WO2023215344A2 - Compositions and methods for treating cluster-tic syndrome - Google Patents

Compositions and methods for treating cluster-tic syndrome Download PDF

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Publication number
WO2023215344A2
WO2023215344A2 PCT/US2023/020771 US2023020771W WO2023215344A2 WO 2023215344 A2 WO2023215344 A2 WO 2023215344A2 US 2023020771 W US2023020771 W US 2023020771W WO 2023215344 A2 WO2023215344 A2 WO 2023215344A2
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psilocybin
subject
day
cbd
maintenance dose
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PCT/US2023/020771
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French (fr)
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WO2023215344A3 (en
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Mark Wingertzahn
Jeffrey Jewell
Daniel CARCILLO
Stacey ABBY
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Wesana Health Inc.
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Publication of WO2023215344A3 publication Critical patent/WO2023215344A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Cluster-tic syndrome is a rare clinical condition characterized by cluster headache coexisting with ipsilateral trigeminal neuralgia. These patients require treatment directed at both cluster headache and trigeminal neuralgia to achieve remission.
  • each of the two conditions, cluster headache and trigeminal neuralgia can be difficult to successfully manage with existing therapies. Medical therapy usually consists of a combination of drugs used to treat trigeminal neuralgia and cluster headache and is often unsuccessful. Thus, there exists a need for additional therapies for cluster-tic syndrome.
  • the method including administering to the subject at least one loading dose comprising between about 5 mg and 30 mg of psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 0.25 mg to about 3 mg of psilocybin and between about 50 mg to about 600 mg of cannabidiol (CBD), inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome.
  • the symptom of cluster-tic syndrome includes at least one of attacks of facial pain, paroxysms, autonomic features, a sense of restlessness, agiation, and combinations thereof.
  • the autonomic features include at least one of lacrimation, conjunctival injection, nasal congestion rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof.
  • at least one loading dose is administered prior to the at least one maintenance dose.
  • at least one maintenance dose is administered prior to the at least one leading dose.
  • the loading dose includes about 10 mg psilocybin.
  • the loading dose includes about 25 mg psilocybin.
  • the loading dose includes about 30 mg psilocybin.
  • the psilocybin is amorphous psilocybin.
  • the CBD includes synthetic CBD. In some embodiments, the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD.
  • the loading dose is administered prior to an initial maintenance dose by at least seven days. In some embodiments two or more loading doses are administered over a 6 month time period. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the maintenance dose is formulated in a single dosage form. In some embodiments, the maintenance dose is formulated in multiple dosage forms.
  • a symptom of cluster-tic syndrome in a subject, the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has been suspected or diagnosed as having cluster- tic syndrome.
  • the symptom of cluster-tic syndrome includes at least one of unilateral attacks of facial pain, paroxysms, autonomic features, and combinations thereof.
  • the autonomic features include at least one of lacrimation, conjunctival injection, nasal congestion, rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, rhinorrhea, and combinations thereof.
  • the psilocybin is synthetic psilocybin.
  • the synthetic psilocybin is amorphous psilocybin.
  • the CBD is synthetic CBD.
  • the CBD includes between about 400 mg and 600 mg CBD.
  • the CBD includes between about 500 mg and 600 mg CBD.
  • the CBD includes about 600 mg CBD.
  • the maintenance dose is administered every day.
  • the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments the maintenance dose is formulated in a single dosage form. In some embodiments the maintenance dose is formulated in multiple dosage forms.
  • a symptom of cluster-tic syndrome in a subject suspected or diagnosed as having cluster-tic syndrome, the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has received a loading dose of about 25 mg to about 30 mg of psilocybin.
  • the symptom of cluster-tic syndrome includes at least one of unilateral attacks of facial pain, autonomic features, restlessness, and combinations thereof.
  • the autonomic features include at least one of ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea, nasal congestion, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof.
  • the psilocybin is synthetic psilocybin.
  • the synthetic psilocybin is amorphous psilocybin.
  • the CBD is synthetic CBD.
  • the CBD includes between about 400 mg and 600 mg CBD.
  • the CBD includes between about 500 mg and 600 mg CBD.
  • the CBD includes about 600 mg CBD.
  • the maintenance dose is administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the maintenance dose is formulated in a single dosage form. In some embodiments, the maintenance dose is formulated in multiple dosage forms.
  • kits for reducing a symptom of cluster-tic syndrome in a subject comprising administering to a subject in need thereof and having received a loading dose of about 25 mg to about 30 mg of psilocybin, at least one maintenance dose of a combination of about 0.25 mg to about 3.0 mg of synthetic psilocybin and about 50 mg to about 600 mg of sy nthetic cannabidiol, wherein the at least one maintenance dose is administered to the subject about 1 to about 28 days after the subject received the loading dose, to thereby reduce the symptom of cluster-tic syndrome in the subject.
  • the synthetic psilocybin is amorphous psilocybin.
  • the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the dose of psilocybin includes between about 10 mg and 30 mg. In some embodiments, the loading dose of psilocybin includes about 10 mg. In some embodiments, the loading dose of psilocybin includes about 20 mg.
  • the loading dose of psilocybin includes about 25 mg. In some embodiments, the loading dose of psilocybin includes about 30 mg. In some embodiments, the loading dose is administered prior to an initial maintenance dose by at least seven days. In some embodiments, two or more loading doses are administered over a 6 month time period.
  • the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 1 mg to about 600 mg of a neurotransmitter activity modulator, inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome-associated depression.
  • the neurotransmitter activity modulator is selected from the group consisting of a tricyclic antidepressant, an SSRI, and SNRI, and an NRI.
  • the neurotransmitter activity modulator includes a tricyclic antidepressant.
  • the neurotransmitter activity modulator includes an SSRI. In some embodiments, the neurotransmitter activity modulator includes an SNRI. In some embodiments, the neurotransmitter activity modulator includes an NRI. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 500 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 400 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 300 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 200 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 100 mg of the neurotransmitter activity modulator. In some embodiments, the subject has received a loading dose of between 25 mg and 30 mg psilocybin.
  • Cluster-tic syndrome is a condition that can include three types of pain: trigeminal neuralgia pain (paroxysmal, short lasting, and severe), cluster headache pain (severe pain of variable length with autonomic phenomena), and a third type of pain which is a mixture of the first two and may be provoked by trigger points or by moving the neck.
  • Trigeminal neuralgia (TN) pain can be clinically identified by paroxysmal, stereotyped attacks of usually intense, sharp, superficial, or stabbing pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve.
  • TN pain is limited to the distribution of the trigeminal nerve.
  • TN pain tends to occur in paroxysms and is maximal at or near onset. Facial muscle spasms can be seen with severe pain.
  • the pain is often described as electric, shock-like, or stabbing. It usually lasts from one to several seconds, but may occur repetitively, anywhere from 0 to more than 50 times a day. A refractory period of several minutes during which a paroxysm cannot be provoked is common.
  • TN pain Some patients with longstanding TN pain may have continuous dull pain that is present between paroxysms of pain. TN pain is typically unilateral, although occasionally the pain becomes bilateral over time. Most patients with TN pain experience triggered pain. Continuous pain between attacks is sometimes present in many patients. It is typically milder than the paroxysmal attacks and is typically characterized as dull or tingling, though the intensity and quality may fluctuate.
  • TN TN-induced neurodegeneration
  • Other causes of TN via nerve compression may include vestibular schwannoma (acoustic neuroma), meningioma, epidermoid or other cyst, or, rarely, a saccular aneurysm or arteriovenous malformation.
  • the mechanism by which compression of the nerve leads to symptoms may to be related to demyelination in a circumscribed area around the compression.
  • Demyelination of one or more of the trigeminal nerve pathways may be caused by multiple sclerosis, tumors located at the cerebellopontine angle, or other structural lesions of the brainstem. In multiple sclerosis, a plaque of demyelination typically occurs in the root entry zone of the trigeminal nerve, although vascular compression also has been noted.
  • TN pain is variable. Episodes may last weeks or months, followed by pain-free intervals of weeks to years, although most remissions last for only a few months. Recurrence is common, and some patients have concomitant persistent background facial pain. Most often, the condition tends to wax and wane in severity and frequency of pain exacerbations.
  • Cluster headache pain can be described as attacks of severe unilateral pain, accompanied by ipsilateral cranial autonomic symptoms and/or restlessness or agitation. Cluster headache pain is typically described as severe and sharp or stabbing in quality. Patients are typically restless and often prefer to pace about or sit and rock back and forth with cluster headache pain. Some patients may report cutaneous allodynia. Symptoms most commonly occur in periorbital or temporal regions. Cluster headache pain is unilateral, and the symptoms often remain on the same side of the head during a single attack. In some cases, the symptoms can switch to the other side during a different cluster attack (so-called side shift).
  • Cluster headache pain can persist for 15 minutes up to 3 hours in duration and may strike from once every other day to up to eight times a day. These frequently recurring attacks can occur in a cluster or bout and are typically separated by periods of remission when patients are asymptomatic.
  • the cluster headache pain is episodic.
  • the cluster headache pain is chronic. In the episodic form of cluster headache pain, recurring daily attacks can persist for several weeks in a single bout and can be followed by a period of remission. In some embodiments, a cluster bout can last 6 - 12 weeks. In the chronic form, attacks can occur without significant periods of remission.
  • Cluster headache pain can be debilitating and associated with psychiatric comorbidity, including depression and suicidal ideation. In some cases, cluster headache pain can be associated with head trauma. In some cases, cluster headache pain is associated with smoking. Neuroimaging with magnetic resonance imaging (MRI) of the brain with gadolinium contrast can be used to exclude an underlying cause (e.g., structural lesions) for all patients with suspected cluster headache pain.
  • MRI magnetic resonance imaging
  • Autonomic symptoms associated with cluster headache pain may occur during the acute attack.
  • the autonomic symptoms are ipsilateral to the headache and may include ptosis (upper eyelid droop), miosis (excessive constriction of the pupil), lacrimation (tearing), conjunctival injection, rhinorrhea (runny nose), and/or nasal congestion. Sweating and increased cutaneous blood flow may also occur during the attack, particularly in areas of sympathetic deficit.
  • Some patients with cluster headache pain have chronic signs of sympathetic paralysis such as miosis and ptosis that transiently intensify during acute attacks. In some cases, sympathetic disturbances persist on the previously affected side of the face in patients whose cluster headache pain has switched sides.
  • cannabinoid is meant a group of chemicals known to activate cannabinoid receptors in cells.
  • cannabinoids are obtained from Cannabis plants.
  • the cannabinoid is synthetic.
  • the cannabinoid is endogenous to an animal, i.e., an endocannabinoid.
  • the cannabinoid is derived from a plant, e.g., a plant of genus cannabis, i.e., a phytocannabinoid.
  • a plant e.g., a plant of genus cannabis, i.e., a phytocannabinoid.
  • cannabinoids include the following molecules: Cannabichromene (CBC), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV), Cannabichromevannic acid (CBCVA), Cannabicyclol (CBL), Cannabicyclohc acid (CBLA), Cannabicyclovarin (CBLV), Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBD A), Cannabidiorcol (CBD-C1), Cannabi divarin (CBDV), Cannabidivarinic acid (CBDV A), Cannabielsoic acid B (CBEA-B), Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerolic acid (CBGA), Cannabigerolic acid monomethyl
  • the term "cannabinoid” refers to a compound chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDV A, CBG, CBGA, CBGV, or CBGVA.
  • the cannabinoid is cannabidiol (CBD).
  • CBD cannabidiol
  • the cannabinoid is a nanoparticulate, for example a nanoparticulate CBD.
  • the cannabinoid is in the form of a Cannabis plant extract, optionally wherein the plant extract is free of THC (tetrahydrocannabinol) or THCA (tetrahydrocannabinolic acid).
  • CBD canidiol
  • cannabidiol is synthetic.
  • psilocybin is meant [3-(2-dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate having the CAS number 520-52-5 and the structure, pharmaceutically acceptable salts thereof.
  • psilocybin is synthetic.
  • the psilocybin is amorphous psilocybin.
  • psilocybin is extracted from a biological sample.
  • psilocin 4-hydroxy-N,N-dimethyltryptamine, having the CAS number
  • psilocin is alternatively referred to as 4-HO-DMT, psilocine, psilocyn, or psilotsin.
  • the psilocin is synthetic.
  • any of the compounds of the present disclosure may be, in various embodiments, present in its protonated or deprotonated (salt or freebase) forms or mixtures thereof. The form of a compound may depend on context, for example the pH of the solution or composition. Further, unless otherwise specified, a pharmaceutically acceptable salt of any of the compounds discussed herein is contemplated as being suitable for use in the compositions, methods, and/or compositions of the present disclosure.
  • administer can refer to dosing, treating, giving, or providing.
  • Administering or administration can refer to one particular administration event.
  • administering or administration can refer to an administration protocol, wherein parts of the composition are provided at intervals, wherein administering can refer to a part or the whole of the treatment protocol.
  • agent can refer to any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
  • ameliorate can refer to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • alteration can refer to a change in a measured quantity.
  • the change can be an increase or a decrease.
  • an alteration includes a 10% change, a 25% change, a 40% change, a 50% change, a 60% change, a 70% change, an 80% change, a 90% change, or a 95% or greater change.
  • ingredients include only the listed components along with the normal impurities present in commercial materials and with any other additives present at levels which do not affect the operation of the disclosure, for instance at levels less than 5% by weight or less than 1% or even 0.5% by weight.
  • derivative can refer to a compound retaining a physiological activity of an original compound.
  • the derivative of a compound has substantially the same or improved activity relative to the starting compound.
  • the derivative may be a metabolite of the original compound from which it is derived.
  • the derivative may be produced in some embodiments according to standard principles of medicinal chemistry.
  • the derivative may exhibit a lesser degree of activity than the starting material, so long as sufficient activity is retained as to be therapeutically effective.
  • the derivative of a compound may exhibit improved solubility, reduced toxicity, improved potency, enhanced uptake, and the like.
  • the derivative can be a derivative of a cannabinoid or of psilocybin/psilocin.
  • the derivative can be a prodrug form of a compound.
  • an effective amount or “therapeutically effective amount” can refer to the amount of an agent required to reduce the symptoms of a condition relative to a reference.
  • a reference is an untreated patient or is the state of the subject at an earlier point in time (e.g., prior to treatment).
  • the effective amount ameliorates the symptoms of the condition.
  • the effective amount of active compound(s) used to practice the present disclosure for therapeutic treatment of a condition varies depending upon the manner of administration, the age, body weight, and general health of the subject.
  • isolated can refer to material that is free to vary ing degrees from components which normally accompany it as found in its native state.
  • an “essentially pure” compound has a degree of purity of up to at least 90%, 95%, or 99% by weight.
  • essentially pure means free from other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes.
  • Isolate denotes a degree of separation from original source or surroundings.
  • Purify denotes a degree of separation that is higher than isolation. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, high performance liquid chromatography (HPLC) or mass spectroscopy (e.g., GC/MS or LC/MS/MS).
  • obtaining as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent.
  • “pharmaceutically acceptable salt” can refer to salts or esters prepared using pharmaceutically acceptable non-toxic bases or acids.
  • the base or acid includes inorganic bases or acids and/or organic bases or acids.
  • “reduces” can refer to a negative alteration of at least about 10%, 25%, 50%, 75%, or 100%.
  • “reference” can refer to a standard or control condition. In some embodiments, the reference is the state of a subject prior to treatment. The state of a subject may include the symptoms experienced prior to treatment. In other embodiments, a reference is the state of an untreated control patient.
  • the mammal can refer to a mammal.
  • the mammal is a human or non-human mammal, such as a bovine, equine, canine, ovine, feline, or rodent such as a rat or mouse.
  • the terms “patient” and “subject” are used interchangeably.
  • the subject may be male or female.
  • the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject.
  • the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age.
  • the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • the terms “treat,” “treating,” “treatment,” and the like can refer to reducing, preventing, and/or ameliorating a condition and/or symptoms associated therewith It will be appreciated that, although not precluded, treating a disorder or condition does not require that the condition or symptoms associated therewith be completely eliminated.
  • the condition is cluster-tic syndrome or a risk of suffering from cluster- tic syndrome.
  • the disorder is cluster-tic syndrome.
  • MedDRA Medical Dictionary for Regulatory Activities
  • a maintenance dose of the present disclosure comprises a sufficiently low dose of psilocybin or a derivative thereof to avoid or reduce the occurrence in a subject administered the psilocybin or derivative thereof of an adverse psychedelic event.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • compositions and methods that are useful for treatment or prevention of cluster-tic syndrome.
  • compositions and methods are useful in the treatment or prevention of cluster-tic syndrome.
  • compositions of the present disclosure in various embodiments comprise psilocybin or a derivative thereof and/or a cannabinoid, and/or a neurotransmitter activity modulator.
  • the compositions of the disclosure include one or more of psilocybin or a derivative thereof, a cannabinoid, and a neurotransmitter activity modulator.
  • the compositions are pharmaceutical compositions or nutraceutical compositions (e.g., dietary supplements and functional foods) comprising one or more pharmaceutically acceptable additives (e.g., a carrier, excipient, or diluent).
  • the compositions can be used for the treatment of cluster-tic syndrome or symptoms thereof.
  • one or more compositions described herein can be added to a second composition described herein.
  • compositions and methods described herein include psilocybin or a derivative of psilocybin, either of which may be purified from a natural source (e.g., a mushroom plant) or synthetic (i.e., manufactured by artificial means, such as by organic synthesis in a laboratory).
  • a source of psilocybin in the composition is dried Psilocybe cubensis or a member of the genus Psilocybe (e.g., Psilocybe azurescens, P. semilanceata, or P. cyanescens).
  • the psilocybin is synthetic psilocybin.
  • the psilocybin is amorphous psilocybin.
  • the amorphous psilocybin can be sprayed onto a filler or other composition (e.g., a CBD and/or neurotransmitter activity modulator composition).
  • the psilocybin is deuterated psilocybin.
  • the derivative of psilocybin is a metabolite of psilocybin (e.g., psilocin).
  • the psilocin is naturally extracted.
  • the psilocin is synthetic.
  • the psilocin is amorphous. In some embodiments, the psilocin is deuterated. In some embodiments the derivative of psilocybin is a prodrug of psilocybin.
  • prodrug is meant a therapeutically inactive compound that can be metabolized in a subject’s body to produce a therapeutically active compound.
  • the psilocybin derivative is selected from one or more of the following: [3-(2 -Dimethylaminoethyl)-! H-indol-4-yl] dihydrogen phosphate; 4- hydroxytryptamine; 4-hydroxy-N,N-dimethyltryptamine; [3-(2- methylaminoethyl)- 1 H- indol-4-yl] dihydrogen phosphate; 4-hydroxy-N-methyltryptamine; [3-(armnoethyl)-l H- indol-4-yl] dihydrogen phosphate; [3-(2 -trimethylaminoethyl)- 1 H-indol-4-yl] dihydrogen phosphate; and 4-hydroxy-N,N,N-trimethyltryptamine.
  • the composition comprises psilocybin in an amount of about or at least about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0. 1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%.
  • the composition comprises psilocybin in an amount of no more than about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 v %, or 80 wt%.
  • the composition may include synthetic psilocybin or a derivative thereof in an amount of from about 1 mg to about 100 mg.
  • the psilocybin is synthetic psilocybin.
  • the psilocybin is crystalline psilocybin.
  • the psilocybin is amorphous psilocybin.
  • the psilocybin is deuterated psilocybin.
  • compositions may include synthetic psilocybin or a derivative thereof in an amount from about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 34 mg, about 1 mg to about 33 mg, about 1 mg to about 32 mg, about 1 mg to about 31 mg, about 1 mg to about 30 mg, about 1 mg to about 29 mg, about 1 mg to about 28 mg, about 1 mg to about 27 mg, about 1 mg to about 26 mg, about 1 mg to about 25 mg, about 1 mg to about 24 mg, about 1 mg to about 23 mg, about 1 mg to about 22 mg, about 1 mg to about 21 mg, about 1 mg to about 20 mg, about 1 mg to about 19 mg, about 1 mg to about 18 mg, about 1 mg to about 15 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about
  • the synthetic psilocybin or derivative thereof or psilocin or derivative thereof can be calculated based on the subject’s body weight.
  • the composition comprises about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg of the subject’s body weight.
  • the synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.1 mg/kg to about 1 mg/kg, about 0.2 mg/kg to about 1 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.4 mg/kg to about 1 mg/kg, about 0. 1 mg/kg to about 0.9 mg/kg, about 0.1 mg/kg to about 0.8 mg/kg, about 0.1 mg/kg to about 0.7 mg/kg, about 0. 1 mg/kg to about 0.6 mg/kg, about 0. 1 mg/kg to about 0.5 mg/kg, about 0.
  • the composition may include natural psilocybin or a derivative thereof in an amount of from about 0.5 g to about 6 g.
  • the psilocybin or derivative there, or the psilocin or derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis.
  • the psilocybin is in the form of natural dried mushroom.
  • the psilocybin is an extract from natural dried mushrooms. This includes about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1.0 g, about 1.2 g, about
  • compositions may include psilocybin or a derivative thereof in an amount from about 0.5 g mg to about 6 g, about 1 g to about 6 g, about 1 g to about 5 g, about 1 g to about 4 g, about 1 g to about 3 g, about 1 g to about 2 g, about 2 g to about 6 g, about 2 g to about 5g, about 2 g to about 4 g, about 2 g to about 3 g, about 3 g to about 6 g, about 3 g to about 6 g, about 3 g to about 5 g, about 3 g to about 4 g, about 4 g to about 6 g, about 4 g to about 5 g.
  • the amount of psilocybin or derivative thereof or psilocin or derivative thereof is about
  • the composition may include psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis.
  • the psilocybin is an extract from natural dried mushrooms.
  • the composition can be calculated based on the subject’s body weight.
  • the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg O/kg O,' about 0.06 mg O/kg O,' about 0.07 mg O/kg O,' about 0.08 mg O/kg O,' about 0.09 mg O/kg O,' about
  • 0. 1 mg/kg about 0. 11 mg/kg, about 0.12 mg/kg, about 0. 13 mg/kg, about 0. 14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, or about 0.2 mg/kg of the subject’s body weight.
  • the psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the composition comprises about 0.01 mg/kg to about 0.2 mg/kg, about 0.02 mg/kg to about 0.2 mg/kg, about 0.03 mg/kg to about 0.2 mg/kg, about 0.04 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.2 mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0. 0.07 mg/kg to about 0. 0.
  • the composition may include an amount of synthetic psilocybin or a derivative thereof that provides from about 0.01 mg up to about 10 mg of the psilocybin or the derivative thereof. This includes about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 0.4 mg, about 0.41 mg, about
  • the composition may include an amount of synthetic psilocybin that provides from about 0.01 mg up to about 6 mg psilocybin.
