] In some embodiments, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is 0.005 ng / mL or less, 0.01 ng / mL or less, 0.02 ng / mL or less, 0.03 ng / mL or less, 0.04 ng / mL or less, 0.05 ng / mL or less, 0.06 ng / mL or less, 0.07 ng / mL or less, 0.08 ng / mL or less, 0.09 ng / mL or less, 0.1 ng / mL or less, 0.11 ng / mL or less, 0.12 ng / mL or less, 0.15 ng / mL or less, 0.17 ng / mL or less Bottom, 0.2ng / mL or less, 0.23ng / mL or less, 0.25ng / mL or less, 0.28ng / mL or less, 0.3ng / mL or less, 0.33ng / mL or less, 0.35ng / mL or less, 0.37ng / mL or less, 0.4ng / mL or less, 0.43ng / mL or less, 0.45n g / mL or less, 0.47ng / mL or less, 0.5ng / mL or less, 0.53ng / mL or less, 0.55ng / mL or less, 0.57ng / mL or less, 0.6ng / mL or less, 0.63ng / mL or less, 0.65ng / mL or less, 0.67ng / mL or less, 0.7ng / mL or less, 0.73ng / mL or less, 0.75ng / mL or less, 0.78ng / mL or less, 0.8ng / mL or less, 0.83ng / mL or less, 0.85ng / mL or less, 0.87ng / mL or less, 0.9ng / mL or less, 0.95ng / mL or less, 1ng / mL or less, 1.1ng / mL or less Bottom, 1.2ng / mL or less, 1.3ng / mL or less, 1.4ng / mL or less, 1.5ng / mL or less, 1.6ng / mL or less, 1.7ng / mL or less, 1.8ng / mL or less, 1.9ng / mL or less, 2ng / mL or less, 2.1ng / mL or less, 2.2ng / mL or less, 2.3 ng / mL or less, 2.4ng / mL or less, 2.5ng / mL or less, 2.6ng / mL or less, 2.7ng / mL or less, 2.8ng / mL or less, 2.9ng / mL or less, 3ng / mL or less, 3.1ng / mL or less, 3.2ng / mL or less, 3.3ng / mL or less, 3.4ng / mL 3.5ng / mL or less, 3.6ng / mL or less, 3.7ng / mL or less, 3.8ng / mL or less, 3.9ng / mL or less, 4ng / mL or less, 4.1ng / mL or less, 4.2ng / mL or less, 4.3ng / mL or less, 4.4ng / mL or less, 4.5ng / mL or less, 4.a maximum plasma concentration (C) of the 5HT receptor agonist, a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., an active form thereof) of 6 ng / mL or less, 4.7 ng / mL or less, 4.8 ng / mL or less, 4.9 ng / mL or less, 5 ng / mL or less, 5.1 ng / mL or less, 5.2 ng / mL or less, 5.3 ng / mL or less, 5.4 ng / mL or less, 5.5 ng / mL or less, 5.6 ng / mL or less, 5.7 ng / mL or less, 5.8 ng / mL or less, or 6 ng / mL or less. max ) is provided to the subject in an amount and / or formulation that does not result in

[0213] In some embodiments, the pharmaceutical composition is an oral, buccal, nasal, or inhaled formulation. In some embodiments, the pharmaceutical composition is in the form of a spray, aerosol, mist, mist, ointment, cream, gel, paste, salve, solution, suspension, tincture, patch, and atomized vapor.

[0214] Treatment regimen In some embodiments, any pharmaceutical composition, formulation, or 5HT receptor agonist drug disclosed herein is administered for therapeutic use.In some embodiments, the pharmaceutical composition, formulation, or 5HT receptor agonist drug is administered once a day, twice a day, three times a day, or more.In some embodiments, the pharmaceutical composition, formulation, or 5HT receptor agonist drug is administered daily, every day, every other day, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month, or more.In some embodiments, the pharmaceutical composition, formulation, or 5HT receptor agonist drug is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years, or more.

[0215] In some embodiments, one or more pharmaceutical compositions are administered simultaneously, sequentially, or at regular intervals. In some embodiments, one or more pharmaceutical compositions are administered simultaneously. Optionally, one or more pharmaceutical compositions are administered sequentially. In a further example, one or more pharmaceutical compositions are administered at regular intervals (e.g., a first pharmaceutical composition is administered on the same day, followed by at least one, two, three, four, five, or more days before administering at least a second pharmaceutical composition).

[0216] In some embodiments, two or more different pharmaceutical compositions are co-administered.In some instances, two or more different pharmaceutical compositions are co-administered simultaneously.In some cases, two or more different pharmaceutical compositions are co-administered consecutively without any gap between administrations.In other cases, two or more different pharmaceutical compositions are co-administered consecutively with about 0.5 hours, 1 hour, 2 hours, 3 hours, 12 hours, 1 day, 2 days or more gap between administrations.

[0217] In some embodiments, the amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the identity (e.g., body weight) of the subject or host requiring treatment, but will nevertheless be routinely determined in a manner known to those of skill in the art according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, and the subject or host being treated. In some instances, the desired dosage is conveniently presented as a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, e.g., as two, three, four, or more sub-doses per day.

[0218] The foregoing ranges are suggestive only, and given the large number of variables involved in any particular treatment regimen, substantial deviations from these recommendations are not uncommon. Such dosages will vary depending on many variables, including, but not limited to, the activity of the compound being used, the disease or condition being treated, the mode of administration, the requirements of the particular subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0219] Kits / Products In some embodiments herein, kits and products are provided for use with one or more pharmaceutical compositions, formulations, and / or dosage forms of 5HT receptor agonists or their pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs disclosed herein.Such kits include a carrier, package, or container that is partitioned to contain one or more containers, such as vials or tubes, each of which contains one of the separate elements used in the methods disclosed herein.Suitable containers include, for example, bottles, vials, syringes, and test tubes.In other embodiments, the container is made of various materials, such as glass or plastic.

[0220] The products provided herein include packaging materials. Examples of packaging materials for pharmaceutical products include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material appropriate for the selected formulation and intended mode of administration and treatment.

[0221] For example, the container contains a composition of a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof disclosed herein. Such kits optionally include identifying statements or labels or instructions for use in the methods disclosed herein.

[0222] The kit typically includes a label and / or instructions listing the contents, as well as a package insert with instructions for use. A set of instructions is also typically included.

[0223] In one embodiment, the label is on or associated with the container. In one embodiment, a label is attached to a container when letters, numbers, or other characters forming the label are affixed, molded, or engraved into the container itself. When present in a receptacle or carrier that also holds the container, the label is associated with the container, for example, as a package insert. In one embodiment, the label is used to indicate that the contents are intended for use in a particular therapeutic application. The label further provides instructions for using the contents, for example, in the methods disclosed herein.

[0224] In some embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms comprising a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof. The pack may contain, for example, metal or plastic foil, such as a blister pack. In some embodiments, the pack comprises a pharmaceutical composition described herein and a second agent. In some embodiments, the pharmaceutical composition is provided in a pack or dispenser device containing one or more unit dosage forms comprising a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof and one or more unit dosage forms comprising a second agent. In some embodiments, the second agent is a placebo. In some embodiments, the second agent is a therapeutic agent. In some embodiments, the pack is configured to aid patient compliance regarding which agent should be taken at what time and / or on what day. In some embodiments, the pack or dispenser device is accompanied by instructions for administration. In another embodiment, the pack or dispenser also carries a notice attached to the container in a format prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals, which notice reflects the government agency's approval of the drug form for human or animal use. Such notice is, for example, the label approved by the U.S. Food and Drug Administration for prescription drugs or approved product inserts. In one embodiment, the composition comprising a 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug is also prepared in a suitable container and labeled for the treatment of an indicated condition.

[0225] definition 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 the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit the scope of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is open-ended.

[0226] The section headings used herein are for organizational purposes only and should not be construed as limiting the specific inventive subject matter disclosed.

[0227] As used herein, the terms "individual," "subject," and "patient" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. None of the terms are limited to situations characterized by the supervision (e.g., full-time or intermittent) of a health care professional (e.g., a physician, registered nurse, bedside nurse, physician assistant, nursing assistant, or hospice worker).

[0228] As used herein, ranges and amounts can be expressed as "about" a particular value or range. "About" includes the exact amount. Thus, "about 5 μL" means "about 5 μL" and "5 μL." In general, the term "about" includes amounts that are expected to be within experimental error.

[0229] The terms "controlled-release dosage form" and "controlled-release layer" are used interchangeably and are defined as those in which the drug release characteristics over time and / or location are selected to achieve therapeutic or convenience objectives not achieved by conventional immediate-release dosage forms. The rate at which the active agent is released from the controlled-release layer or dosage form is controlled by the characteristics of the dosage form and / or by physiological or environmental conditions used in combination rather than alone. Controlled-release dosage forms are used to maintain drug plasma concentrations within a therapeutic window. In one embodiment, the controlled-release dosage form provides a steady-state plasma C max / C min The therapeutically effective amount of the active agent is administered once a day so that the ratio is less than the therapeutic index, and the drug concentration is maintained at a constant level effective to provide therapeutic benefit over a period of time (e.g., 24 hours). In some embodiments, the controlled-release dosage form maintains a nearly constant or gradually decreasing drug release rate so that the plasma concentration remains nearly constant over time. In some embodiments, the controlled-release dosage form is designed to rapidly increase the plasma concentration of the drug, which remains nearly constant within the therapeutic range of the drug over a period of time (e.g., 24 hours). Alternatively, in some other embodiments, the controlled-release dosage form is designed to rapidly increase the plasma concentration of the drug, and the plasma concentration does not remain constant, but decreases at a rate such that the plasma concentration remains within the therapeutic range over a period of time (e.g., 24 hours).

