Compositions and methods for treating post-traumatic stress disorder

Abstract

This specification provides methods and compositions for treating, relieving, or preventing post-traumatic stress disorder (PTSD). The therapeutic methods and compositions described herein include the use of at least one norepinephrine inhibitor and at least one enteractogen for treating, relieving, or preventing PTSD. The therapeutic methods and compositions described herein include at least one α 2A - This also includes the use of an adrenaline receptor agonist and at least one hallucinogen. TIFF2026517765000002.tif78128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 499,089, titled "COMPOSITIONS AND METHODS FOR TREATING POST-TRAUMATIC STRESS DISORDER," filed on 28 April 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Statement concerning federal government-funded research This invention was made with government support under MH122733 granted by the National Institutes of Health. The government has certain rights to this invention. [Background technology]

[0003] background While MDMA (3,4-methylenedioxymethamphetamine) has shown efficacy in Phase 3 clinical trials for PTSD, it has several undesirable side effects, such as potential for abuse (addiction), cardiovascular effects, and neurotoxicity. In contrast, hallucinogens enhance structural plasticity in the prefrontal cortex. Therefore, there is an urgent need to develop safe and effective treatments for PTSD that do not have negative side effects.

[0004] This disclosure addresses this unmet need. [Overview of the project]

[0005] In one aspect, a method is provided for treating, relieving, and / or preventing post-traumatic stress disorder in a subject in need. In a particular embodiment, the method includes administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a norepinephrine inhibitor (NEI) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In a particular embodiment, the method includes administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an enterogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In a particular embodiment, the pharmaceutical composition comprising the NEI and the pharmaceutical composition comprising the enterogen are formulated as a single dose or as separate doses. In a particular embodiment, post-traumatic stress disorder in the subject is treated, relieved, or prevented.

[0006] In another context, a method for treating, relieving, and / or preventing post-traumatic stress disorder in subjects in need. In a particular embodiment, the method comprises a therapeutically effective amount of α 2A - The method includes administering a pharmaceutical composition comprising an adrenergic receptor agonist (AARA) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer to a subject. In certain embodiments, the method includes administering a pharmaceutical composition comprising a therapeutically effective amount of a hallucinogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer to a subject. In certain embodiments, the pharmaceutical composition comprising the AARA and the pharmaceutical composition comprising the hallucinogen are formulated as a single dose or as separate doses. In certain embodiments, post-traumatic stress disorder in the subject is treated, remitted, or prevented. [Brief explanation of the drawing]

[0007] The drawings generally illustrate various aspects of the present application as examples, not as limitations.

[0008] [Figure 1A] Figure 1A shows the injection of the fluorescent biosensor (AAV9-hSyn-GRABNE2h) into the mPFC and the implantation of fibers into this region. [Figure 1B] Figure 1B shows examples of individual traces of NE (norepinephrine) levels in response to the injection of saline and MDMA. [Figure 1C] Figure 1C shows a schematic diagram of an automatic detection device for head-shaking behavior for use in mice with magnetic ear tags. [Figure 1D] Figure 1D shows a schematic diagram of a proposed non-limiting mechanism of the action of MDMA. Without being bound by theory, MDMA increases the release of 5-HT (5-hydroxytryptamine), and 5-HT acts on the 5-HT2A receptor, increasing head-shaking. MDMA also increases the release of NE through binding to the NE transporter. The administration of reboxetine can block the NE transporter, thereby inhibiting the release of NE from MDMA. [Figure 1E] Figure 1E shows the left panel illustrating NE levels when reboxetine (n = 7) and fluoxetine (n = 7) were administered together with the injection of MDMA. The right panel of Figure 1E shows the average dF / F between 600 and 1000 seconds. Paired t-test P = 0.0173 (*), t = 3.500, df = 5). [Figure 1F] Figure 1F shows the left panel illustrating head-shaking for 30 minutes when reboxetine (10 mg / kg) or saline was administered 1 minute before MDMA (5 mg / kg). Unpaired t-test p = 0.0001 (***), t = 6.069, df = 10. The right panel of Figure 1F shows the time course of head-shaking per minute in the case of reboxetine (10 mg / kg) or saline + MDMA (5 mg / kg).

[0009] [Figure 2]Figures 2A - 2C show aspects of the methods and compositions described herein in various embodiments. Figure 2A shows a schematic diagram of a proposed non - limiting model of the action and drug function of MDMA. Without being bound by theory, it was hypothesized that NE reduced the head - twitch response via the α2 - adrenergic receptor. Yohimbine, an α2 - antagonist, was hypothesized to block the binding of NE and increase the number of head - twitches. Figure 2B shows head - twitches over 30 minutes when yohimbine (2 mg / kg) or distilled water was administered 10 minutes before MDMA (10 mg / kg). Unpaired T - test p = 0.0133 (*), t = 3.166, df = 8. Figure 2C shows the time - course of head - twitches per minute when MDMA (10 mg / kg) was used with yohimbine (2 mg / kg) or distilled water.

[0010] [Figure 3] Figure 3A shows a schematic diagram of a proposed non - limiting model of the action and drug function of MDMA. Without being bound by theory, it was hypothesized that NE was reducing the head - twitch response via the α2 - adrenergic receptor. Administration of reboxetine blocks the release of NE from MDMA, but in the absence of NE, guanfacine, an α2 - agonist, binds to the α2 - receptor and inhibits the head - twitch response. Figure 3B shows head - twitches over 30 minutes when guanfacine (0.15 mg / kg) or saline was administered 30 minutes before MDMA (10 mg / kg) and reboxetine (10 mg / kg) was administered 1 minute before MDMA. Unpaired T - test p = 0.0016 (**), t = 4.283, df = 10. Figure 3C shows the time - course of head - twitches per minute when MDMA (10 mg / kg) was used with guanfacine (0.15 mg / kg) or saline and reboxetine (10 mg / kg).

[0011] [Figure 4]Figure 4A shows a schematic diagram of a proposed non-limiting model of the action and pharmacokinetics of psilocybin. Psilocybin is a 5-HT2A receptor agonist, but in the absence of NE, guanfacine, an α2 agonist, binds to the α2 receptor and inhibits the nodding response. Figure 4B shows the 30-minute nodding response after administration of guanfacine (0.15 mg / kg) or saline 30 minutes prior to psilocybin (1 mg / kg). Unpaired t-test p=0.0081(**), t=3.296, df=10. Figure 4C shows the time course of nodding per minute with guanfacine (0.15 mg / kg) or saline and psilocybin (1 mg / kg). [Modes for carrying out the invention]

[0012] Detailed explanation Next, we will refer in detail to certain aspects of the subject matter of this disclosure. The subject matter of this disclosure will be described in conjunction with the enumerated claims, but it should be understood that the subject matter described herein is not intended to limit the scope of the claims to the subject matter of this disclosure.

[0013] Throughout this document, values ​​expressed in range form should be interpreted flexibly to include not only the numbers explicitly stated as upper and lower limits of the range, but also all individual numbers or subranges that are contained within the range as if each number and subrange were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also individual values ​​within the indicated range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). The notation "approximately X to Y" is equivalent to "approximately X to approximately Y" unless otherwise indicated. Similarly, the notation "approximately X, Y, or approximately Z" is equivalent to "approximately X, approximately Y, or approximately Z" unless otherwise indicated.

[0014] In this document, the terms “a,” “an,” or “the” are used to refer to one or more unless the context clearly indicates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The phrases “at least one of A and B” or “at least one of A or B” are synonymous with “A, B, or A and B.” In addition, any phrases or terminologies used herein that are not otherwise defined are for illustrative purposes only and not for limitation. Any use of section headings is intended to aid in reading the document and should not be interpreted as limiting, and information relating to a section heading may occur within or outside that particular section.

[0015] In the methods described herein, unless a temporal or operational order is explicitly stated, the operations may be performed in any order. Furthermore, the specified operations may be performed simultaneously unless the language of the claim explicitly states that they are performed separately. For example, the operation described in the claim to perform X and the operation described in the claim to perform Y may be performed simultaneously within a single operation, and the resulting process falls within the scope of the process language described in the claim.

[0016] definition As used herein, the term “about” may allow some degree of variation in a value or range, for example, within 10%, 5%, or 1% of the upper or lower limits of the stated value or range, and includes the exact stated value or range.

[0017] As used herein, the term “substantially” means at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%, or the majority or most of it. As used herein, the term “substantially absent” means that the substance is not present at all, or the amount present does not affect the material properties of the composition containing the substance, and the composition is less than approximately 0 wt% to approximately 5 wt%, or approximately 0 wt% to approximately 1 wt%, or approximately 5 wt% or less, or approximately 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or approximately 0.001 wt% or less. This may mean that the amount is equal to or less than wt%, or is greater than approximately 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or approximately 0.001 wt% or less. The term "substantially contained" means that the composition is approximately 0 wt% to approximately 5 wt% of the substance, or approximately 0 wt% to approximately 1 wt%, or approximately 5 wt% or less, or approximately 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or less than approximately 0.001 wt%, or approximately 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or approximately 0.001 wt% or less, or approximately 4.5 This can mean having trace amounts such as wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or more than approximately 0.001 wt%, or approximately 0 wt%.

[0018] As used herein, the term "selected independently of" means that the groups referred to are the same, different, or a mixture thereof, unless the context clearly dictates otherwise. Thus, under this definition, "X 1 , X 2 , and X 3 are selected independently of the noble gases" includes, for example, the case where X 1 , X 2 , and X 3 are all the same, the case where X 1 , X 2 , and X 3 are all different, the case where X 1 and X 2 are the same but X 3 is different, and other similar combination scenarios.

[0019] As used herein, the term "room temperature" means a temperature of about 15°C to 28°C.

[0020] As used herein, the term "standard temperature and pressure" means 20°C and 101 kPa.

[0021] As used herein, the term "composition" or "pharmaceutical composition" means a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates the administration of the compound to a patient or subject. A plurality of techniques for administering the compound exist in the art and include, but are not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, ophthalmic administration, pulmonary administration, and topical administration.

[0022] A "disease" is a health condition of an animal in which the animal cannot maintain homeostasis and the animal's health continues to deteriorate unless the disease remits.

[0023] In contrast, a "disorder" in animals is a state of health in which the animal can maintain homeostasis, but its health is less favorable than if it were not disordered. Leaving a disorder untreated does not necessarily lead to a further deterioration of the animal's health.