  • Other non-limiting ranges include about 0. 1 mg up to about 9 mg, about 0. 1 mg up to about 8 mg, about 0.1 mg up to about 7 mg, about 0. 1 mg up to about 6 mg, about 0. 1 mg up to about 5 mg, about 0. 1 mg up to about 4 mg, about 0. 1 mg up to about 3 mg, about 0. 1 mg up to about 2 mg, about 0. 1 mg up to about 1 mg, about 0. 1 mg up to about 0.9 mg, about 0. 1 mg up to about 0.8 mg, about 0. 1 mg up to about 0.7 mg, about 0. 1 mg up to about 0.6 mg, about 0.
  • the synthetic psilocybin or derivative thereof or psilocin or derivative thereof can be calculated based on the subject’s body weight.
  • the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0 08 mg/kg, about 0.09 mg/kg, or about 0. 1 mg/kg of the subject’s body weight.
  • the synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.01 mg/kg to about 0.
  • the composition may include natural psilocybin or a derivative thereof in an amount of from about 0.05 g to about 0.6 g.
  • the psilocybin or derivative thereof, or the psilocin or derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis.
  • the psilocybin is an extract from natural dried mushrooms.
  • compositions may include natural psilocybin or a derivative thereof in an amount from about 0.05 g mg to about 0.6 g, about 0.1 g to about 0.6 g, about 0. 1 g to about 0.5 g, about 0.1 g to about 0.4 g, about 0. 1 g to about 0.3 g, about 0.
  • the amount of psilocybin or derivative thereof or psilocin or derivative thereof is about 0.25 g to about 0.5 g of dried mushrooms.
  • the composition may include natural psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis, wherein the composition comprises about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.017 mg/kg, about 0.018 mg/kg, about 0.019 mg/kg, or about 0.02 mg/kg of the subject’s body weight.
  • the natural psilocybin or a derivative thereof comprises about 0.001 mg/kg to about 0.02 mg/kg, about 0.002 mg/kg to about 0.02 mg/kg, about 0.003 mg/kg to about 0.02 mg/kg, about 0.004 mg/kg to about 0.02 mg/kg, about 0.005 mg/kg to about 0.02 mg/kg, about 0.006 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.02 mg/kg, about 0.008 mg/kg to about 0.02 mg/kg, about 0.009 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.01 mg/kg, about 0.006 mg/kg to about 0.011 mg/kg, about 0.005 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg of the subject’s body weight.
  • the psilocybin may be isolated, extracted, purified, crystalline, amorphous, or deuterated psilocybin.
  • the psilocybin is purified psilocybin manufactured under Good Manufacturing Practices (GMP) conditions.
  • GMP Good Manufacturing Practices
  • the cannabidiol may be synthetic cannabidiol or may be purified cannabidiol that has been extracted from a natural source.
  • the cannabidiol can be full synthetic cannabidiol, nano-emulsified cannabidiol, deuterated cannabidiol, naturally extracted cannabidiol, or amorphous cannabidiol.
  • the cannabinoid can be a nanoparticulate cannabinoid, such as nanoparticulate cannabidiol.
  • the nanoparticulate cannabinoid increases absorption of the cannabinoid.
  • the absorption is increased between 5% and 50% better than nonnanoparticulate formulations of the cannabinoid. In some embodiments, the absorption is increased between 10% and 50%, between 15% and 50%, between 20% and 40%, between 20% and 35%, between 25% and 30% better than non-nanoparticulate formulations of the cannabinoid. In some embodiments, the absorption is increased about 10% more, about 15% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more than non-nanoparticulate formulations of the cannabinoid. In some embodiments, additional synthetic cannabinoids such as CBG or CBA and/or synthetic terpenes can be added to confer additional functionality.
  • CBG or CBA and/or synthetic terpenes can be added to confer additional functionality.
  • an extract can be prepared by contacting plant material with supercritical or subcritical carbon dioxide.
  • an extract can be prepared by contacting plant material with a heated gas (e.g., at a temperature in excess of 100°C) sufficient to volatilize one or more components of the plant material to be extracted and condensing the vapor to form an extract.
  • the composition of the methods and compositions described herein can include a cannabinoid or a derivative thereof.
  • the composition can include the cannabinoid in combination with psilocybin or a derivative thereof.
  • the composition comprises a cannabinoid or a derivative thereof in an amount of about or at least about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40
  • the composition comprises a cannabinoid or a derivative thereof in an amount of no more than about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%.
  • compositions may include from about 1 mg to about 1000 mg of a cannabinoid.
  • the cannabinoid in various embodiments is cannabidiol (CBD).
  • CBD cannabidiol
  • the cannabinoid is synthetic CBD.
  • the compositions may include, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg
  • compositions may include a synthetic cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about
  • the compositions may include a synthetic cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about
  • the synthetic cannabidiol or derivative thereof can be calculated based on the subject’s body weight.
  • the composition comprises about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, or about 15 mg/kg of the subject’s body weight.
  • the synthetic cannabidiol or a derivative thereof can comprise about 1 mg/kg to about 15 mg/kg, about 1 mg/kg to about 13 mg/kg, about 1 mg/kg to about 11 mg/kg, about 2 mg/kg to about 11 mg/kg, about 3 mg/kg to about 10 mg/kg, about 4 mg/kg to about 9 mg/kg of the subject’s body weight.
  • the cannabidiol or derivative thereof can be a natural cannabidiol, for example in the form of a full kief.
  • the composition comprises about 1 to about 1000 mg of natural cannabidiol, for example, about 1 mg, about 5, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80
  • CBD cannabinoid
  • the composition comprises natural CBD in an amount from about 1-1000 mg, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81,
  • the composition comprises natural CBD in an amount from about 1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about 250
  • the compositions may include a natural cannabinoid (e.g., in the form of a full kief) in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about
  • the natural cannabidiol can be calculated based on the subject’s body weight.
  • the composition comprises about 0. 1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, or about 3.0 mg/kg of the subject’s body weight.
  • the natural cannabidiol can comprise about 0. 1 mg/kg to about 3 mg/kg, about 0.2 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 3 mg/kg, about 0.4 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 3 mg/kg, about 0.6 mg/kg to about 3 mg/kg, about 0.7 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 2.9 mg/kg, about 0.5 mg/kg to about 2.8 mg/kg, about 0.5 mg/kg to about 2.7 mg/kg, about 0.5 mg/kg to about 2.6 mg/kg, about 0.5 mg/kg to about 2.5 mg/kg, about 0.7 mg/kg to about 2.9 mg/kg, about 0.7 mg/kg to about 2.8 mg/kg, about 0.7 mg/kg to about 2.7 mg/kg, about 0.7 mg/kg to about 2.6 mg/kg, or about 0.7 mg/kg to about 2.5 mg/kg of the subject’s body weight.
  • the compositions can comprise a neurotransmitter activity modulator.
  • the neurotransmitter activity modulator in some embodiments is a serotonergic drug, a dopaminergic drug, an anxiolytic drug, and/or an adrenergic drug.
  • neurotransmitter activity modulator refers to a compound or composition that reacts with or influences activity at a neurotransmitter receptor.
  • the neurotransmitter activity modulator is a serotonergic drug, an adrenergic receptor, a dopamine receptor, a GABAergic receptor, a glutaminergic receptor, a histaminergic receptor, a cholinergic receptor, an opioid receptor, or a glycinergic receptor.
  • a neurotransmitter activity modulator binds on a neurotransmitter receptor.
  • a neurotransmitter activity modulator indirectly affects a neurotransmitter receptor, e.g., via interactions affecting the reactivity of other molecules at a neurotransmitter receptor.
  • a neurotransmitter activity modulator is an agonist.
  • a neurotransmitter activity modulator is an antagonist.
  • a neurotransmitter activity modulator acts (either directly or indirectly) at more than one type of neurotransmitter receptor.
  • the neurotransmitter activity modulator is a compound that influences activity at one or more of the following receptors: serotonin receptor, adrenergic receptor, dopamine receptor, GABA receptor, glutaminergic receptor, histaminergic receptor, cholinergic receptor, opioid receptor, glycinergic receptor, alpha 1 and alpha 2 receptors, sigma 1 and sigma 2 receptors, and muscarinic receptors.
  • Non-limiting examples of neurotransmitter activity modulators include aripiprazole, bupropion, citalopram, clomipramine, dextroamphetamine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, quetiapine, reboxetine, risperidone, sertraline, and venlafaxine.
  • a serotonergic drug refers to a compound that binds to, blocks, or otherw ise influences activity at a serotonin receptor.
  • a serotonergic drug binds to a serotonin receptor.
  • a serotonergic drug indirectly affects a serotonin receptor, e.g., via interactions affecting the reactivity of other molecules at the serotonin receptor.
  • a serotonergic drug is an agonist, e.g., a compound activating a serotonin receptor.
  • a serotonergic drug is an antagonist, e.g., a compound binding but not activating a serotonin receptor, e.g., blocking a receptor.
  • a serotonergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation.
  • a serotonergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).
  • a serotonergic drug is an antidepressant.
  • a serotonergic drug is a tricyclic antidepressant (TCA).
  • a serotonergic drug is an anxiolytic. In one embodiment, a serotonergic drug is a selective serotonin reuptake inhibitor (SSRI). In one embodiment, a serotonergic drug is a selective serotonin norepinephrine reuptake inhibitor (SNRI).
  • SSRI selective serotonin reuptake inhibitor
  • SNRI selective serotonin norepinephrine reuptake inhibitor
  • the serotonergic drug is chosen from alprazolam, amphetamine, aripiprazole, a/api rone, a barbiturate, bromazepam, bupropion, buspirone, a cannabinoid, chlordiazepoxide, citalopram, clonazepam, clorazepate, dextromethorphan, diazepam, duloxetine, escitalopram, fluoxetine, flurazepam, fluvoxamine, lorazepam, lysergic acid diethylamide, lysergamide, 3,4- methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, phenethylamine, psicaine, oxazepam, reboxetine, serenic, serotonin, sertraline, temazepam, tram
  • the serotonergic drug is a tricyclic antidepressant (TCA), which can include amineptine, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, desipramine, demexiptiline, dibenzepin, dimetacrine, doxepin, fluacizine, imipramine, imipraminoxide, iprinodole, lofepramine, maprotiline, melitracen, metapramine, nitroxazepine, nortripyline, noxiptiline, opipramol, protriptyline, propizepine, tianeptine, trimipramine, and quinupramine.
  • TCA tricyclic antidepressant
  • the serotonergic drug is a selective serotonin reuptake inhibitor (SSRI), which can include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone.
  • SSRI selective serotonin reuptake inhibitor
  • the serotonergic drug is a serotonin norepinephrine reuptake inhibitor (SNRI), which can include desvenlafaxine, duloxetine, levormlnacipran, venlafaxine, and desvenlafaxine.
  • SNRI serotonin norepinephrine reuptake inhibitor
  • tricyclic, SSRI, SNRI, and NRI are descriptive terms, wherein a particular compound could be described by one or more of the previous terms. Additionally, there may be neurotransmitter activity modulators contemplated by the current disclosure which may be described by other or additional terms (e.g., buproprion can be described as an atypical antidepressant).
  • a dopaminergic drug refers to a compound that binds, blocks, or otherwise influences activity at a dopamine receptor.
  • a dopaminergic drug is a dopamine transporter inhibitor.
  • a dopaminergic drug is a vesicular monoamine transporter inhibitor.
  • a dopaminergic drug is chosen from amineptine, apomorphine, benzylpiperazine, bromocriptine, cabergoline, chlorpromazine, clozapine, dihydrexidine, domperidone, dopamine, fluphenazine, haloperidol, ketamine, loxapine, methamphetamine, olanzapine, pemoline, perphenazine, pergolide, phencyclidine, phenethylamine, phenmetrazine, pimozide, piribedil, a psychostimulant, reserpine, risperidone, ropinirole, tetrabenazine, thioridazine, or a combination thereof.
  • an adrenergic drug refers to a compound that binds, blocks, or otherwise influences activity at an adrenergic receptor.
  • an adrenergic drug binds to an adrenergic receptor.
  • an adrenergic drug indirectly affects an adrenergic receptor, e.g., via interactions affecting the reactivity of other molecules at the adrenergic receptor.
  • an adrenergic drug is an agonist, e.g., a compound activating an adrenergic receptor.
  • an adrenergic drug is an antagonist, e.g., a compound binding but not activating an adrenergic receptor, e.g., blocking a receptor.
  • an adrenergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation.
  • an adrenergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.).
  • an adrenergic drug is an antidepressant.
  • an adrenergic drug is a norepinephrine transporter inhibitor (NRI).
  • an adrenergic drug is a vesicular monoamine transporter inhibitor.
  • an adrenergic drug is chosen from adrenaline, agmatine, amoxapine, aptazapine, atomoxetine, bupropion, clonidine, doxepin, duloxetine, esmirtazpine, mianserin, mirabegron, mirtazapine, norepinephrine, phentolamine, phenylephrine, piperoxan, reserpine, ntodrine, setiptiline, tesofensine, timolol, trazodone, trimipramine, or xylazine.
  • an adrenergic drug is considered to be a norepinephrine reuptake inhibitor (NRI).
  • NRI norepinephrine reuptake inhibitor
  • an NRI can include bupropion or atomoxetine.
  • compositions of the present disclosure contain an anxiolytic drug.
  • anxiolytic drugs include alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam.
  • the compositions of the present disclosure contain an antidepressant.
  • Non-limiting examples of antidepressants include buproprion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.
  • compositions comprising a therapeutically effective combination of cannabidiol and/or a derivative thereof, and/or psilocybin and/or a derivative thereof, and/or psilocin and/or a derivative thereof, and/or a neurotransmitter activity modulator, and various combinations thereof.
  • the therapeutically effective combination of cannabidiol, and/or psilocybin, and/or psilocin may be provided as a combination composition wherein each of the cannabidiol, and/or psilocybin, and/or psilocin are provided as separate compositions in separate dosage forms, or may be provided as a combination composition wherein each of the cannabidiol, and/or psilocybin, and/or psilocin are provided in a single composition, in a single dosage forms or multiple dosage forms containing divided doses of the composition.
  • a combination composition may include one or more capsules containing psilocybin and/or psilocin, one or more capsules containing cannabidiol, and one or more capsules containing a neurotransmitter activity modulator, or may include one or more capsules containing each of psilocybin and/or psilocin, cannabidiol, and a neurotransmitter activity modulator.
  • two or more of psilocybin and/or psilocin, cannabidiol, and a neurotransmitter activity modulator may be provided in the same composition, in a single dosage forms or multiple dosage forms containing divided doses.
  • a combination composition may include one or more capsules containing cannabidiol and one or more capsules containing psilocybin and/or psilocin only, or one or more capsules containing neurotransmitter activity modulators and psilocybin, and one or more capsules containing cannabidiol only, or one or more capsules containing neurotransmitter activity modulators and cannabidiol, and one or more capsules containing mushroom blends, wherein the psilocybin may be contained in either type of capsule.
  • one or more or all of the compositions may optionally further comprise a pharmaceutically acceptable carrier or excipient suitable for oral administration.
  • the maintenance dose can be a solid dosage form or a liquid.
  • compositions optionally may further include a composition comprising a loading dose of psilocybin as described herein, in a single dosage form or multiple dosage forms containing divided doses.
  • a loading dose can be a solid dosage form or a liquid.
  • a composition can include psilocybin or derivatives thereof, in combination with a neurotransmitter activity modulator.
  • the neurotransmitter activity modulator is a serotonergic neurotransmitter activity modulator.
  • the neurotransmitter activity modulator is a tricyclic antidepressant.
  • the neurotransmitter activity modulator is an SSRI.
  • the neurotransmitter activity modulator is an SNRI.
  • the neurotransmitter activity modulator is a norepinephrine reuptake inhibitor (NRI).
  • the combination composition can comprise a single dosage form or multiple dosage forms containing divided doses of the composition.
  • the combination composition can comprise separate dosages or dosage forms for the different combination components.
  • a composition can include adding one of identified psilocybin, and/or CBD, and/or neurotransmitter activity modulator compositions to another identified composition (e.g., psilocybin, and/or CBD, and/or neurotransmitter activity modulator).
  • composition of the disclosure can include adding psilocybin to any of the identified neurotransmitter activity modulators identified herein (e.g., adding psilocybin to a tricyclic antidepressant, an SSRI, and SNRI, and/or an NRI).
  • compositions described herein can be manufactured by conventional methods, such as those including mixing, dissolving, granulating, levigating, emulsifying, encapsulating, and/or lyophilization processes.
  • the compositions can be formulated in accordance with conventional practices, optionally with one or more pharmaceutically acceptable carriers or excipients suitable for oral administration.
  • Combination products with complementary, additive, or synergistic mechanisms of action can provide greater efficacy while reducing adverse effect profiles.
  • Combination products are frequently used in the therapeutic management of multiple and complex diseases/conditions including but not limited to methods for treating cluster-tic syndrome.
  • Other neurological conditions or symptoms associated with cluster-tic syndrome e.g., ipsilateral to the headache cranial autonomic symptoms and a sense of restlessness or agitation
  • CBD cannabidiol
  • Psilocybin O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine
  • Psilocin 4-hydroxy- N,N-dimethyltryptamine
  • Psilocin is the active molecule that produces the pharmacologic effects of a selective agonist of serotonin (5-HT) family of receptors, which includes the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes.
  • Psilocybin also significantly decreases 11 C-raclopride binding potential bilaterally in the caudate nucleus and putamen, which results in a reciprocal increase in endogenous dopamine.
  • Dual actions from the presynaptic and postsynaptic 5-HT2A receptor activation by psilocin forms a cyclic feedback process for 5-HT2A receptor activation of glutamate effects in the central nervous system, leading to a complex cortical-thalamic neurocircuitry.
  • psilocybin activation of 5-HT2A may impact nociception modulation pathways.
  • 5-HT2A receptor activation causes upregulation of genes associated with neuroplasticity and suppresses TNF-a-induced inflammation.
  • Cannabidiol (2-[(6R)-3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l- yl]-5- pentylbenzene-l,3-diol) is a phytocannabinoid derived from Cannabis species, which is devoid of psychoactive activity, with analgesic, anti- inflammatory, and neuroprotective, and anxiolytic activities.
  • cannabidiol Upon administration, cannabidiol (CBD) exerts activity through various mechanisms.
  • Cannabidiol binds to CB1 receptor and changes the binding site through negative allosteric modulation which is thought to provide its anxiolytic properties (e.g., mitigation of the anxiety associated with THC consumption).
  • Cannabidiol can act as a positive modulator of 5HT1 A-mediated neurotransmission or as an agonist at transient receptor potential cation channel subfamily V member 1 (TRPV1) and peroxisome proliferator- activated receptor gamma (PPARy) receptors.
  • CBD also increases the natural cannabinoid anandamide levels by blocking reuptake and inhibiting the enzymatic breakdow n of anandamide.
  • Cannabidiol has been shown to promote a complex set of changes in crucial intracellular pathway s such as mammalian target of rapamycin (mTOR), autophagy, and glycogen synthase kinase 3 beta (GSK30) resulting in neuroprotection, decreased inflammation and increased neuroplasticity which suggests benefits for overall CNS health and in management of neuropsychiatric disease.
  • CBD exerts antinociceptive properties through binding CB1R and modulating the descending pathway from the periaqueductal gray (PAG) and rostral ventral medulla in the midbrain through the spinal cord.
  • cannabinoids can modulate signaling viaN-type calcium channels, GABA receptor ion channels, and 5-HT3 receptor activated ion channels.
  • cannabidiol demonstrates positive effects on attenuating psychotic, anxiety, and depressive-like behaviors.
  • the integrated combination product(s) of psilocybin and CBD results in therapeutic synergistic benefits by increasing cerebral blood flow, improving neuronal crosstalk, and establishing new neural connections that directly affect serotonergic pathways and provide beneficial neuroprotective and antiinflammatory effects.
  • serotonergic activity modulators for example tricyclic antidepressants, SSRIs, and SNRIs can have synergistic and beneficial activities when taken with (e.g., in a single composition or in a schedule or regimen) psilocybin and/or psilocin.
  • An example of a synergistic effect is a greater than expected antidepressant effect when a serotonergic activity modulator is administered in conjunction with or after administration of a psilocybin loading dose.
  • administration of a psilocybin loading dose along with a serotonergic activity modulator increases the antidepressant effect as compared to psilocybin and/or psilocin alone, the serotonergic activity modulator alone, and is more than an additive effect of the psilocybin and serotonergic activity' modulator together.
  • administration of a psilocybin loading dose allows for less serotonergic activity' modulator to be administered while achieving the same antidepressant effect associated with a higher dosage of serotonergic activity modulator. This can be especially advantageous for some serotonergic activity modulators have a significant side effect profile, including cardiovascular and neurological toxicity.
  • the tricyclic antidepressant class of drugs can be associated with severe overdose symptoms, including fatal drug poisoning. Therefore, at least one advantage of the compositions and methods described herein is the ability to elicit a particular antidepressant effect while administering less tricyclic antidepressant than if the tricyclic antidepressant were administered alone. Thus, an advantage of the compositions and methods described herein can include decreasing adverse risk profiles associated with serotonergic activity modulators.
  • Norepinephrine reuptake inhibitors can have synergistic and beneficial activities when taken with (e.g., in a single composition or in a schedule or regimen) psilocybin and/or psilocin.
  • compositions and methods described herein can include decreasing risk profiles associated with NRIs or SNRIs.
  • compositions of the present disclosure can include various additives or other components.
  • compositions of the present disclosure may contain a pain reliever (e g., ADVIL, or MOTRIN IB), a triptan (e g., IMITREX, MAXALT, or TOSYMRA), a dihydroegerotamine (e.g., D.H.E. 45, or MIGRANAL), a lasmiditan (e.g., REYVOW), a ubrogepant (e.g., UBRELVY), an opioid, an anti -nausea drug, or various combinations thereof.
  • a pain reliever e g., ADVIL, or MOTRIN IB
  • a triptan e g., IMITREX, MAXALT, or TOSYMRA
  • a dihydroegerotamine e.g., D.H.E. 45, or MIGRANAL
  • a lasmiditan e.g., REYVOW
  • a ubrogepant e
  • compositions of the present disclosure may be administered with or formulated to contain an antibody composition directed to migraine, including but not limited to, erenumab, eptinezumab, fremanezumab, galcanezumab.
  • the compositions may comprise a blood-pressure lowering medication (e.g., beta blockers such as propranolol and metoprolol tartrate; or calcium channel blockers such as verapamil), an anti-seizure drug (e.g., valproate and topnmamate), or various combmations thereof.
  • a blood-pressure lowering medication e.g., beta blockers such as propranolol and metoprolol tartrate; or calcium channel blockers such as verapamil
  • an anti-seizure drug e.g., valproate and topnmamate
  • compositions of the present disclosure contain a flavoring agent.
  • the flavoring agent comprises vanillin and/or peppermint.
  • the flavoring agent is a carbohydrate (e.g., a sugar).