[0230] The term "controlled-release matrix" refers to a polymeric matrix capable of delivering a bioactive agent at a controlled rate over a period of time. While there may be an initial burst phase, the overall release kinetics of the bioactive agent from this matrix is ​​generally linear, such that a relatively constant supply of bioactive agent is released over a desired period of time. This period may vary from a few hours to several days, depending on the bioactive agent and its intended use. Generally, it is preferred that the percentage of bioactive agent released from the controlled matrix over the treatment period be relatively high (e.g., at least about 50%, at least about 75%, at least about 90%, or at least about 95%) to avoid consumption of unreleased bioactive agent.

[0231] The term "immediate release" layer or dosage form refers to the release of an active agent almost immediately after administration. For example, immediate release includes, but is not limited to, nearly complete dissolution within about 1 hour upon contact with gastric fluid. The immediate release component may also be referred to as immediate release. When used in connection with the dissolution profile discussed herein, the term "immediate release" refers to the portion of the dosage form disclosed herein that delivers the active agent over a period of less than 1 hour.

[0232] As used herein, the terms "coating composition," "coat composition," "coating solution," "coat solution," "coat suspension," and "coat suspension" are used interchangeably and are defined to mean a mixture of excipients used to create a controlled-release coating. The coating composition is applied to a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof to form an intermediate coating, which, upon curing, forms the controlled-release coating.

[0233] The term "effective amount," "pharmacologically effective amount," or "therapeutically effective amount" refers to a non-toxic but sufficient amount of an agent to produce a desired biological, therapeutic, and / or preventative result. This result may be the reduction and / or alleviation of signs, symptoms, or causes of a disease, or other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of the 5HT receptor agonist disclosed herein or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug itself, or a composition comprising the 5HT receptor agonist disclosed herein or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug, required to produce a clinically significant reduction in a disease. The appropriate effective amount in any individual case may be determined by one skilled in the art using routine experimentation.

[0234] In some instances, the term "low dose" herein refers to an amount of a therapeutic agent (e.g., a 5HT receptor agonist or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof) that is sufficient to produce a desired biological, therapeutic, and / or prophylactic result, but not so much as to induce undesirable effects (e.g., hallucinatory experiences, perturbations in the user's sense of reality or perception, etc.).

[0235] The term "mucoadhesive" refers to an agent that adheres to a mucosa. A mucosa is composed of one or more layers of epithelial cells overlying a layer of loose connective tissue. Examples of mucosa include, but are not limited to, lingual mucosa, bronchial mucosa, endometrium, esophageal mucosa, gastric mucosa, intestinal mucosa, nasal mucosa, olfactory mucosa, oral mucosa, penile mucosa, vaginal mucosa, and anal mucosa.

[0236] The term "transmucosal administration" refers to a route of administration in which a drug diffuses through a mucous membrane. This administration may refer to inhalation, nasal, sublingual, vaginal, rectal, or ocular routes.

[0237] The term "5HT receptor agonist drug" refers to a 5HT receptor agonist as a free base, or a derivative or analog thereof. This term includes salts, solvates, metabolites, prodrugs, isomers, tautomers, isotopic derivatives, etc. of 5HT receptor agonists. In some embodiments, the derivatives, analogs, salts, solvates, metabolites, prodrugs, isomers, tautomers, isotopic derivatives, etc. are pharmaceutically acceptable derivatives, analogs, salts, solvates, metabolites, prodrugs, isomers, tautomers, isotopic derivatives, etc. of 5HT receptor agonists.

[0238] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is contained.

[0239] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or, in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation (Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D.Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002). Pharmaceutical salts are generally more soluble than non-ionic species and dissolve rapidly in gastric and intestinal fluids, making them useful in solid dosage forms. Furthermore, their solubility is often affected by pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules may be in equilibrium with their neutral forms, thereby modulating their passage through biological membranes.

[0240] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to obtain a "pharmaceutically acceptable acid addition salt." In some embodiments, the compounds described herein (i.e., in free base form) are basic and are reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, metaphosphoric acid, nitric acid, phosphoric acid, and sulfuric acid. Organic acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and gluconic acid (D). , glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, monomethyl fumarate, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0241] In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salts.

[0242] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to obtain a "pharmaceutically acceptable base addition salt." In some embodiments, the compounds described herein are acidic and react with a base. In such situations, the acidic protons of the compounds described herein are exchanged with metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein coordinate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as, but not limited to, arginine and lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0243] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms, i.e., solvates. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and are formed during the process of separating or purifying a compound with a pharmaceutically acceptable solvent, such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the process described herein. In addition, the compounds provided herein may exist in both solvated and unsolvated forms.

[0244] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of said compounds that possess the same type of activity.

[0245] In some embodiments, moieties on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic rings to metabolic reactions include, but are not limited to, halogen, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0246] In another embodiment, the compounds described herein are isotopically (e.g., with a radioisotope) or by other means, including, but not limited to, with a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0247] The compounds described herein include isotopically labeled compounds, which are identical to those listed in the various formulas and structures presented herein, except that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 In one embodiment, the isotopes of the isotopically labeled compounds described herein, e.g., 3 H and 14Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium can confer a type of therapeutic advantage due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein are substituted with deuterium.

[0248] In some embodiments, the compounds described herein contain one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein also include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0249] If desired, individual stereoisomers can be obtained by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In certain embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is achieved using covalent diastereomeric derivatives of the compounds described herein. In other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is achieved by chromatography, or by formation of diastereomeric salts and separation by recrystallization, chromatography, or a combination thereof (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981). In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0250] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. For example, a prodrug may be orally bioavailable, whereas the parent drug is not. A prodrug may also be a substrate for a transporter. Additionally, or alternatively, a prodrug has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the prodrug is designed to increase effective water solubility. Non-limiting examples of prodrugs include the compounds described herein, which are administered as esters ("prodrugs") that are subsequently metabolically hydrolyzed to yield the active entity. Another example of a prodrug is a short peptide (polyamino acid) bonded to an acid group, which is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, the prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0251] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, "Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.," Academic, 1985, vol. 42, pp. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38. each of which is incorporated herein by reference. In some embodiments, the hydroxyl group of the compounds disclosed herein is used to form a prodrug, where the hydroxyl group is incorporated into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, or the like. In some embodiments, the hydroxyl group in the compounds disclosed herein is a prodrug, where the hydroxyl is subsequently metabolized in vivo to provide a carboxylic acid group. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug), where the ester or amide is subsequently metabolized in vivo to provide a carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs.

[0252] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo as described herein to produce a compound described herein, are included within the scope of the claims. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0253] In additional or further embodiments, the compounds described herein are metabolized after administration to an organism to produce metabolic products that are subsequently used to provide a desired effect, including a desired therapeutic effect.

[0254] A "metabolite" of a compound disclosed herein is a derivative of that compound formed upon metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed upon metabolism of the compound. As used herein, the term "metabolized" refers to the totality of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) by which a particular substance is transformed by an organism. Thus, enzymes may produce specific structural changes to a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0255] A compound is "dissolved" when it is "in solution," but does not spontaneously come out of solution to form a separate phase. To be dissolved, a compound does not need to be completely separated at the molecular level, but must remain in solution to be effective in treating a disease or disorder. A dissolved compound may exist in micellar, emulsified, or liposomal form. "Solubility" generally refers to the amount of compound dissolved in a solvent. Suitable solvents include aqueous and non-aqueous solvents.

[0256] "Sparingly soluble" means that only a small amount of the compound is soluble in the solvent. Sparingly soluble is not an absolute term, but depends on the amount of compound required for effective treatment of a disease or disorder. A compound is sparingly soluble if the solubility is less than desired for effective treatment of a disease or disorder.

[0257] "Enhanced solubility" means a higher solubility than the 5HT receptor agonist or its pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug alone. Enhanced solubility in water can be useful because many body fluids, such as blood, are water-based (aqueous), and drugs with high water solubility may have higher bioavailability. Although the exact solubility of a compound in pure water is not the same as in an aqueous solution such as blood, the solubility of a composition in pure water is often a good indicator of its solubility in other aqueous solutions.

[0258] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. The compounds presented herein may exist as tautomers. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by switching of a single bond and an adjacent double bond. A chemical equilibrium of tautomers exists for bonding configurations where tautomerization can occur. All tautomeric forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on various factors, including temperature, solvent, and pH. Some examples of tautomer interconversions include the following:

[0259] [ka]

[0260] As used herein, the term "flavoring agent" refers to taste receptor blockers, compounds that mask the chalkiness, harshness, drying, and / or astringency characteristics of the active compound, compounds that reduce throat catch, as well as compounds that impart flavor.