[0024] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” mean the amount of an active substance that is non-toxic but sufficient to produce a desired biological effect. Such effect may be a reduction and / or mitigation of the signs, symptoms, or causes of a disease, or any other desired change in any biological system. The appropriate therapeutic dose in any individual case can be determined by those skilled in the art using conventional experimentation.

[0025] As used herein, the term "efficacy" means the maximum effect (Emax) achieved in the assay.

[0026] As used herein, the term “pharmaceutically acceptable” means a substance, such as a carrier or diluent, that does not inhibit the biological activity or properties of a compound and is relatively nontoxic; that is, the substance can be administered to an individual without causing undesirable biological effects or harmfully interacting with any of the components of the composition contained in the composition.

[0027] As used herein, the term "pharmaceutically acceptable salt" means a salt of an administered compound prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic acids or inorganic bases, organic acids or organic bases, solvates, hydrates, or inclusion complexes thereof.

[0028] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and bisulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids may be selected from the classes of aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid, and examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0029] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, alkali metal salts, alkaline earth metal salts, and metal salts including transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compounds, for example, by reacting them with a suitable acid or base.

[0030] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in transporting or delivering the compounds described herein into or to a patient so that the compounds described herein can perform their intended function. Typically, such constructs are transported or delivered from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation containing the compounds described herein and is not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, suitable substances used in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carriers” include any coatings, antimicrobials, and antifungals, as well as absorption retarders, that are compatible with the activity of the compounds described herein and are physiologically acceptable to the patient. Auxiliary active compounds may also be incorporated into the composition. “pharmaceutically acceptable carriers” may further include pharmaceutically acceptable salts of the compounds described herein.Other additional components that may be included in pharmaceutical compositions used by the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0031] The terms “patient,” “subject,” or “individual” are used interchangeably herein and mean any animal, or its cells, whether in vitro or in situ, to which the methods described herein can be applied. In a non-limiting embodiment, patient, subject, or individual is human.

[0032] As used herein, the term "potency" means the dose (ED) required to produce half of the maximum reaction. 50 ) means.

[0033] "Therapeutic" treatment is a procedure administered to a person exhibiting symptoms of a disease with the aim of reducing or eliminating the symptoms of that disease.

[0034] As used herein, the terms “treatment” or “to treat” are defined as the application or administration of a therapeutic agent, i.e., one of the compounds or compounds(s) described herein (alone or in combination with other pharmaceutically active agents), to a patient for the purpose of curing, healing, alleviating, reducing, altering, treating, relieving, improving, or influencing the condition or symptoms of the condition intended herein, or the application or administration of a therapeutic agent to tissue or cell lines isolated from a patient having the condition or symptoms of the condition intended herein (e.g., for diagnostic or ex vivo application). Such treatments may be specifically adapted or modified based on knowledge derived from the field of pharmacological genomics.

[0035] As used herein, “administered concurrently” means administered in the shortest possible time, within the actual physical limits of the patient’s ability to take the dosage form, or within the actual physical capabilities of the healthcare professional administering the dosage form. In some embodiments, “administered concurrently” includes simultaneous administration.

[0036] therapeutic composition i. Enteractogens and NEI This specification provides an enterogen useful in this disclosure. This specification provides a norepinephrine inhibitor (NEI) useful in this disclosure.

[0037] This specification provides therapeutic compositions comprising at least one enterogen and at least one norepinephrine inhibitor (NEI).

[0038] Suitable enterogens include, for example, MDMA (3,4-methylenedioxymethamphetamine), MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxy-N-ethylamphetamine), MDOH (3,4-methylenedioxy-N-hydroxyamphetamine), MBDB (1,3-benzodioxolyl-N-methylbutanamine), 5-APB (1-benzofuran-5-ylpropane-2-amine), 5-MAPB (1-(benzofuran-5-yl)-N-methylpropane-2-amine), 6-APB (6- Examples include (2-aminopropyl)benzofuran), 6-MAPB (1-(benzofuran-6-yl)-N-methylpropan-2-amine), methylone (3,4-methylenedioxy-N-methylcathinone), mephedrone (4-methylmethcathinone), GHB (γ-hydroxybutyrate), αMT (α-methyltryptamine), αET (α-ethyltryptamine), and MDAI (5,6-methylenedioxy-2-aminoindan), and include their solvates, enantiomers, diastereomers, tautomers, and salts (such as pharmaceutically acceptable salts).

[0039] Appropriate NEIs include, for example, atomoxetine ((R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine), reboxetine (rel-(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine), biloxazine ((RS)-2-[(2-ethoxyphenoxy)methyl]morpholine), amedalin (UK-3540-1), daredalin (UK-3557-15), ediboxetine (LY-2216684), esreboxetine (AXS-14; PNU-165442G), lortalamine (LM-1404), nisoxetine (LY-94,939), and talopram (tasulopram) (Lu Examples include 3-010), talsprum (Lu 5-005), and tandamin (AY-23,946), and include their solvates, enantiomers, diastereomers, tautomers, and salts (such as pharmaceutically acceptable salts).

[0040] The therapeutic composition may be in separate or single dosage forms. Separate dosage forms of the therapeutic composition described herein mean that an enterogen is present in a first dosage form that can be administered by any of the delivery methods described herein, and an NEI is present in a second dosage form that can be administered by any of the delivery methods described herein. Separate dosage forms may contain only enterogen as the pharmaceutically active ingredient, or only NEI as the pharmaceutically active ingredient. Each separate dosage form may independently further contain one or more pharmaceutically acceptable carriers or excipients as described herein. Therefore, the pharmaceutically acceptable carrier or excipient in the NEI-containing dosage form may be the same as or different from the pharmaceutically acceptable carrier or excipient in the enterogen-containing dosage form.

[0041] Entactogen-containing formulations can be formulated as single or separate formulations with anti-abuse properties. Anti-abuse properties can be achieved through: 1) the use of an enteractogen prodrug, 2) the use of intractable matrix formulation technology, and 3) the addition of an antagonist to the product formulation. In a particular embodiment, an enteractogen acid addition salt formulation can be used as an anti-abuse property, where the enteractogen is insoluble in human mucosa but becomes bioavailable when exposed to the gastrointestinal environment. In certain non-limiting embodiments, dosage forms having abuse-preventive properties can be formulated as described in, for example, US 7,842,307, GB 2238478A, US 7,230,005, WO 2010 / 044842, WO 2013 / 003845, EP 1611880, US 7,510,726, US 7,399,488, US 2009 / 0215808, US 2010 / 0249045, WO 2010 / 105672, WO 2010 / 066034, and US 10,420,729, etc., the disclosures of which are incorporated herein by reference.

[0042] If the dosage form is a single solid dosage form such as a tablet, the dosage form can be formulated such that the NEI is an immediate-release component and the enteractogen is a delayed-release or sustained-release component. Alternatively, if the dosage form is a single solid dosage form such as a tablet, the dosage form can be formulated such that the enteractogen is an immediate-release component and the NEI is a delayed-release or sustained-release component. The dosage forms of the NEI and enteractogen can be formulated as a pharmaceutical composition containing at least pharmaceutically acceptable excipients or carriers, either as a single dosage form or as separate dosage forms.

[0043] In a particular embodiment, a single dose form or separate dose forms contain approximately 1 to approximately 1000 mg, or approximately 1 to approximately 500 mg, or approximately 1 to approximately 400 mg, or approximately 1 to approximately 300 mg, or approximately 1 to approximately 250 mg, or approximately 1 to approximately 200 mg, or approximately 1 to approximately 150 mg, or approximately 1 to approximately 100 mg, or approximately 1 to approximately 90 mg, or approximately 1 to approximately 80 mg, or approximately 1 to approximately 70 mg, or approximately 1 to approximately 60 mg, or approximately 1 to approximately 50 mg, or approximately 1 to approximately 40 mg, or approximately 1 to approximately 30 mg, or approximately 1 to approximately 20 mg, or approximately 1 to approximately 10 mg of an enteractogen, or its solvate, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.In a particular embodiment, a single dose or separate doses may be approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240 ,245,250,255,260,265,270,275,280,285,290,295,300,305,310,315,320,325,330,335,340,345,350,355,360,365,370,375,380,385,390,395,400,405,410,415,420,425,430,435,440,445,450,455,460,465,470,475,480,485,490,495 ,500,505,510,515,520,525,530,535,540,545,550,555,560,565,570,575,580,585,590,595,600,605,610,615,620,625,630,635,640,645,650,655,660,665,670,675,680,685,690,695,700,705,710,715,720,725,730,735,740,745,750 It contains 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg of enteractogen, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.

[0044] In certain embodiments, a single dose or separate doses contain about 100, 105, 110, 115, 102, 125, 130, 135, or 150 mg of an enteractogen or its solvate, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt. In certain embodiments, a single dose or separate doses contain about 125 mg of MDMA.

[0045] In a particular embodiment, a single dosage form or separate dosage forms contain approximately 1 to approximately 1000 mg, or approximately 1 to approximately 500 mg, or approximately 1 to approximately 400 mg, or approximately 1 to approximately 300 mg, or approximately 1 to approximately 250 mg, or approximately 1 to approximately 200 mg, or approximately 1 to approximately 150 mg, or approximately 1 to approximately 100 mg, or approximately 1 to approximately 90 mg, or approximately 1 to approximately 80 mg, or approximately 1 to approximately 70 mg, or approximately 1 to approximately 60 mg, or approximately 1 to approximately 50 mg, or approximately 1 to approximately 40 mg, or approximately 1 to approximately 30 mg, or approximately 1 to approximately 20 mg, or approximately 1 to approximately 10 mg of NEI, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.In a particular embodiment, a single dose or separate doses may be approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225 ,230,235,240,245,250,255,260,265,270,275,280,285,290,295,300,305,310,315,320,325,330,335,340,345,350,355,360,365,370,375,380,385,390,395,400,405,410,415,420,425,430,435,440,445,450,455,460,465,470,475,480,485 ,490,495,500,505,510,515,520,525,530,535,540,545,550,555,560,565,570,575,580,585,590,595,600,605,610,615,620,625,630,635,640,645,650,655,660,665,670,675,680,685,690,695,700,705,710,715,720,725,730,735,740,745 It contains 750, 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg of NEI, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.

[0046] In certain embodiments, a single or separate dosage form contains approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg of NEI, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In certain embodiments, a single or separate dosage form contains 8 mg of reboxetine.