  • the compositions can comprise a pharmaceutically acceptable carrier, such as diluents, fillers, salts, buffers, stabilizers, solubilizers, and the like.
  • the compositions can comprise an anti -caking and/or anti-clumping agent, e.g., a desiccant.
  • the compositions may contain pharmaceutically acceptable excipients for modifying conditions such as pH, osmolarity, taste (e.g., a flavoring agent), viscosity, sterility, lipophilicity, and/or solubility.
  • diluents, carriers, or excipients will depend on the desired dosage form, which may in turn be dependent on the intended route of administration to a subject.
  • the compositions can comprise an antioxidant.
  • the antioxidant can be selected from ascorbic acid, lycopene, tocopherol, melatonin, retinol, astaxanthin, lutein, apigenin, carnosine, selenium, zinc, curcumin, and/or a salt or derivative thereof.
  • a composition may comprise small amounts of liquid that are negligible in the final measurement of a sample.
  • Solid carriers and excipients are generally known in the art and include, as nonlimiting examples, magnesium carbonate, magnesium stearate, talc, sugar, or lactose.
  • compositions of the present disclosure may be formulated as pharmaceutical or nutraceutical dosage forms.
  • the compositions of the present disclosure are formulated as dosage forms for administration to a subject.
  • the dosage form can be a solid dosage form (e g., tablets, capsules, powders, dispersible granules, cachets, and suppositories, including sustained release and delayed release formulations. Powders and tablets in various embodiments may comprise from about 0.1% to about 70% active ingredient. Tablets, powders, cachets, fast-dissolving films, liquids, extracts, tinctures, and capsules are all non-limiting examples of suitable dosage forms for oral administration.
  • the dosage form is a cream. Standard texts, such as “Remington’s Pharmaceutical Science”, 17 th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable dosage forms, without undue experimentation.
  • the compositions of the present disclosure may be combined with a food to be consumed by a subject.
  • the dosage forms of the present disclosure may include a solid (e.g., a powder) or liquid (e.g., a tincture, solution, or extraction) combined with a solid and/or liquid food for consumption by a subject.
  • the liquid food may be a beverage (e.g., water or a smoothie).
  • the dosage form may be a foodstuff (e.g., a nutritional powder).
  • the compositions of the present disclosure may be used as a food ingredient.
  • the dosage form may be a sachet.
  • the sachet may in some embodiments be dissolvable in water.
  • Liquid dosage forms may be administered orally or by intravenous, intracerebral, intraperitoneal, parenteral, or intramuscular injection, or infusion.
  • Sterile injectable formulations may comprise a sterile solution or suspension of an active agent in a non-toxic, pharmaceutically acceptable diluent or solvent.
  • Dosage forms, including liquid dosage forms also include solutions, sprays, or other suitable dosage forms for intranasal, buccal, or sublingual administration. Suitable liquid dosage forms include solutions, suspensions, and emulsions.
  • the pharmaceutical formulation is a parenteral dosage form.
  • the dosage form is suitable for transdermal administration, including creams, lotions, aerosols, and/or emulsions. These dosage forms may be included in transdermal patches of a matrix or reservoir type.
  • the pharmaceutical formulation is an oral dosage form.
  • the pharmaceutical composition comprises a tablet.
  • the pharmaceutical composition comprises a capsule.
  • the pharmaceutical composition comprises a dry powder.
  • the pharmaceutical composition comprises a solution.
  • more than one dosage form is administered to the subject at substantially the same time. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule.
  • the therapeutic dose may be split among multiple tablets or capsules.
  • the subject may be administered 5 tablets or capsules each comprising 5 mg of psilocybin.
  • the subject may be administered 3 tablets or capsules each comprising 10 mg of psilocybin.
  • an oral dosage form comprises a functional fdler.
  • the functional fdler may be a silicified filler, such as, but not limited to silicified microcrystalline cellulose (SMCC).
  • SMCC silicified microcrystalline cellulose
  • the oral dosage form comprises high compatibility grades of SMCC with a particle size range of from about 45 to 150 microns. A mixture of two functional fillers having different particle size ranges may be used with the weight percentages of the two favoring the larger sized particles.
  • the silicified microcrystalline filler may comprise a first filler, having a particle size range of from about 45 to 80 microns in an amount of up to 30%, up to 20%, up to 15%, or less by weight of filler, and a second filler, having a particle size range of from about 90 to 150 microns, in an amount of up to 70%, up to 80%, up to 85%, or more, by weight of filler.
  • the formulation may further comprise or consist essentially of a disintegrant, including without limitation sodium starch glycolate; a glidant, including without limitation colloidal silicon dioxide; and a lubricant, including without limitation sodium stearyl fumarate.
  • a disintegrant including without limitation sodium starch glycolate
  • a glidant including without limitation colloidal silicon dioxide
  • a lubricant including without limitation sodium stearyl fumarate.
  • the oral dosage form may comprise a disintegrant such as sodium starch glycolate.
  • one or more compositions of the present disclosure are administered to a subject as separate dosage forms.
  • one or more components of a composition are administered as separate dosage forms.
  • the dosage form comprises one, two, three, or more pills.
  • the dosage form comprises different compositions each in a separate form; for example, a pill in combination with a liquid solution or two pills in combination with a liquid solution.
  • the dosage form comprises a first composition in a first dosage form, a second composition in a second dosage form, a third composition in a third dosage form, and various combinations thereof.
  • the composition is suitable for inhalation.
  • the composition may contain solutions and solids in powder form.
  • the composition may comprise a composition combined with a pharmaceutically acceptable carrier, such as an inert compressed gas.
  • the composition is suitable for transdermal administration, including creams, lotions, aerosols, and/or emulsions. These compositions may be included in transdermal patches of a matrix or reservoir type.
  • a cannabinoid may be administered in any suitable dosage form, such as any oral, or transmucosal dosage form, such as may be selected from tinctures, fast-dissolving tablets, tablets, solutions, gums, gummies, and for application to a site in the oral cavity.
  • suitable dosage form such as any oral, or transmucosal dosage form, such as may be selected from tinctures, fast-dissolving tablets, tablets, solutions, gums, gummies, and for application to a site in the oral cavity.
  • synthetic cannabidiol or purified cannabidiol may be administered in an oral dosage form, such as in an oral capsule.
  • the methods for treating cluster-tic syndrome or symptoms thereof with a composition comprising a cannabinoid and/or a derivative thereof, and/or psilocybin and/or a derivative thereof, and various combinations thereof include administering compositions comprising psilocybin, or a derivative thereof, and a neurotransmitter activity modulator (e.g., a tricyclic, SNRI, SSRI, or NRI antidepressant) (e.g., together in one dosage form administered at least once or multiple times, and/or in separate dosage forms (i.e., with psilocybin or derivative thereof being in one dosage form and the neurotransmitter activity modulator(s) being in another, separate dosage form, with each being administered at least once or multiple times).
  • a neurotransmitter activity modulator e.g., a tricyclic, SNRI, SSRI, or NRI antidepressant
  • the present disclosure provides methods of treating or preventing cluster-tic syndrome, symptoms thereof, and/or associated conditions thereof (e.g., cluster-tic syndrome- associated depression) which comprise administering a therapeutically effective amount of a composition of the present disclosure.
  • the method includes the step of administering to a subject (e.g., a mammal) a therapeutic amount of a composition of the present disclosure sufficient to treat the condition and/or a symptom thereof, under conditions such that the condition or symptom thereof is treated.
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a composition described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). An individual may be identified as in need of such treatment using any of the methods described herein.
  • the disclosure provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of a diagnostic measurement (e.g., any of the measurements described herein below) in a subject suffering from or susceptible to a condition or symptoms thereof associated with cluster-tic syndrome (e g., cluster tic- syndrome-associated depression), in which the subject has been administered a therapeutic amount of a compound described herein sufficient to treat the disease or symptoms thereof.
  • the level of diagnostic measurement determined in the method can be compared to known levels of the diagnostic measurement in either healthy normal controls or in other afflicted patients to establish the subject’s condition status.
  • a second level of the diagnostic measurement in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy.
  • a pre-treatment level of diagnostic marker in the subject is determined prior to beginning treatment according to the methods of the present disclosure; this pre-treatment level of the diagnostic measurement can then be compared to the level of diagnostic measurement in the subject after the treatment commences, to determine the efficacy of the treatment.
  • provided herein are methods of treating or preventing cluster-tic syndrome, or one or more symptoms thereof, as disclosed above, in a patient in need thereof, comprising orally administering to the patient a therapeutically effective composition containing psilocybin and/or a derivative thereof, and/or cannabidiol and/or a derivative thereof, or various combinations thereof.
  • the methods for treating cluster-tic syndrome, symptoms thereof, and/or associated conditions thereof include administering compositions comprising psilocybin, or a derivative thereof, and a neurotransmitter activity modulator (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant) (e.g., together in one dosage form administered at least once or multiple times, and/or in separate dosage forms (i.e., with psilocybin or derivative thereof being in one dosage form and the neurotransmitter activity modulator(s) being in another, separate dosage form, with each being administered at least once or multiple times).
  • a neurotransmitter activity modulator e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant
  • the methods may be performed with any of the psilocybin, cannabidiol, neurotransmitter activity modulator compositions described above.
  • An effective combination of psilocybin and/or a derivative thereof, cannabidiol and/or a derivative thereof, and/or neurotransmitter activity modulator, or various combinations thereof may be administered in a single dosage form or in multiple dosage forms, which may be administered concurrently (i.e., at the same time) or in divided doses over the course of a day, such as in two, three, four, or more, divided doses.
  • the composition is administered in a single dose (in single or multiple dosage forms) once a day, optionally on an empty stomach or on a full stomach.
  • each of the psilocybin or a derivative thereof, and/or cannabidiol or a derivative thereof, and/or neurotransmitter activity modulator may be provided in one or more separate dosage forms (e.g., one or more capsules containing psilocybin, and one or more capsules containing cannabidiol), or a single composition may comprise two or more of a neurotransmitter activity modulator, and cannabidiol (e.g., one or more capsules containing a neurotransmitter activity modulator and cannabidiol and one or more capsules containing psilocybin only, one or more capsules containing a neurotransmitter activity modulator and psilocybin and one or more capsules containing cannabidiol only, or one or more capsules containing a neurotransmitter activity modulator and cannabidiol and one or more capsules containing a neurotransmitter activity modulator only, where
  • the subject is administered a loading dose of psilocybin, psilocin, a derivative thereof, or combinations thereof, either before or after receiving a maintenance dose of psilocybin, psilocin, a derivative thereof, or combinations thereof.
  • the loading dose composition or dosage form of psilocybin can comprise a higher concentration of psilocybin or a derivative thereof than the maintenance dose.
  • the loading dose of psilocybin, psilocin, a derivative thereof, or combinations thereof, may include psilocybin or a derivative thereof in an amount of from about 1 mg to about 100 mg.
  • the psilocybin is synthetic psilocybin.
  • the psilocybin is crystalline psilocybin.
  • the psilocybin is amorphous psilocybin.
  • the psilocy bin is deuterated psilocybin.
  • the loading dose of synthetic psilocybin or a derivative thereof may include psilocybin or a derivative thereof in an amount from about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 34 mg, about 1 mg to about 33 mg, about 1 mg to about 32 mg, about 1 mg to about 31 mg, about 1 mg to about 30 mg, about 1 mg to about 29 mg, about 1 mg to about 28 mg, about 1 mg to about 27 mg, about 1 mg to about 26 mg, about 1 mg to about 25 mg, about 1 mg to about 24 mg, about 1 mg to about 23 mg, about 1 mg to about 22 mg, about 1 mg to about 21 mg, about 1 mg to about 20 mg, about 1 mg to about 19 mg, about 1 mg to about 18 mg, about 1 mg to about 15 mg, about 1 mg
  • the loading dose of synthetic psilocybin or derivative thereof or psilocin or derivative thereof can be calculated based on the subject’s body weight.
  • the loading dose of synthetic psilocybin comprises about 0. 1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg of the subject’s body weight.
  • the loading dose of synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.
  • 1 mg/kg to about 1 mg/kg about 0.2 mg/kg to about 1 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.4 mg/kg to about 1 mg/kg, about 0.1 mg/kg to about 0.9 mg/kg, about 0. 1 mg/kg to about 0.8 mg/kg, about 0. 1 mg/kg to about 0.7 mg/kg, about 0. 1 mg/kg to about 0.6 mg/kg, about 0. 1 mg/kg to about 0.5 mg/kg, about 0.
  • the loading dose of natural psilocybin may include from about 0.5 g to about 6 g of dried mushrooms, such as Psilocybe cubensis. This includes about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1.0 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, about 5.0 g, about 5.2 g, about 5.4 g, about 5.6 g, about 5.8 g, about 6.0 g.
  • the loading dose may include psilocybin or a derivative thereof in an amount from about 0.5 g mg to about 6 g, about 1 g to about 6 g, about 1 g to about 5 g, about 1 g to about 4 g, about 1 g to about 3 g, about 1 g to about 2 g, about 2 g to about 6 g, about 2 g to about 5 g, about 2 g to about 4 g, about 2 g to about 3 g, about 3 g to about 6 g, about 3 g to about 5 g, about 3 g to about 4 g, about 4 g to about 6 g, about 4 g to about 5 g.
  • the loading dose of psilocybin or derivative thereof or psilocin or derivative thereof is about 5 g of dried mushrooms.
  • the dried mushrooms includes Psilocybe of Psilocybe cubensis.
  • the loading dose of natural psilocybin may include a dried mushroom, such as Psilocybe cubensis, which can be calculated based on the subject’s body weight.
  • the loading dose comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.11 mg/kg, about 0.12 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.
  • the loading dose psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the loading dose comprises about 0.01 mg/kg to about 0.2 mg/kg, about 0.02 mg/kg to about 0.2 mg/kg, about 0.03 mg/kg to about 0.2 mg/kg, about 0.04 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.2 mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.1 mg/kg, about 0.06 mg/kg to about 0.11 mg/kg, about 0.05 mg/kg to about 0. 13 mg/kg, about 0.4 mg/kg to about 0.13 mg/kg, about 0.4 mg/kg to about 0.13 mg/kg, about 0.4 mg/
  • the loading dose is administered in conjunction with a psychological support session. In some embodiments, the loading dose is not administered in conjunction with a psychological support session. This could be because the loading dose selected may be low enough to not alter the subject’s state of consciousness.
  • the subject is administered a maintenance dose either before or after receiving a loading dose.
  • the subject is administered a maintenance dose in the absence of a loading dose of psilocybin.
  • a maintenance dose includes psilocybin and/or psilocin or a derivative thereof.
  • the maintenance dose can comprise a lower concentration of psilocybin or a derivative thereof than the loading dose.
  • the maintenance dose includes a cannabinoid, such as cannabidiol (CBD).
  • the maintenance dose includes a neurotransmitter activity modulator (e g , a tricyclic, SNRI, SSRI, or NRI antidepressant).
  • a maintenance dose includes one or more of a maintenance dose of psilocybin, CBD, a neurotransmitter activity modulator (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant).
  • a neurotransmitter activity modulator e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant.
  • a maintenance dose may include an amount of synthetic psilocybin or a derivative thereof that provides from about 0.01 mg/day up to about 10 mg/day of the psilocybin or the derivative thereof. This includes about 0.01 mg/day, about 0.02 mg/day, about 0.03 mg/day, about 0.04 mg/day, about 0.05 mg/day, about 0.06 mg/day, about 0.07 mg/day, about 0.08 mg/day, about 0.09 mg/day, about 0.1 mg/day, about 0.11 mg/day, about 0.12 mg/day, about 0.13 mg/day, about 0.14 mg/day, about 0.15 mg/day, about 0.16 mg/day, about 0.17 mg/day, about 0.18 mg/day, about 0.19 mg/day, about 0.2 mg/day, about 0.21 mg/day, about 0.22 mg/day, about 0.23 mg/day, about 0.24 mg/day, about 0.25 mg/day, about 0.26 mg/day, about 0.27 mg/day, about 0.28 mg/day, about 0.29 mg/
  • the dosage form may include an amount of psilocybin that provides from about 0.01 mg/day up to about 6 mg/day psilocybin.
  • Other non-limiting ranges include about 0. 1 mg/day up to about 9 mg/day, about 0. 1 mg/day up to about 8 mg/day, about 0. 1 mg/day up to about 7 mg/day, about 0.1 mg/day up to about 6 mg/day, about 0.1 mg/day up to about 5 mg/day, about 0. 1 mg/day up to about 4 mg/day, about 0. 1 mg/day up to about 3 mg/day, about 0.1 mg/day up to about 2 mg/day, about 0. 1 mg/day up to about 1 mg/day, about 0. 1 mg/day up to about 0.9 mg/day, about 0.
  • a maintenance dose of synthetic psilocybin or derivative thereof or psilocin or derivative thereof can be calculated based on the subject’s body weight.
  • the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0. 1 mg/kg of the subject’s body weight.
  • the maintenance dose of synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.01 mg/kg to about 0.1 mg/kg, about 0.02 mg/kg to about 0.1 mg/kg, about 0.03 mg/kg to about 0. 1 mg/kg, about 0.04 mg/kg to about 0.
  • a maintenance dose may include natural psilocy bin or a derivative thereof in the form of a dried mushroom, such as Psilocybe cubensis may include an amount of from about 0.05 g to about 0.6 g. This includes about 0.05 g, about 0.06 g, about 0.07 g, about 0.08 g, about 0.09 g, about 0.1 g, about 0.12 g, about 0.14 g, about 0.16 g, about 0.18 g, about 0.2 g, about 0.22 g, about 0.24 g, about 0.26 g, about 0.28 g, about 0.30 g, about 0.32 g, about 0.34 g, about 0.36 g, about 0.38 g, about 0.4 g, about 0.42 g, about 0.44 g, about 0.46 g, about 0.48 g, about 0.5 g, about 0.52 g, about 0.54 g, about 0.56 g, about 0.58 g, about 0.6 g.
  • a maintenance dose of natural psilocybin or a derivative thereof may include psilocybin or a derivative thereof in an amount from about 0.05 g mg to about 0.6 g, about 0. 1 g to about 0.6 g, about 0.1 g to about 0.5 g, about 0. 1 g to about 0.4 g, about 0.1 g to about 0.3 g, about 0.
  • the maintenance dose of natural psilocybin or derivative thereof or psilocin or derivative thereof is about 0.25 g to about 0.5 g of dried mushrooms.
  • a maintenance dose of natural psilocybin or a derivative thereof, or psilocin or a derivative thereof in the form of a dried mushroom, such as Psilocybe cubensis can be determined based on the subject’s body weight.
  • the natural psilocybin comprises about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.017 mg/kg, about 0.018 mg/kg, about 0.019 mg/kg, or about 0.02 mg/kg of the subject’s body weight.
  • the natural psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the composition comprises about 0.001 mg/kg to about 0.02 mg/kg, about 0.002 mg/kg to about 0.02 mg/kg, about 0.003 mg/kg to about 0.02 mg/kg, about 0.004 mg/kg to about 0.02 mg/kg, about 0.005 mg/kg to about 0.02 mg/kg, about 0.006 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.02 mg/kg, about 0.008 mg/kg to about 0.02 mg/kg, about 0.009 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.01 mg/kg, about 0.006 mg/kg to about 0.011 mg/kg, about 0.005 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.014 mg
  • a maintenance dose may include from about 1 mg to about 1000 mg of a cannabinoid.
  • the cannabinoid in various embodiments is cannabidiol (CBD).
  • CBD cannabidiol
  • the maintenance dose may include, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about
  • a maintenance dose may include a synthetic cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about
  • a maintenance dose may include a synthetic cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to
  • I mg to about 250 mg about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg.
  • a maintenance dose of synthetic cannabidiol or derivative thereof can be calculated based on the subject’s body weight.
  • the composition comprises about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about
  • the maintenance dose of synthetic cannabidiol or a derivative thereof can comprise about 1 mg/kg to about 15 mg/kg, about 1 mg/kg to about 13 mg/kg, about 1 mg/kg to about 11 mg/kg, about 2 mg/kg to about 11 mg/kg, about 3 mg/kg to about 10 mg/kg, about 4 mg/kg to about 9 mg/kg of the subject’s body weight.
  • a maintenance dose cannabidiol or derivative thereof can be a natural cannabidiol, for example in the form of a full kief.
  • a maintenance dose of natural cannabidiol comprises about 1 to about 2000 mg of natural cannabidiol, for example, about 1 mg, about 50, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740
  • a maintenance dose may include a natural cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about
  • a maintenance dose may include a natural cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg.
  • a natural cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about
  • a maintenance dose of natural cannabidiol can be calculated based on the subject’s body weight.
  • a maintenance dose of natural cannabidiol comprises about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.
  • a maintenance dose natural cannabidiol can comprise about 0.1 mg/kg to about 3 mg/kg, about 0.2 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 3 mg/kg, about 0.4 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 3 mg/kg, about 0.6 mg/kg to about 3 mg/kg, about 0.7 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 2.9 mg/kg, about 0.5 mg/kg to about 2.8 mg/kg, about 0.5 mg/kg to about 2.7 mg/kg, about 0.5 mg/kg to about 2.6 mg/kg, about 0.5 mg/kg to about 2.5 mg/kg, about 0.7 mg/kg to about 2.9 mg/kg, about 0.7 mg/kg to about 2.8 mg/kg, about 0.7 mg/kg to about 2.7 mg/kg, about 0.7 mg/kg to about 2.6 mg/kg, or about 0.7 mg/kg to about 2.5 mg/kg of the subject’s body weight.
  • a maintenance dose may include an amount of a neurotransmitter activity modulator or a derivative thereof (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant) that provides from about 1 mg to about 600 mg of the neurotransmitter activity modulator.
  • a neurotransmitter activity modulator or a derivative thereof e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant
  • the neurotransmitter activity modulator or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg,
  • the amount of neurotransmitter activity modulator can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about
  • a maintenance dose may include about 1 mg to about 500 mg of a tricyclic antidepressant.
  • the neurotransmitter activity modulator or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg
  • the amount of tricyclic antidepressant or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145
  • the tricyclic antidepressant can include between about 1 mg and about 300 mg imipramine.
  • the imipramine or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg
  • the amount of imipramine or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 1 10 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about
  • a maintenance dose may include about 1 mg to about 600 mg of an SSRI.
  • the SSRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg,
  • the amount of SSRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1
  • a maintenance dose may include about 1 mg to about 600 mg of an SNRI.
  • the SNRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg,
  • the amount of SNRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1
  • a maintenance dose may include about 1 mg to about 600 mg of an NRI.