[0261] The term "enhancer" as used herein refers to agents that act to increase membrane permeability and / or increase the solubility of a particular active. These two issues can be crucial to the properties of a formulation. Examples include: Chelating agents: EDTA, citric acid, sodium salicylate, methoxysalicylate (see Senel & Hincal: JCR 72 2001 133-144; Malhalingam et al.: AAPS Pharmascitech 2007(8)vol 3 Article 55). Surfactants: sodium lauryl sulfate, polyoxyethylene, POE-9-lauryl ether, POE-20-cetyl ether, benzalkonium chloride, 23-lauryl ether, cetylpyridium chloride, cetyltrimethylammonium bromide, amphoteric surfactants, and cationic surfactants. Membrane disrupting compounds such as powdered alcohols (e.g., menthol and ethanol) and compounds such as lipophilic enhancers that are safe for oral administration (Nicolazzo, Reid and Finnin J Pharmaceutical Sciences Vol 93, No 8 Aug. 2004 2054-2063). Fatty acids such as oleic acid, capric acid, lauric acid, lauric acid / propylene glycol, methyl oleate, lysophosphatidylcholine, phosphatidylcholine (Sudhakar et al. JCR 114 (2006) 15-40), and oleic acid co-administered with PEG 200 (Lee and Kellaway Int J Pharmaceutics 204 (2000) 137-144). Lysalbinic acid (Starokadomdkyy & Dubey Int J Pharmaceutics 308(2006)149-154). Non-surfactants such as unsaturated cyclic ureas.Others: glycosaminoglycans (GAGs), aprotinin, azone, cyclodextrin, dextran sulfate, curcumin, menthol, polysorbate 80, sulfoxide, and various alkyl glycosides; chitosan-4-thiobutyramide, chitosan-4-thiobutyramide / GSH, chitosan-cysteine, chitosan-(85% N-deacetylated), poly(acrylic acid)-homocysteine, polycarbophil-cysteine, polycarbophil-cysteine / GSH, chitosan-4-thioethylamide / GSH, chitosan-4-thioglycolic acid; and hyaluronic acid of three molecular weights (Sandri et al.: J Pharmacy and Pharmacology). 2004, 56: 1083-1090); bile salts (dihydroxy and trihydroxy), sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate (Artusi et al.: Int J Pharmaceutics 250 (2003) 203-213); and propanolol hydrochloride (Akbari et al.: Il Farmaco 59 (2004) 155-161).

[0262] As used herein, the term "complexing agent" includes agents in the group consisting of cyclodextrin, calcium acetate, poly(methyl vinyl ether / maleic anhydride).

[0263] The term "treating" and grammatical equivalents as used herein include achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Similarly, a therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that an improvement in the patient is observed, even though the patient may still be affected by the underlying disease. For prophylactic benefit, the method may be performed or the composition administered to a patient at risk of developing a disease or who reports one or more physiological symptoms of such a disease, even if a diagnosis of the disease has not been made.

[0264] While high drug solubility is generally desirable, those skilled in the art will recognize that there are other considerations in formulating pharmaceutical compositions, such as viscosity, stability, and potential toxicity, which may result in a less soluble composition being more desirable for a particular treatment or delivery method, as long as the amount of available drug is sufficient for the application. The pharmaceutical compositions disclosed herein allow for the optimization of these factors. [Example]

[0265] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. [Example]

[0266] Oral formulation of 5HT receptor agonist A psilocybin pharmaceutical composition is prepared as follows: 150 g of psilocybin is mixed with 30.4 g of pregelatinized starch, 23.8 g of microcrystalline cellulose, 6.1 g of polyvinylpyrrolidone, and 6.1 g of sodium starch glycolate. The mixture is blended for approximately 10 minutes. The resulting pharmaceutical composition is formulated into an appropriate dosage form. [Example]

[0267] Controlled-Release Dosage Forms A controlled-release dosage form of psilocybin 25 mg tablets is prepared as follows.

[0268] [Table 9]

[0269] All of the psilocybin and silicon dioxide are transferred to a V-blender and blended for approximately 10 minutes. The blended material is then discharged into a fluid bed granulator and granulated in the presence of an aqueous polyvinyl alcohol solution.

[0270] After drying, the granules are sized through a 0.40 mm screen. The screened granules are then transferred to a V-blender and blended with the atomized glyceryl behenate for approximately 10 minutes. Finally, magnesium stearate is added and blended for approximately 10 more minutes.

[0271] The psilocybin tablet cores were then coated with a controlled-release coating formulation. The coating process was carried out in an apparatus equipped with a coating chamber. The bottom screen had a mesh size of 200 μm and the spray nozzle had a size of 1 mm.

[0272] The coated tablets are allowed to dry for approximately 30 minutes. After coating, the tablets are placed in an oven and cured at 62±2°C for approximately 2 hours.

[0273] The psilocybin tablet cores are then coated with a coating formulation to increase their weight to 14% w / w or 16% w / w of the tablet core, and cured in an oven at about 60 to about 75°C for about 2 to about 15 hours. The controlled-release layer-coated psilocybin cores are then further coated with an immediate-release layer containing 15 mg of bromethazine hydrochloride. [Example]

[0274] Psilocybin controlled-release matrix A controlled-release matrix containing psilocybin is prepared as follows: A mixture of 25% psilocybin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof (e.g., psilocybin HCl), is combined with a polymeric matrix, such as PLGA polymer, and melt-extruded using a twin-screw extruder (available from American LEISTRITZ Extruder Corp. USA, Somerville, NJ 08876). Psilocybin is continuously fed from the twin-screw extruder into a loss-in-weight feeder (available from K-Iron International, Inc., Pitman, NJ 08071). The polymeric matrix is ​​fed in a similar manner. The ratio of bioactive agent to polymeric matrix is ​​adjusted by the relative mass flow rates of the bioactive agent from the first feeder and the polymeric matrix from the second feeder. The feeders and extruder are purged with dry air and nitrogen gas to maintain low humidity. The polymeric matrix is ​​melted in the extruder, which is operated at a temperature of 120°C. The psilocybin is not melted, but is mixed within the molten, fluid polymer matrix. An extruder forces or extrudes the mixed bioactive agent and polymer matrix through a rectangular opening or die, forming the material into an extrudate about 5 to about 10 mm wide and about 50 to about 250 μm thick. After the extrudate cools, it is cut into strips of the desired length and packaged. The strips are individually placed into sterile pouches, such as foil-foil pouches (available from Oliver Products, 445 Sixth Street, NW, Grand Rapids, Mich. 49504 USA), and sealed. [Example]

[0275] Transmucosal Administration of Psilocybin Compositions A pharmaceutical composition for nasal transmucosal administration containing psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, or prodrug thereof is formulated into a suitable form and administered by spray as an external agent.

[0276] To prepare the spray, psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug (e.g., psilocybin HCl) is dissolved or suspended in a solvent (e.g., water, ethylene glycol, or glycerin). The concentration of psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug in the solution is about 5 mg / mL to about 50 mg / mL. A mucoadhesive (e.g., Carbopol 974P) is added to the resulting solution. The concentration of the mucoadhesive in the resulting mixture is about 1 mg / mL to about 25 mg / mL. The resulting pharmaceutical solution is filled into a container equipped with a specific spray device (valve) with a low-viscosity propellant. For this purpose, pressure is used to spray the pharmaceutical solution in the form of a smog. The dosage of pharmaceutical compositions containing psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof is 0.1 mg to 10 mg / kg / day, depending on the composition used and / or the patient's condition. [Example]

[0277] Preparation of liposomal psilocybin formulations

[0278] [Table 10]

[0279] Soy lecithin, tetraglycol, and dimethyl isosorbide are heated to approximately 70-75°C. Dissolve psilocybin, cholesterol, and butylhydroxytoluene in the heated mixture. Stir until completely dissolved. Heat approximately one-third of the water in a separate tube to 80-95°C. Dissolve the preservatives methylparaben and propylparaben in the heated water with stirring. After the solution has cooled to approximately 25°C, add edetate disodium, sodium chloride, sodium hydroxide, and citric acid. Add the remaining water and stir to obtain a complete solution. Transfer the organic mixture to the aqueous mixture using a vacuum while homogenizing the combination in a high-shear mixer until a homogenous product is observed. Add hydroxypropyl methylcellulose to the biphasic mixture using a vacuum while homogenizing in a mixer. The homogenizer is a Silverson high-shear mixer operating at approximately 3000 rpm. Single bilayer liposomes are formed. The white lipogel cream is ready for use. [Example]

[0280] Preparation of psilocybin nanoparticle formulations 750 mg (theoretical 15 mg / ml) of a diblock copolymer consisting of a 30 kD poly(d,l-lactic acid), a 2 kD PEG (PLA-PEG), and 250 mg (theoretical 5 mg / ml) of psilocybin were mixed in 20 ml of ethyl acetate (Solution A). 175 mg of lecithin E80 and 90 mg of sodium oleate were dispersed in 50 ml of a 5% w / v glucose solution (Solution B). Solution A was emulsified in Solution B using an Ultra-Turrax stirrer, and the pre-emulsion was then introduced into a Microfluidizer 110 S.RTM. homogenizer at 10°C for approximately 10 minutes. The recovered emulsion volume was approximately 70 ml (70 g). The ethyl acetate was removed using a rotary evaporator under reduced pressure (100 mm of mercury) to reduce the suspension volume to approximately 45 ml (45 g). [Example]

[0281] Preparation of psilocybin gel formulation

[0282] [Table 11]

[0283] Five milliliters of acetic acid solution is titrated to a pH of approximately 4.0. Chitosan is added to bring the pH to approximately 5.5. Psilocybin is then dissolved in the chitosan solution. This solution is sterilized by filtration. A 5-ml solution of disodium glycerophosphate in water is also prepared and sterilized. The two solutions are mixed at 37°C for two hours to form the desired gel. [Example]

[0284] Preparation of gel / liposomal psilocybin formulations

[0285] [Table 12]

[0286] Liposomes were prepared in the presence of psilocybin by reverse-phase evaporation. Lipids in chloroform or chloroform-methanol (2:1, v / v) were deposited on the side of a tube by evaporation of the organic solvent. The lipid film was redissolved in diethyl ether, and an aqueous phase containing 20 mM Hepes and 144 mM NaCl (pH 7.4, 300 mOsm / kg) was added. The mixture was sonicated to obtain a homogeneous emulsion, and the organic solvent was removed under vacuum. The preparation was extruded to obtain the desired liposome size, and free components were removed by size-exclusion chromatography using a Sephadex G-50 column (Amersham Pharmacia Biotech, Uppsala, Sweden).