[0047] In certain embodiments, the NEI is administered before the administration of the enterogen. In certain embodiments, the NEI may be administered approximately 1, 5, 10, 15, 30, or 60 minutes before the administration of the enterogen. In certain embodiments, the NEI may be administered approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours before the administration of the enterogen. In certain embodiments, the NEI and enterogen are administered simultaneously, for example, as part of a single dosage form or as part of separate dosage forms taken together at the same time.

[0048] In a certain aspect, the enterogen is MDMA.

[0049] In a certain manner, NEI is reboxetine.

[0050] ii. Hallucinogens and α 2A - Adrenaline receptor agonist This specification provides hallucinogens useful in this disclosure. This specification provides α useful in this disclosure. 2A - Adrenergic receptor agonists (AARAs) are provided.

[0051] In this specification, at least one hallucinogen and at least one α 2A -A therapeutic composition containing an adrenaline receptor agonist (AARA) is provided.

[0052] Suitable hallucinogens include, for example, psilocybin, 2C-B (4-bromo-2,5-dimethoxyphenethylamine), ketamine (racemic, R-ketamine, or S-ketamine), DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-dimethyltryptamine), LSA (d-lysergic acid amide), and LSD (lysergic acid diethylamide), including their solvates, enantiomers, diastereomers, tautomers, and salts (such as pharmaceutically acceptable salts). In certain embodiments, psilocybin is isolated, pure psilocybin that is substantially free of any other substances found in Psilocybe mushroom species. Psilocybin can be at least 95%, 96%, 97%, 98%, 99%, or 99.9% pure psilocybin.

[0053] Suitable AARAs include, for example, clonidine, dexmedetomidine, fadolimidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, methyldopa, methylnorepinephrine, norepinephrine, detomidine, and lofexidine, and include their solvates, enantiomers, diastereomers, tautomers, and salts (such as pharmaceutically acceptable salts).

[0054] The therapeutic composition may be in separate dosage forms or a single dosage form. Separate dosage forms of the therapeutic composition described herein mean that a hallucinogen is present in a first dosage form that can be administered by any of the delivery methods described herein, and AARA is present in a second dosage form that can be administered by any of the delivery methods described herein. Separate dosage forms may contain only the hallucinogen as the active pharmaceutical ingredient, or only AARA as the active pharmaceutical ingredient. Each separate dosage form may independently further contain one or more pharmaceutically acceptable carriers or excipients as described herein. Therefore, the pharmaceutically acceptable carrier or excipient in the AARA-containing dosage form may be the same as or different from the pharmaceutically acceptable carrier or excipient in the hallucinogen-containing dosage form.

[0055] The dosage form containing the hallucinogen can be formulated as a single dosage form or as separate dosage forms, with abuse prevention properties. Abuse prevention properties can be achieved by 1) the prodrug of the hallucinogen, 2) the difficult-to-process matrix formulation technology, and 3) the addition of an antagonist to the product formulation. In a particular embodiment, an example of an abuse prevention property is a formulation of an acid-added salt of the hallucinogen, which is insoluble in human mucosa but becomes bioavailable when exposed to the gastrointestinal environment. In certain non-limiting embodiments, dosage forms having abuse-preventive properties can be formulated as described in, for example, US 7,842,307, GB 2238478A, US 7,230,005, WO 2010 / 044842, WO 2013 / 003845, EP 1611880, US 7,510,726, US 7,399,488, US 2009 / 0215808, US 2010 / 0249045, WO 2010 / 105672, WO 2010 / 066034, and US 10,420,729, etc., the disclosures of which are incorporated herein by reference.

[0056] If the dosage form is a single solid dosage form such as a tablet, the dosage form can be formulated such that AARA is an immediate-release component and the hallucinogen is a delayed-release or sustained-release component. Alternatively, if the dosage form is a single solid dosage form such as a tablet, the dosage form can be formulated such that the hallucinogen is an immediate-release component and AARA is a delayed-release or sustained-release component. The dosage forms of AARA and the hallucinogen can be formulated as a pharmaceutical composition containing at least pharmaceutically acceptable excipients or carriers, either as a single dosage form or as separate dosage forms.

[0057] In a particular embodiment, a single dose form or separate dose forms contain approximately 1 to approximately 1000 mg, or approximately 1 to approximately 500 mg, or approximately 1 to approximately 400 mg, or approximately 1 to approximately 300 mg, or approximately 1 to approximately 250 mg, or approximately 1 to approximately 200 mg, or approximately 1 to approximately 150 mg, or approximately 1 to approximately 100 mg, or approximately 1 to approximately 90 mg, or approximately 1 to approximately 80 mg, or approximately 1 to approximately 70 mg, or approximately 1 to approximately 60 mg, or approximately 1 to approximately 50 mg, or approximately 1 to approximately 40 mg, or approximately 1 to approximately 30 mg, or approximately 1 to approximately 20 mg, or approximately 1 to approximately 10 mg of a hallucinogen, or a solvate, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.In a particular embodiment, a single dose or separate doses may be approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240 ,245,250,255,260,265,270,275,280,285,290,295,300,305,310,315,320,325,330,335,340,345,350,355,360,365,370,375,380,385,390,395,400,405,410,415,420,425,430,435,440,445,450,455,460,465,470,475,480,485,490,495 ,500,505,510,515,520,525,530,535,540,545,550,555,560,565,570,575,580,585,590,595,600,605,610,615,620,625,630,635,640,645,650,655,660,665,670,675,680,685,690,695,700,705,710,715,720,725,730,735,740,745,750 It contains 755, 760, 765, 770, 775, 780, 785, 790, 795, 800, 805, 810, 815, 820, 825, 830, 835, 840, 845, 850, 855, 860, 865, 870, 875, 880, 885, 890, 895, 900, 905, 910, 915, 920, 925, 930, 935, 940, 945, 950, 955, 960, 965, 970, 975, 980, 985, 990, 995, or 1000 mg of a hallucinogen, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.

[0058] In certain embodiments, a single or separate dosage form contains about 5, 10, 15, 20, 25, 30, 35, or 40 mg of a hallucinogen, or its solvate, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof. In certain embodiments, a single or separate dosage form contains about 25 mg of psilocybin, or its solvate, enantiomer, diastereomer, tautomer, or pharmaceutically acceptable salt thereof.

[0059] In a particular embodiment, a single dosage form or separate dosage forms contain approximately 1 to approximately 1000 mg, or approximately 1 to approximately 500 mg, or approximately 1 to approximately 400 mg, or approximately 1 to approximately 300 mg, or approximately 1 to approximately 250 mg, or approximately 1 to approximately 200 mg, or approximately 1 to approximately 150 mg, or approximately 1 to approximately 100 mg, or approximately 1 to approximately 90 mg, or approximately 1 to approximately 80 mg, or approximately 1 to approximately 70 mg, or approximately 1 to approximately 60 mg, or approximately 1 to approximately 50 mg, or approximately 1 to approximately 40 mg, or approximately 1 to approximately 30 mg, or approximately 1 to approximately 20 mg, or approximately 1 to approximately 10 mg of AARA, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.In a particular embodiment, a single dose or separate doses may be approximately 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220 ,225,230,235,240,245,250,255,260,265,270,275,280,285,290,295,300,305,310,315,320,325,330,335,340,345,350,355,360,365,370,375,380,385,390,395,400,405,410,415,420,425,430,435,440,445,450,455,460,465,470,475,480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, 735, 740, 7 Contains 45,750,755,760,765,770,775,780,785,790,795,800,805,810,815,820,825,830,835,840,845,850,855,860,865,870,875,880,885,890,895,900,905,910,915,920,925,930,935,940,945,950,955,960,965,970,975,980,985,990,995, or 1000 mg of AARA, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts.

[0060] In certain embodiments, a single or separate dosage form contains about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, or 10 mg of AARA, or its solvates, enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts. In certain embodiments, a single or separate dosage form contains about 1 to about 4 mg of guanfacine.

[0061] In certain embodiments, AARA is administered before or after the administration of a hallucinogen. In certain embodiments, AARA may be administered approximately 1, 5, 10, 15, 30, or 60 minutes before the administration of a hallucinogen. In certain embodiments, AARA may be administered approximately 1, 5, 10, 15, 30, or 60 minutes after the administration of a hallucinogen. In certain embodiments, AARA may be administered approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours before the administration of a hallucinogen. In certain embodiments, AARA may be administered approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after administration of the hallucinogen. In certain embodiments, AARA and the hallucinogen may be administered simultaneously, for example, as part of a single dosage form or as part of separate dosage forms taken together at the same time.

[0062] In a certain manner, the hallucinogen is psilocybin.

[0063] In a particular aspect, AARA is guanfacine.

[0064] Compositions containing the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, compositions are formulated for routes of administration such as oral or parenteral, e.g., percutaneous, permucosal (e.g., sublingual, lingual, (trans) buccal, (trans) urethral, ​​vagina (e.g., transvaginal and perival), nasal (intra) and (trans) rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0065] Non-restrictive considerations MDMA is currently in Phase 3 clinical trials to treat post-traumatic stress disorder (PTSD) and appears to show substantial efficacy in reducing PTSD symptoms. In certain embodiments, MDMA can enhance psychotherapy for PTSD by increasing attention to traumatic memories or by enhancing extinction learning. PTSD is characterized by changes in learning, and in this context, enhancing extinction learning may improve PTSD treatment. In mice, fear extinction enhancement studies have shown that MDMA enhances the extinction of auditory fear associations by serotonin (5-HT) release, and this effect can be replicated by direct injection of MDMA into the medial prefrontal cortex (mPFC) or amygdala.

[0066] MDMA makes it easier for patients to relapse of traumatic memories and is called an "entactogen" ("going within to bring out"). Drug discrimination tests have shown that animals can distinguish between the enteractogen and classic hallucinogens (5-HT). 2AThis paper distinguishes enterogens from agonists and demonstrates that the subjective effects of enterogens in humans also differ from those of classical hallucinogens. Mechanistically, enterogens act like stimulants, releasing norepinephrine (NE) and dopamine (DA) through monoamine transporters, but differ from stimulants in that they also release 5-HT. Within the enterogen class, there is considerable diversity in in vitro selectivity for monoamine transporters. The relationship between MDMA's in vivo monoamine-releasing effect and specific mechanisms related to therapeutic plasticity remains unclear.

[0067] Pharmacological dissociation studies have established the roles of individual monoamines in the behavioral effects of MDMA. The release of 5-HT is linked to the release of 5-HT in the nucleus accumbens. 1B Prosocial behavior and 5-HT through activation 2A It leads to enhanced fear extinction through receptors. The rewarding and addictive effects of MDMA are mediated by dopamine release in the nucleus accumbens. Increased locomotion induced by MDMA is associated with noradrenaline α1 receptors in rodents and humans, and NE release contributes to euphoria and cardiovascular activation. Further elucidation of the receptor-dependent effects of MDMA may enable the development of enteractogens with improved efficacy and tolerability in PTSD.