  • the NRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about
  • the amount of NRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 5 mg
  • the NR1 or derivative thereof can comprise about 5 mg to about 600 mg, about 10 mg to about 600 mg, about 15 mg to about 600 mg, about 20 mg to about 600 mg, about 25 mg to about 600 mg, about 30 mg to about 600 mg, about 35 mg to about 600 mg, about 40 mg to about 600 mg, about 45 mg to about 600 mg, about 50 mg to about 600 mg, about 55 mg to about 600 mg, about 60 mg to about 600 mg, about 65 mg to about 600 mg, about 70 mg to about 600 mg, about 75 mg to about 600 mg, about 80 mg to about 600 mg, about 85 mg to about 600 mg, about 90 mg to about 600 mg, about 95 mg to about 600 mg, about 100 mg to about 600 mg, about 105 mg to about 600 mg, about 110 mg to about 600 mg, about 115 mg to about 600 mg, about 120 mg to about 600 mg, about 125 mg to about 600 mg, about 130 mg to about 600 mg, about 135 mg to about 600 mg, about 140 mg to about 600 mg, about 145 mg to about 600 mg, or about 150 mg
  • the loading dose is administered once about every 1 week, 2 weeks, 3 weeks 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks.
  • the loading dose is administered once about every 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.
  • the loading dose is administered only once during an indicated time period. In some embodiments, the loading dose is administered more than once during an indicated time period.
  • a subject is administered a loading dose of psilocybin or a denvative thereof and is not administered any further psilocybin until a subsequent loading dose after one of the time periods specified above. In some embodiments of the disclosure, a subject is administered a loading dose of psilocybin or a derivative thereof and is not administered any further psilocybin or a derivative thereof until
  • a subject is administered a loading dose of psilocybin or a derivative thereof and is not administered any further psilocybin or derivative thereof until 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months,
  • Administration of the loading dose of psilocybin or a derivative thereof may occur one day or more before commencing the maintenance dose, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, or more days, before commencing the maintenance dose.
  • administration of the loading dose of psilocybin or a derivative thereof may occur 1 to 28 days before commencing the maintenance dose, 1 to 14 days before commencing the maintenance dose, 1 to 7 days before commencing the maintenance dose, 1 to 3 days before commencing the maintenance dose, or 1 day before commencing the maintenance dose.
  • the loading dose of psilocybin is administered about 7 days to about 21 days before commencing an initial maintenance dose.
  • the loading dose of psilocybin is administered about 10 days to about 15 days before commencing the initial maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 12 days to about 15 days before commencing an initial maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 14 days before commencing an initial maintenance dose.
  • administration of the loading dose of psilocybin or a derivative thereof occurs about two weeks before commencing the maintenance dose.
  • the methods described herein may comprise administering one or more loading dose(s) of psilocybin or a derivative thereof (as described above) after commencing a maintenance dose.
  • Administration of one or more loading dose(s) of psilocybin or a derivative thereof may occur one day or more after commencing the maintenance dose, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, or more days, after commencing the maintenance protocol.
  • administration of the loading dose of psilocybin or a derivative thereof may occur 1 to 28 days after commencing the maintenance dose, 1 to 14 days after commencing the maintenance dose, 1 to 7 days after commencing the maintenance dose, 1 to 3 days after commencing the maintenance dose, or 1 day after commencing the maintenance dose.
  • administration of the loading dose of psilocybin or a derivative thereof occurs about two weeks after commencing the maintenance dose.
  • two or more loading doses are administered after beginning administration of a maintenance dose.
  • the two or more loading doses are on a predetermined schedule (e.g., to be administered at months 1 and 3 after beginning administration of a maintenance dose).
  • the two or more loading doses are administered on an ad hoc basis, based on patient symptoms during the course of treatment of the maintenance dose.
  • the maintenance dose of psilocybin can be administered on administered on a daily basis or on a scheduled basis.
  • a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week.
  • Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off.
  • a scheduled basis includes two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off.
  • a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six out of every seven days.
  • the method may comprise administering the composition by a weekly protocol consisting of daily administration of a maintenance dose composition for 3-5 consecutive days followed by no administration for 1-3 consecutive days.
  • a weekly protocol or schedule is sometimes referred herein as a “maintenance therapy.”
  • the maintenance dose is administered according to a weekly regimen.
  • the maintenance dose of cannabinoid can be administered on administered on a daily basis or on a scheduled basis.
  • a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week.
  • Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off.
  • a scheduled basis includes two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off.
  • a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six days out of every seven days. Additional schedules are within the scope of the disclosure.
  • the maintenance dose of a neurotransmitter activity modulator can be administered on administered on a daily basis or on a scheduled basis.
  • a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week.
  • Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off.
  • a scheduled basis includes two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off.
  • a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six days out of every seven days. Additional schedules are within the scope of the disclosure.
  • Administration of psilocybin or a derivative thereof and/or a cannabidiol or a derivative thereof may be continued on an as-needed basis, including for about or at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months.
  • administering the composition as a maintenance dose as outlined above may be continued for consecutive weeks, including for 2, 3, 4, or more consecutive weeks, or for consecutive months, including for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more consecutive months, including for 1-12 months, for 1-24 months, or longer.
  • compositions described herein e.g., of psilocybin, cannabidiol, neurotransmitter activity modulator, and combinations thereof
  • cannabidiol e.g., cannabidiol
  • neurotransmitter activity modulator e.g., neurotransmitter activity modulator, and combinations thereof
  • compositions described herein can be administered for the treatment of symptoms associated with cluster-tic syndrome, or conditions associated with cluster-tic syndrome (e.g. cluster-tic syndrome-associated depression) with one or more other therapies selected from the group consisting of carbamazepine, oxcarbazepine, gabapentin, lamotrigine, baclofen, botulinum toxin inj ections, pregabalin, phenytoin, topiramate, tizanidine, levetiracetam, misoprostol, topiramate, tocainide, pimozide, duloxetine, eslicarbazepin, vixotngine, opioids, lidocaine, fosphenytoin, sumatriptan, and combinations thereof.
  • therapies selected from the group consisting of carbamazepine, oxcarbazepine, gabapentin, lamotrigine, baclofen, botulinum toxin inj ections, pregab
  • compositions described herein can be administered with one or more other therapies selected from the group consisting of carbamazepine, oxcarbazepine, and combinations thereof. In some embodiments, the compositions described herein can be administered with one or more other therapies selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, tizanidine, and combinations thereof.
  • compositions described herein can be administered for the treatment of symptoms associated with cluster-tic syndrome, or conditions associated with cluster-tic syndrome (e.g., cluster-tic syndrome-associated depression) with one or more other therapies selected from the group consisting of 100% oxygen, triptans (e.g., sumatriptan, zolmitriptan), lidocaine, ergotamine, dihydroergotamine, octreotide, or combinations thereof.
  • therapies selected from the group consisting of 100% oxygen, triptans (e.g., sumatriptan, zolmitriptan), lidocaine, ergotamine, dihydroergotamine, octreotide, or combinations thereof.
  • compositions described herein can be administered for the treatment of cluster-tic syndrome with one or more other therapies selected from the group consisting of verapamil, glucocorticoids, dihydroergotamine, prednisone, topiramate, lithium, triptans, CGRP targeted medication (e.g., galcanezumab), topiramate, melatonin, valproate, capsaicin, baclofen, indomethacin, ketamine, pasireotide, nasal carbon dioxide, lysergic acid diethylamide (LSD), botox, civamide, suboccipital steroid injection, warfarin, prednisone, or combinations thereof.
  • CGRP targeted medication e.g., galcanezumab
  • topiramate melatonin
  • valproate e.g., melatonin
  • capsaicin melatonin
  • baclofen melatonin
  • indomethacin
  • compositions of the disclosure may be provided as separate compositions and/or in separate or multiple dosage forms, including divided doses, from the other therapies.
  • the compositions of the disclosure may be formulated with one or more of the other therapies in the same dosage form.
  • the methods of the disclosure can still be practiced when the compositions of the disclosure and/or the other therapies are administered in a dosage form different from the previous administration of that particular composition or other therapy.
  • compositions of the disclosure may be administered before, concurrent with, or after the other therapies.
  • the methods of the disclosure include administering one or more other therapies on the same schedule as the compositions of the disclosure.
  • the methods of the disclosure include administering one or more other therapies on a different schedule as the compositions of the disclosure.
  • a subject with cluster-tic syndrome may be treated with a low/maintenance dose of psilocybin and CBD, every other day.
  • the subject may be treated with one or more of the other therapies on one or more “off days” of the psilocybin + CBD treatment.
  • a subject with cluster-tic syndrome may have been treated with one or more of the other therapies before beginning treatment with one or more of the compositions of the disclosure. In some embodiments, a subject with cluster-tic syndrome may have been treated with one or more of the other therapies before beginning treatment with one of the methods of the disclosure. In some embodiments, a subject may have experienced refractory symptoms after treatment with one or more of the other therapies. In some embodiments, a subject may not have been previously administered a therapy to treat cluster-tic syndrome or symptoms thereof prior to administration of the compositions described herein.
  • compositions described herein e.g., of psilocybin, cannabidiol, neurotransmitter activity modulator, and combinations thereof
  • cannabidiol e.g., cannabidiol
  • neurotransmitter activity modulator e.g., neurotransmitter activity modulator, and combinations thereof
  • the neurostimulation treatment may include, but is not limited to noninvasive vagus nerve stimulation, deep brain stimulation, sphenopalatine ganglion stimulation, occipital nerve stimulation, and combinations thereof.
  • the surgical treatment may include, but is not limited to microvascular decompression, gamma knife surgery, controlled lesioning of the trigeminal ganglion or root by mechanical compression (e.g., balloon compression), peripheral neurectomy (e.g., incision, alcohol injection, radiofrequency lesioning, cryotherapy), radiofrequency thermocoagulation, glycerol rhizolysis, internal neurolysis, stereotactic radiosurgery.
  • the surgical treatment may include radiofrequency thermocoagulation, glycerol ganglio-rhizolysis, microvascular decompression, alcohol injection, gamma knife radiosurgery, nerve sectioning, and combinations thereof.
  • a subject with cluster-tic syndrome may have been treated with one or more neurostimulation protocols and/or one or more surgical therapies before beginning treatment with one or more of the compositions of the disclosure.
  • a subject may have experienced refractory symptoms after treatment with one or more of the surgical therapies.
  • a subject may not have previously undergone surgical therapy before beginning treatment with one or more of the compositions and/or methods of the disclosure.
  • a subject may be treated with one or more compositions of the disclosure before the subject undergoes surgical treatment for cluster-tic syndrome or symptoms thereof.
  • the methods of the present disclosure may comprise having a subject participate in one or more pre- and/or post-administration psychological support session(s).
  • the methods of the present disclosure involve administering psychotherapy to a patient.
  • the subject participates in at least one psychological support session before administration of a composition of the present disclosure (“pre-administration psychological support session”).
  • Administration of the composition may be referred to as an “administration session”.
  • the composition administered during the administration session comprises psilocybin or a derivative thereof.
  • a pre-administration psychological support session may be held about 1 month prior to the administration session.
  • a pre-administration psychological support session may be held about 2 weeks prior to the administration.
  • a pre- administration psychological support session may be held about 1 week prior to the administration.
  • a pre-administration psychological support session may be held about 3 days prior to the administration.
  • a pre- administration psychological support session may be held about 1 day prior to the administration.
  • a pre-administration psychological support session may be held on the same day as and prior to administration.
  • the subject may participate in one, two, three, four, five, six, seven, or eight pre-administration psychological support sessions. In some embodiments, the subject may participate in at least two pre-administration psychological support sessions. In some embodiments, the subject may participate in at least three pre-administration psychological support sessions. In some embodiments, the subject may participate in pre- administration psychological support sessions at least once per week, for at least two or three weeks prior to the administration. In some embodiments, the subject may additionally participate in a pre-administration psychological support session the day before the administration.
  • the pre-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a person administering the psychological support.
  • the psychological support sessions may be group sessions, wherein more than one subject meets with a single person administering the psychological support, or more than one person administering the psychological support.
  • one or more of the subject’s family members or friends may be present at the pre-administration psychological support session(s)
  • the goals of the pre-administration session may include (i) establishing therapeutic alliance between subject and person administering the psychological support; (ii) answering the subject’s questions and addressing any concerns; and/or (iii) demonstrating and practicing the skills of self- directed inquiry and experiential processing.
  • the pre-administration psychological support sessions focus on discussion of possible effects, and/or preparing subjects for a dosing session by practicing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting relevant therapeutic goals, building rapport, and/or establishing therapeutic alliance.
  • skills of self-directed inquiry and experiential processing may be demonstrated and/or practiced.
  • the subject may be supervised by one or more trained person administering the psychological supports.
  • the person administering the psychological support supervising the subject during the administration may be the same person administering the psychological support from the subject’s pre-administration psychological support session(s), or may be a different person administering the psychological support.
  • the person administering the psychological support(s) may provide psychological support to the subject as necessary.
  • the term “psychological support” refers to any measure(s) taken by the person administering the psychological support during the administration to ensure the safety of the subject and maximize the clinical effectiveness of the administration.
  • the psychological support may be anything done by the person administering the psychological support to (1) to ensure psychological safety of the subject; (2) to allow the subject’s subjective experience to unfold naturally within the boundaries of the therapeutic intention set at the preparation; (3) to maintain participant’s attention and awareness on the experience of the present moment thus allowing exposure and processing of the challenging emotional states and personal memories; and/or (4) to generate insights and solutions for the resolution of challenging personal situations, conflicts and traumatic experiences.
  • the main therapeutic goals of the person administering the psychological support during the administration are to (i) minimize extreme anxiety, and (ii) provide appropriate support that enables the skills and processes of self-directed inquiry and experiential processing.
  • the level of psychological support will vary during the various stages of the subject’s experience during an administration session (e.g., the initial stage, the early stage, the peak stage, and the late stage).
  • the type of psychological support will vary during the various stages of the subject’s experience (e.g., the initial stage, the early stage, the peak stage, and the late stage). Because non-dual, ego- dissolution or “unitive” experiences have been shown to positively correlate with the magnitude and durability of the clinical response, the person administering the psychological support will, in some embodiments, attend to such states with particular care.
  • a subj ect may experience of a compromised sense of self during the subject’s experience.
  • an ego dissolution experience is a spontaneously occurring state of consciousness where there is a reduction in the self- referential awareness that defines normal waking consciousness, resulting in a compromised sense of “self .
  • a unitive experience is an experience characterized by a sense of unity or “oneness” that exceeds sensory or cognitive apprehension.
  • psychological support may be used to reduce severe and/or prolonged anxiety. Anxiety prior to or during the onset of psilocybin effects is not uncommon, and the person administering the psychological supports may be specially trained to recognize and actively manage subjects through such periods of anxiety until the subject is comfortable enough to continue on their own.
  • the person administering the psychological support may encourage the subject to lie down, practice relaxation and breathing exercises, and/or listen to calming music.
  • the person administering the psychological support may remind the subject that their primary task during this session is to simply collect new and interesting experiences which can then be discussed with the person administering the psychological support after the session.
  • the person administering the psychological support may remind the participant of the purpose of the therapy and the role of experiential processing, namely allowing the participant to be open and curious to whatever arises and encountering thoughts and feelings previously unknown to them.
  • the person administering the psychological support emphasizes that this process inherently requires letting go and a willing passivity to the psychedelic experience.
  • the person administering the psychological support may encourage the subject to put on an eye mask, such as a Mindfold eyeshade.
  • the person administering the psychological support encourages the subject to put on the eye mask before, during, or after the onset of the psilocybin’s active metabolite, psilocin’s effects.
  • the person administering the psychological support may encourage the subject to put on headphones and listen to music.
  • the headphones reduce outside noise (e.g., “noise cancelling” headphones).
  • person administering the psychological supports may, in some embodiments, actively guide participants through such experiences without interpreting or judging the experiences or giving advice. Once participants are comfortable, the person administering the psychological support may encourage them to again engage in introspection.
  • the psychological support comprises mindfulness-based therapy or CBT cognitive behavioral therapy (CBT).
  • CBT CBT cognitive behavioral therapy
  • the psychological support is informed by a functional theory of human behavior called Perceptual Control Theory.
  • a person administering the psychological support provides psychological support for approximately 4-8 hours immediately after administration of the loading composition.
  • subjects may be encouraged to engage in post-administration integration sessions with their person administering the psychological support.
  • Integration is a process that involves processing, or embodying, a psychedelic experience within a therapeutic context. The process initially begins by the subject verbalizing and reflecting upon any experience from the administration session and discussing it openly with their person administering the psychological support.
  • Successful integration of an experience accommodates for emotional changes and comprises of translating experiences into new insights, perspectives, and subsequently new behaviors that can be used to benefit the subject’s quality of life. New perspectives might in turn influence the participant’s current knowledge or values and lead to new ways of relating to cognitions, emotions, behaviors, and physical experiences.
  • the goals and supportive methods used by the person administering the psychological support throughout integration sessions should remain consistent, regardless of the intensity or content of the subjective experience explored by the subject.
  • a post-administration psychological support session may be held on the same day as the administration session, after the effects of the psilocin have substantially worn off.
  • a post-administration psychological support session may be held the day after, two days after, three days after, four days after, five days after, six days after, one week after, two weeks after, three weeks after one month after, two months after, three months after, six months after, or twelve months after the administration session.
  • the subject may participate in one, two, three, four, five, six, seven, or eight post-administration psychological support sessions. In some embodiments, the subject may participate in at least two, or at least three post-administration psychological support sessions.
  • the post-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a person administering the psychological support.
  • the psychological support sessions may be group sessions, wherein more than one subject meets with a single person administering the psychological support, or more than one person administering the psychological support.
  • one or more of the subject’s family members or friends may be present at the post-administration psychological support session(s).
  • psychological support may be provided remotely to a subject.
  • a person administering the psychological support providing psy chological support may not be in the same room, the same building, or in the same facility as a subject.
  • Remote psychological support may be provided, for example by telephone (i.e., by voice call), by video call or video conference, by text, or by email.
  • a pre-admimstration therapy session is conducted remotely.
  • a post-administration therapy session e.g., an integration session is conducted remotely.
  • Such methods include assessing the physical, psychological, and/or neurological state of a subject.
  • the methods can be used to select a subject for receiving a composition of the present disclosure and/or to monitor the subject’s psychological and/or neurological condition after or while being treated for a neurological or psychological condition by one of the methods of the disclosure.
  • cluster-tic syndrome e.g., lower intensity and/or frequency of an episode(s)
  • cluster-tic syndrome-associated symptoms and improved quality of life measures e.g., improved problem solving, improved concentration. improving thinking, and improved general well-being
  • Efficacy of treatment can be confirmed by clinical evaluation using means known in the art, such as, but not limited to, assessing functional improvement (e.g., reduction of one or more of irritability , anxiety and/or light/noise sensitivity, and/or improvement in one or more of appetite, concentration, memory, sleep, overall well-being, problem-solving, and multitasking ability), as may be measured using validated subjective quality of life assessments, for example.
  • functional improvement e.g., reduction of one or more of irritability , anxiety and/or light/noise sensitivity, and/or improvement in one or more of appetite, concentration, memory, sleep, overall well-being, problem-solving, and multitasking ability
  • assessments may be used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome.
  • the assessments can be used to assess, monitor, or otherwise evaluate physical function, functional disability, global function, safety, and tolerability of treatment, and/or patient satisfaction with treatment.
  • the evaluation is the Spatial Working Memory (SWM) test.
  • the subject is evaluated using the spatial working memory between errors (SWMBE) score.
  • the subject is evaluated using the spatial working memory strategy (SWMS) score.
  • the subject is evaluated using the Rapid Visual Information Processing (RVP) test is utilized to evaluate the safety and efficacy of a composition.
  • SWM Spatial Working Memory
  • SWMS spatial working memory strategy
  • RVP Rapid Visual Information Processing
  • the subject is evaluated using the Paired Associates Learning (PAL). In some embodiments, the subject is evaluated using the Emotion Recognition Task (ERT) test. In some embodiments, the subject is evaluated using the Intra- Extra Dimensional Set Shift (IED) test. In some embodiments, the subject is evaluated using the One Touch Stockings (OTS) of Cambridge test. In some embodiments, the subject is evaluated using the Digit Span Forward (DSF) test. In some embodiments, the subject is evaluated using the Five Dimension Altered States of Consciousness questionnaire (5D- ASC). In some embodiments, the subject is evaluated using the Positive and Negative Affect Schedule (PANAS). In some embodiments, the subject is evaluated using the NEO-Five Factor Inventory (NEO-FFI) test.
  • PAL Paired Associates Learning
  • ERT Emotion Recognition Task
  • IED Intra- Extra Dimensional Set Shift
  • OTS One Touch Stockings
  • DSF Digit Span Forward
  • the subject is evaluated using the Five Dimension Altered States of Consciousness questionnaire
  • the subject is evaluated using the Symptom Checklist-90 item (SCL-90) questionnaire. In some embodiments, the subject is evaluated using the Life Changes Inventory (LCI) questionnaire. In some embodiments, the subject is evaluated using the Social Cognition Panel scales. In some embodiments, the subject is evaluated using the HIT-6. In some embodiments, the subject is evaluated using the Cluster Headache Quality of life scale (CHQ). In some embodiments, the subject is evaluated using the Cluster Headache Scales (CHS). In some embodiments, the assessment used may be, but is not limited to, the Penn Facial Pain Scale, Pain Disability Index, Patient Global Impression of Change Scale.
  • pain thresholds, reports of pain relief, or pain management is used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome.
  • the pain thresholds, reports of pain relief, or pain management may be evaluated by using a pain diary or tracking application.
  • the pain diary or tracking application may track attack frequency, pain intensity or severity, duration or refractory period of pain, pain-free time, remission time, trigger sensitivity, and/or the use of rescue medication/use of acute pain management treatments.
  • pain scales that can be used to assess pain intensity, including but not limited to visual analogue scales (VAS), numerical rating scales, facial pain scales, and verbal ratings of pain.
  • the scales are multidimensional questionnaires designed to assess pain, such as the McGill Pain Questionnaire and Brief Pain Ivenoriscual Analogue Score (VAS) to assess pain or other pain scale.
  • the subject is evaluated using the Reading the Mind in the Eyes Test (RMET).
  • RMET Reading the Mind in the Eyes Test
  • one or more of the subject after treating according to the methods of the disclosure, improves by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %
  • the subject is evaluated using the Toronto Empathy Questionnaire (TEQ). In some embodiments, the subject is evaluated using the Scale of Social Responsibility (SSR). In some embodiments, the subject is evaluated using the Sheehan Suicidality Tracking Scale (SSTS). In some embodiments, the subject is evaluated using the Tellegen Absorption Scale.
  • TEQ Toronto Empathy Questionnaire
  • SSR Scale of Social Responsibility
  • SSTS Sheehan Suicidality Tracking Scale
  • Tellegen Absorption Scale Tellegen Absorption Scale.
  • the subject is physically examined.
  • a physical examination includes, but is not limited to, an examination of the subject’s general appearance, including an examination of the skin, neck, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities and musculoskeletal system.
  • body weight and height of a subject are assessed.
  • body mass index is considered.
  • the subject is evaluated using an electrocardiogram (ECG) is utilized to evaluate the safety and/or efficacy of a composition.