[0287] To prepare the chitosan-glycerophosphate formulation, titrate a 5 ml solution of acetic acid to a pH of approximately 4.0. Chitosan is added to bring the pH to approximately 5.5. This solution is sterilized by filtration. A 5 ml solution of disodium glycerophosphate in water is also prepared and sterilized. The two solutions are mixed at 37°C for 2 hours to form the desired gel. The chitosan-glycerophosphate solution is gently mixed with the liposomes at room temperature. [Example]

[0288] Clinical trials to establish the maximum dose of psilocybin that does not result in hallucinogenic events Adult individuals (e.g., 25-50 years old) will be administered various doses of a 5HT receptor agonist (e.g., psilocybin) to establish the dose at which the individual produces a hallucinogenic event in the primary endpoint. The study will also administer the 5HT receptor agonist at various frequencies (e.g., daily, every other day, twice a week, once a week, once every two weeks, etc.) to determine the most effective dosing regimen that does not produce a hallucinogenic event in the endpoint. This dose and dosing regimen will be used in the clinical trials described below. Separate cohorts of individuals will be administered different dosage forms. The first cohort receives an immediate-release 5HT receptor agonist, the second cohort receives a controlled-release 5HT receptor agonist, the third cohort receives a dosage form (or combination) comprising an immediate-release component (e.g., coating) and a controlled-release component (core), each containing a 5HT receptor agonist, and the fourth cohort receives a dosage form similar to the third cohort except that the controlled-release component further comprises an additional agent (e.g., an anti-inflammatory agent). [Example]

[0289] Effects of 5HT receptor agonists on major depressive disorder The depression-reducing activity of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) will be investigated in a 12-week, double-blind, placebo-controlled, parallel-group, randomized study in depressed adult volunteers.

[0290] The study will be conducted in human subjects in accordance with the current version of the Declaration of Helsinki and the ICH Note for Guidance on Good Clinical Practice.

[0291] The inclusion criteria for human subjects were: patients with depression, age 18–55 years, and a body mass index (BMI) of 18–30 kg / m 2 Individuals must be able to provide written informed consent, have not smoked for at least 6 months, and have not taken any medications in the 2 weeks prior to screening, except for occasional acetaminophen (2 months for enzyme-inducing medications). Individuals will be confined to the clinical facility from the day before dosing until 72 hours after their last dose on Day 17, and will return to the facility for a follow-up visit on Day 21 ± 1.

[0292] Evaluation items The primary efficacy endpoints were: a. Individualized assessment of depression using the Montgomery-Asberg Depression Rating Scale Secondary efficacy endpoints were as follows: a. Individualized assessment of mood symptom change using GRID-Hamilton b. Recorded hallucinogenic experiences

[0293] Treatment regimen Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0294] Effects of 5HT receptor agonists on obsessive-compulsive disorder (OCD) The activity of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) in reducing OCD symptoms will be investigated in a 2-week, double-blind, placebo-controlled, parallel-group, randomized study in adult volunteers diagnosed with OCD.

[0295] The study will be conducted in human subjects in accordance with the current version of the Declaration of Helsinki and the ICH Note for Guidance on Good Clinical Practice.

[0296] The inclusion criteria for human subjects were a formal clinical diagnosis of depression, age 20–60 years, and a body mass index (BMI) of 18–30 kg / m 2 Individuals must be within 12 months of receiving treatment, provide written consent, and have not received any medications in the 2 weeks prior to screening (2 months for enzyme-inducing medications) except for occasional acetaminophen. Individuals will be confined to the clinical facility from the day before dosing until 72 hours after their last dose on Day 17, and will return to the facility for a follow-up visit on Day 21 ± 1.

[0297] Evaluation items The primary efficacy endpoints were: Individualized assessment of OCD symptoms measured with the Acute Yale-Brown Obsessive-Compulsive Scale (A-YBOCS) b.Effects on the severity of obsessive-compulsive disorder symptoms Secondary efficacy endpoints were as follows: a. Individualized assessment of mood symptom change using GRID-Hamilton b. Recorded hallucinogenic experiences

[0298] Treatment regimen Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0299] Facilitating smoking cessation with 5HT receptor agonists The ability of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, or twice weekly) to aid smoking cessation (or reduce nicotine dependence or as nicotine replacement therapy) will be investigated in an 8-week, double-blind, placebo-controlled, parallel-group, randomized trial in adult volunteers who smoke an average of at least 10 cigarettes daily.

[0300] The study will be conducted in accordance with the current version of the Declaration of Helsinki and the ICH Notes to Guidance on Good Clinical Practice.

[0301] Inclusion criteria were male and female individuals who smoked an average of at least 10 cigarettes daily, aged 20–60 years, and had a body mass index (BMI) of 18–30 kg / m 2 Subjects must have received no medication for 2 weeks prior to screening (2 months for enzyme-inducing drugs), be able to provide written consent, and be off any medication except for occasional acetaminophen.

[0302] Evaluation items The primary efficacy endpoints were: a. Number of days until first cigarette b. Number of days without smoking c. Number of cigarettes per day Secondary efficacy endpoints were as follows: a. Frequency and severity of nicotine cravings b. Recorded hallucinogenic experiences Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0303] 5HT receptor agonists promote reduction of alcohol dependence The ability of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) to reduce alcohol dependence will be investigated in a 3-month, double-blind, placebo-controlled, randomized trial in adult men consuming at least 5 units of alcohol daily.

[0304] The study will be conducted in accordance with the current version of the Declaration of Helsinki and the ICH Notes to Guidance on Good Clinical Practice.

[0305] Inclusion criteria were adult males consuming at least 5 units of alcohol daily (1 unit of alcohol is 1 measurement of distilled spirits (ABV 37.5%), 1 / 2 pint or more of average strength (4%) beer, or 1 glass (85 mL) of average strength (12%) wine), aged 25–65 years, able to provide written consent, and free from any medications for 2 weeks prior to screening (2 months for enzyme-inducing medications) except for occasional acetaminophen.

[0306] Evaluation items The primary efficacy endpoints were: Number of days without consuming alcohol b. Number of alcoholic drinks consumed per day c. Number of days of heavy drinking (defined as more than 4 units per day) Secondary efficacy endpoints were as follows: a. The frequency and severity of alcohol cravings b. Individual assessment of mood symptom change using GRID-Hamilton c. Recorded hallucinogenic experiences

[0307] Treatment regimen Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered every other day Group 2 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 3 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 4 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered once a week Group 10 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 11 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 12 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 13 (n = 5): Placebo administered once every 3 weeks Group 14 (n=10): Administered immediate-release 5HT receptor agonist Group 15 (n=10): Administered controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0308] 5HT receptor agonists for the treatment of migraine The ability of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) to treat migraine will be investigated in a four-month, double-blind, placebo-controlled, randomized trial in adults who experience an average of at least one migraine headache per month.

[0309] The study will be conducted in human subjects in accordance with the current version of the Declaration of Helsinki and the ICH Note for Guidance on Good Clinical Practice.

[0310] The inclusion criteria were adult males, aged 20-50 years, experiencing at least one migraine headache per month on average, and a body mass index (BMI) of 18-30 kg / m 2 Subjects must be able to provide written consent within the past two weeks and have not received any medication for two weeks prior to screening (two months for enzyme-inducing drugs).

[0311] Evaluation items The primary efficacy endpoints were: a. Rapid change in pain intensity during migraine attacks b. Rapid change in nausea / vomiting c. Sudden change in photophobia d. Rapid change in phonophobia e. Time to first migraine attack f. Change in duration of migraine attacks g. Change in migraine attack frequency

[0312] Treatment regimen Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0313] The effect of 5HT receptor agonists on the treatment of opioid use The efficacy of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) in treating opioid-dependent individuals will be investigated in a 16-week, double-blind, placebo-controlled, parallel-group, randomized study in opioid-dependent adults.

[0314] The study will be conducted in human subjects in accordance with the current version of the Declaration of Helsinki and the ICH Note for Guidance on Good Clinical Practice.

[0315] Inclusion criteria were male and female individuals actively using one or more opioids (e.g., prescription opioids such as oxycodone, hydrocodone, fentanyl, tramadol, or illicit opioids such as heroin), age 18–55 years, and body mass index (BMI) 18–30 kg / m 2 Those who have not smoked for at least six months and who can provide written consent are eligible.