[0068] Various enteractogens, fear extinction behavior, 5-HT and NE release, and 5-HT 2A The induction of addictive behavior was investigated. Fear extinction was systematically compared among multiple enterogens to determine whether other drugs in this class share putative therapeutic effects with MDMA. To characterize the effects of neuromodulators, in vivo neurotransmitter release measurements and behaviors were compared among multiple enterogens and hallucinogens. Pharmacological manipulation was used to investigate the behavioral effects of 5-HT13 on MDMA. 2AA previously unreported role of NE in its interaction with agonism (receptor activation) has been revealed.

[0069] Since MDMA is hypothesized to function as a treatment for PTSD by enhancing fear extinction, the enhancement of fear extinction to auditory cues was evaluated using a 3-day paradigm and compared with that of enteractogens. To determine the different roles of 5-HT and NE release in the action of enteractogens, the different neuromodulatory release properties among multiple enteractogens were elucidated using in vivo behavioral and physiological approaches. 2A Receptor activity is hallucinogenic 5-HT 2A This can be identified using the head-shaking response (HTR), which is a rapid head movement caused by agonists and / or indirectly by drugs that induce serotonin release. Using an automated magnetometer HTR assay, the 5-HT of enteractogen drugs can be identified. 2A Activity was evaluated. Furthermore, the dynamics of neuromodulator release after drug infusion were individually identified using fiber photometry and fluorescent GPCR-based sensors for 5-HT and NE. This approach enables high temporal resolution and high specificity measurements of neurotransmitter release, allowing for accurate observation of neuromodulator levels after enteractogen infusion.

[0070] Entactogen's NE-releasing effect and HTR Since differences in NE release characteristics among multiple enterogens were predicted by in vitro transporter affinity studies, NE release kinetics were determined. After enterogen administration, in vivo NE kinetics in the mPFC (Figure 1A) were measured with high temporal resolution using fiber photometry with a GPCR-based sensor. Physical manipulation associated with intraperitoneal injection induces a transient increase in NE (Figure 1B).

[0071] Although not bound by theory, it was hypothesized that NE can suppress the head-shaking response to enteractogen (Figure 1C-D). Since enteractogen induces NE release via the presynaptic NE transporter (NET), NE release from MDMA was blocked using reboxetine (NET inhibitor) (1 minute pretreatment; reboxetine + MDMA). Co-administration of reboxetine 1 minute prior to MDMA infusion suppressed NE release, as confirmed by fiber photometry of the NE GRAB sensor (GRAB-NE2h, Figure 1E). This effect was selective: NET inhibition (reboxetine, 10 mg / kg, n=7) suppressed NE release, but SERT inhibition (fluoxetine, 10 mg / kg, n=7) did not suppress NE release (Figure 1E).

[0072] We compared saline + MDMA with reboxetine + MDMA to determine if NE release is the cause of MDMA's lower HTR kinetics. Consistent with this hypothesis, reboxetine + MDMA induced a greater number of head bobs than saline + MDMA (30 minutes; Figure 1F). Temporally, the increase in head bobs in the reboxetine + MDMA group lasted for at least 30 minutes (Figure 1F right). While not constrained by theory, it appears that with MDMA, lower NE levels are associated with higher head bobs.

[0073] Blocking of HTR by NE is mediated by α2 adrenergic receptors. The α2 antagonist yohimbine (2 mg / kg, n=5) was administered before MDMA (yohimbine + MDMA; Figures 2A-2C). In fact, yohimbine + MDMA increased HTR compared to vehicle + MDMA (Figures 3A-3C, unpaired t-test p=0.0133, t=3.166, df=8). Similar to reboxetine, the suppression of norepinephrine-mediated blocking was most pronounced after the first dose and lasted for 30 minutes (Figures 4A-4C).

[0074] By blocking α2 receptors, MDMA's 5-HT receptors are effective against head shaking. 2ASince the mechanism of action was clarified, we activated this receptor with guanfacine (Figures 3A-3C). Previously, it had been found that blocking NE release from MDMA with reboxetine resulted in more head bobbing. If the inhibitory effect of NE is mediated by the α2 receptor, then adding guanfacine (MDMA + reboxetine + guanfacine) should reduce head bobbing. In this new cohort (MDMA + reboxetine + / - guanfacine, 0.15 mg / kg), head bobbing was suppressed by α2 agonism (receptor activation) (Figure 3B).

[0075] α2-5-HT in behavior 2A To better understand the effects of receptor interactions, 5-HT with stronger HTR 2A Guanfacine was tested against the receptor agonist psilocybin (Figures 4A-4C). In fact, guanfacine was able to suppress psilocybin's HTR (psilocybin + guanfacine vs. psilocybin + saline (n=7; Figure 4B)) and block the previously identified temporal peak. The noradrenergic α2NE receptor is responsible for 5-HT of MDMA. 2A It is also possible to bidirectionally regulate the effects and suppress these effects of classic hallucinogens.

[0076] The hyperphysiological release of NE by MDMA is triggered by the activation of α2 norepinephrine receptors, leading to head-shaking behavior (5-HT). 2A It was found to counteract the downstream effects of agonism. Therefore, this study found that 5-HT indirectly counteracts agonism. 2A The role of NE in counteracting the effects was clarified.

[0077] Despite the observation that NE suppresses the head-shaking response, the specific neural circuits contributing to this counter-state have not been identified. 5-HT to mPFC 2ALocal injection of agonists can induce HTR, but the specificity and circuit basis of this phenomenon remain unclear. Nose bobbing also simultaneously results in apparent widespread activation of cortical and hippocampal circuits. MDMA-induced NE release acts on α2 receptors to 5-HT 2A It counteracts agonist activity. Interestingly, the α2 receptor has a well-characterized effect on pyramidal cells in layer V of the mPFC, and this is also related to 5-HT 2A It has been suggested that this mediates the effects. Furthermore, the noradrenergic effect of MDMA has been identified as contributing to subjective euphoria from MDMA in humans and increased locomotion in mice. Circuit-specific recording and manipulation of the NE pathway may further elucidate how the different monoamine effects of MDMA interact with each other.

[0078] The use of fluorescent GRAB sensors and fiber photometry provided crucial insights into the in vivo mechanism of enteractogen release. The combination of high temporal resolution and molecular specificity allowed the inventors to infer the neuromodulatory release properties of enteractogen. This approach was used to observe the precise manipulation of NE release and NET blockade by MDMA. These sensors, in combination with genetically modified animals, enable spatial and cell-type localization, further clarifying differences between specific regions of enteractogen-induced monoamine release and potentially identifying downstream circuits affected by drug administration.

[0079] 5-HT 2AAgonism plays a crucial role in generating structural plasticity after hallucinogenic drugs and may also contribute to the enhancement of fear extinction. An important caveat is that MDMA also induces social behavior in mice and humans—enhancing prosocial behavior and trust may influence the effectiveness of psychotherapy. Understanding the mechanisms of this therapeutic effect is essential, as MDMA-assisted psychotherapy may be an important and necessary treatment for PTSD. The results presented herein suggest clear, surprising, and unexpected neuromodulatory roles of NE and 5-HT in the action of MDMA.

[0080] The compounds described herein may have one or more stereocenters, each stereocenter may exist independently in (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic compounds. It should be understood that the compounds described herein encompass racemic compounds, brightly active compounds, positional isomers, and stereoisomers, or combinations thereof, having the therapeutically useful properties described herein. Preparation of optically active compounds is achieved by any suitable method, including, but not limited to, recrystallization techniques for racemic compounds, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as the therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional recrystallization, distillation, and chromatography.

[0081] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of any compound having the structure of any compound described herein, as well as metabolites and active metabolites of these compounds having the same kind of activity. Solvates include water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohols (e.g., ethanol) solvates, and acetates, etc. In certain embodiments, the compounds described herein exist in solvated forms with water and pharmaceutically acceptable solvents such as ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0082] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0083] In certain embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” means an active substance that is converted in vivo to a parent drug. In certain embodiments, when administered in vivo, the prodrug is chemically converted to a biological, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0084] In certain embodiments, a portion of the compounds described herein, such as an aromatic ring, is susceptible to various metabolic reactions. By introducing appropriate substituents to the aromatic ring structure, these metabolic pathways may be reduced, minimized, or eliminated. Suitable substituents for reducing or eliminating the metabolic susceptibility of the aromatic ring in certain embodiments include, but are merely illustrative, deuterium, halogens, or alkyl groups.

[0085] Methods of treating, relieving, and / or preventing This disclosure includes methods for treating, relieving, and / or preventing post-traumatic stress disorder (PTSD) using the compounds and / or compositions described herein. The methods described herein also function to treat, relieve, and / or prevent at least one symptom of PTSD. Symptoms of PTSD include, but are not limited to, being agitated by things that remind you of what happened; experiencing nightmares, vivid memories, or flashbacks of the event that make you feel as if the traumatic event is happening again; feeling emotionally disconnected from others; losing interest in or interest in things that were previously important to you; being constantly on guard; feeling irritable or having outbursts of anger; having sleep disturbances; being unable to concentrate; being jumpy or easily startled; frequently avoiding places and things that remind you of what happened; using alcohol and / or drugs to numb your senses; thinking about harming yourself or others; constantly being absorbed in work; and being withdrawn and isolated from others. In certain embodiments, the methods described herein also function to treat, induce remission, and / or prevent at least two, three, four, five, or more symptoms of PTSD. The methods described herein can be used when administering any dose of the enteractogen, NEI, hallucinogen, or AARA described herein.

[0086] In certain embodiments, a method is provided for treating, relieving, and / or preventing post-traumatic stress disorder in a subject in need. In certain embodiments, the method comprises administering a therapeutically effective amount of at least one norepinephrine inhibitor (NEI) or a solvate, enantiomer, diastereomer, tautomer, or (pharmaceutically acceptable) salt of the subject to the subject. In certain embodiments, the method comprises administering a therapeutically effective amount of at least one enteractogen or a solvate, enantiomer, diastereomer, tautomer, or (pharmaceutically acceptable) salt of the subject to the subject. In certain embodiments, post-traumatic stress disorder in the subject is treated, relieved, or prevented.