  • ECG electrocardiogram
  • a Standard 12- lead ECG is obtained.
  • vital signs of a subject are used to evaluate safety and/or efficacy of a composition. Vital signs include, but are not limited to, blood pressure (BP), respiratory rate, oral body temperature, and pulse. In some embodiments, blood pressure is taken after a subject has been sitting down for at least three minutes.
  • clinical laboratory tests are utilized to evaluate the safety and/or efficacy of a composition.
  • the clinical laboratory tests include blood samples and/or urine samples.
  • hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential) and platelet count are measured to evaluate safety and/or efficacy of a composition.
  • albumin alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect and total), calcium, chloride, creatine kinase, creatinine, y- glutamyl transferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, sodium, blood urea nitrogen and/or uric acid are measured to evaluate the safety and/or efficacy of a composition.
  • urine is tested for pregnancy and/or illicit drugs.
  • the subject is monitored by monitoring the signs or symptoms of depression in a subject before, during, and/or after treatment with a composition of the present disclosure.
  • the sign or symptom of depression is measured according to a diary assessment, an assessment by clinician or caregiver, a clinical rating scale, an imaging test, or a blood or CSF test.
  • the sign or symptom of depression in a subject is measured using a neuropsychological assessment or clinical rating scale.
  • the neuropsychological assessment or clinical rating scale is the Hamilton Depression Rating Scale, the Clinical Global Impression (CGI) Scale, the Montgomery -Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory' (BDI), the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology (IDS), the Quick Inventory of Depressive Symptomatology (QIDS), the Columbia-Suicide Severity' Rating Scale, or the Suicidal Ideation Attributes Scale.
  • CGI Clinical Global Impression
  • MADRS Montgomery -Asberg Depression Rating Scale
  • BDI Beck Depression Inventory'
  • QIDS Quick Inventory of Depressive Symptomatology
  • Columbia-Suicide Severity' Rating Scale or the Suicidal Ideation Attributes Scale.
  • the sign or symptom of depression in a subject is measured using the Hamilton Depression Rating (HAM-D) scale.
  • the subject’s HAM-D score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Clinical Global Impression (CGI) scale.
  • CGI scale is a 3-item scale that measures illness severity, global improvement or change, and therapeutic response.
  • the CGI is rated on a 7-point scale, with the severity of illness measured using a range of responses from 1 (normal) through 7 (amongst the most severely ill subjects).
  • the subject’s CGI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Montgomery- Asberg Depression Rating Scale (MADRS).
  • the subject’s MADRS score decreases by betw een about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Beck Depression Inventory (BDI).
  • BDI Beck Depression Inventory
  • the BDI is a 21 -item, self-report rating inventory that measures characteristic attitudes and symptoms of depression.
  • a score of 17-20 indicates borderline clinical depression, a score of 21 -30 indicates moderate depression, a score of 31 - 40 indicates severe depression, and over 40 indicates extreme depression.
  • the subject’s BDI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Zung Self-Rating Depression Scale.
  • the Zung Self-Rating Depression Scale is a 20-item self- report questionnaire that measures the psychological and somatic symptoms associated with depression. The questionnaire takes about 10 minutes to complete, and items are framed in terms of positive and negative statements. Each item is scored on a Likert scale ranging from 1 to 4. A total score is derived by summing the individual item scores, and ranges from 20 to 80. Most people with depression score between 50 and 69, while a score of 70 and above indicates severe depression.
  • the subject’s Zung Self-Rating Depression score decreases by between about 5 % and about 1 0 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Raskin Depression Rating Scale.
  • the subject after treatment with the methods described herein, decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Inventory' of Depressive Symptomatology (IDS).
  • IDS Inventory' of Depressive Symptomatology
  • the subject’s IDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Quick Inventory of Depressive Symptomatology (QIDS).
  • QIDS Quick Inventory of Depressive Symptomatology
  • the subject’s QIDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Young Mania Rating Scale (YMRS).
  • YMRS Young Mania Rating Scale
  • a total score is derived by summing the individual item scores; scores between 9-15 indicate mild mania, scores between 16-25 indicate moderate mania, and scores 26 or greater indicate severe mania.
  • the subject’s YMRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Columbia-Suicide Severity Rating Scale (C-SSRS).
  • C-SSRS measures the severity of suicidal ideation and behavior.
  • a subject is considered to have suicidal ideation and/or behavior if they answer “yes” to any of the 10 questions.
  • the subject’s C-SSRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression in a subject is measured using the Suicidal Ideation Attributes Scale (SID AS).
  • SID AS measures the presence and severity of suicidal thoughts.
  • the subject’s SID AS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • cluster-tic syndrome or a sign or symptom of cluster-tic syndrome (e.g., attack) in a subject is evaluated for secondary causes using an imaging test before, during, or after treatment with the methods described herein.
  • the imaging test is a CT scan.
  • the imaging test is a functional MRI scan.
  • the functional MRI scan measures the blood oxygen leveldependent (BOLD) response as an indicator of brain activity and/or functional connectivity.
  • BOLD response is measured in the subject at resting state, in response to emotional faces, or in response to music.
  • the BOLD response in a region of the brain increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the BOLD response in the amygdala increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the BOLD response in a region of the brain decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the BOLD response in the amygdala decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
  • the sign or symptom of depression associated with cluster-tic syndrome is measured using a marker for depression in the blood or cerebral spinal fluid.
  • the marker for depression is measured in the subject before, during, or after treatment with the methods or compositions described herein.
  • the marker for depression is red blood cell folate, serum folate, vitamin Bl 2, plasma homocysteine, serum methylfolate, and/or testing for one or more of brain-derived neurotrophic factor (BDNF) Val66Met, bone morphogenetic protein rs41271330, and/or 5- HTTLPR polymorphisms.
  • BDNF brain-derived neurotrophic factor
  • the marker for depression decreases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 110 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
  • the marker for depression increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 110 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
  • sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome.
  • the sensory testing is quantitative sensory testing (QST).
  • QST monitors and evaluates the patient’s sensory thresholds of vibration, cold, warmth, heat pain, and cold pain.
  • the sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome is somatosensory evoked potentials (SEPs) or far-field potentials (FFPs), including but not limited to nerve, root, brainstem, subcortical FFPs.
  • the sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome is assessment of trigeminal reflexes.
  • the trigeminal reflexes that could be assessed include comeal reflex, blink reflex, masseter inhibitory periods, and jaw-jerk.
  • pain thresholds, reports of pain relief, or pain management is used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome.
  • the pain thresholds, reports of pain relief, or pain management may be evaluated by using a pain diary or tracking application.
  • the pain diary or tracking application may track attack frequency, pain intensity or severity, duration or refractory period of pain, pain-free time, remission time, trigger sensitivity, and/or the use of rescue medication/use of acute pain management treatments.
  • pain scales that can be used to assess pain intensity, including but not limited to visual analogue scales (VAS), numerical rating scales, facial pain scales, and verbal ratings of pain.
  • the scales are multidimensional questionnaires designed to assess pain, such as the McGill Pain Questionnaire and Brief Pain Ivenoriscual Analogue Score (VAS) to assess pain or other pain scale.
  • assessments may be used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome.
  • the assessments can be used to assess, monitor, or otherwise evaluate physical function, functional disability, global function, safety, and tolerability of treatment, and/or patient satisfaction with treatment.
  • the assessment used may be, but is not limited to, the Penn Facial Pain Scale, Pain Disability Index, Patient Global Impression of Change Scale.
  • cluster -tic syndrome can be studied in the superior salivatory nucleus stimulation model.
  • trigeminal distribution of pain is determined by dural meningeal artery vasodilation and neuronal firing in the trigeminocervical complex and cranial autonomic symptoms such as lacrimation or tearing is measured by changes in blood flow in the lacrimal gland/duct.
  • nitroglycerin can induce cluster-tic syndrome symptoms such as decreased food consumption, increased facial signs of discomfort, hypersensitivity to touch, cold, and heat, anxiety -like behaviors and some lightaversion.
  • Inflammatory Soup (IS) model can also be used to assess symptoms and treatments of cluster-tic syndrome.
  • IS Inflammatory Soup
  • CFA Complete Freund’s Adjuvant
  • the IS model is based on the fact that natural behaviors in rodents, such as exploratory behavior, locomotor activity, rearing, or even food and water consumption, can be decreased during a painful event. Some animal behaviors, however, are exacerbated in response to nociception, such as grooming, freezing, head twitch response (wet dog shake/head shake), eye closure or eye blinking. All of these spontaneous behaviors can be assessed in preclinical research as indirect markers for noxious experience.
  • a pain state (e.g., cluster-tic syndrome) can be elicited by administering to the animal a mixture of histamine, serotonin, bradykinin, and PGE2.
  • Pharmacological interventions can also be administered to the animal in order to evaluate whether the pharmacological interventions ameliorate the pain associated with cluster-tic syndrome.
  • Another animal model that may be used to assess cluster-tic syndrome is a spontaneous trigeminal allodynia model.
  • the spontaneous trigeminal allodynia model is a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment.
  • This model system is a genetic model in which a Sprague-Dawley rat was discovered with a changing periorbital pain threshold. Subsequent breeding demonstrated that the trait is inherited. Pharmacologic interventions can be administered to the rats and evaluated to determine whether the pharmacologic interventions ameliorated the pain.
  • CCI Chronic Constriction Injury
  • Neuropathic Pain Models can be assessed for multiple behaviors including allodynia (mechanical, heal or cold) using von Frey test, plantar test, or acetone test.
  • Electrophysiology can be assessed using compound muscle action potential (CMAP), Nerve conduction velocity, and sensory nerve action potential. Imaging is also often used similar to that used to evaluate cluster-tic syndrome in humans including PET/ SPECT CT, functional ultrasound, MRI, and functional MRI (fMRI).
  • the von Frey task is a measure of pain tolerance. The test involves gradual increases in the size of filaments that poke the center of the rat’s hind paw, with larger filament size being indicative of higher mechanical nociceptive (or pain) thresholds.
  • animal models of pain including forms of headache (e.g., cluster-tic syndrome)
  • testing is highly dependent upon measurements of nociception. Both acute and chronic pain assessments assist in the translational value pharmacologic agents used to treat cluster-tic syndrome.
  • Other tests of pain include the acetone evaporation test, Hargreaves’ test, and testing with a dynamic plantar aesthesiometer.
  • animal models of cognitive impairment may be examined in addition to animal models of pain, as pam can interfere with normal cognitive functions.
  • Spatial learning and memory are the most studied aspects of cognition in animal model studies, the Morris water maze (MWM), is among the tasks most frequently used.
  • the MWM consists of a circular pool of water that contains an escape platform and is surrounded by visual spatial cues that the rodent can use to assist it in locating the escape platform.
  • Measures that assess ability to locate the platform including search latency, swim path, distance traveled, time spent in the platform quadrant, and search strategy/efficiency (e.g., direct and circle swims) can be used to assess spatial learning and memory.
  • the Novel Object Recognition (NOR) test evaluates recognition memory' and involves placing a rodent in an open field that contains familiar and/or novel objects.
  • the animal will be familiarized with two objects, and following an intertrial time interval, one of these original/familiar objects will be replaced with a novel object.
  • the novel object is typically recognized and preferred by healthy rodents.
  • the animal models of anxiety and depression may be examined in addition to animal models of pain, as chronic pain may lead to these secondary conditions.
  • Depression and anxiety assessments assist in the translational value of pharmacologic agents used to treat cluster-tic syndrome as well as cluster-tic syndrome associated anxiety and/or depression.
  • Animal models of anxiety and depression can include, but are not limited to, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), or tail suspension test (TST).
  • EPM elevated plus maze
  • OFT forced swim test
  • TST tail suspension test
  • Many cluster-tic syndrome subjects experience a psychiatric illness in connection to cluster-tic syndrome, with depression and anxiety the most common presentations.
  • EPM Elevated Plus Maze
  • the EPM test is widely used to study anxiety and has been used to identify deficits in regions such as the limbic regions, hippocampus, amygdala, and dorsal raphe.
  • the animal is placed at the junction of the four arms of the maze, two of which are closed by walls and two are open. The animal is placed facing an open arm and the time spent or number of entries in the open or closed arms of the maze is recorded. The time spent in the closed arms correlates to anxiety, since the animal lacks the drive to explore the open arm that is less safe.
  • the Open Field Test assesses the animal’s locomotor activity, exploratory behavior, and anxiety.
  • the test places the animal in a square, rectangle, or circular box with set spacing requirements and the animal’s exploratory behavior is monitored.
  • Two factors are known to influence anxiety-like behavior in the open field. The first is social isolation and the second is stress/aversion created by the brightly lit, unprotected, novel test environment. Rodents exposed to the novel experimental arena typically spend greater time exploring the periphery rather than the center area.
  • other anxiety behaviors such as grooming, rearing, and defecation are typically recorded.
  • the Forced Swim Test is one of the most frequently used behavior tasks used to assess depression behaviors. Rodents are placed in an inescapable transparent tank filled with water and their escape related mobility behavior is measured to evaluate depression. Increased time spent immobile in the tank correlates with depression traits such as despair and disengagement from stress coping.
  • the Tail Suspension Test is another frequently used test used to assess depression behaviors. Rodents are suspended by their tails and monitored for the amount of time the rodent exhibits escape behaviors. As with the FST, increased time spent immobile correlates with depression traits such as despair and disengagement from stress coping.
  • the animal model of anxiety, and/or depression is a social interactions test.
  • Many tests may be used to support the potential social function benefits associated with the combination(s) (psilocybin, CBD, psilocybin + CBD, and/or psilocybin + neurotransmitter activity modulator) including but not limited to the social interactions test.
  • the Social Interactions Test includes the introduction of an unfamiliar animal to the test animal as a social stimulus and the degree of social interest is quantified at various time points.
  • the animal model is a motor test.
  • Cluster-tic syndrome may affect the mechanical aspects of motor behavior, balance disturbances, and social interactions. Balance requires complex interactions and integration of many neural and musculoskeletal systems.
  • Beam walking tasks are specifically advantageous for testing motor impairments in animals given that they are not subject to practice effects and do not have any memory or learning components.
  • Animals are evaluated for beam-balance latency by placing the animal on a narrow beam and measuring the duration of the time that the animal can remain on the beam.
  • the animal is evaluated using a social interactions test.
  • the Social Interactions Test includes the introduction of an unfamiliar animal to the test animal as a social stimulus and the degree of social interest is quantified at various time points.
  • neurite outgrowth may be assessed utilizing primary rat cortical cultures.
  • various cell lines and tissue analysis may be used to assess the pathophysiological indicators, pathways, and markers associated with cluster-tic syndrome, such as, but not limited to, human potassium ion channel expressing cell lines, rat CB2 cannabinoid GPCR expressing cell lines, human NMDA receptor cell lines, and/or human sodium ion channel expressing cell lines.
  • kits for the treatment and/or prevention of cluster-tic syndrome, and/or symptoms thereof comprising a composition of the present disclosure.
  • the composition comprises psilocybin or a derivative thereof, and/or cannabidiol (CBD), and/or a neurotransmiter activity modulator, or combinations thereof.
  • CBD cannabidiol
  • the kit can include instructions for a treatment regimen.
  • the instructions provided in a kit according to the present disclosure may be directed to suitable dosages and administration frequencies.
  • the kit may comprise safety information relating to components of compositions contained within the kit.
  • the kit may contain a survey for assessing safety and/or efficacy of the composition(s) or information directing a subject to a website or smartphone/tablet application for assessing safety and/or efficacy of the compositions(s).
  • the kit may contain separate compartments or containers for storing different compositions and/or compositions to be administered to a subject.
  • the containers can be boxes, ampoules, botles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • an agent of the disclosure is provided together with instructions for administering the agent to a subject presently experiencing or at risk of suffering cluster-tic syndrome.
  • the instructions will generally include information about the use of the composition(s) for the treatment of the injury or syndrome.
  • the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment; precautions; warnings; indications; counterindications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • the instructions may be provided on a portable electronic storage medium (e.g., a DVD, a CD, or a USB drive) or the instructions may be stored on a remote server and accessible through the use of a smart phone or tablet application or a web browser.

Abstract

As described below, the present disclosure features compositions containing a cannabidiol (CBD) and/or psilocybin. The present disclosure also features methods for treating or preventing cluster-tic syndrome, or symptoms thereof, with a cannabidiol and/or psilocybin. The present disclosure also features compositions and methods of using psilocybin in combination with a neurotransmitter activity modulator for the treatment cluster-tic syndrome, or comorbidities thereof (e.g., depression).

Description

COMPOSITIONS AND METHODS FOR TREATING CLUSTER-TIC SYNDROME
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Application Serial No. 63/337,971 filed May 3, 2022, the entirety of which is incorporated herein by reference.
BACKGROUND
Cluster-tic syndrome is a rare clinical condition characterized by cluster headache coexisting with ipsilateral trigeminal neuralgia. These patients require treatment directed at both cluster headache and trigeminal neuralgia to achieve remission. However, each of the two conditions, cluster headache and trigeminal neuralgia, can be difficult to successfully manage with existing therapies. Medical therapy usually consists of a combination of drugs used to treat trigeminal neuralgia and cluster headache and is often unsuccessful. Thus, there exists a need for additional therapies for cluster-tic syndrome.
SUMMARY
Provided herein are methods for reducing a symptom of cluster-tic syndrome in a subject in need thereof, the method including administering to the subject at least one loading dose comprising between about 5 mg and 30 mg of psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 0.25 mg to about 3 mg of psilocybin and between about 50 mg to about 600 mg of cannabidiol (CBD), inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome. In some embodiments, the symptom of cluster-tic syndrome includes at least one of attacks of facial pain, paroxysms, autonomic features, a sense of restlessness, agiation, and combinations thereof. In some embodiments, the autonomic features include at least one of lacrimation, conjunctival injection, nasal congestion rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof. In some embodiments, at least one loading dose is administered prior to the at least one maintenance dose. In some embodiments, at least one maintenance dose is administered prior to the at least one leading dose. In some embodiments, the loading dose includes about 10 mg psilocybin. In some embodiments, the loading dose includes about 25 mg psilocybin. In some embodiments, the loading dose includes about 30 mg psilocybin. In some embodiments, the psilocybin is amorphous psilocybin. In some embodiments, the CBD includes synthetic CBD. In some embodiments, the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD. In some embodiments, the loading dose is administered prior to an initial maintenance dose by at least seven days. In some embodiments two or more loading doses are administered over a 6 month time period. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the maintenance dose is formulated in a single dosage form. In some embodiments, the maintenance dose is formulated in multiple dosage forms.
Provided herein are methods for reducing a symptom of cluster-tic syndrome in a subject, the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has been suspected or diagnosed as having cluster- tic syndrome. In some embodiments, the symptom of cluster-tic syndrome includes at least one of unilateral attacks of facial pain, paroxysms, autonomic features, and combinations thereof. In some embodiments, the autonomic features include at least one of lacrimation, conjunctival injection, nasal congestion, rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, rhinorrhea, and combinations thereof. In some embodiments, the psilocybin is synthetic psilocybin. In some embodiments, the synthetic psilocybin is amorphous psilocybin. In some embodiments, the CBD is synthetic CBD. In some embodiments the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments the maintenance dose is formulated in a single dosage form. In some embodiments the maintenance dose is formulated in multiple dosage forms.
Provided herein are methods for reducing a symptom of cluster-tic syndrome in a subject suspected or diagnosed as having cluster-tic syndrome, the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has received a loading dose of about 25 mg to about 30 mg of psilocybin. In some embodiments, the symptom of cluster-tic syndrome includes at least one of unilateral attacks of facial pain, autonomic features, restlessness, and combinations thereof. In some embodiments, the autonomic features include at least one of ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea, nasal congestion, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof. In some embodiments, the psilocybin is synthetic psilocybin. In some embodiments, the synthetic psilocybin is amorphous psilocybin. In some embodiments, wherein the CBD is synthetic CBD. In some embodiments, the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the maintenance dose is formulated in a single dosage form. In some embodiments, the maintenance dose is formulated in multiple dosage forms.
Provided herein are methods of reducing a symptom of cluster-tic syndrome in a subject, comprising administering to a subject in need thereof and having received a loading dose of about 25 mg to about 30 mg of psilocybin, at least one maintenance dose of a combination of about 0.25 mg to about 3.0 mg of synthetic psilocybin and about 50 mg to about 600 mg of sy nthetic cannabidiol, wherein the at least one maintenance dose is administered to the subject about 1 to about 28 days after the subject received the loading dose, to thereby reduce the symptom of cluster-tic syndrome in the subject. In some embodiments, the synthetic psilocybin is amorphous psilocybin. In some embodiments, the CBD includes between about 400 mg and 600 mg CBD. In some embodiments, the CBD includes between about 500 mg and 600 mg CBD. In some embodiments, the CBD includes about 600 mg CBD. In some embodiments, the maintenance dose is administered every day. In some embodiments, the maintenance dose is administered according to a predetermined schedule. In some embodiments, the maintenance dose is not administered every day. In some embodiments, the maintenance dose is administered for five out of every seven days. In some embodiments, the dose of psilocybin includes between about 10 mg and 30 mg. In some embodiments, the loading dose of psilocybin includes about 10 mg. In some embodiments, the loading dose of psilocybin includes about 20 mg. In some embodiments, the loading dose of psilocybin includes about 25 mg. In some embodiments, the loading dose of psilocybin includes about 30 mg. In some embodiments, the loading dose is administered prior to an initial maintenance dose by at least seven days. In some embodiments, two or more loading doses are administered over a 6 month time period.
Provided herein are methods of treating cluster-tic syndrome-associated depression in a subject, the method comprising administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and administering to the subject at least one maintenance dose comprising between about 1 mg to about 600 mg of a neurotransmitter activity modulator, inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome-associated depression. In some embodiments, the neurotransmitter activity modulator is selected from the group consisting of a tricyclic antidepressant, an SSRI, and SNRI, and an NRI. In some embodiments, the neurotransmitter activity modulator includes a tricyclic antidepressant. In some embodiments, the neurotransmitter activity modulator includes an SSRI. In some embodiments, the neurotransmitter activity modulator includes an SNRI. In some embodiments, the neurotransmitter activity modulator includes an NRI. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 500 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 400 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 300 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 200 mg of the neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator includes about 1 mg to 100 mg of the neurotransmitter activity modulator. In some embodiments, the subject has received a loading dose of between 25 mg and 30 mg psilocybin.
Other features and advantages of the disclosure will be apparent from the detailed description, and from the claims
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this disclosure belongs. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.
Cluster-tic syndrome is a condition that can include three types of pain: trigeminal neuralgia pain (paroxysmal, short lasting, and severe), cluster headache pain (severe pain of variable length with autonomic phenomena), and a third type of pain which is a mixture of the first two and may be provoked by trigger points or by moving the neck.