[0316] Evaluation items The primary efficacy endpoints were: Frequency of opioid use (assessed by urine analysis) b. Maximum withdrawal period c. Number of days of withdrawal d. Number of patients retained in the study e. Number of abstinence participants Secondary efficacy endpoints were as follows: a. Frequency and severity of drug cravings g. Change in migraine attack frequency Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0317] 5HT receptor agonists in the treatment of cocaine use disorder (CUD) The efficacy of a 5HT receptor agonist (e.g., psilocybin) administered under four dosing regimens (once daily, every other day, once weekly, and twice weekly) in reducing cocaine use in patients diagnosed with CUD will be investigated in a 16-week, double-blind, placebo-controlled, parallel-group, randomized trial in adults diagnosed with CUD.

[0318] The study will be conducted in human subjects in accordance with the current version of the Declaration of Helsinki and the ICH Note for Guidance on Good Clinical Practice.

[0319] The inclusion criteria for human subjects were a clinical diagnosis of CUD, age 18–65 years, and a body mass index (BMI) of 18–30 kg / m 2 Subjects were required to be able to provide written consent, not smoke for at least 6 months, and not take any medications for 2 weeks (2 months for enzyme-inducing drugs) prior to screening, except for occasional acetaminophen and cocaine.

[0320] Evaluation items The primary efficacy endpoints were: a. Difference in the number of patients exhibiting cocaine withdrawal between the treatment and placebo groups Secondary efficacy endpoints were as follows: b. Recorded hallucinogenic experiences Individuals are randomized into 16 groups. Group 1 (n=5): Placebo administered once a week Group 2 (n=10): Administered an immediate-release 5HT receptor agonist once a week Group 3 (n=10): Administered a controlled-release 5HT receptor agonist once a week Group 4 (n=10): Administered immediate-release + controlled-release 5HT receptor agonist once weekly Group 5 (n=5): Placebo administered twice a week Group 6 (n=10): Administered an immediate-release 5HT receptor agonist twice weekly Group 7 (n=10): Controlled-release 5HT receptor agonist administered twice weekly Group 8 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered twice weekly Group 9 (n=5): Placebo administered every other day Group 10 (n=10): Administered immediate-release 5HT receptor agonist every other day Group 11 (n=10): Controlled-release 5HT receptor agonist administered every other day Group 12 (n=10): Immediate-release + controlled-release 5HT receptor agonist administered every other day Group 13 (n=5): Placebo administered daily Group 14 (n=10): Daily immediate-release 5HT receptor agonist Group 15 (n=10): Daily controlled-release 5HT receptor agonist Group 16 (n=10): Daily immediate-release + controlled-release 5HT receptor agonist In this study, the drug will be provided as a tablet to be taken with water, for example 30 minutes after a standard meal. A matching placebo tablet will be provided. [Example]

[0321] Dose-finding study Psilocybin was tested at doses ranging from 0.03 to 10.0 mg / kg administered subcutaneously (SC). Behavioral symptoms, including wet dog shakes (WDS) and back muscle contractions (BMC), were associated with 5-HT 2A This is characteristic of receptor activity and may result in psychomotor symptoms. While no behavioral symptoms were observed when psilocybin was administered SC at 0.03–0.1 mg / kg, significant behavioral symptoms were observed when psilocybin was administered IP at 0.3 mg / kg or higher. These results suggest that the SC dose range of 0.03–0.1 mg / kg is preferable for investigating the cognitive-enhancing and motivation-enhancing effects of psilocybin (Figure 1). There are parallels between behaviors such as WDS in rats and hallucinations in humans (Behavioral Neurobiology of Psychedelic Drugs, Halberstadt, Adam, Vollenweider, Franz X., Nichols, David E. (Eds.), Springer, 2018, p. 161).

[0322] Compared to the stimulant drug, low doses of psilocybin produced a mild stimulant effect, increasing distance traveled by ~0.3- to 0.4-fold at low doses (Figure 2A), while high doses produced a slight decrease in distance traveled. The stimulant drug significantly increased distance traveled with gradually increasing doses, reflecting direct locomotor stimulant properties not seen with psilocybin.

[0323] Efficacy test In this study, we investigated the effects of psilocybin on motivational and attentional endophenotypes in the progressive ratio (PR) and 5-choice reaction time task (5-CSRTT) tests using SC psilocybin at doses ranging from 0.05 to 0.2 mg / kg. For each test, a group of outbred Long-Evans rats was first tested as a responder group on the PR and 5CSRTT. Each group was then divided into subgroups based on performance tertiles and exposed to various psilocybin doses immediately before retesting. As described below, rats in the lowest tertile subgroup responded differently from rats in the highest tertile.

[0324] The PR test was used to determine how willingly subjects worked for food (i.e., a test of motivation). Based on a lever-press response, a single 45 mg food pellet (i.e., reinforcer) was made available to the test animal. To obtain each successive pellet, the animal was required to make an increasing number of lever presses. Typically, a progression of 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, etc., derived from the following formula was used: ratio=[5 xe (0.2 x reinforver#) -5]

[0325] Hungry test animals did not consider 45 mg of food pellets sufficient, and so were driven to repeatedly press the lever to obtain multiple food pellets. At some point, the animals gave up because the effort to obtain one pellet was deemed meaningless (i.e., they reached a "yield point," at which point they were deemed unable to obtain a food pellet in 20 minutes).

[0326] Psilocybin was administered SC to rats at 0.05, 0.1, and 0.2 mg / kg, and none of these doses was found to produce significant changes in the number of lever presses or yield points (i.e., rewards obtained) when tested across the entire test population of 36 rats.

[0327] Rats were then subclassified into tertiles based on the number of food lever presses at the lowest limit. From the study population of 36 animals, 12 animals were identified as low responders, characterized by low motivation and potentially corresponding to a low-motivation endophenotype representing clinical depression. 12 animals were identified as high responders. A statistically significant difference was observed between high and low responders. Psilocybin administered at 0.05–0.2 mg / kg SC had no effect on responding in the high responder subgroup (Figure 2). However, psilocybin at 0.05 mg / kg increased food responding in the low responder subgroup, whereas a dose of 0.1 mg / kg did not. This demonstrates the motivation-enhancing effects of psilocybin in a population corresponding to a low-motivation endophenotype representing clinical depression.

[0328] The 5CSRTT involves assessing a subject's response to a brief visual stimulus (Higgins, Guy, & Silenieks, Leonardo. (2017). Rodent Test of Attention and Impulsivity: The 5-Choice Serial Reaction Time Task: The 5-Choice Serial Reaction Time Task. 10.1002 / cpph.27). Animals are trained to make a nose-poke response to the stimulus location to collect a food reward. This task allows experimenters to measure animal performance in multiple domains, including: -Note -impulse -persistence -Reaction speed

[0329] A strength of this study is its flexible structure for subject load. - Standard test conditions (0.75 s stimulus duration (SD), 5 s inter-trial interval (ITI), 100 trials) - Multiple short stimulus durations (mSD) (SD between 0.03 and 1 sec) -Fixed length ITI (5 seconds vs. 10 seconds ITI) -Multiple very short ITIs (2-5 seconds ITI) -250 long trials

[0330] SC administration of 0.05 mg / kg psilocybin produced cognitive enhancing effects (measured as % Hits, # Correct / (# Correct + # Error + # Omitted)) when tested in a test population of 24 rats under standard conditions, i.e., a 5CSRTT with a 75-second SD, a 5-second ITI, and 100 trials. * 100) was observed (p=0.05, t-test). * ) indicates statistically significant difference vs. vehicle (Figure 3A). Cognitive enhancement (measured as % hits, # correct / (# correct + # incorrect) *A small, non-significant increase in the variability of the response time (calculated as 100) was observed (Figure 3B). No effects on performance, such as response speed or number of completed trials, were observed. No effects on premature or perseverative responding were observed in this experiment.

[0331] Accuracy (%Correct, #correct / (#correct+#error) * When this population was divided into tertiles according to performance based on the %Correct and %Hit scores, the lowest performance tertile (N = 8) was considered to be inattentive, potentially representing the inattentive endophenotype of depression (Figure 6A). Inattentive rats also scored poorly on %Hit (Figure 6B), and their response speed was slower (Figure 6D). Similar to the PR test, the effects of psilocybin at 0.05 and 0.1 mg / kg on accuracy (%Correct and %Hit) in the 5CSRTT were significantly stronger in inattentive rats compared to the vehicle-treated group (Figures 6C and 6E). Asterisks ( * ) indicates statistically significant difference vs. vehicle. Psilocybin at 0.05 mg / kg also increased response speed in the less attentive cohort compared to the vehicle-treated group (FIG. 6D).

[0332] Premature (PREM) and perseverative (PSV) responses were measured using the 5CSRTT test with a longer duration between stimulus and reward. Increasing the ITI from 5 s (baseline) to 10 s (test condition) increased PREM / PSV responses. SC administration of 0.05 mg / kg psilocybin, tested in a test population of 24 rats, increased PREM and PSV responses (p = 0.05, t-test) under a 10 s ITI (Figure 4A). Low-responders (N = 8) showed significant improvements with both 0.05 and 0.1 mg / kg psilocybin (Figure 4B, p < 0.01, t-test), and this subgroup of rats showed significantly increased premature and perseverative responses compared to the vehicle-treated group. Both PREM and PSV behaviors are examples of executive cognitive functions and similarly involve regions of the prefrontal cortex, namely 5-HT. 2A Requires receptor-rich brain regions.