[0087] A method for treating, relieving, and / or preventing post-traumatic stress disorder in a subject in need, in a particular embodiment. In a particular embodiment, the method comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of a norepinephrine inhibitor (NEI) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In a particular embodiment, the method comprises administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an enterogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In a particular embodiment, the pharmaceutical composition comprising the NEI and the pharmaceutical composition comprising the enterogen are formulated as a single dose or as separate doses. In a particular embodiment, post-traumatic stress disorder in a subject is treated, relieved, or prevented.

[0088] In certain embodiments, NEI or its solvates, enantiomers, diastereomers, tautomers, or (pharmaceutically acceptable) salts are atomoxetine ((R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine), reboxetine (rel-(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine), bilo The following are selected from the group consisting of xazine ((RS)-2-[(2-ethoxyphenoxy)methyl]morpholine), amedalin (UK-3540-1), daredalin (UK-3557-15), ediboxetine (LY-2216684), esreboxetine (AXS-14; PNU-165442G), lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talspram (Lu 5-005), and tandamin (AY-23,946).

[0089] In certain embodiments, an enteractogen or its solvate, enantiomer, diastereomer, tautomer, or (pharmaceutically acceptable) salt is MDMA (3,4-methylenedioxymethamphetamine), MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxy-N-ethylamphetamine), MDOH (3,4-methylenedioxy-N-hydroxyamphetamine), MBDB (1,3-benzodioxolyl-N-methylbutanamine), 5-APB (1-benzofuran-5-ylpropane-2-amine) The following are selected from the group consisting of 5-MAPB (1-(benzofuran-5-yl)-N-methylpropane-2-amine), 6-APB (6-(2-aminopropyl)benzofuran), 6-MAPB (1-(benzofuran-6-yl)-N-methylpropane-2-amine), methylone (3,4-methylenedioxy-N-methylcathinone), mephedrone (4-methylmethcathinone), GHB (γ-hydroxybutyrate), αMT (α-methyltryptamine), αET (α-ethyltryptamine), and MDAI (5,6-methylenedioxy-2-aminoindan).

[0090] In certain embodiments, the NEI is reboxetine. In certain embodiments, the enterogen is MDMA. In certain embodiments, approximately 1 mg to approximately 1000 mg of the NEI is administered to the subject.

[0091] In a specific embodiment, approximately 1 mg to approximately 1000 mg of enteractogen is administered to the target.

[0092] In a particular embodiment, the NEI is administered to the subject 1 minute to 24 hours before the subject is administered the enterogen.

[0093] In certain aspects, NEI and enteractogen are administered simultaneously.

[0094] In a particular aspect, NEI and enteractogen are in a single dosage form.

[0095] In a certain manner, a single dosage form may include an abuse prevention formulation.

[0096] In certain embodiments, NEIs and enteractogens are administered independently by routes independently selected from the group consisting of oral, transdermal, transmucosal, nasal (intra) and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and local administration.

[0097] In a particular embodiment, a method is provided for treating, relieving, and / or preventing post-traumatic stress disorder in a subject in need. In a particular embodiment, the method comprises a therapeutically effective amount of at least one α 2A- The method comprises administering an adrenergic receptor agonist (AARA) or a solvate, enantiomer, diastereomer, tautomer, or (pharmaceutically acceptable) salt thereof to a subject. In a particular embodiment, the method comprises administering a therapeutically effective amount of at least one hallucinogen or a solvate, enantiomer, diastereomer, tautomer, or (pharmaceutically acceptable) salt thereof to a subject. In a particular embodiment, post-traumatic stress disorder in the subject is treated, remitted, or prevented.

[0098] A method for treating, relieving, or preventing post-traumatic stress disorder in a subject in need, in a particular embodiment. In a particular embodiment, the method comprises a therapeutically effective amount of α 2A - The method includes administering a pharmaceutical composition to a subject comprising an adrenergic receptor agonist (AARA) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In certain embodiments, the method includes administering a pharmaceutical composition to a subject comprising a therapeutically effective amount of a hallucinogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. In certain embodiments, the pharmaceutical composition comprising the AARA and the pharmaceutical composition comprising the hallucinogen are formulated as a single dose or as separate doses. In certain embodiments, post-traumatic stress disorder in the subject is treated, remitted, or prevented.

[0099] In a particular embodiment, AARA or its solvates, enantiomers, diastereomers, tautomers, or (pharmaceutically acceptable) salts are selected from the group consisting of clonidine, dexmedetomidine, fadorumidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, methyldopa, methylnorepinephrine, norepinephrine, detomidine, and lofexidine.

[0100] In certain embodiments, hallucinogens or their solvates, enantiomers, diastereomers, tautomers, or (pharmaceutically acceptable) salts are selected from the group consisting of psilocybin, 2C-B (4-bromo-2,5-dimethoxyphenethylamine), ketamine, DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-dimethyltryptamine), LSA (d-lysergic acid amide), and LSD (lysergic acid diethylamide).

[0101] In a particular aspect, AARA is guanfacine.

[0102] In a certain manner, the hallucinogen is psilocybin.

[0103] In a specific embodiment, approximately 1 mg to approximately 1000 mg of AARA is administered to the target.

[0104] In a particular embodiment, approximately 1 mg to approximately 1000 mg of hallucinogens are administered to the subject.

[0105] In a specific embodiment, AARA is administered to the subject 1 minute to 24 hours before the hallucinogen is administered to the subject.

[0106] In certain embodiments, AARA and hallucinogens are administered simultaneously.

[0107] In certain embodiments, AARA and hallucinogens are in a single dosage form.

[0108] In certain aspects, a single dosage form may include an abuse prevention formulation.

[0109] In certain embodiments, AARA and hallucinogens are administered independently by routes independently selected from the group consisting of oral, dermal, mucosal, nasal and rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

[0110] The method described herein comprises the step of administering a therapeutically effective amount of at least one compound described herein to a target, the compound optionally being formulated in a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further comprises the step of administering an additional therapeutic agent for treating PTSD or its symptoms to a target.

[0111] In certain embodiments, administering the compounds described herein to a subject allows for the administration of a lower dose of an additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve similar results in treating PTSD or its symptoms in the subject. For example, in certain embodiments, the compounds described herein enhance the activity of the additional therapeutic agent, thereby enabling the lower dose of the additional therapeutic agent to provide the same effect.

[0112] In a particular embodiment, the compounds and therapeutic agents described herein are co-administered to a subject. In other embodiments, the compounds and therapeutic agents described herein are co-formulated and co-administered to a subject.

[0113] In one particular aspect, the subject is a mammal. In another aspect, the mammal is a human.

[0114] Combination therapy Compounds useful within the scope of the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating PTSD or its symptoms. These additional therapeutic agents may include compounds that are commercially available or available to those skilled in the art through synthesis. These additional therapeutic agents are known to treat or reduce the symptoms of PTSD.

[0115] In various embodiments, synergistic effects are observed when the compounds described herein are administered together with one or more additional therapeutic agents or compounds. For example, the synergistic effect is observed when Sigmoid-E max The effects of drug combinations can be calculated using suitable methods such as the formula (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), Loewe's additive formula (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the median-effect formula (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each of the formulas mentioned above can be applied to experimental data to create corresponding graphs that help evaluate the effects of drug combinations. The corresponding graphs associated with the formulas mentioned above are the concentration-action curve, the isobologram curve, and the combination index curve, respectively.

[0116] Dosage / Prescription The administration regimen may affect what constitutes the effective dose. The therapeutic formulation may be administered to subjects before or after the onset of PTSD or its symptoms. Furthermore, divided doses, as well as staggered dosages, may be administered daily or consecutively, or by continuous infusion or bolus injection. In addition, the dosage of the therapeutic formulation may be increased or decreased proportionally as indicated by the urgency of the treatment or prevention situation.

[0117] The administration of the compositions described herein to patients, preferably mammals, more preferably humans, may be carried out using known methods in doses and durations effective in treating PTSD or its symptoms in the patient. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the patient's state of disease or disability; the patient's age, sex, and weight; and the performance of the therapeutic compound in treating PTSD or its symptoms in the patient. The administration regimen may be adjusted to provide an optimal therapeutic response. For example, multiple divided doses may be administered daily, or the dose may be reduced proportionally as indicated by the urgency of the treatment situation. A non-limiting example of the effective dose range of the therapeutic compounds described herein is about 1 to 5,000 mg / kg body weight / day. Those skilled in the art can test the relevant factors and make a determination regarding the effective amount of the therapeutic compound without excessive experimentation.

[0118] The actual dose levels of the active ingredients in the pharmaceutical compositions described herein may be modified to obtain an amount of the active ingredient that is not toxic to the patient and is effective in achieving a desirable therapeutic response for a particular patient, composition, and mode of administration.

[0119] In particular, the selected dosage level is determined by a variety of factors, including the activity of the specific compound being used, the time of administration, the compound's elimination rate, the duration of treatment, other drugs, compounds, or substances used in combination with the compound, the patient being treated's age, sex, weight, condition, overall health, and medical history, as well as similar factors well known in the medical field.

[0120] A medical doctor with the usual skills in this technology, such as a physician or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dose of the compound described herein used in the pharmaceutical composition at a level lower than the amount required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0121] In certain embodiments, it is particularly advantageous to formulate compounds in unitary dosage forms for ease of administration and uniformity of dosage. As used herein, unitary dosage form means physically distinct units suitable as unitary dosages for a patient to be treated; each unit contains a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect, along with the required pharmaceutical vehicle. The unitary dosage forms of the compounds described herein are determined by and rely directly on (a) the distinctive characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of formulation / formulation of such therapeutic compounds.

[0122] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein contain a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0123] The carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Often, it is preferable to include isotonic agents in the composition, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol and sorbitol. Extension of the absorption of the injectable composition can be achieved by including absorption-delaying agents in the composition, such as aluminum monostearate or gelatin.

[0124] In certain embodiments, the compositions described herein are administered to a patient in doses ranging from one to five times per day or more. In other embodiments, the compositions described herein are administered to a patient in doses ranging from daily, every two days, every three days to once a week and once every two weeks, but are not limited to these. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein will vary from person to person depending on many factors, including age, the disease or disorder being treated, sex, overall health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to any particular administration regimen, and the exact dose and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors relating to the patient.