Trigeminal neuralgia (TN) pain can be clinically identified by paroxysmal, stereotyped attacks of usually intense, sharp, superficial, or stabbing pain in the distribution of one or more branches of the fifth cranial (trigeminal) nerve. TN pain is limited to the distribution of the trigeminal nerve. TN pain tends to occur in paroxysms and is maximal at or near onset. Facial muscle spasms can be seen with severe pain. The pain is often described as electric, shock-like, or stabbing. It usually lasts from one to several seconds, but may occur repetitively, anywhere from 0 to more than 50 times a day. A refractory period of several minutes during which a paroxysm cannot be provoked is common. Some patients with longstanding TN pain may have continuous dull pain that is present between paroxysms of pain. TN pain is typically unilateral, although occasionally the pain becomes bilateral over time. Most patients with TN pain experience triggered pain. Continuous pain between attacks is sometimes present in many patients. It is typically milder than the paroxysmal attacks and is typically characterized as dull or tingling, though the intensity and quality may fluctuate.
One mechanism of TN is compression of the trigeminal nerve root, but brainstem lesions also account for a small proportion of cases. Other causes of TN via nerve compression may include vestibular schwannoma (acoustic neuroma), meningioma, epidermoid or other cyst, or, rarely, a saccular aneurysm or arteriovenous malformation. The mechanism by which compression of the nerve leads to symptoms may to be related to demyelination in a circumscribed area around the compression. Demyelination of one or more of the trigeminal nerve pathways may be caused by multiple sclerosis, tumors located at the cerebellopontine angle, or other structural lesions of the brainstem. In multiple sclerosis, a plaque of demyelination typically occurs in the root entry zone of the trigeminal nerve, although vascular compression also has been noted.
TN pain is variable. Episodes may last weeks or months, followed by pain-free intervals of weeks to years, although most remissions last for only a few months. Recurrence is common, and some patients have concomitant persistent background facial pain. Most often, the condition tends to wax and wane in severity and frequency of pain exacerbations. Cluster headache pain can be described as attacks of severe unilateral pain, accompanied by ipsilateral cranial autonomic symptoms and/or restlessness or agitation. Cluster headache pain is typically described as severe and sharp or stabbing in quality. Patients are typically restless and often prefer to pace about or sit and rock back and forth with cluster headache pain. Some patients may report cutaneous allodynia. Symptoms most commonly occur in periorbital or temporal regions. Cluster headache pain is unilateral, and the symptoms often remain on the same side of the head during a single attack. In some cases, the symptoms can switch to the other side during a different cluster attack (so-called side shift).
Cluster headache pain can persist for 15 minutes up to 3 hours in duration and may strike from once every other day to up to eight times a day. These frequently recurring attacks can occur in a cluster or bout and are typically separated by periods of remission when patients are asymptomatic. In some cases, the cluster headache pain is episodic. In some cases, the cluster headache pain is chronic. In the episodic form of cluster headache pain, recurring daily attacks can persist for several weeks in a single bout and can be followed by a period of remission. In some embodiments, a cluster bout can last 6 - 12 weeks. In the chronic form, attacks can occur without significant periods of remission.
Cluster headache pain can be debilitating and associated with psychiatric comorbidity, including depression and suicidal ideation. In some cases, cluster headache pain can be associated with head trauma. In some cases, cluster headache pain is associated with smoking. Neuroimaging with magnetic resonance imaging (MRI) of the brain with gadolinium contrast can be used to exclude an underlying cause (e.g., structural lesions) for all patients with suspected cluster headache pain.
Autonomic symptoms associated with cluster headache pain may occur during the acute attack. In some cases, the autonomic symptoms are ipsilateral to the headache and may include ptosis (upper eyelid droop), miosis (excessive constriction of the pupil), lacrimation (tearing), conjunctival injection, rhinorrhea (runny nose), and/or nasal congestion. Sweating and increased cutaneous blood flow may also occur during the attack, particularly in areas of sympathetic deficit. Some patients with cluster headache pain have chronic signs of sympathetic paralysis such as miosis and ptosis that transiently intensify during acute attacks. In some cases, sympathetic disturbances persist on the previously affected side of the face in patients whose cluster headache pain has switched sides.
By “cannabinoid” is meant a group of chemicals known to activate cannabinoid receptors in cells. In various embodiments, cannabinoids are obtained from Cannabis plants. In some embodiments, the cannabinoid is synthetic. In one embodiment, the cannabinoid is endogenous to an animal, i.e., an endocannabinoid. In one embodiment, the cannabinoid is derived from a plant, e.g., a plant of genus cannabis, i.e., a phytocannabinoid. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied (similar and different) effects. Non-limiting examples of cannabinoids include the following molecules: Cannabichromene (CBC), Cannabichromenic acid (CBCA), Cannabichromevarin (CBCV), Cannabichromevannic acid (CBCVA), Cannabicyclol (CBL), Cannabicyclohc acid (CBLA), Cannabicyclovarin (CBLV), Cannabidiol (CBD), Cannabidiol monomethylether (CBDM), Cannabidiolic acid (CBD A), Cannabidiorcol (CBD-C1), Cannabi divarin (CBDV), Cannabidivarinic acid (CBDV A), Cannabielsoic acid B (CBEA-B), Cannabielsoin (CBE), Cannabielsoin acid A (CBEA-A), Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerolic acid (CBGA), Cannabigerolic acid monomethylether (CBGAM), Cannabigerovarin (CBGV), Cannabigerovarinic acid (CBGVA), Cannabinodiol (CBND), Cannabinodivarin (CBDV), Cannabinol (CBN), Cannabinol methylether (CBNM), Cannabinol- C2 (CBN-C2), Cannabinol-C4 (CBN-C4), Cannabinolic acid (CBN A), Cannabiorcool (CBN-C1), Cannabivarin (CBV), Cannabitriol (CBT), Cannabitriolvarin (CBTV), 10-Ethoxy-9- hydroxy-delta-6a-tetrahydrocannabinol, Cannbicitran (CBT), Cannabiripsol (CBR), 8,9- Dihydroxy-delta-6a-tetrahydrocannabinol, Delta-8- tetrahydrocannabinol (A6-THC), Delta-8- tetrahydrocannabinolic acid (A5-THCA), Delta-9- tetrahydrocannabinol (THC), Delta-9- tetrahydrocannabinol-C4 (THC-C4), Delta-9- tetrahydrocannabinolic acid A (THC A- A), Delta- 9- tetrahydrocannabinolic acid B (THCA- B), Delta-9-tetrahydrocannabinolic acid-C4 (THCA- C4), Delta-9-tetrahydrocannabiorcol (THC-C1 ), Delta-9-tetrahydrocannabiorcolic acid (THCA-C1), Delta-9- tetrahydrocannabivarin (THCV), Delta-9-tetrahydrocannabivarinic acid (THCVA), 10- Oxo- delta-6a-tetrahydrocannabinol (OTHC), Cannabichromanon (CBCF), Cannabifuran (CBF), Cannabiglendol, Delta-9-cis-tetrahydrocannabinol (cis-THC), Tryhydroxy-delta-9- tetrahydrocannabinol (triOH-THC), Dehydrocannabifuran (DCBF), and 3,4,5,6-Tetrahydro- 7- hydroxy -alpha-alpha-2 -trimethyl-9-n-propyl-2,6-methano-2H-l -benzoxocin-5-methanol. In one embodiment, the term "cannabinoid" refers to a compound chosen from THC, THCA, THCV, THCVA, CBC, CBCA, CBCV, CBCVA, CBD, CBDA, CBDV, CBDV A, CBG, CBGA, CBGV, or CBGVA. In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the cannabinoid is a nanoparticulate, for example a nanoparticulate CBD. In some embodiments, the cannabinoid is in the form of a Cannabis plant extract, optionally wherein the plant extract is free of THC (tetrahydrocannabinol) or THCA (tetrahydrocannabinolic acid).
By “cannabidiol (CBD)” is meant 2-[(6R)-3-methyl-6-prop-l-en-2-ylcyclohex-2-en-
1- yl]-5-pentylbenzene-l,3-diol having CAS number 13956-29-1 and the structure,
Figure imgf000009_0001
embodiments, cannabidiol is synthetic.
By “psilocybin” is meant [3-(2-dimethylaminoethyl)-lH-indol-4-yl] dihydrogen phosphate having the CAS number 520-52-5 and the structure,
Figure imgf000009_0002
pharmaceutically acceptable salts thereof. In some embodiments, psilocybin is synthetic. In some embodiments, the psilocybin is amorphous psilocybin. In other embodiments, psilocybin is extracted from a biological sample.
By “psilocin” is meant 4-hydroxy-N,N-dimethyltryptamine, having the CAS number
Figure imgf000009_0003
520-53-6 and the structure, , and pharmaceutically acceptable salts thereof.
In some embodiments, “psilocin” is alternatively referred to as 4-HO-DMT, psilocine, psilocyn, or psilotsin. In some embodiments, the psilocin is synthetic. Unless otherwise specified, any of the compounds of the present disclosure may be, in various embodiments, present in its protonated or deprotonated (salt or freebase) forms or mixtures thereof. The form of a compound may depend on context, for example the pH of the solution or composition. Further, unless otherwise specified, a pharmaceutically acceptable salt of any of the compounds discussed herein is contemplated as being suitable for use in the compositions, methods, and/or compositions of the present disclosure.
By “administer” can refer to dosing, treating, giving, or providing. Administering or administration can refer to one particular administration event. In other embodiments, administering or administration can refer to an administration protocol, wherein parts of the composition are provided at intervals, wherein administering can refer to a part or the whole of the treatment protocol.
By “agent” can refer to any small molecule chemical compound, antibody, nucleic acid molecule, or polypeptide, or fragments thereof.
By “ameliorate” can refer to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
By “alteration” can refer to a change in a measured quantity. The change can be an increase or a decrease. As used herein, an alteration includes a 10% change, a 25% change, a 40% change, a 50% change, a 60% change, a 70% change, an 80% change, a 90% change, or a 95% or greater change.
In this disclosure, “comprises,” “comprising,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like; “consisting essentially of’ or “consists essentially” likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments. Any embodiments specified as “comprising” a particular component(s) or element(s) are also contemplated as “consisting of’ or “consisting essentially of’ the particular component(s) or element(s) in some embodiments.
By “consist essentially” can refer to that the ingredients include only the listed components along with the normal impurities present in commercial materials and with any other additives present at levels which do not affect the operation of the disclosure, for instance at levels less than 5% by weight or less than 1% or even 0.5% by weight.
By “derivative” can refer to a compound retaining a physiological activity of an original compound. In some embodiments, the derivative of a compound has substantially the same or improved activity relative to the starting compound. The derivative may be a metabolite of the original compound from which it is derived. The derivative may be produced in some embodiments according to standard principles of medicinal chemistry. In some embodiments, the derivative may exhibit a lesser degree of activity than the starting material, so long as sufficient activity is retained as to be therapeutically effective. The derivative of a compound may exhibit improved solubility, reduced toxicity, improved potency, enhanced uptake, and the like. The derivative can be a derivative of a cannabinoid or of psilocybin/psilocin. The derivative can be a prodrug form of a compound.
As used herein, “effective amount” or “therapeutically effective amount” can refer to the amount of an agent required to reduce the symptoms of a condition relative to a reference. In one embodiment, a reference is an untreated patient or is the state of the subject at an earlier point in time (e.g., prior to treatment). In some embodiments, the effective amount ameliorates the symptoms of the condition. The effective amount of active compound(s) used to practice the present disclosure for therapeutic treatment of a condition varies depending upon the manner of administration, the age, body weight, and general health of the subject.
The terms “isolated,” “essentially pure”, “purified,” or “biologically pure” can refer to material that is free to vary ing degrees from components which normally accompany it as found in its native state. In some embodiments, an “essentially pure” compound has a degree of purity of up to at least 90%, 95%, or 99% by weight. In some embodiments “essentially pure” means free from other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, high performance liquid chromatography (HPLC) or mass spectroscopy (e.g., GC/MS or LC/MS/MS).
As used herein, “obtaining” as in “obtaining an agent” includes synthesizing, purchasing, or otherwise acquiring the agent.
As used herein, “pharmaceutically acceptable salt” can refer to salts or esters prepared using pharmaceutically acceptable non-toxic bases or acids. In some embodiments, the base or acid includes inorganic bases or acids and/or organic bases or acids.
As used herein, “reduces” can refer to a negative alteration of at least about 10%, 25%, 50%, 75%, or 100%. As used herein, “reference” can refer to a standard or control condition. In some embodiments, the reference is the state of a subject prior to treatment. The state of a subject may include the symptoms experienced prior to treatment. In other embodiments, a reference is the state of an untreated control patient.
As used herein, “subject” can refer to a mammal. In various embodiments, the mammal is a human or non-human mammal, such as a bovine, equine, canine, ovine, feline, or rodent such as a rat or mouse. As used herein, the terms “patient” and “subject” are used interchangeably. The subject may be male or female. The subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about 30-35, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age.
Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
As used herein, the terms “treat,” “treating,” “treatment,” and the like can refer to reducing, preventing, and/or ameliorating a condition and/or symptoms associated therewith It will be appreciated that, although not precluded, treating a disorder or condition does not require that the condition or symptoms associated therewith be completely eliminated. In various embodiments, the condition is cluster-tic syndrome or a risk of suffering from cluster- tic syndrome. In some embodiments, the disorder is cluster-tic syndrome.
Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.
Unless specifically stated or obvious from context, as used herein, the term “about” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
As used herein, the following Medical Dictionary for Regulatory Activities (MedDRA) terms are considered to be adverse events that are psychedelic in nature: altered mood, altered state of consciousness, autoscopy, delusional perception, disinhibition, dissociation, dissociative identity disorder, dreamy state, emotional disorder, euphoric mood, feeling abnormal, hallucination, hyperacusis, hyperaesthesia, hypoaesthesia, illusion, paranoia, parosmia, photophobia, sensory disturbance, time perception altered, thinking abnormal, synaesthesia, substance-induced psychotic distress, and somatic hallucination. In various embodiments, a maintenance dose of the present disclosure, as described further below, comprises a sufficiently low dose of psilocybin or a derivative thereof to avoid or reduce the occurrence in a subject administered the psilocybin or derivative thereof of an adverse psychedelic event.
Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
DETAILED DESCRIPTION
The disclosure features compositions and methods that are useful for treatment or prevention of cluster-tic syndrome. In some embodiments, the compositions and methods are useful in the treatment or prevention of cluster-tic syndrome.
Compositions
The compositions of the present disclosure in various embodiments comprise psilocybin or a derivative thereof and/or a cannabinoid, and/or a neurotransmitter activity modulator. In some embodimets the compositions of the disclosure include one or more of psilocybin or a derivative thereof, a cannabinoid, and a neurotransmitter activity modulator. In some embodiments, the compositions are pharmaceutical compositions or nutraceutical compositions (e.g., dietary supplements and functional foods) comprising one or more pharmaceutically acceptable additives (e.g., a carrier, excipient, or diluent). The compositions can be used for the treatment of cluster-tic syndrome or symptoms thereof. In some embodiments, one or more compositions described herein can be added to a second composition described herein.
Psilocybin and Derivatives Thereof
The compositions and methods described herein include psilocybin or a derivative of psilocybin, either of which may be purified from a natural source (e.g., a mushroom plant) or synthetic (i.e., manufactured by artificial means, such as by organic synthesis in a laboratory). In some embodiments, a source of psilocybin in the composition is dried Psilocybe cubensis or a member of the genus Psilocybe (e.g., Psilocybe azurescens, P. semilanceata, or P. cyanescens). In some embodiments, the psilocybin is synthetic psilocybin. In some embodiments, the psilocybin is amorphous psilocybin. In some embodiments, the amorphous psilocybin can be sprayed onto a filler or other composition (e.g., a CBD and/or neurotransmitter activity modulator composition). In some embodiments, the psilocybin is deuterated psilocybin. In some embodiments, the derivative of psilocybin is a metabolite of psilocybin (e.g., psilocin). In some embodiments, the psilocin is naturally extracted. In some embodiments, the psilocin is synthetic. In some embodiments the psilocin is amorphous. In some embodiments, the psilocin is deuterated. In some embodiments the derivative of psilocybin is a prodrug of psilocybin. By “prodrug” is meant a therapeutically inactive compound that can be metabolized in a subject’s body to produce a therapeutically active compound.
In various embodiments, the psilocybin derivative is selected from one or more of the following: [3-(2 -Dimethylaminoethyl)-! H-indol-4-yl] dihydrogen phosphate; 4- hydroxytryptamine; 4-hydroxy-N,N-dimethyltryptamine; [3-(2- methylaminoethyl)- 1 H- indol-4-yl] dihydrogen phosphate; 4-hydroxy-N-methyltryptamine; [3-(armnoethyl)-l H- indol-4-yl] dihydrogen phosphate; [3-(2 -trimethylaminoethyl)- 1 H-indol-4-yl] dihydrogen phosphate; and 4-hydroxy-N,N,N-trimethyltryptamine.
In some embodiments, the composition comprises psilocybin in an amount of about or at least about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0. 1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%. In some embodiments, the composition comprises psilocybin in an amount of no more than about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 v %, or 80 wt%.
The composition may include synthetic psilocybin or a derivative thereof in an amount of from about 1 mg to about 100 mg. In some embodiments, the psilocybin is synthetic psilocybin. In some embodiments, the psilocybin is crystalline psilocybin. In some embodiments, the psilocybin is amorphous psilocybin. In some embodiments, the psilocybin is deuterated psilocybin. This includes about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 6 mg 2, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg, and any amounts therebetween.
The compositions may include synthetic psilocybin or a derivative thereof in an amount from about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 34 mg, about 1 mg to about 33 mg, about 1 mg to about 32 mg, about 1 mg to about 31 mg, about 1 mg to about 30 mg, about 1 mg to about 29 mg, about 1 mg to about 28 mg, about 1 mg to about 27 mg, about 1 mg to about 26 mg, about 1 mg to about 25 mg, about 1 mg to about 24 mg, about 1 mg to about 23 mg, about 1 mg to about 22 mg, about 1 mg to about 21 mg, about 1 mg to about 20 mg, about 1 mg to about 19 mg, about 1 mg to about 18 mg, about 1 mg to about 15 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 34 mg, about 10 mg to about 33 mg, about 10 mg to about 32 mg, about 10 mg to about 31 mg, about 10 mg to about 30 mg, about 10 mg to about 29 mg, about 10 mg to about 28 mg, about 10 mg to about 27 mg, about 10 mg to about 26 mg, about 10 mg to about 25 mg, about 10 mg to about 24 mg, about 10 mg to about 23 mg, about 10 mg to about 22 mg, about 10 mg to about 21 mg, about 10 mg to about 20 mg, about 10 mg to about 19 mg, about 10 mg to about 18 mg, about 10 mg to about 15 mg, about 15 mg to about 90 mg, about 15 mg to about 80 mg, about 15 mg to about 70 mg, about 15 mg to about 60 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 34 mg, about 15 mg to about 33 mg, about 15 mg to about 32 mg, about 15 mg to about 31 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 35 mg, about 21 mg to about 35 mg, about 22 mg to about 35 mg, about 22 mg to about 35 mg, about 23 mg to about 35 mg, about 24 mg to about 35 mg, about 25 mg to about 35 mg, about 20 mg to about 34 mg, about 21 mg to about 34 mg, about 22 mg to about 34 mg, about 23 mg to about 34 mg, about 23 mg to about 33 mg, about 23 mg to about 32 mg, about 23 mg to about 31 mg, about 24 mg to about 35 mg, about 24 mg to about 34 mg, about 24 mg to about 33 mg, about 24 mg to about 32 mg, about 24 mg to about 31 mg, about 24 mg to about 30 mg, about 25 mg to about 35 mg, about 25 mg to about 34 mg, about 25 mg to about 33 mg, about 25 mg to about 32 mg, about 25 mg to about 31 mg, or about 25 mg to about 30 mg psilocybin.
In some embodiments, the synthetic psilocybin or derivative thereof or psilocin or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg of the subject’s body weight. In some embodiments, the synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.1 mg/kg to about 1 mg/kg, about 0.2 mg/kg to about 1 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.4 mg/kg to about 1 mg/kg, about 0. 1 mg/kg to about 0.9 mg/kg, about 0.1 mg/kg to about 0.8 mg/kg, about 0.1 mg/kg to about 0.7 mg/kg, about 0. 1 mg/kg to about 0.6 mg/kg, about 0. 1 mg/kg to about 0.5 mg/kg, about 0. 1 mg/kg to about 0.4 mg/kg, about 0.2 mg/kg to about 0.8 mg/kg, about 0.3 mg/kg to about 0.7 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, about 0.3 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45 mg/kg, or about 0.3 mg/kg to about 0.4 mg/kg of the subject’s body weight.
The composition may include natural psilocybin or a derivative thereof in an amount of from about 0.5 g to about 6 g. In some embodiments, the psilocybin or derivative there, or the psilocin or derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis. In some embodiments, the psilocybin is in the form of natural dried mushroom. In some embodiments, the psilocybin is an extract from natural dried mushrooms. This includes about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1.0 g, about 1.2 g, about
1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about
4.4 g, about 4.6 g, about 4.8 g, about 5.0 g, about 5.2 g, about 5.4 g, about 5.6 g, about 5.8 g, about 6.0 g. The compositions may include psilocybin or a derivative thereof in an amount from about 0.5 g mg to about 6 g, about 1 g to about 6 g, about 1 g to about 5 g, about 1 g to about 4 g, about 1 g to about 3 g, about 1 g to about 2 g, about 2 g to about 6 g, about 2 g to about 5g, about 2 g to about 4 g, about 2 g to about 3 g, about 3 g to about 6 g, about 3 g to about 5 g, about 3 g to about 4 g, about 4 g to about 6 g, about 4 g to about 5 g. In some embodiments, the amount of psilocybin or derivative thereof or psilocin or derivative thereof is about 5 g of dried mushrooms.
The composition may include psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis. In some embodiments, the psilocybin is an extract from natural dried mushrooms. The composition can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg O/kg O,' about 0.06 mg O/kg O,' about 0.07 mg O/kg O,' about 0.08 mg O/kg O,' about 0.09 mg O/kg O,' about
0. 1 mg/kg, about 0. 11 mg/kg, about 0.12 mg/kg, about 0. 13 mg/kg, about 0. 14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, or about 0.2 mg/kg of the subject’s body weight. In some embodiments the psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the composition comprises about 0.01 mg/kg to about 0.2 mg/kg, about 0.02 mg/kg to about 0.2 mg/kg, about 0.03 mg/kg to about 0.2 mg/kg, about 0.04 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.2 mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0. 1 mg/kg, about 0.06 mg/kg to about 0.11 mg/kg, about 0.05 mg/kg to about 0.13 mg/kg, about 0.4 mg/kg to about 0.13 mg/kg, about 0.4 mg/kg to about 0. 14 mg/kg, about 0.4 mg/kg to about 0.14 mg/kg of the subject’s body weight.