[0333] At doses that produced no effect in hallucinogenic animals, improvements in outcomes on measures of motivation, attention, accuracy, reaction speed, perseveration, and cognitive engagement were observed in low-performing animals. Improvements in low-performing animals demonstrate the utility of non-hallucinogenic doses of psilocybin in treating behavioral and cognitive disorders involving these behaviors, including, but not limited to, depression, anxiety, apathy, low motivation, attention disorders, impairments in executive function and cognitive engagement, obsessive-compulsive disorder, and neurocognitive disorders. At these same doses, no adverse effects of psilocybin were observed on performance; i.e., there was no evidence of reduced motivation, deficits in motor control, or deficits in attention or reaction speed. The positive effects of low-dose psilocybin appear to be most pronounced in the low-performing subgroup based on three studies. SC administration of psilocybin at 0.05–0.2 mg / kg (PR) and 0.05–0.1 mg / kg (5CSRTT) resulted in one PR (motivation) and two 5CSRTT (attention) trials. Significant improvements were observed in low-performing animals regarding: -Increase in lever presses and yield point in PR test (0.05mg / kg) -%Correct and %Hit in 5CSRTT (0.05 and 0.1 mg / kg) -Increased reaction rate in the 5CSRTT (0.05 mg / kg) -5CSRTT PREM / PSV (0.05 and 0.1 mg / kg) with an ITI of 10 seconds [Example]

[0334] The PK of psilocybin and psilocin in rats was evaluated using psilocybin at 0.05, 0.1, 1, and 10 mg / kg. Psilocybin doses that positively affected behavior in animals with poor performance in the PR and 5CSRTT, i.e., 0.05-0.1 mg / kg, were significantly lower than the corresponding C of psilocin at 0.05 mg / kg. max The C of psilocin at a dose of 0.1 mg / kg was ~7 ± 2 ng / ml at 30 min. max was found to be ~12±3 ng / ml at 30 minutes (Figure 5).

[0335] Details of the plasma concentration studies are shown in Tables 1–8 (psilocybin) and 9–16 (psilocin). Values ​​in italics are below the lower limit of quantitation (BLQ, <1 ng / mL) but were included in the calculations. Values ​​in bold and underlined were considered outliers and omitted from the calculations. Measured dosing solution concentrations were 0.0460, 0.0967, 0.948, and 9.65 mg / mL for 0.05, 0.1, 1, and 10 mg / mL, respectively.

[0336] [Table 13]

[0337] [Table 14]

[0338] [Table 15]

[0339] [Table 16]

[0340] [Table 17]

[0341] [Table 18]

[0342] [Table 19]

[0343] [Table 20]

[0344] [Table 21]

[0345] [Table 22]

[0346] [Table 23]

[0347] [Table 24]

[0348] [Table 25]

[0349] [Table 26]

[0350] [Table 27]

[0351] [Table 28]

[0352] While preferred embodiments have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It will be understood that various alternatives to the embodiments described herein may be utilized in practicing the present disclosure.

[0353] Numbered Embodiments Embodiment 1 is a pharmaceutical composition, the pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; b) a pharmaceutically acceptable excipient; and c) optionally one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; Includes.

[0354] Embodiment 2 is the pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is a low-dose pharmaceutical composition.

[0355] Embodiment 3 is the pharmaceutical composition of embodiment 2, wherein the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount that does not result in adverse side effects, such as a hallucinatory experience.

[0356] Embodiment 4 is a method for treating a rheumatoid arthritis, wherein after administration to an individual, the low-dose pharmaceutical composition provides the individual with a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of less than 6 ng / mL. max 4. The pharmaceutical composition of any one of embodiments 2 or 3, wherein

[0357] In a fifth embodiment, after administration to an individual, the low-dose pharmaceutical composition provides the individual with a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of at least 0.5 ng / mL and less than 6 ng / mL (e.g., about 1 ng / mL to about 5.5 ng / mL, about 2 ng / mL to about 5 ng / mL, etc.). max 5. The pharmaceutical composition of any one of embodiments 1 to 4, wherein

[0358] Embodiment 6 is the pharmaceutical composition of any one of embodiments 1 to 5, wherein the pharmaceutical composition comprises a controlled-release component.

[0359] Embodiment 7 is a method for treating a rheumatoid arthritis, wherein after administration to an individual, the pharmaceutical composition provides the individual with a minimum plasma concentration (C) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of about 0.1 ng / mL. min ) and the minimum plasma concentration (C min ) is determined 2 to 12 hours (or 2 to 24 hours, or 2 to 48 hours, or 2 to 72 hours, etc.) after administration to said individual.

[0360] Embodiment 8 is a method for treating a rheumatoid arthritis (RA) disease, wherein after administration to an individual, the pharmaceutical composition provides the individual with a minimum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of about 0.1 ng / mL to about 0.5 ng / mL. min ) and the minimum plasma concentration (C min ) is determined 2 to 12 hours (or 2 to 24 hours, or 2 to 48 hours, or 2 to 72 hours, etc.) after administration to said individual.

[0361] Embodiment 9 is the pharmaceutical composition of any one of embodiments 1 to 8, wherein the pharmaceutical composition comprises an immediate release component.

[0362] Embodiment 10 is the pharmaceutical composition of any one of embodiments 1 to 9, wherein the pharmaceutical composition is an oral, buccal, nasal, or inhaled formulation.

[0363] Embodiment 11 is the pharmaceutical composition of any one of Embodiments 1 to 10, wherein the pharmaceutically acceptable excipient comprises water, purified water, saline, liposomes, mineral oil, alcohol, or any combination thereof.

[0364] Embodiment 12 is the pharmaceutical composition of any one of Embodiments 1 to 11, wherein the pharmaceutical composition further comprises an effective amount of a vasoconstrictor.

[0365] Embodiment 13 is a pharmaceutical composition of embodiment 12, wherein the vasoconstrictor is epinephrine, phenylephrine, methoxamine, norepinephrine, zolmitriptan, tetrahydrozoline, naphazoline, or a combination thereof.

[0366] Embodiment 14 is the pharmaceutical composition of any one of embodiments 1 to 13, wherein the pharmaceutical composition further comprises an effective amount of a stimulant, antihistamine, antiemetic, antidepressant, anti-inflammatory, growth factor, lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, a 5HT receptor antagonist, or a combination thereof.

[0367] Embodiment 15 is a pharmaceutical composition of any one of embodiments 1 to 14, wherein the pharmaceutical composition is in the form of a spray, aerosol, mist, mist, ointment, cream, gel, paste, salve, solution, suspension, tincture, patch, and atomized vapor.

[0368] Embodiment 16 is the pharmaceutical composition of any one of Embodiments 1 to 15, wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, is present in an amount of about 0.1 mg to about 50 mg (e.g., about 0.1 mg to about 10 mg, or about 0.2 mg to about 5 mg).

[0369] Embodiment 17 is the pharmaceutical composition of any one of Embodiments 1 to 16, wherein the pharmaceutical composition further comprises a controlled release matrix.

[0370] Embodiment 18 is a pharmaceutical composition according to embodiment 17, wherein the maximum plasma concentration is between about 2 ng / ml and 6 ng / ml.

[0371] Embodiment 19 is the pharmaceutical composition of embodiment 17, wherein the maximum plasma concentration is between about 2 ng / ml and about 5 ng / ml.

[0372] Embodiment 20 is a pharmaceutical composition according to embodiment 17, wherein the maximum plasma concentration is between about 4 ng / ml and 6 ng / ml.

[0373] Embodiment 21 is the pharmaceutical composition of embodiment 17, wherein the maximum plasma concentration is between about 2 ng / ml and about 4 ng / ml.

[0374] Embodiment 22 is the pharmaceutical composition of embodiment 17, wherein the maximum plasma concentration is from about 1 ng / ml to about 4 ng / ml.

[0375] Embodiment 23 is the pharmaceutical composition of embodiment 17, wherein the maximum plasma concentration is from about 1 ng / ml to about 4 ng / ml.

[0376] Embodiment 24 is the pharmaceutical composition of embodiment 17, wherein upon oral administration to a subject, the composition has a maximum plasma concentration of about 1 ng / ml or greater.

[0377] Embodiment 25 is a method for determining the minimum plasma concentration (C min 25. The pharmaceutical composition of any one of embodiments 17 to 24, wherein the saturation level of the saturation level is between about 0.1 ng / ml and about 0.4 ng / ml.

[0378] Embodiment 26 is a method for determining the minimum plasma concentration (C min 25. The pharmaceutical composition of any one of embodiments 17 to 24, wherein the saturation level of the saturation level is between about 0.2 ng / ml and about 0.4 ng / ml.

[0379] Embodiment 27 is directed to a method for determining the minimum plasma concentration (C min 25. The pharmaceutical composition of any one of embodiments 17 to 24, wherein the IL-10 ...

[0380] Embodiment 28 is the pharmaceutical composition of any one of embodiments 17 to 27, wherein the pharmaceutical composition comprises 5 mg or less of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0381] Embodiment 29 is the pharmaceutical composition of any one of embodiments 17 to 27, wherein the pharmaceutical composition comprises 3 mg or less of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0382] Embodiment 30 is the pharmaceutical composition of any one of embodiments 17 to 27, wherein the pharmaceutical composition comprises about 5 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0383] Embodiment 31 is the pharmaceutical composition of any one of embodiments 17 to 27, wherein the pharmaceutical composition comprises about 3 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0384] Embodiment 32 is the pharmaceutical composition of any one of embodiments 17 to 31, wherein the pharmaceutical composition is formulated to be administered to a subject about once a week.