[0125] The compounds described herein for administration are approximately 1 μg to 10,000 mg, approximately 20 μg to 9,500 mg, approximately 40 μg to 9,000 mg, approximately 75 μg to 8,500 mg, approximately 150 μg to 7,500 mg, approximately 200 μg to 7,000 mg, approximately 350 μg to 6,000 mg, approximately 500 μg to 5,000 mg, approximately 750 μg to 4,000 mg, approximately 1 mg to 3,000 mg, approximately 10 mg to 2,500 mg, approximately 20 mg to 2,000 mg, approximately 25 mg to 1,500 mg, approximately 30 mg to 1,000 mg, approximately 40 mg to 900 mg, approximately 50 mg to 800 mg, approximately 60 mg to 750 mg, and approximately 70 mg to 600 mg. mg, approximately 80 mg to approximately 500 mg, and any whole or partial increment in between.

[0126] In some embodiments, the dose of the compound described herein is about 1 mg to about 2,500 mg. In some embodiments, the dose of the compound described herein used in the composition described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any whole or partial increment thereof.

[0127] In a particular embodiment, the composition described herein is a packaged pharmaceutical composition comprising a container for holding a therapeutically effective amount of the compound described herein, either alone or in combination with a second pharmaceutically active substance; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient.

[0128] The formulations may be used in combination with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration known in the art. Pharmaceutical preparations may be sterilized and, if desired, mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic buffering, and colorants, flavorings, and / or aromatic substances. They may also be combined, if desired, with other activators, such as other analgesics.

[0129] The routes of administration for any of the compositions described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. Compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as oral or parenteral, percutaneous, transmucosal (e.g., sublingual, tongue, (trans) buccal, (trans) urethral, ​​vagina (e.g., transvaginal and perivaginal), nasal (intra) and (trans) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0130] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gelatin capsules (gel caps), lozenges, dispersants, suspensions, liquids, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, lozenges, creams, ointments, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosol preparations for inhalation, and compositions and preparations for intravesical administration. It should be understood that the preparations and compositions described herein are not limited to the specific preparations and compositions described herein.

[0131] Oral administration For oral administration, tablets, sugar-coated preparations, liquids, drops, suppositories, or capsules, caplets, and gelatin capsules are particularly suitable. Compositions intended for oral use may be prepared according to any method known in the art, and such compositions may contain one or more active ingredients selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrating agents such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for refinement or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0132] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means using pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). If desired, tablets may be coated using appropriate methods and coating materials, for example, the OPADRY® film coating system available from Colorcon, West Point, Pa. (e.g., OPADRY® OY type, OYC type, Organic Enteric OY-P type, Aqueous Enteric OY-A type, OY-PM type, and OPADRY® White, 32K18400). Liquid preparations for oral administration may be in the form of liquids, syrups, or suspensions. Liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible oils); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid).

[0133] The compositions described herein may be prepared, packaged, or sold in formulations suitable for oral or buccal administration. Tablets containing the compounds described herein may be made, for example, by compressing or molding the active ingredient together with one or more additional ingredients, as is optional. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granular preparation, mixed with one or more binders, lubricants, excipients, surfactants, and dispersants, using a suitable device. Wet tablets may be made by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to moisten the mixture, using a suitable device. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulators and disintegrants, dispersants, surfactants, disintegrants, binders, and lubricants.

[0134] Suitable dispersants include, but are not limited to, potato starch, sodium starch glycolate, poloxamer 407, or poloxamer 188. Each of the dispersants may be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of the dispersants shall be present in an amount of at least approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% They may be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0135] Surfactants include cationic, anionic, or nonionic surfactants, or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbetopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen bromide, laurylmethylgluceth-10 hydroxypropyldimonium chloride, tetramethylammonium hydroxide, tonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamide-2-methylpropanesulfonic acid, alkylbenzene sulfonate, ammonium lauryl sulfate, ammonium perfluorononanoate, doxart, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoate, perfluorooctanesulfonic acid, perfluoro Octanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl glucosyl Decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, nonoxynol-9, nonoxynol derivatives, nonylphenoxypolyethoxyethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl β-D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glyceride,Examples include pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated beef tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. Each of the one or more surfactants may be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of one or more surfactants is present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% It can be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0136] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose® 80 (75% α-lactose monohydrate and 25% cellulose powder), mannitol, pregelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granular lactose. One or more diluents may be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of the diluents shall be at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% They may be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0137] Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methylcellulose, sodium starch glycolate, pregelatinized starch, povidone, sodium carboxymethylcellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicon dioxide, crospovidone, and alginic acid. One or more granulating or disintegrating agents may be present individually in the composition in amounts ranging from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of the granulating or disintegrating agents shall be present in an amount of at least approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% They may be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0138] Suitable binders include, but are not limited to, gelatin, acacia, pregelatinized corn starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamide, sucrose, dextrose, maltose, gelatin, and polyethylene glycol. Each of the one or more binders may be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of the one or more binders is present in an amount of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% They may be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0139] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. Each of the lubricants may be present individually in the composition in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. Each of the lubricants shall be present in an amount of at least approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form; approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% They may be present individually in the composition in amounts greater than w / w; or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w.

[0140] Tablets may be uncoated or coated using known methods to achieve delayed disintegration in the target gastrointestinal tract, thereby resulting in sustained release and absorption of the active ingredient. For example, materials such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. As a further example, tablets may be coated using the methods described in U.S. Patents 4,256,108, 4,160,452, and 4,265,874 to form osmotically controlled release tablets. Tablets may further contain sweeteners, flavorings, colorings, preservatives, or combinations of some of these to result in a pharmaceutically refined and palatable preparation.

[0141] The tablets may also be enterically coated such that the coating begins to dissolve at a specific pH, for example, about pH 5.0 to about pH 7.5, thereby releasing the compounds described herein. The coating may contain, for example, EUDRAGIT® L, S, FS, and / or E polymers having acidic or alkaline groups, enabling the release of the compounds described herein at specific locations, including any desired site in the intestine. The coating may also contain, for example, EUDRAGIT® RL and / or RS polymers having cationic or neutral groups, enabling the time-controlled release of the compounds described herein by pH-dependent expansion.

[0142] Parenteral administration For parenteral administration, the compounds described herein may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses and / or continuous infusions. Optionally, suspensions, solutions, or emulsions in oily or aqueous vehicles containing other formulation agents such as suspensions, stabilizers, and / or dispersants may also be used.

[0143] The sterile injection forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using appropriate dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injection preparations may be sterile injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and physiological saline. Sterilized non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injections, and naturally pharmaceutically acceptable oils, such as olive oil or castor oil, and especially their polyoxyethylated derivatives, are also useful. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants such as lauryl alcohol, stearyl alcohol, or oleyl alcohol, or similar alcohols, or similar alcohols.

[0144] Further forms of administration Further dosage forms suitable for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Further dosage forms suitable for use with the compounds and compositions described herein also include those described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Further dosage forms suitable for use in the compounds and compositions described herein also include those described in PCT applications WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0145] Controlled-release formulations and drug delivery systems In certain embodiments, the formulations described herein may include, but are not limited to, short-release formulations, rapid-offset formulations, and controlled-release formulations such as sustained-release formulations, delayed-release formulations, and pulsed-release formulations.

[0146] The term "sustained-release" is used in its traditional sense to refer to a drug formulation that provides a sustained release of the drug over a long period, resulting in a substantially constant blood level of the drug over a long period, though not necessarily. This period may be one month or longer, and should be longer than that of the same amount of drug administered in bolus form.

[0147] For sustained release, compounds can be formulated with a suitable polymer or hydrophobic material that imparts sustained-release properties to the compound. Therefore, compounds for use in the methods described herein can be administered in the form of microparticles, for example, by injection, or by embedding in the form of wafers or disks.

[0148] In some cases, the dosage form used can provide the delayed or controlled release of one or more active ingredients contained therein, for example, using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, to achieve a desired release profile in various proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use in the pharmaceutical compositions described herein. Thus, single-unit dosage forms suitable for oral administration and adapted for controlled release, such as tablets, capsules, gelatin capsules, and caplets, are encompassed by the compositions and dosage forms described herein.

[0149] Most controlled-release drugs share the common goal of improving pharmacotherapy beyond what is achieved by their uncontrolled forms. Ideally, the use of optimally designed controlled-release formulations in medical procedures is characterized by utilizing the minimum amount of active pharmaceutical ingredient to heal or control a condition in the shortest possible time. Advantages of controlled-release formulations include extended drug activity, reduced dosing frequency, and increased patient compliance. In addition, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as the blood level of the drug, and thus influence the occurrence of side effects.

[0150] Most controlled-release formulations are designed to release a certain amount of the drug initially to rapidly produce the desired therapeutic effect, and then gradually and continuously release the remaining amount of the drug to maintain this level of therapeutic effect over a long period. To maintain this constant level of the drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug that is metabolized and excreted from the body.

[0151] The controlled release of the active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term “controlled-release ingredient” is defined herein as a compound that facilitates the controlled release of the active ingredient, and includes, but is not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof. In one embodiment, the compounds described herein are administered to a patient using a sustained-release formulation, either alone or in combination with another pharmaceutically active substance.

[0152] The term "delayed release" is used herein in its conventional sense and refers to a drug formulation that results in the initial release of the drug after a certain delay following administration, which may, but not necessarily, range from approximately 10 minutes to up to approximately 12 hours.

[0153] The term "pulsed release" is used herein in its conventional sense and refers to a drug formulation that results in the release of a drug in such a way that it produces a pulsed plasma profile of the drug after administration.

[0154] The term "immediate release," used in its traditional sense, refers to a drug formulation that releases the drug immediately after administration.

[0155] As used herein, short-term means any period of time including, up to approximately 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after drug administration, and any increments thereof, in whole or in part.

[0156] As used herein, rapid elimination means up to approximately 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after administration of the drug, and any period including all or any increments thereof.

[0157] Administration The therapeutically effective dose or amount of the compounds described herein depends on the patient's age, sex, and weight, the patient's current medical condition, and the progression of PTSD or its symptoms in the patient being treated. Those skilled in the art can determine the appropriate dosage based on these and other factors.

[0158] Appropriate doses of the compounds described herein may range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg per day, for example, from about 5 mg to about 250 mg. These doses may be administered as a single dose or in multiple doses, for example, 1 to 4 times or more per day. When multiple doses are used, the amount of each dose may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses at an interval of about 12 hours.

[0159] It is understood that the amount of the compound administered per day may be daily, every other day, every two days, every three days, every four days, or every five days, as an example of non-limiting administration. For example, in every-other-day administration, a dose of 5 mg per day may be started on Monday, with the first subsequent dose of 5 mg per day administered on Wednesday, and the second subsequent dose of 5 mg per day administered on Friday.