[0385] Embodiment 33 is the pharmaceutical composition of any one of embodiments 17 to 31, wherein the pharmaceutical composition is formulated to be administered to a subject about once every two weeks.

[0386] Embodiment 34 is a method for determining the minimum plasma concentration (C min ) is measured 24 to 48 hours after administration.

[0387] Embodiment 35 is a method for determining the minimum plasma concentration (C min) is measured 48 to 72 hours after administration.

[0388] Embodiment 36 is a method for determining the minimum plasma concentration (C min ) is measured 72 to 96 hours after administration.

[0389] Embodiment 37 is directed to a method for determining the minimum plasma concentration (C min ) is measured 96 to 120 hours after administration.

[0390] In embodiment 38, the pharmaceutical composition is a compound having a minimum plasma concentration (C ) determined 120 to 144 hours after administration. min 34. The pharmaceutical composition according to any one of embodiments 17 to 33, wherein

[0391] Embodiment 39 is the pharmaceutical composition of any one of embodiments 1 to 38, wherein the pharmaceutical composition comprises an oral dosage form comprising a (e.g., immediate-release or controlled-release) layer or coating and a controlled-release core, wherein the layer or coating comprises (i) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and optionally (ii) one or more second agents, wherein the one or more second agents are stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory agents, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, 5HT receptor antagonists, or any combination thereof; and the controlled-release core comprises a) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; b) at least one pharmaceutically acceptable excipient; and c) optionally one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; d) optionally one or more agents selected from the group consisting of stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory agents, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, 5HT receptor antagonists, or any combination thereof; Includes.

[0392] Embodiment 40 is the pharmaceutical composition of any one of embodiments 1 to 38, wherein the pharmaceutical composition comprises an oral dosage form comprising a (e.g., immediate-release or controlled-release) layer or coating and a controlled-release core, wherein the layer or coating comprises (i) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof, and optionally (ii) one or more second agents, wherein the one or more second agents are stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory agents, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, or a 5HT receptor antagonist; and the controlled-release core comprises a) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof (stimulants, antihistamines, antiemetics, antidepressants, anti-inflammatory drugs, growth factors, lithium compounds, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, tryptophan, lysergic acid diethylamide, 5HT receptor antagonists, or any combination thereof); b) a buffer solution; c) water; d) optionally one or more agents selected from the group consisting of preservatives, flavorings, sweeteners, surfactants, antifoaming agents, and suspending aids; Includes.

[0393] Embodiment 41 is a pharmaceutical composition according to embodiment 39 or 40, wherein the immediate release layer comprises at least about 1 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0394] Embodiment 42 is a pharmaceutical composition according to embodiment 39 or 40, wherein the immediate-release layer comprises at most about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0395] Embodiment 43 is the pharmaceutical composition of embodiment 39 or 40, wherein the immediate release layer comprises from about 1 mg to about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0396] Embodiment 44 is the pharmaceutical composition of embodiment 39 or 40, wherein the immediate-release layer comprises from about 2 mg to about 40 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0397] Embodiment 45 is the pharmaceutical composition of embodiment 39 or 40, wherein the immediate release layer comprises about 3 mg to about 30 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0398] Embodiment 46 is the pharmaceutical composition of embodiment 39 or 40, wherein the immediate release layer comprises about 5 mg to about 20 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0399] Embodiment 47 is the pharmaceutical composition of embodiment 39 or 40, wherein the immediate release layer comprises about 1 mg to about 10 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0400] Embodiment 47 is a pharmaceutical composition according to embodiment 39 or 40, wherein the immediate release layer comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0401] Embodiment 49 is a pharmaceutical composition according to any one of embodiments 39 to 48, wherein the controlled release core comprises at least about 10 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0402] Embodiment 50 is a pharmaceutical composition according to any one of embodiments 39 to 48, wherein the controlled release core comprises at most about 300 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0403] Embodiment 51 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises from about 10 mg to about 300 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0404] Embodiment 52 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises from about 15 mg to about 250 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0405] Embodiment 53 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises about 20 mg to about 200 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0406] Embodiment 54 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises about 30 mg to about 150 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0407] Embodiment 55 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises about 40 mg to about 100 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0408] Embodiment 56 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises about 10 mg to about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0409] Embodiment 57 is a pharmaceutical composition of any one of embodiments 39 to 48, wherein the controlled release core comprises about 10 mg to about 30 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0410] Embodiment 58 is a pharmaceutical composition according to any one of embodiments 39 to 48, wherein the controlled release core comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0411] Embodiment 59 is a pharmaceutical composition of any one of embodiments 1 to 58, wherein the pharmaceutically acceptable excipient is selected from the group consisting of fillers, binders, suspending agents, disintegrants, lubricants, and combinations thereof.

[0412] Embodiment 60 is the pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition comprises a filler.

[0413] Embodiment 61 is the pharmaceutical composition of embodiment 60, wherein the amount of filler is about 10% to about 20% by weight of the total weight of the composition.

[0414] Embodiment 62 is the pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition comprises a binder.

[0415] Embodiment 63 is the pharmaceutical composition of embodiment 62, wherein the amount of binder is about 5% to about 15% by weight of the total weight of the composition.

[0416] Embodiment 64 is the pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition comprises a suspending agent.

[0417] Embodiment 65 is the pharmaceutical composition of embodiment 64, wherein the amount of the suspending agent is about 1% to about 5% by weight of the total weight of the composition.

[0418] Embodiment 66 is the pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition comprises a disintegrant.

[0419] Embodiment 67 is the pharmaceutical composition of embodiment 66, wherein the amount of disintegrant is from about 1% to about 5% by weight of the total weight of the composition.

[0420] Embodiment 68 is the pharmaceutical composition of embodiment 59, wherein the pharmaceutical composition comprises a lubricant.

[0421] Embodiment 69 is the pharmaceutical composition of embodiment 68, wherein the amount of the lubricant is about 1% to about 5% by weight of the total weight of the composition.

[0422] Embodiment 70 is the pharmaceutical composition of any one of embodiments 39 to 69, wherein the pharmaceutical composition further comprises a surfactant.

[0423] Embodiment 71 is the pharmaceutical composition of embodiment 70, wherein the amount of surfactant is from about 0.1% to about 2% by weight of the total weight of the composition.

[0424] Embodiment 72 is the pharmaceutical composition of embodiment 70, wherein the amount of surfactant is from about 1% to about 15% by weight of the total weight of the composition.

[0425] Embodiment 73 is a pharmaceutical composition according to any one of embodiments 39 to 72, wherein the pharmaceutical composition is a tablet or capsule.

[0426] Embodiment 74 is the pharmaceutical composition of embodiment 73, wherein the pharmaceutical composition is a capsule.

[0427] Embodiment 75 is the pharmaceutical composition of embodiment 73, wherein the pharmaceutical composition is a tablet.

[0428] Embodiment 76 is a pharmaceutical composition according to any one of embodiments 39 to 75, wherein the pharmaceutical composition further comprises a preservative.

[0429] Embodiment 77 is the pharmaceutical composition of embodiment 76, wherein the amount of the preservative is from about 0.1% to about 2% by weight of the total weight of the composition.

[0430] Embodiment 78 is a pharmaceutical composition according to any one of embodiments 39 to 77, wherein the pharmaceutical composition further comprises an antifoaming agent.

[0431] Embodiment 79 is the pharmaceutical composition of embodiment 78, wherein the amount of antifoaming agent is from about 0.1% to about 1% by weight of the total weight of the composition.

[0432] Embodiment 80 is a pharmaceutical composition according to any one of embodiments 39 to 79, wherein the pharmaceutical composition comprises a flavoring agent.

[0433] Embodiment 81 is a pharmaceutical composition according to any one of embodiments 39 to 80, wherein the pharmaceutical composition comprises a sweetener.

[0434] Embodiment 82 is a pharmaceutical composition according to any one of embodiments 39 to 81, wherein the pharmaceutical composition is formulated and / or packaged for repeated administration to a subject about once a week (or more frequently, such as 2-3 times a week, daily, etc.).

[0435] Embodiment 83 is a pharmaceutical composition according to any one of embodiments 39 to 81, wherein the pharmaceutical composition is formulated and / or packaged for repeated administration to a subject about once every two weeks (or less frequently).

[0436] Embodiment 84 is a pharmaceutical composition according to one of embodiments 39 to 81, wherein the pharmaceutical composition is repeatedly administered to a subject about once a month.

[0437] Embodiment 85 is the pharmaceutical composition of any one of embodiments 1 to 38, wherein the pharmaceutical composition comprises a buccal composition comprising: (a) a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof; (b) a matrix that releases the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, at a predetermined rate for transport across the oral membrane, the matrix comprising: (i) flavoring agents, (ii) an enhancer; (iii) Complexing agents, and mixtures thereof a matrix including (c) one or more pharmaceutically acceptable excipients; Includes.

[0438] Embodiment 86 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises at least about 10 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0439] Embodiment 87 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises at most about 300 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0440] Embodiment 88 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 10 mg to about 300 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0441] Embodiment 89 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 15 mg to about 250 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0442] Embodiment 90 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 20 mg to about 200 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0443] Embodiment 91 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 30 mg to about 150 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0444] Embodiment 92 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 40 mg to about 100 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0445] Embodiment 93 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 10 mg to about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0446] Embodiment 94 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 10 mg to about 30 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0447] Embodiment 95 is the pharmaceutical composition of embodiment 85, wherein the pharmaceutical composition comprises about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0448] Embodiment 96 is a pharmaceutical composition according to any one of embodiments 85 to 95, wherein the enhancer is selected from the group consisting of surfactants, bile salts, bile salt derivatives, fatty acids, fatty acid derivatives, sulfoxides, chelating agents, alcohols, polyols, and polymers.