[0160] If the patient's condition improves, the administration of the compounds described herein may be continued at the discretion of the physician; or the dose of the administered drug may be temporarily reduced or temporarily suspended for a certain period (i.e., a “drug-free day”). The length of the drug-free day may be arbitrary and vary between two days and one year, and examples only include 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. Dose reductions during drug-free days can range from 10% to 100%, with examples including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0161] Once the patient's condition improves, a maintenance dose is administered as needed. Thereafter, the dose, frequency, or both of these doses are reduced to a level that maintains improvement in the disease. In certain embodiments, the patient may require long-term intermittent treatment if symptoms and / or infection recur.

[0162] The compounds described herein can be formulated in unit dose forms. The term “unit dose form” means a physically distinct unit appropriate as a unit dose for the patient receiving treatment, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect, along with an optional and appropriate pharmaceutical carrier. Unit dose forms may be for once-daily administration or for multiple daily administrations (e.g., approximately 1 to 4 times or more per day). When multiple daily administrations are used, the unit dose forms may be the same or different for each dose.

[0163] The toxicity and therapeutic efficacy of such treatment regimens may be determined, optionally, in cell cultures or experimental animals, and are not limited to, LD 50 (The dose at which 50% of the population dies) and ED50 This involves determining the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic effects and therapeutic effects is the LD50. 50 and ED 50 This is a therapeutic index expressed as a ratio between [a certain value] and [another value]. Data obtained from cell culture assays and animal studies are optionally used when formulating the range of doses for use in humans. The dose of such compounds is preferably ED with minimal toxicity. 50 It is within the range of circulating concentrations. Within this range, the dosage may vary depending on the form and route of administration used. [Examples]

[0164] Various aspects of this application can be better understood by referring to the following examples provided as illustrations. The scope of this application is not limited to the examples shown herein.

[0165] Experimental method animal All experiments were conducted using 6-8 week old wild-type C57BL6 / J background mice purchased from Jackson Laboratories. The animals were housed in groups, maintained on a 12-hour / 12-hour light-dark cycle, and given free access to samples and water. All experiments were conducted during the light cycle (7:00-19:00).

[0166] Preparation and administration of drugs The drugs were administered intraperitoneally (IP) at a rate of 0.01 mL / kg using an insulin syringe. MDMA, psilocybin, reboxetine, and guanfacine were purchased from Cayman Chemicals (Ann Arbor, MI) and dissolved in physiological saline. Yohimbine was purchased from Sigma Aldrich (St. Louis, MO) and dissolved in distilled water.

[0167] In fear conditioning studies, the drug was administered 30 minutes before the start of the study. In 5-HT and NE photometry studies, the drug was administered 5 minutes after the start of recording to obtain baseline measurements, immediately before placing the mice in the empty box. In HTR dose-response curve studies, the drug was administered immediately before the start of the study. In HTR and photometry studies with reboxetine and fluoxetine, these inhibitors were injected 1 minute before administering the enterogen. Guanfacine was injected 15 minutes before administering reboxetine or psilocybin. In HTR studies, yohimbine was administered 2 minutes before administering MDMA.

[0168] surgery In all stereotactic surgical procedures, mice were first placed in a stereotactic device (Stoelting) and anesthetized with isoflurane in oxygen (3-5% during induction, gradually decreasing to 1-2% during surgery). Eye drops were applied to the eyes. Hair was removed with scissors or an electric razor (Phillips), the scalp was incised, and the skull was exposed. Next, a craniotomy was performed on the mPFC using a rotary tool (Dremel) or a dental drill. Then, 0.5 μL of AAV9-hSyn-NE2h (WZ Biosciences) virus (1 × 10⁻¹⁶) was administered. 13A Hamilton syringe was filled with genome copies / mL. The tip of the syringe was then placed over the craniotomy and lowered to the injection site. The injection targeted the prefrontal cortex (AP: +1.6~2.1 mm AP, ML: ±0.3 mm, DV: 1.3 mm subdural). The virus was then injected at a rate of 0.1 μL / min. After injection, the syringe was left in place for at least 5 minutes and then slowly withdrawn from the craniotomy. Fiber implantation was performed immediately after virus injection. A fiber optic implant (0.2 mm core, Neurophotometrics) was cut to a length of 3 mm. The implant was held in a stereotactic device and lowered to the virus injection coordinates. The implant was then fixed with quick-drying adhesive cement (C&B Metabond, Parkell). The mouse was then removed from the device and returned to its home cage. All mice received intraperitoneal administration of carprofen (5 mg / kg, Zoetis) post-surgery and for two days post-surgery. All behavioral studies were performed at least three weeks post-surgery.

[0169] Fiber photometry Mice used in fiber photometry experiments were subjected to the surgical procedures described herein approximately 4–8 weeks prior to the experimental sessions. A crossover design was used in these experiments, with each animal receiving all drug conditions over several days (with one day between each condition). The cohort of animals used to measure 5-HT received MDMA (12 mg / kg) and saline. The cohort for NE received MDMA (12 mg / kg) and saline. NE blocker photometry studies using fluoxetine and reboxetine were performed using cohorts from the NE studies, with all animals receiving fluoxetine (10 mg / kg) + MDMA (12 mg / kg) and reboxetine (10 mg / kg) + MDMA (12 mg / kg) over two experimental sessions with one day between sessions. In this case, when animals were used in two photometry studies, the cohorts were run at least two weeks after the completion of the first experiment.

[0170] Fiber photometry of sensor fluorescence was performed using the FP3002 fiber photometry system (Neurophotometrics). A fiber optic cable (Doric) connected to the FP3002 was attached to the fiber optic implant via a ceramic sleeve. Light at the excitation wavelength (470 nm) and the isosbestic point reference wavelength (415 nm) was generated from an LED and transmitted to the fiber optic implant through the fiber optic cable. The emission from the fluorescence sensor was then captured using an sCMOS camera. The excitation wavelength was used at 10% output, and the 470 nm and 415 nm excitations were interleaved at a total sampling rate of 40 Hz, resulting in a 20 Hz recording for each channel. Since 415 nm is not the true isosbestic point of GRABNE, analysis was performed only using the 470 nm excitation channel.

[0171] The records were saved and analyzed offline. For each record, the fluorescence change due to injection was calculated as a percentage change from the mean before injection. Fluorescence from the 470 nm channel was extracted for 120 to 240 seconds and used as the baseline. The percentage change in each test was calculated as a percentage change from the mean signal from 120 to 240 seconds after the start of the recording before drug administration: i.e., dF / F = ((signal) - (mean signal from 120 to 240 seconds after the start of recording)) / (mean signal from 120 to 240 seconds after the start of recording). Analysis was performed using a custom MATLAB script, and statistical analysis was performed using MATLAB or GraphPad Prism 9.

[0172] Head shake response Head-shaking response (HTR) was evaluated using C57BL / 6J mice (7-12 weeks old). Mice were ear-tagged >3 days after arrival at the animal facility and rested for at least 3 days before behavioral testing. Small magnets (SuperMagnetMan-N45 magnets, 3 mm diameter, 0.5 mm thickness) were attached to the ear tags (Stoelting-La Pias Aluminum Ear Tags) with adhesive >2 days before ear tagging. The experimental setup, including the experimental apparatus for analysis and Matlab code, was modified from Gonzales-Maeso and Kwan.

[0173] Doses were randomly assigned, age-matched controls were injected with saline, and drug conditions were randomly assigned. At least three animals per sex were used for each drug dose and condition. If animals were used in more than one HTR experiment, the experimental sessions were spaced at least one week apart. Two animals were used at a time. Immediately after ip injection of hallucinogen or enterogen, animals were placed in separate plastic boxes within a large chamber (Home Depot - 28 in. W × 32 in. H × 21.5 in. D), and HTR was measured for 10 minutes for dose-response curves and for 30 minutes for other circuit-level HTR experiments (Figures 2A-2C, 3A-3C, and 4A-4C). A small lamp was placed behind the large chamber, and a high-speed camera (Basler - acA1920-155um) was suspended from the ceiling to record images of the animals inside the plastic boxes. Between each recording, the plastic boxes were cleaned with 70% ethanol. The number of head oscillations was imported into Prism and used to create graphs, and appropriate statistics were performed for analysis.

[0174] The terms and expressions used herein are for illustrative purposes only and not for limitation, and the use of such terms and expressions is not intended to exclude any equivalent or part of any of the features shown and described, and it is recognized that various modifications are possible within the scope of the embodiments of this application. Accordingly, although this application describes certain embodiments and any features, it should be understood that modifications and changes to the compositions, methods, and concepts disclosed herein may be adopted by those skilled in the art, and such modifications and changes will be considered within the scope of the embodiments of this application.

[0175] List of types The following aspects are provided, and their numbering should not be interpreted as representing a level of importance. Embodiment 1 is a method for treating, relieving, and / or preventing post-traumatic stress disorder in a person who needs it, i) Pharmaceutical compositions comprising a therapeutically effective amount of a norepinephrine inhibitor (NEI) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof; and ii) A pharmaceutical composition comprising a therapeutically effective amount of an enteractogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. The process includes administering the substance to the subject, The pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enteractogen are formulated as a single dosage form or as separate dosage forms, and Post-traumatic stress disorder in the subject is treated, remitted, or prevented. The above method is provided. Embodiment 2 is an embodiment in which the NEI is atomoxetine ((R)-N-methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine), reboxetine (rel-(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine), biloxazine ((RS)-2-[(2-ethoxyphenoxy)methyl]morpholine), amedalin (UK-3540-1), daredalin (UK-3557-15), ediboxetine (LY-2216684), esreboxetine (AXS-14; PNU-165442G), lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talspram (Lu The present invention provides a method according to Embodiment 1, selected from the group consisting of 5-005), and tandamin (AY-23,946), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof. Embodiment 3 is an embodiment in which the enterogen is MDMA (3,4-methylenedioxymethamphetamine), MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxy-N-ethylamphetamine), MDOH (3,4-methylenedioxy-N-hydroxyamphetamine), MBDB (1,3-benzodioxolyl-N-methylbutanamine), 5-APB (1-benzofuran-5-ylpropane-2-amine), 5-MAPB (1-(benzofuran-5-yl)-N-methylpropane-2-amine), 6-APB (6-(2-aminopropyl The present invention provides a method according to Embodiment 1, selected from the group consisting of benzofuran, 6-MAPB (1-(benzofuran-6-yl)-N-methylpropan-2-amine), methylone (3,4-methylenedioxy-N-methylcathinone), mephedrone (4-methylmethcathinone), GHB (γ-hydroxybutyrate), αMT (α-methyltryptamine), αET (α-ethyltryptamine), and MDAI (5,6-methylenedioxy-2-aminoindan), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof. Embodiment 4 provides the method according to any one of Embodiments 1 to 3, wherein the NEI is reboxetine. Embodiment 5 provides the method according to any one of Embodiments 1 to 4, wherein the enterogen is MDMA. Embodiment 6 provides the method according to any of Embodiments 1 to 5, wherein the subject is administered about 1 mg to about 1000 mg of the NEI. Embodiment 7 provides the method according to any of Embodiments 1 to 6, wherein the subject is administered approximately 1 mg to approximately 1000 mg of the enteractogen. Embodiment 8 provides the method according to any one of Embodiments 1 to 7, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen are formulated as separate dosage forms. Embodiment 9 provides a method according to any one of Embodiments 1 to 8, wherein the pharmaceutical composition containing the enteractogen is administered to the subject approximately 1 minute to approximately 24 hours before the administration of the pharmaceutical composition containing the enteractogen to the subject. Embodiment 10 provides the method according to any one of Embodiments 1 to 9, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen are administered simultaneously. Embodiment 11 provides the method according to any one of Embodiments 1 to 10, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen are formulated as a single dosage form. Embodiment 12 provides the method according to any one of Embodiments 1 to 11, wherein the single dosage form includes an abuse prevention formulation. Embodiment 13 provides the method according to any one of Embodiments 1 to 12, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enteractogen are administered independently by a route independently selected from the group consisting of oral, transdermal, transmucosal, nasal (intra) and (trans)rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and local administration. Embodiment 14 provides the method according to any one of Embodiments 1 to 14, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen each independently further comprises at least one pharmaceutically acceptable carrier or excipient. Embodiment 15 is a method for treating, relieving, and / or preventing post-traumatic stress disorder in a person who needs it, i) Pharmaceutical compositions comprising a therapeutically effective amount of an α2A-adrenergic receptor agonist (AARA) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof; and ii) A pharmaceutical composition comprising a therapeutically effective amount of a hallucinogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. The process includes administering the substance to the subject, The pharmaceutical composition containing the AARA and the pharmaceutical composition containing the hallucinogen are formulated as a single dosage form or as separate dosage forms; and Post-traumatic stress disorder in the subject is treated, goes into remission, or is prevented. The above method is provided. Embodiment 16 provides the method according to Embodiment 15, wherein the AARA is selected from the group consisting of clonidine, dexmedetomidine, fadorumidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, methyldopa, methylnorepinephrine, norepinephrine, detomidine, and lofexidine, or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof. Embodiment 17 provides the method according to any one of Embodiments 15 to 16, wherein the hallucinogen is selected from the group consisting of psilocybin, 2C-B (4-bromo-2,5-dimethoxyphenethylamine), ketamine, DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-dimethyltryptamine), LSA (d-lysergic acid amide), and LSD (lysergic acid diethylamide), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof. Embodiment 18 provides the method according to any one of Embodiments 15 to 17, wherein the AARA is guan facine. Embodiment 19 provides the method according to any one of Embodiments 15 to 18, wherein the hallucinogen is psilocybin. Embodiment 20 provides the method according to any of Embodiments 15 to 19, wherein the subject is administered about 1 mg to about 1000 mg of the AARA. Embodiment 21 provides the method according to any of Embodiments 15 to 20, wherein the subject is administered about 1 mg to about 1000 mg of the hallucinogen. Embodiment 22 provides the method according to any one of Embodiments 15 to 21, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are formulated as separate dosage forms. Embodiment 23 provides a method according to any one of Embodiments 15 to 22, wherein the pharmaceutical composition containing the hallucinogen is administered to the subject about 1 minute to about 24 hours before the pharmaceutical composition containing the hallucinogen is administered to the subject. Embodiment 24 provides the method according to any one of Embodiments 15 to 23, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are administered simultaneously. Embodiment 25 provides the method according to any one of Embodiments 15 to 24, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are formulated as a single dosage form. Embodiment 26 provides the method according to any one of Embodiments 15 to 25, wherein the single dosage form includes an abuse prevention formulation. Embodiment 27 provides a method according to any one of Embodiments 15 to 26, wherein the pharmaceutical composition comprising AARA and the pharmaceutical composition comprising the hallucinogen are administered independently by a route independently selected from the group consisting of oral, transdermal, transmucosal, nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. Embodiment 28 provides the method according to any one of embodiments 15 to 27, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen each independently further comprises at least one pharmaceutically acceptable carrier or excipient.

Claims

1. A method for treating, relieving, and / or preventing post-traumatic stress disorder in subjects who need it, i) Pharmaceutical compositions comprising a therapeutically effective amount of a norepinephrine inhibitor (NEI) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof; and ii) A pharmaceutical composition comprising a therapeutically effective amount of an enteractogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. The process includes administering the substance to the subject, The pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enteractogen are formulated as a single dosage form or as separate dosage forms, and Post-traumatic stress disorder in the subject is treated, remitted, or prevented. The aforementioned method.

2. The aforementioned NEIs are atomoxetine ((R)-N-methyl-3-phenyl-3-(o-tolyloxy)propane-1-amine), reboxetine (rel-(2R)-2-[(R)-(2-ethoxyphenoxy)(phenyl)methyl]morpholine), biloxazine ((RS)-2-[(2-ethoxyphenoxy)methyl]morpholine), amedalin (UK-3540-1), daredalin (UK-3557-15), ediboxetine (LY-2216684), esreboxetine (AXS-14; PNU-165442G), lortalamine (LM-1404), nisoxetine (LY-94,939), talopram (taslopram) (Lu 3-010), talspram (Lu The method according to claim 1, selected from the group consisting of 5-005), and tandamin (AY-23,946), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof.

3. The aforementioned entactogens are MDMA (3,4-methylenedioxymethamphetamine), MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxy-N-ethylamphetamine), MDOH (3,4-methylenedioxy-N-hydroxyamphetamine), MBDB (1,3-benzodioxolyl-N-methylbutanamine), 5-APB (1-benzofuran-5-ylpropane-2-amine), 5-MAPB (1-(benzofuran-5-yl)-N-methylpropane-2-amine), 6-APB (6-(2-aminopropyl The method according to claim 1, selected from the group consisting of benzofuran, 6-MAPB (1-(benzofuran-6-yl)-N-methylpropan-2-amine), methylone (3,4-methylenedioxy-N-methylcathinone), mephedrone (4-methylmethcathinone), GHB (γ-hydroxybutyrate), αMT (α-methyltryptamine), αET (α-ethyltryptamine), and MDAI (5,6-methylenedioxy-2-aminoindan), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof.

4. The method according to claim 2, wherein the NEI is reboxetine.

5. The method according to claim 3, wherein the enterogen is MDMA.

6. The method according to claim 1, wherein the subject is administered approximately 1 mg to approximately 1000 mg of the NEI.

7. The method according to claim 1, wherein the subject is administered approximately 1 mg to approximately 1000 mg of the enteractogen.

8. The method according to claim 1, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen are formulated as separate dosage forms.

9. The method according to claim 8, wherein the pharmaceutical composition containing the NEI is administered to the subject approximately 1 minute to approximately 24 hours before the pharmaceutical composition containing the enteractogen is administered to the subject.

10. The method according to claim 1, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enteractogen are administered simultaneously.

11. The method according to claim 1, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the entertactogen are formulated as a single dosage form.

12. The method according to claim 1, wherein the single dosage form includes an abuse prevention formulation.

13. The method according to claim 1, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enteractogen are administered independently by a route independently selected from the group consisting of oral, transdermal, transmucosal, nasal (intra) and (trans)rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and local administration.

14. The method according to claim 1, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enterogen each independently further comprises at least one pharmaceutically acceptable carrier or excipient.

15. A method for treating, relieving, and / or preventing post-traumatic stress disorder in subjects who need it, i) A therapeutically effective dose of α 2A -Pharmaceutical compositions comprising an adrenergic receptor agonist (AARA) or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof; and ii) A pharmaceutical composition comprising a therapeutically effective amount of a hallucinogen or a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer, or tautomer thereof. The process includes administering the substance to the subject, The pharmaceutical composition containing the AARA and the pharmaceutical composition containing the hallucinogen are formulated as a single dosage form or as separate dosage forms; and Post-traumatic stress disorder in the subject is treated, goes into remission, or is prevented. The aforementioned method.

16. The method according to claim 15, wherein the AARA is selected from the group consisting of clonidine, dexmedetomidine, fadorumidine, guanfacine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, methyldopa, methylnorepinephrine, norepinephrine, detomidine, and lofexidine, or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof.

17. The method according to claim 15, wherein the hallucinogen is selected from the group consisting of psilocybin, 2C-B (4-bromo-2,5-dimethoxyphenethylamine), ketamine, DMT (N,N-dimethyltryptamine), 5-MeO-DMT (5-methoxy-dimethyltryptamine), LSA (d-lysergic acid amide), and LSD (lysergic acid diethylamide), or pharmaceutically acceptable salts, solvates, enantiomers, diastereomers, or tautomers thereof.

18. The method according to claim 16, wherein the AARA is guanfacine.

19. The method according to claim 17, wherein the hallucinogen is psilocybin.

20. The method according to claim 15, wherein the subject is administered about 1 mg to about 1000 mg of the AARA.

21. The method according to claim 15, wherein the subject is administered about 1 mg to about 1000 mg of the hallucinogen.

22. The method according to claim 15, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are formulated as separate dosage forms.

23. The method according to claim 22, wherein the pharmaceutical composition containing the hallucinogen is administered to the subject approximately 1 minute to approximately 24 hours before the subject is administered the pharmaceutical composition containing the hallucinogen.

24. The method according to claim 15, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are administered simultaneously.

25. The method according to claim 15, wherein the pharmaceutical composition containing AARA and the pharmaceutical composition containing the hallucinogen are formulated as a single dosage form.

26. The method according to claim 15, wherein the single dosage form includes an abuse prevention formulation.

27. The method according to claim 15, wherein the pharmaceutical composition comprising AARA and the pharmaceutical composition comprising the hallucinogen are administered independently by a route independently selected from the group consisting of oral, dermal, mucosal, nasal (intra) and (trans)rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and local administration.

28. The method according to claim 15, wherein the pharmaceutical composition containing the NEI and the pharmaceutical composition containing the enterogen each independently further comprises at least one pharmaceutically acceptable carrier or excipient.

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