[0449] Embodiment 97 is the pharmaceutical composition of any one of embodiments 1 to 38, wherein the pharmaceutical composition comprises a dosage form for nasal administration, wherein the dosage form comprises: (a) a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof; (b) a penetration enhancer; and (c) one or more pharmaceutically acceptable excipients; Includes.

[0450] Embodiment 98 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises at most about 5 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0451] Embodiment 99 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises at least about 0.5 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0452] Embodiment 100 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises from about 0.5 mg to about 2 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0453] Embodiment 101 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises from about 0.5 mg to about 5 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0454] Embodiment 102 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises from about 1 mg to about 4 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0455] Embodiment 103 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises about 2 mg to about 3 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0456] Embodiment 104 is the pharmaceutical composition of embodiment 97, wherein the dosage form comprises about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0457] Embodiment 105 is a pharmaceutical composition according to any one of embodiments 97 to 104, wherein the penetration enhancer is selected from the group consisting of bile salts, surfactants, fatty acids, fatty acid derivatives, glycerides, chelating agents, salicylates, and polymers.

[0458] Embodiment 106 is a pharmaceutical composition according to any one of embodiments 97 to 105, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a filler, a binder, a suspending agent, a disintegrant, a lubricant, and combinations thereof.

[0459] Embodiment 107 is the pharmaceutical composition of any one of embodiments 1 to 38, wherein the pharmaceutical composition comprises a patch, the patch comprising (i) a backing layer and (ii) an adhesive layer, the adhesive layer comprising: (a) a 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof; (b) rubber-based adhesive and / or silicone-based adhesive Includes.

[0460] Embodiment 108 is a pharmaceutical composition according to any one of embodiments 1 to 107, wherein the 5HT receptor agonist is a 5HT2 receptor agonist.

[0461] Embodiment 109 is the pharmaceutical composition of embodiment 108, wherein the 5HT2 receptor agonist is one or more of a 5HT2A receptor agonist, a 5HT2B receptor agonist, and a 5HT2C receptor agonist.

[0462] Embodiment 110 is the pharmaceutical composition of embodiment 108, wherein the 5HT2 receptor agonist is a 5HT2A receptor agonist or a 5HT2C receptor agonist.

[0463] Embodiment 111 is the pharmaceutical composition of embodiment 108, wherein the 5HT2 receptor agonist is a 5HT2A receptor agonist and a 5HT2C receptor agonist.

[0464] Embodiment 112 is a pharmaceutical composition according to any one of embodiments 1 to 111, wherein the 5HT receptor agonist is psilocin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0465] Embodiment 113 is a pharmaceutical composition according to any one of embodiments 1 to 112, wherein the 5HT receptor agonist is psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0466] Embodiment 114 is a pharmaceutical composition, the pharmaceutical composition comprising: a) a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; b) a pharmaceutically acceptable excipient; and c) optionally one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; Including, the pharmaceutical composition is a low-dose pharmaceutical composition; After administration to an individual, the pharmaceutical composition provides the individual with a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of less than 6 ng / mL. max ), and the 5HT receptor agonist is psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof; or The 5HT receptor agonist is psilocybin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0467] Embodiment 115 is a pharmaceutical composition comprising an oral dosage form comprising an immediate release top layer and a controlled release core, wherein the immediate release top layer comprises (i) the one or more 5HT receptor agonists are psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, and (ii) one or more second agents, wherein the one or more second agents are a stimulant, an antihistamine, an antiemetic, an antidepressant, an anti-inflammatory, a growth factor, a lithium compound, resveratrol, phosphatidylcholine, curcumin, magnesium, melatonin, pregnenolone, ginseng, or lysergic acid diethylamide; and the controlled release core comprises a) one or more 5HT receptor agonists, or pharmaceutically acceptable salts, solvates, metabolites, derivatives, or prodrugs thereof; b) at least one pharmaceutically acceptable excipient; and c) optionally one or more agents selected from the group consisting of surfactants, preservatives, flavorings, sweeteners, and antifoaming agents; Including, the pharmaceutical composition is a low dose pharmaceutical composition; and After administration to an individual, the pharmaceutical composition provides the individual with a maximum plasma concentration (C ) of the 5HT receptor agonist, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof, of less than 6 ng / mL. max ) results.

[0468] Embodiment 116 is the pharmaceutical composition of embodiment 115, wherein the 5HT receptor agonist is psilocin, or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

[0469] Embodiment 117 is a pharmaceutical composition according to embodiment 115, wherein the 5HT receptor agonist is psilocybin or a pharmaceutically acceptable salt, solvate, metabolite, derivative, or prodrug thereof.

Claims

1. A pharmaceutical composition for improving cognitive engagement motivation in a subject in need thereof, comprising: The pharmaceutical composition comprises: a) a therapeutically effective amount of one or more 5HT receptor agonists, or pharmaceutically acceptable salts or solvates thereof, wherein the 5HT receptor agonist is psilocybin or psilocin; and b) Pharmaceutically acceptable excipients Including, the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is a non-hallucinogenic amount of from about 0.1 mg to about 6 mg; wherein said psilocybin or psilocin is the only active agent; the subject is pre-administered with psilocybin or psilocin at a dose of 6 mg or less of psilocybin or psilocin; Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of about 0.1 mg to about 5 mg.

3. The pharmaceutical composition of claim 1, wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of about 0.5 mg to about 4.5 mg.

4. The pharmaceutical composition of claim 1, comprising a dosage form that, when administered to a subject, provides a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, in an amount that is not sufficient to produce a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of 6 ng / mL.

5. The pharmaceutical composition of claim 1, comprising a dosage form that provides a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, in an amount that, when administered to a subject, results in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of from about 0.001 ng / mL to about 10 ng / mL.

6. The pharmaceutical composition of claim 1, comprising a dosage form that, when administered to a subject, provides a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, in an amount that is not sufficient to result in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of 5.9 ng / mL.

7. The pharmaceutical composition of claim 1, comprising a dosage form that provides a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, in an amount that, when administered to a subject, results in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of from about 0.1 ng / mL to about 6 ng / mL.

8. The pharmaceutical composition of claim 1, comprising a dosage form that, when administered to a subject, provides a therapeutically effective amount of a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, in an amount that results in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of at least 0.5 ng / mL after at least 6 hours.

9. The pharmaceutical composition described in claim 1, wherein the pharmaceutical composition is a low-dose pharmaceutical composition.

10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a controlled release component.

11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a controlled-release component and an immediate-release component.

12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises an oral dosage form.

13. A pharmaceutical composition comprising a 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, for use in the preparation of a medicament for managing or treating a disease, disorder, or one or more symptoms thereof in a subject in need thereof, comprising: the medicament comprises a therapeutically effective amount of a non-hallucinogenic amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, from about 0.1 mg to about 6 mg; the 5HT receptor agonist is psilocybin or psilocin; wherein said psilocybin or psilocin is the only active agent; When the use comprises multiple administrations, the pharmaceutical composition comprising the psilocybin or psilocin is administered to the subject for at least one month, and the pharmaceutical composition is administered at least once per week within the at least one month period, with no more than five days between each administration of the multiple administrations. Pharmaceutical compositions.

14. The pharmaceutical composition of claim 13, wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of about 0.1 mg to about 5 mg.

15. The pharmaceutical composition of claim 13, wherein the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is present in an amount of about 0.5 mg to about 4.5 mg.

16. The pharmaceutical composition described in claim 13, wherein the pharmaceutical composition is a low-dose pharmaceutical composition.

17. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises a controlled release component.

18. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises a controlled-release component and an immediate-release component.

19. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is provided to a subject in need thereof in an amount and / or formulation that does not result in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of 6 ng / mL.

20. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the 5HT receptor agonist, or pharmaceutically acceptable salt or solvate thereof, is provided to a subject in need thereof in an amount and / or formulation that results in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or pharmaceutically acceptable salt or solvate thereof, of from about 0.001 ng / mL to about 10 ng / mL.

21. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is provided to a subject in need thereof in an amount and / or formulation that does not result in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of 5.9 ng / mL.

22. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the 5HT receptor agonist, or pharmaceutically acceptable salt or solvate thereof, is provided to a subject in need thereof in an amount and / or formulation that results in a maximum plasma concentration (C max ) of the active form of the 5HT receptor agonist, or pharmaceutically acceptable salt or solvate thereof, of from about 0.1 ng / mL to about 6 ng / mL.

23. The pharmaceutical composition of claim 13, wherein the therapeutically effective amount of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, is provided to a subject in need thereof in an amount and / or formulation that results in a plasma concentration of the active form of the 5HT receptor agonist, or a pharmaceutically acceptable salt or solvate thereof, of at least 0.5 ng / mL after at least 6 hours.

24. The pharmaceutical composition of claim 13, wherein the 5HT receptor agonist is psilocin, or a pharmaceutically acceptable salt or solvate thereof.

25. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is administered orally.

26. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is administered to a subject in need thereof once a day, every other day, three times a week, twice a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, or three times a month.

27. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is administered at least once a day.

Images