The composition may include an amount of synthetic psilocybin or a derivative thereof that provides from about 0.01 mg up to about 10 mg of the psilocybin or the derivative thereof. This includes about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.21 mg, about 0.22 mg, about 0.23 mg, about 0.24 mg, about 0.25 mg, about 0.26 mg, about 0.27 mg, about 0.28 mg, about 0.29 mg, about 0.3 mg, about 0.31 mg, about 0.32 mg, about 0.33 mg, about 0.34 mg, about 0.35 mg, about 0.36 mg, about 0.37 mg, about 0.38 mg, about 0.39 mg, about 0.4 mg, about 0.41 mg, about 0.42 mg, about 0.43 mg, about 0.44 mg, about 0.45 mg, about 0.46 mg, about 0.47 mg, about 0.48 mg, about 0.49 mg, about 0.5 mg, about 0.51 mg, about 0.52 mg, about 0.53 mg, about 0.54 mg, about 0.55 mg, about 0.56 mg, about 0.57 mg, about 0.58 mg, about 0.59 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg, and any amounts therebetween. For example, the composition may include an amount of synthetic psilocybin that provides from about 0.01 mg up to about 6 mg psilocybin. Other non-limiting ranges include about 0. 1 mg up to about 9 mg, about 0. 1 mg up to about 8 mg, about 0.1 mg up to about 7 mg, about 0. 1 mg up to about 6 mg, about 0. 1 mg up to about 5 mg, about 0. 1 mg up to about 4 mg, about 0. 1 mg up to about 3 mg, about 0. 1 mg up to about 2 mg, about 0. 1 mg up to about 1 mg, about 0. 1 mg up to about 0.9 mg, about 0. 1 mg up to about 0.8 mg, about 0. 1 mg up to about 0.7 mg, about 0. 1 mg up to about 0.6 mg, about 0. 1 mg up to about 0.5 mg, about 0.1 mg up to about 0.4 mg, 0.2 mg up to about 9 mg, about 0.2 mg up to about 8 mg, about 0.2 mg up to about 7 mg, about 0.2 mg up to about 6 mg, about 0.2 mg up to about 5 mg, about 0.2 mg up to about 4 mg, about 0.2 mg up to about 3 mg, about 0.25 mg up to about 3 mg, about 0.2 mg up to about 2 mg, about 0.2 mg up to about 1 mg, about 0.2 mg up to about 0.9 mg, about 0.2 mg up to about 0.8 mg, about 0.2 mg up to about 0.7 mg, about 0.2 mg up to about 0.6 mg, about 0.2 mg up to about 0.5 mg, about 0.2 mg up to about 0.4 mg, about 0.2 mg up to about 0.3 mg, about 0.25 mg up to about 0.4 mg, about 0.3 mg up to about 0.4 mg, about 0.5 mg up to about 9 mg, about 0.5 mg up to about 8 mg, about 0.5 mg up to about 7 mg, about 0.5 mg up to about 6 mg, about 0.5 mg up to about 5 mg, about 0.5 mg up to about 4 mg, about 0.5 mg up to about 3 mg, about 0.5 mg up to about 2 mg, about 0.5 mg up to about 1 mg, about 1 mg up to about 9 mg, about 1 mg up to about 8 mg, about 1 mg up to about 7 mg, about 1 mg up to about 6 mg, about 1 mg up to about 5 mg, 1 mg up to about 4 mg, about 1 mg up to about 3 mg, about 1 mg up to about 2 mg of psilocybin.
In some embodiments, the synthetic psilocybin or derivative thereof or psilocin or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0 08 mg/kg, about 0.09 mg/kg, or about 0. 1 mg/kg of the subject’s body weight. In some embodiments, the synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.01 mg/kg to about 0. 1 mg/kg, about 0.02 mg/kg to about 0.1 mg/kg, about 0.03 mg/kg to about 0.1 mg/kg, about 0.04 mg/kg to about 0.1 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.08 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.06 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.01 mg/kg to about 0.04 mg/kg, about 0.02 mg/kg to about 0.08 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.06 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.03 mg/kg to about 0.045 mg/kg, or about 0.03 mg/kg to about 0.04 mg/kg of the subject’s body weight.
The composition may include natural psilocybin or a derivative thereof in an amount of from about 0.05 g to about 0.6 g. In some embodiments, the psilocybin or derivative thereof, or the psilocin or derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis. In some embodiments, the psilocybin is an extract from natural dried mushrooms. This includes about 0.05 g, about 0.06 g, about 0.07 g, about 0.08 g, about 0.09 g, about 0.1 g, about 0.12 g, about 0.14 g, about 0.16 g, about 0.18 g, about 0.2 g, about 0.22 g, about 0.24 g, about 0.26 g, about 0.28 g, about 0.30 g, about 0.32 g, about 0.34 g, about 0.36 g, about 0.38 g, about 0.4 g, about 0.42 g, about 0.44 g, about 0.46 g, about 0.48 g, about 0.5 g, about 0.52 g, about 0.54 g, about 0.56 g, about 0.58 g, about 0.6 g. The compositions may include natural psilocybin or a derivative thereof in an amount from about 0.05 g mg to about 0.6 g, about 0.1 g to about 0.6 g, about 0. 1 g to about 0.5 g, about 0.1 g to about 0.4 g, about 0. 1 g to about 0.3 g, about 0. 1 g to about 0.2 g, about 0.2 g to about 0.6 g, about 0.2 g to about 0.5 g, about 0.2 g to about 0.4 g, about 0.2 g to about 0.3 g, about 0.3 g to about 0.6 g, about 0.3 g to about 0.5 g, about 0.3 g to about 0.4 g, about 0.4 g to about 0.6 g, about 0.4 g to about 0.5 g. In some embodiments, the amount of psilocybin or derivative thereof or psilocin or derivative thereof is about 0.25 g to about 0.5 g of dried mushrooms.
The composition may include natural psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, such as Psilocybe cubensis, wherein the composition comprises about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.017 mg/kg, about 0.018 mg/kg, about 0.019 mg/kg, or about 0.02 mg/kg of the subject’s body weight. In some embodiments the natural psilocybin or a derivative thereof comprises about 0.001 mg/kg to about 0.02 mg/kg, about 0.002 mg/kg to about 0.02 mg/kg, about 0.003 mg/kg to about 0.02 mg/kg, about 0.004 mg/kg to about 0.02 mg/kg, about 0.005 mg/kg to about 0.02 mg/kg, about 0.006 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.02 mg/kg, about 0.008 mg/kg to about 0.02 mg/kg, about 0.009 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.01 mg/kg, about 0.006 mg/kg to about 0.011 mg/kg, about 0.005 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg of the subject’s body weight.
As noted above, the psilocybin may be isolated, extracted, purified, crystalline, amorphous, or deuterated psilocybin. In some embodiments, the psilocybin is purified psilocybin manufactured under Good Manufacturing Practices (GMP) conditions.
Cannabinoids and Derivatives Thereof
The cannabidiol may be synthetic cannabidiol or may be purified cannabidiol that has been extracted from a natural source. In some embodiments, the cannabidiol can be full synthetic cannabidiol, nano-emulsified cannabidiol, deuterated cannabidiol, naturally extracted cannabidiol, or amorphous cannabidiol. In some embodiments, the cannabinoid can be a nanoparticulate cannabinoid, such as nanoparticulate cannabidiol. In some embodiments, the nanoparticulate cannabinoid increases absorption of the cannabinoid. In some embodiments, the absorption is increased between 5% and 50% better than nonnanoparticulate formulations of the cannabinoid. In some embodiments, the absorption is increased between 10% and 50%, between 15% and 50%, between 20% and 40%, between 20% and 35%, between 25% and 30% better than non-nanoparticulate formulations of the cannabinoid. In some embodiments, the absorption is increased about 10% more, about 15% more, about 20% more, about 25% more, about 30% more, about 35% more, about 40% more, about 45% more, about 50% more than non-nanoparticulate formulations of the cannabinoid. In some embodiments, additional synthetic cannabinoids such as CBG or CBA and/or synthetic terpenes can be added to confer additional functionality.
Various methods are available in the art for obtaining an extract from a natural source (e.g., a cannabidiol-containing extract). For example, an extract can be prepared by contacting plant material with supercritical or subcritical carbon dioxide. In some embodiments, an extract can be prepared by contacting plant material with a heated gas (e.g., at a temperature in excess of 100°C) sufficient to volatilize one or more components of the plant material to be extracted and condensing the vapor to form an extract.
As set forth above, the composition of the methods and compositions described herein can include a cannabinoid or a derivative thereof. The composition can include the cannabinoid in combination with psilocybin or a derivative thereof. In some embodiments, the composition comprises a cannabinoid or a derivative thereof in an amount of about or at least about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%. In some embodiments, the composition comprises a cannabinoid or a derivative thereof in an amount of no more than about 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.75 wt%, 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%. In some embodiments, the cannabinoid is cannabidiol.
The compositions may include from about 1 mg to about 1000 mg of a cannabinoid. The cannabinoid in various embodiments is cannabidiol (CBD). In some embodiments, the cannabinoid is synthetic CBD. The compositions may include, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg cannabinoid (e.g., CBD), or any amount there between. Thus, the compositions may include a synthetic cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about 300 mg to about 1000 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg, about 300 mg to about 700 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 350 mg to about 700 mg, about 350 mg to about 650 mg, about 350 mg to about 600 mg. In some embodiments, the compositions may include a synthetic cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg.
In some embodiments, the synthetic cannabidiol or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, or about 15 mg/kg of the subject’s body weight. In some embodiments, the synthetic cannabidiol or a derivative thereof can comprise about 1 mg/kg to about 15 mg/kg, about 1 mg/kg to about 13 mg/kg, about 1 mg/kg to about 11 mg/kg, about 2 mg/kg to about 11 mg/kg, about 3 mg/kg to about 10 mg/kg, about 4 mg/kg to about 9 mg/kg of the subject’s body weight.
In some embodiments, the cannabidiol or derivative thereof can be a natural cannabidiol, for example in the form of a full kief. In some embodiments, the composition comprises about 1 to about 1000 mg of natural cannabidiol, for example, about 1 mg, about 5, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129, about 130 mg, about 131 mg, about 132 mg, about
133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg cannabinoid (e.g., CBD), or any amount therebetween. In some embodiments, the composition comprises natural CBD in an amount from about 1-1000 mg, e.g., about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, about 600, about 625, about 650, about 675, about 700, about 725, about 750, about 775, about 800, about 825, about 850, about 875, about 900, about 925, about 950, about 975, or about 1000 mg cannabinoid (e.g., CBD), or any amount therebetween. In some embodiments, the composition comprises natural CBD in an amount from about 1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about 300 mg to about 1000 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg, about 300 mg to about 700 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 350 mg to about 700 mg, about 350 mg to about 650 mg, about 350 mg to about 600 mg. In some embodiments, the compositions may include a natural cannabinoid (e.g., in the form of a full kief) in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg.
In some embodiments, the natural cannabidiol, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 0. 1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, or about 3.0 mg/kg of the subject’s body weight. In some embodiments, the natural cannabidiol can comprise about 0. 1 mg/kg to about 3 mg/kg, about 0.2 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 3 mg/kg, about 0.4 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 3 mg/kg, about 0.6 mg/kg to about 3 mg/kg, about 0.7 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 2.9 mg/kg, about 0.5 mg/kg to about 2.8 mg/kg, about 0.5 mg/kg to about 2.7 mg/kg, about 0.5 mg/kg to about 2.6 mg/kg, about 0.5 mg/kg to about 2.5 mg/kg, about 0.7 mg/kg to about 2.9 mg/kg, about 0.7 mg/kg to about 2.8 mg/kg, about 0.7 mg/kg to about 2.7 mg/kg, about 0.7 mg/kg to about 2.6 mg/kg, or about 0.7 mg/kg to about 2.5 mg/kg of the subject’s body weight. Neurotransmitter Activity Modulators
In various embodiments, the compositions can comprise a neurotransmitter activity modulator. The neurotransmitter activity modulator in some embodiments is a serotonergic drug, a dopaminergic drug, an anxiolytic drug, and/or an adrenergic drug.
As used herein, the term “neurotransmitter activity modulator” or neuromodulator refers to a compound or composition that reacts with or influences activity at a neurotransmitter receptor. In some embodiments, the neurotransmitter activity modulator is a serotonergic drug, an adrenergic receptor, a dopamine receptor, a GABAergic receptor, a glutaminergic receptor, a histaminergic receptor, a cholinergic receptor, an opioid receptor, or a glycinergic receptor. In one embodiment, a neurotransmitter activity modulator binds on a neurotransmitter receptor. In one embodiment, a neurotransmitter activity modulator indirectly affects a neurotransmitter receptor, e.g., via interactions affecting the reactivity of other molecules at a neurotransmitter receptor. In one embodiment, a neurotransmitter activity modulator is an agonist. In one embodiment, a neurotransmitter activity modulator is an antagonist. In one embodiment, a neurotransmitter activity modulator acts (either directly or indirectly) at more than one type of neurotransmitter receptor. In some embodiments, the neurotransmitter activity modulator is a compound that influences activity at one or more of the following receptors: serotonin receptor, adrenergic receptor, dopamine receptor, GABA receptor, glutaminergic receptor, histaminergic receptor, cholinergic receptor, opioid receptor, glycinergic receptor, alpha 1 and alpha 2 receptors, sigma 1 and sigma 2 receptors, and muscarinic receptors.
Non-limiting examples of neurotransmitter activity modulators include aripiprazole, bupropion, citalopram, clomipramine, dextroamphetamine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, quetiapine, reboxetine, risperidone, sertraline, and venlafaxine.
As used herein, the term “serotonergic drug” refers to a compound that binds to, blocks, or otherw ise influences activity at a serotonin receptor. In one embodiment, a serotonergic drug binds to a serotonin receptor. In one embodiment, a serotonergic drug indirectly affects a serotonin receptor, e.g., via interactions affecting the reactivity of other molecules at the serotonin receptor. In one embodiment, a serotonergic drug is an agonist, e.g., a compound activating a serotonin receptor. In one embodiment, a serotonergic drug is an antagonist, e.g., a compound binding but not activating a serotonin receptor, e.g., blocking a receptor. In one embodiment, a serotonergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation. In one embodiment, a serotonergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.). In one embodiment, a serotonergic drug is an antidepressant. In some embodiments, a serotonergic drug is a tricyclic antidepressant (TCA). In one embodiment, a serotonergic drug is an anxiolytic. In one embodiment, a serotonergic drug is a selective serotonin reuptake inhibitor (SSRI). In one embodiment, a serotonergic drug is a selective serotonin norepinephrine reuptake inhibitor (SNRI).
In some embodiments, the serotonergic drug is chosen from alprazolam, amphetamine, aripiprazole, a/api rone, a barbiturate, bromazepam, bupropion, buspirone, a cannabinoid, chlordiazepoxide, citalopram, clonazepam, clorazepate, dextromethorphan, diazepam, duloxetine, escitalopram, fluoxetine, flurazepam, fluvoxamine, lorazepam, lysergic acid diethylamide, lysergamide, 3,4- methylenedioxymethamphetamine, milnacipran, mirtazapine, naratriptan, paroxetine, pethidine, phenethylamine, psicaine, oxazepam, reboxetine, serenic, serotonin, sertraline, temazepam, tramadol, triazolam, a tryptamine, venlafaxine, vortioxetine, and/or derivatives and/or combinations thereof.
In some embodiments, the serotonergic drug is a tricyclic antidepressant (TCA), which can include amineptine, amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, desipramine, demexiptiline, dibenzepin, dimetacrine, doxepin, fluacizine, imipramine, imipraminoxide, iprinodole, lofepramine, maprotiline, melitracen, metapramine, nitroxazepine, nortripyline, noxiptiline, opipramol, protriptyline, propizepine, tianeptine, trimipramine, and quinupramine.
In some embodiments, the serotonergic drug is a selective serotonin reuptake inhibitor (SSRI), which can include citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone.
In some embodiments, the serotonergic drug is a serotonin norepinephrine reuptake inhibitor (SNRI), which can include desvenlafaxine, duloxetine, levormlnacipran, venlafaxine, and desvenlafaxine.
A person of skill in the art would understand the terms tricyclic, SSRI, SNRI, and NRI are descriptive terms, wherein a particular compound could be described by one or more of the previous terms. Additionally, there may be neurotransmitter activity modulators contemplated by the current disclosure which may be described by other or additional terms (e.g., buproprion can be described as an atypical antidepressant).
As used herein, the term “dopaminergic drug” refers to a compound that binds, blocks, or otherwise influences activity at a dopamine receptor. In one embodiment, a dopaminergic drug is a dopamine transporter inhibitor. In one embodiment, a dopaminergic drug is a vesicular monoamine transporter inhibitor.
In one embodiment, a dopaminergic drug is chosen from amineptine, apomorphine, benzylpiperazine, bromocriptine, cabergoline, chlorpromazine, clozapine, dihydrexidine, domperidone, dopamine, fluphenazine, haloperidol, ketamine, loxapine, methamphetamine, olanzapine, pemoline, perphenazine, pergolide, phencyclidine, phenethylamine, phenmetrazine, pimozide, piribedil, a psychostimulant, reserpine, risperidone, ropinirole, tetrabenazine, thioridazine, or a combination thereof.
As used herein, the term “adrenergic drug” refers to a compound that binds, blocks, or otherwise influences activity at an adrenergic receptor. In one embodiment, an adrenergic drug binds to an adrenergic receptor. In one embodiment, an adrenergic drug indirectly affects an adrenergic receptor, e.g., via interactions affecting the reactivity of other molecules at the adrenergic receptor. In one embodiment, an adrenergic drug is an agonist, e.g., a compound activating an adrenergic receptor. In one embodiment, an adrenergic drug is an antagonist, e.g., a compound binding but not activating an adrenergic receptor, e.g., blocking a receptor. In one embodiment, an adrenergic drug is an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation. In one embodiment, an adrenergic drug acts (either directly or indirectly) at more than one type of receptor (e.g., 5HT, dopamine, adrenergic, acetylcholine, etc.). In one embodiment, an adrenergic drug is an antidepressant. In one embodiment, an adrenergic drug is a norepinephrine transporter inhibitor (NRI). In one embodiment, an adrenergic drug is a vesicular monoamine transporter inhibitor.
In one embodiment, an adrenergic drug is chosen from adrenaline, agmatine, amoxapine, aptazapine, atomoxetine, bupropion, clonidine, doxepin, duloxetine, esmirtazpine, mianserin, mirabegron, mirtazapine, norepinephrine, phentolamine, phenylephrine, piperoxan, reserpine, ntodrine, setiptiline, tesofensine, timolol, trazodone, trimipramine, or xylazine.
In some embodiments, an adrenergic drug is considered to be a norepinephrine reuptake inhibitor (NRI). In some embodiments, an NRI can include bupropion or atomoxetine.
In some embodiments, the compositions of the present disclosure contain an anxiolytic drug. Non-limiting examples of anxiolytic drugs include alprazolam, an alpha blocker, an antihistamine, a barbiturate, a beta blocker, bromazepam, a carbamate, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, an opioid, oxazepam, temazepam, or triazolam. In some embodiments, the compositions of the present disclosure contain an antidepressant. Non-limiting examples of antidepressants include buproprion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine.
Combination Compositions
Also provided herein are orally admmistrable compositions (e.g., pharmaceutical compositions) comprising a therapeutically effective combination of cannabidiol and/or a derivative thereof, and/or psilocybin and/or a derivative thereof, and/or psilocin and/or a derivative thereof, and/or a neurotransmitter activity modulator, and various combinations thereof. The therapeutically effective combination of cannabidiol, and/or psilocybin, and/or psilocin may be provided as a combination composition wherein each of the cannabidiol, and/or psilocybin, and/or psilocin are provided as separate compositions in separate dosage forms, or may be provided as a combination composition wherein each of the cannabidiol, and/or psilocybin, and/or psilocin are provided in a single composition, in a single dosage forms or multiple dosage forms containing divided doses of the composition. Thus, for example, a combination composition may include one or more capsules containing psilocybin and/or psilocin, one or more capsules containing cannabidiol, and one or more capsules containing a neurotransmitter activity modulator, or may include one or more capsules containing each of psilocybin and/or psilocin, cannabidiol, and a neurotransmitter activity modulator. Alternatively, two or more of psilocybin and/or psilocin, cannabidiol, and a neurotransmitter activity modulator may be provided in the same composition, in a single dosage forms or multiple dosage forms containing divided doses. Thus, for example, a combination composition may include one or more capsules containing cannabidiol and one or more capsules containing psilocybin and/or psilocin only, or one or more capsules containing neurotransmitter activity modulators and psilocybin, and one or more capsules containing cannabidiol only, or one or more capsules containing neurotransmitter activity modulators and cannabidiol, and one or more capsules containing mushroom blends, wherein the psilocybin may be contained in either type of capsule. In any of these embodiments, one or more or all of the compositions may optionally further comprise a pharmaceutically acceptable carrier or excipient suitable for oral administration. In some embodiments, the maintenance dose can be a solid dosage form or a liquid.
The compositions optionally may further include a composition comprising a loading dose of psilocybin as described herein, in a single dosage form or multiple dosage forms containing divided doses. In some embodiments, a loading dose can be a solid dosage form or a liquid.
In some instances, a composition can include psilocybin or derivatives thereof, in combination with a neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator is a serotonergic neurotransmitter activity modulator. In some embodiments, the neurotransmitter activity modulator is a tricyclic antidepressant. In some embodiments the neurotransmitter activity modulator is an SSRI. In some embodiments, the neurotransmitter activity modulator is an SNRI. In some embodiments, the neurotransmitter activity modulator is a norepinephrine reuptake inhibitor (NRI). As with the combination of psilocybin and/or cannabidiol, the combination composition can comprise a single dosage form or multiple dosage forms containing divided doses of the composition. The combination composition can comprise separate dosages or dosage forms for the different combination components. In some instances, a composition can include adding one of identified psilocybin, and/or CBD, and/or neurotransmitter activity modulator compositions to another identified composition (e.g., psilocybin, and/or CBD, and/or neurotransmitter activity modulator). For example, a composition of the disclosure can include adding psilocybin to any of the identified neurotransmitter activity modulators identified herein (e.g., adding psilocybin to a tricyclic antidepressant, an SSRI, and SNRI, and/or an NRI).
The compositions described herein can be manufactured by conventional methods, such as those including mixing, dissolving, granulating, levigating, emulsifying, encapsulating, and/or lyophilization processes. The compositions can be formulated in accordance with conventional practices, optionally with one or more pharmaceutically acceptable carriers or excipients suitable for oral administration.
Therapeutic combination products with complementary, additive, or synergistic mechanisms of action can provide greater efficacy while reducing adverse effect profiles. Combination products are frequently used in the therapeutic management of multiple and complex diseases/conditions including but not limited to methods for treating cluster-tic syndrome. Other neurological conditions or symptoms associated with cluster-tic syndrome (e.g., ipsilateral to the headache cranial autonomic symptoms and a sense of restlessness or agitation) thereof, are also treatable with the methods described herein. The integrated combination of psilocybin and/or psilocin and/or cannabidiol (CBD) provides therapeutic synergistic benefits based on their differences in molecular structure and complementary mechanisms of action on the serotonergic system that yield synergistic physiologic neural health benefits.
Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) and its active metabolite psilocin (4-hydroxy- N,N-dimethyltryptamine) are tryptamine/indolamine hallucinogens that are chemically and structurally related to serotonin. Psilocin is the active molecule that produces the pharmacologic effects of a selective agonist of serotonin (5-HT) family of receptors, which includes the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. Preclinical studies have shown that 5-HT2A receptor activation in the cortical and subcortical structures is one of the primary mechanisms that results in pharmacologic effects. Psilocybin also significantly decreases 11 C-raclopride binding potential bilaterally in the caudate nucleus and putamen, which results in a reciprocal increase in endogenous dopamine. Dual actions from the presynaptic and postsynaptic 5-HT2A receptor activation by psilocin forms a cyclic feedback process for 5-HT2A receptor activation of glutamate effects in the central nervous system, leading to a complex cortical-thalamic neurocircuitry. Further, psilocybin activation of 5-HT2A may impact nociception modulation pathways. 5-HT2A receptor activation causes upregulation of genes associated with neuroplasticity and suppresses TNF-a-induced inflammation. These mechanisms along with a potential for increasing neurogenesis and neural plasticity and improving cerebral blood flow contribute to the established therapeutic benefits of psilocybin to overall central nervous system (CNS) health and in management of disease, including reversing changes in neural connections seen in chronic pain states.
Cannabidiol (2-[(6R)-3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l- yl]-5- pentylbenzene-l,3-diol) is a phytocannabinoid derived from Cannabis species, which is devoid of psychoactive activity, with analgesic, anti- inflammatory, and neuroprotective, and anxiolytic activities. Upon administration, cannabidiol (CBD) exerts activity through various mechanisms. Cannabidiol binds to CB1 receptor and changes the binding site through negative allosteric modulation which is thought to provide its anxiolytic properties (e.g., mitigation of the anxiety associated with THC consumption). Cannabidiol can act as a positive modulator of 5HT1 A-mediated neurotransmission or as an agonist at transient receptor potential cation channel subfamily V member 1 (TRPV1) and peroxisome proliferator- activated receptor gamma (PPARy) receptors. CBD also increases the natural cannabinoid anandamide levels by blocking reuptake and inhibiting the enzymatic breakdow n of anandamide. Cannabidiol has been shown to promote a complex set of changes in crucial intracellular pathway s such as mammalian target of rapamycin (mTOR), autophagy, and glycogen synthase kinase 3 beta (GSK30) resulting in neuroprotection, decreased inflammation and increased neuroplasticity which suggests benefits for overall CNS health and in management of neuropsychiatric disease. CBD exerts antinociceptive properties through binding CB1R and modulating the descending pathway from the periaqueductal gray (PAG) and rostral ventral medulla in the midbrain through the spinal cord. Additionally, cannabinoids can modulate signaling viaN-type calcium channels, GABA receptor ion channels, and 5-HT3 receptor activated ion channels. Additionally, cannabidiol demonstrates positive effects on attenuating psychotic, anxiety, and depressive-like behaviors.
Through complementary mechanisms of action, the integrated combination product(s) of psilocybin and CBD, results in therapeutic synergistic benefits by increasing cerebral blood flow, improving neuronal crosstalk, and establishing new neural connections that directly affect serotonergic pathways and provide beneficial neuroprotective and antiinflammatory effects.
Additionally, serotonergic activity modulators, for example tricyclic antidepressants, SSRIs, and SNRIs can have synergistic and beneficial activities when taken with (e.g., in a single composition or in a schedule or regimen) psilocybin and/or psilocin. An example of a synergistic effect is a greater than expected antidepressant effect when a serotonergic activity modulator is administered in conjunction with or after administration of a psilocybin loading dose. In some embodiments, administration of a psilocybin loading dose along with a serotonergic activity modulator increases the antidepressant effect as compared to psilocybin and/or psilocin alone, the serotonergic activity modulator alone, and is more than an additive effect of the psilocybin and serotonergic activity' modulator together. In some embodiments, administration of a psilocybin loading dose allows for less serotonergic activity' modulator to be administered while achieving the same antidepressant effect associated with a higher dosage of serotonergic activity modulator. This can be especially advantageous for some serotonergic activity modulators have a significant side effect profile, including cardiovascular and neurological toxicity. For example, the tricyclic antidepressant class of drugs can be associated with severe overdose symptoms, including fatal drug poisoning. Therefore, at least one advantage of the compositions and methods described herein is the ability to elicit a particular antidepressant effect while administering less tricyclic antidepressant than if the tricyclic antidepressant were administered alone. Thus, an advantage of the compositions and methods described herein can include decreasing adverse risk profiles associated with serotonergic activity modulators. Norepinephrine reuptake inhibitors (NRIs) can have synergistic and beneficial activities when taken with (e.g., in a single composition or in a schedule or regimen) psilocybin and/or psilocin. As psilocybin activates serotonergic receptors, effecting the serotonergic system, pairing psilocybin with a NRI creating a novel SNRI composition. This novel SNRI composition can have a beneficial adverse effect profile as compared to known SNRI compounds. In some embodiments, the novel composition is more efficacious at treating a symptom of cluster-tic syndrome as compared to known SNRI compounds at a particular dosage. In some embodiments, administration of psilocybin, as a loading dose or a maintenance dose, allows for less NRI to be administered while achieving the same antidepressant effect associated with a higher dosage of NRI or SNRI. Therefore, an advantage of the compositions and methods described herein can include decreasing risk profiles associated with NRIs or SNRIs.
Additives and Other Components
The compositions of the present disclosure can include various additives or other components.
In some embodiments, the compositions of the present disclosure may contain a pain reliever (e g., ADVIL, or MOTRIN IB), a triptan (e g., IMITREX, MAXALT, or TOSYMRA), a dihydroegerotamine (e.g., D.H.E. 45, or MIGRANAL), a lasmiditan (e.g., REYVOW), a ubrogepant (e.g., UBRELVY), an opioid, an anti -nausea drug, or various combinations thereof. In some embodiments, the compositions of the present disclosure may be administered with or formulated to contain an antibody composition directed to migraine, including but not limited to, erenumab, eptinezumab, fremanezumab, galcanezumab. In some embodiments, the compositions may comprise a blood-pressure lowering medication (e.g., beta blockers such as propranolol and metoprolol tartrate; or calcium channel blockers such as verapamil), an anti-seizure drug (e.g., valproate and topnmamate), or various combmations thereof.
In some embodiments, the compositions of the present disclosure contain a flavoring agent. In some embodiments, the flavoring agent comprises vanillin and/or peppermint. In some embodiments, the flavoring agent is a carbohydrate (e.g., a sugar).
In some embodiments, the compositions can comprise a pharmaceutically acceptable carrier, such as diluents, fillers, salts, buffers, stabilizers, solubilizers, and the like. In some embodiments, the compositions can comprise an anti -caking and/or anti-clumping agent, e.g., a desiccant. The compositions may contain pharmaceutically acceptable excipients for modifying conditions such as pH, osmolarity, taste (e.g., a flavoring agent), viscosity, sterility, lipophilicity, and/or solubility. The choice of diluents, carriers, or excipients will depend on the desired dosage form, which may in turn be dependent on the intended route of administration to a subject.
In some embodiments, the compositions can comprise an antioxidant. The antioxidant can be selected from ascorbic acid, lycopene, tocopherol, melatonin, retinol, astaxanthin, lutein, apigenin, carnosine, selenium, zinc, curcumin, and/or a salt or derivative thereof.
A composition may comprise small amounts of liquid that are negligible in the final measurement of a sample. In one example, it is acceptable for a composition of this disclosure to comprise as much as 1 % water as measured by mass percent.
Solid carriers and excipients are generally known in the art and include, as nonlimiting examples, magnesium carbonate, magnesium stearate, talc, sugar, or lactose.
Dosage Forms
The compositions of the present disclosure may be formulated as pharmaceutical or nutraceutical dosage forms. In some embodiments, the compositions of the present disclosure are formulated as dosage forms for administration to a subject. The dosage form can be a solid dosage form (e g., tablets, capsules, powders, dispersible granules, cachets, and suppositories, including sustained release and delayed release formulations. Powders and tablets in various embodiments may comprise from about 0.1% to about 70% active ingredient. Tablets, powders, cachets, fast-dissolving films, liquids, extracts, tinctures, and capsules are all non-limiting examples of suitable dosage forms for oral administration. In some embodiments, the dosage form is a cream. Standard texts, such as “Remington’s Pharmaceutical Science”, 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable dosage forms, without undue experimentation.
In some embodiments, the compositions of the present disclosure may be combined with a food to be consumed by a subject. As a non-limiting example, the dosage forms of the present disclosure may include a solid (e.g., a powder) or liquid (e.g., a tincture, solution, or extraction) combined with a solid and/or liquid food for consumption by a subject. In some embodiments, the liquid food may be a beverage (e.g., water or a smoothie). In some embodiments, the dosage form may be a foodstuff (e.g., a nutritional powder). In some embodiments, the compositions of the present disclosure may be used as a food ingredient.
In some embodiments, the dosage form may be a sachet. The sachet may in some embodiments be dissolvable in water. Liquid dosage forms may be administered orally or by intravenous, intracerebral, intraperitoneal, parenteral, or intramuscular injection, or infusion. Sterile injectable formulations may comprise a sterile solution or suspension of an active agent in a non-toxic, pharmaceutically acceptable diluent or solvent. Dosage forms, including liquid dosage forms, also include solutions, sprays, or other suitable dosage forms for intranasal, buccal, or sublingual administration. Suitable liquid dosage forms include solutions, suspensions, and emulsions.
In some embodiments, the pharmaceutical formulation is a parenteral dosage form. In some embodiments, the dosage form is suitable for transdermal administration, including creams, lotions, aerosols, and/or emulsions. These dosage forms may be included in transdermal patches of a matrix or reservoir type. In some embodiments, the pharmaceutical formulation is an oral dosage form. In some embodiments, the pharmaceutical composition comprises a tablet. In some embodiments, the pharmaceutical composition comprises a capsule. In some embodiments, the pharmaceutical composition comprises a dry powder. In some embodiments, the pharmaceutical composition comprises a solution. In some embodiments, more than one dosage form is administered to the subject at substantially the same time. In some embodiments, the subject may be administered the entire therapeutic dose in one tablet or capsule. In some embodiments, the therapeutic dose may be split among multiple tablets or capsules. For example, for a dose of 25 mg, the subject may be administered 5 tablets or capsules each comprising 5 mg of psilocybin. Alternatively, for a dose of 30 mg, the subject may be administered 3 tablets or capsules each comprising 10 mg of psilocybin.
In some embodiments, an oral dosage form comprises a functional fdler. The functional fdler may be a silicified filler, such as, but not limited to silicified microcrystalline cellulose (SMCC). In some embodiments, the oral dosage form comprises high compatibility grades of SMCC with a particle size range of from about 45 to 150 microns. A mixture of two functional fillers having different particle size ranges may be used with the weight percentages of the two favoring the larger sized particles.
In some embodiments, the silicified microcrystalline filler may comprise a first filler, having a particle size range of from about 45 to 80 microns in an amount of up to 30%, up to 20%, up to 15%, or less by weight of filler, and a second filler, having a particle size range of from about 90 to 150 microns, in an amount of up to 70%, up to 80%, up to 85%, or more, by weight of filler.
The formulation may further comprise or consist essentially of a disintegrant, including without limitation sodium starch glycolate; a glidant, including without limitation colloidal silicon dioxide; and a lubricant, including without limitation sodium stearyl fumarate.
In some embodiments, the oral dosage form may comprise a disintegrant such as sodium starch glycolate.
In some embodiments, one or more compositions of the present disclosure are administered to a subject as separate dosage forms. In some embodiments, one or more components of a composition are administered as separate dosage forms. In some embodiments, the dosage form comprises one, two, three, or more pills. In some embodiments, the dosage form comprises different compositions each in a separate form; for example, a pill in combination with a liquid solution or two pills in combination with a liquid solution. In some embodiments, the dosage form comprises a first composition in a first dosage form, a second composition in a second dosage form, a third composition in a third dosage form, and various combinations thereof.
In some embodiments, the composition is suitable for inhalation. The composition may contain solutions and solids in powder form. In some embodiments, the composition may comprise a composition combined with a pharmaceutically acceptable carrier, such as an inert compressed gas.
In some embodiments, the composition is suitable for transdermal administration, including creams, lotions, aerosols, and/or emulsions. These compositions may be included in transdermal patches of a matrix or reservoir type.
A cannabinoid may be administered in any suitable dosage form, such as any oral, or transmucosal dosage form, such as may be selected from tinctures, fast-dissolving tablets, tablets, solutions, gums, gummies, and for application to a site in the oral cavity. For example, synthetic cannabidiol or purified cannabidiol may be administered in an oral dosage form, such as in an oral capsule.
Methods of Treating Cluster-Tic Syndrome, Symptoms, and Associated Conditions (e.g., Cluster-Tic Syndrome-Associated Depression) Using Compositions Described Herein
Described herein are methods for treating or preventing cluster-tic syndrome or symptoms thereof with a composition comprising a cannabinoid and/or a derivative thereof, and/or psilocybin and/or a derivative thereof, and various combinations thereof. In some embodiments, the methods for treating cluster-tic syndrome or symptom thereof and/or associated conditions thereof (e.g., cluster-tic syndrome-associated depression) include administering compositions comprising psilocybin, or a derivative thereof, and a neurotransmitter activity modulator (e.g., a tricyclic, SNRI, SSRI, or NRI antidepressant) (e.g., together in one dosage form administered at least once or multiple times, and/or in separate dosage forms (i.e., with psilocybin or derivative thereof being in one dosage form and the neurotransmitter activity modulator(s) being in another, separate dosage form, with each being administered at least once or multiple times).
The present disclosure provides methods of treating or preventing cluster-tic syndrome, symptoms thereof, and/or associated conditions thereof (e.g., cluster-tic syndrome- associated depression) which comprise administering a therapeutically effective amount of a composition of the present disclosure. The method includes the step of administering to a subject (e.g., a mammal) a therapeutic amount of a composition of the present disclosure sufficient to treat the condition and/or a symptom thereof, under conditions such that the condition or symptom thereof is treated.
The methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a composition described herein, or a composition described herein to produce such effect. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method). An individual may be identified as in need of such treatment using any of the methods described herein.
In one embodiment, the disclosure provides a method of monitoring treatment progress. The method includes the step of determining a level of a diagnostic measurement (e.g., any of the measurements described herein below) in a subject suffering from or susceptible to a condition or symptoms thereof associated with cluster-tic syndrome (e g., cluster tic- syndrome-associated depression), in which the subject has been administered a therapeutic amount of a compound described herein sufficient to treat the disease or symptoms thereof. The level of diagnostic measurement determined in the method can be compared to known levels of the diagnostic measurement in either healthy normal controls or in other afflicted patients to establish the subject’s condition status. In preferred embodiments, a second level of the diagnostic measurement in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment level of diagnostic marker in the subject is determined prior to beginning treatment according to the methods of the present disclosure; this pre-treatment level of the diagnostic measurement can then be compared to the level of diagnostic measurement in the subject after the treatment commences, to determine the efficacy of the treatment.
In various embodiments, provided herein are methods of treating or preventing cluster-tic syndrome, or one or more symptoms thereof, as disclosed above, in a patient in need thereof, comprising orally administering to the patient a therapeutically effective composition containing psilocybin and/or a derivative thereof, and/or cannabidiol and/or a derivative thereof, or various combinations thereof. In some embodiments, the methods for treating cluster-tic syndrome, symptoms thereof, and/or associated conditions thereof (e.g., cluster-tic syndrome-associated depression) include administering compositions comprising psilocybin, or a derivative thereof, and a neurotransmitter activity modulator (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant) (e.g., together in one dosage form administered at least once or multiple times, and/or in separate dosage forms (i.e., with psilocybin or derivative thereof being in one dosage form and the neurotransmitter activity modulator(s) being in another, separate dosage form, with each being administered at least once or multiple times).
The methods may be performed with any of the psilocybin, cannabidiol, neurotransmitter activity modulator compositions described above.
An effective combination of psilocybin and/or a derivative thereof, cannabidiol and/or a derivative thereof, and/or neurotransmitter activity modulator, or various combinations thereof may be administered in a single dosage form or in multiple dosage forms, which may be administered concurrently (i.e., at the same time) or in divided doses over the course of a day, such as in two, three, four, or more, divided doses. In some embodiments, the composition is administered in a single dose (in single or multiple dosage forms) once a day, optionally on an empty stomach or on a full stomach. If the composition is administered in multiple dosage forms, each of the psilocybin or a derivative thereof, and/or cannabidiol or a derivative thereof, and/or neurotransmitter activity modulator may be provided in one or more separate dosage forms (e.g., one or more capsules containing psilocybin, and one or more capsules containing cannabidiol), or a single composition may comprise two or more of a neurotransmitter activity modulator, and cannabidiol (e.g., one or more capsules containing a neurotransmitter activity modulator and cannabidiol and one or more capsules containing psilocybin only, one or more capsules containing a neurotransmitter activity modulator and psilocybin and one or more capsules containing cannabidiol only, or one or more capsules containing a neurotransmitter activity modulator and cannabidiol and one or more capsules containing a neurotransmitter activity modulator only, wherein the psilocybin may be contained in either type of capsule). In some embodiments, the administration of each of the following components: psilocybin, neurotransmitter activity modulator, cannabidiol occurs within minutes, hours, or days of the administration of the other components.
Loading Dose(s)
In some embodiments, the subject is administered a loading dose of psilocybin, psilocin, a derivative thereof, or combinations thereof, either before or after receiving a maintenance dose of psilocybin, psilocin, a derivative thereof, or combinations thereof. The loading dose composition or dosage form of psilocybin can comprise a higher concentration of psilocybin or a derivative thereof than the maintenance dose.
The loading dose of psilocybin, psilocin, a derivative thereof, or combinations thereof, may include psilocybin or a derivative thereof in an amount of from about 1 mg to about 100 mg. In some embodiments, the psilocybin is synthetic psilocybin. In some embodiments, the psilocybin is crystalline psilocybin. In some embodiments, the psilocybin is amorphous psilocybin. In some embodiments, the psilocy bin is deuterated psilocybin. This includes about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about
28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about
48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg, and any amounts there between.
The loading dose of synthetic psilocybin or a derivative thereof may include psilocybin or a derivative thereof in an amount from about 1 mg to about 100 mg, about 1 mg to about 90 mg, about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 34 mg, about 1 mg to about 33 mg, about 1 mg to about 32 mg, about 1 mg to about 31 mg, about 1 mg to about 30 mg, about 1 mg to about 29 mg, about 1 mg to about 28 mg, about 1 mg to about 27 mg, about 1 mg to about 26 mg, about 1 mg to about 25 mg, about 1 mg to about 24 mg, about 1 mg to about 23 mg, about 1 mg to about 22 mg, about 1 mg to about 21 mg, about 1 mg to about 20 mg, about 1 mg to about 19 mg, about 1 mg to about 18 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 10 mg to about 100 mg, about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 10 mg to about 50 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 34 mg, about 10 mg to about 33 mg, about 10 mg to about 32 mg, about 10 mg to about 31 mg, about 10 mg to about 30 mg, about 10 mg to about 29 mg, about 10 mg to about 28 mg, about 10 mg to about 27 mg, about 10 mg to about 26 mg, about 10 mg to about 25 mg, about 10 mg to about 24 mg, about 10 mg to about 23 mg, about 10 mg to about 22 mg, about 10 mg to about 21 mg, about 10 mg to about 20 mg, about 10 mg to about 19 mg, about 10 mg to about 18 mg, about 10 mg to about 15 mg, about 15 mg to about 90 mg, about 15 mg to about 80 mg, about 15 mg to about 70 mg, about 15 mg to about 60 mg, about 15 mg to about 50 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 34 mg, about 15 mg to about 33 mg, about 15 mg to about 32 mg, about 15 mg to about 31 mg, about 15 mg to about 30 mg, about 20 mg to about 35 mg, about 21 mg to about 35 mg, about 22 mg to about 35 mg, about 22 mg to about 35 mg, about 23 mg to about 35 mg, about 24 mg to about 35 mg, about 25 mg to about 35 mg, about 20 mg to about 34 mg, about 21 mg to about 34 mg, about 22 mg to about 34 mg, about 23 mg to about 34 mg, about 23 mg to about 33 mg, about 23 mg to about 32 mg, about 23 mg to about 31 mg, about 24 mg to about 35 mg, about 24 mg to about 34 mg, about 24 mg to about 33 mg, about 24 mg to about 32 mg, about 24 mg to about 31 mg, about 24 mg to about 30 mg, about 25 mg to about 35 mg, about 25 mg to about 34 mg, about 25 mg to about 33 mg, about 25 mg to about 32 mg, about 25 mg to about 31 mg, or about 25 mg to about 30 mg psilocybin.
In some embodiments, the loading dose of synthetic psilocybin or derivative thereof or psilocin or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the loading dose of synthetic psilocybin comprises about 0. 1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, or about 1.0 mg/kg of the subject’s body weight. In some embodiments, the loading dose of synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0. 1 mg/kg to about 1 mg/kg, about 0.2 mg/kg to about 1 mg/kg, about 0.3 mg/kg to about 1 mg/kg, about 0.4 mg/kg to about 1 mg/kg, about 0.1 mg/kg to about 0.9 mg/kg, about 0. 1 mg/kg to about 0.8 mg/kg, about 0. 1 mg/kg to about 0.7 mg/kg, about 0. 1 mg/kg to about 0.6 mg/kg, about 0. 1 mg/kg to about 0.5 mg/kg, about 0. 1 mg/kg to about 0.4 mg/kg, about 0.2 mg/kg to about 0.8 mg/kg, about 0.3 mg/kg to about 0.7 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, about 0.3 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45 mg/kg, or about 0.3 mg/kg to about 0.4 mg/kg of the subject’s body weight.
The loading dose of natural psilocybin may include from about 0.5 g to about 6 g of dried mushrooms, such as Psilocybe cubensis. This includes about 0.5 g, about 0.6 g, about 0.7 g, about 0.8 g, about 0.9 g, about 1.0 g, about 1.2 g, about 1.4 g, about 1.6 g, about 1.8 g, about 2.0 g, about 2.2 g, about 2.4 g, about 2.6 g, about 2.8 g, about 3.0 g, about 3.2 g, about 3.4 g, about 3.6 g, about 3.8 g, about 4.0 g, about 4.2 g, about 4.4 g, about 4.6 g, about 4.8 g, about 5.0 g, about 5.2 g, about 5.4 g, about 5.6 g, about 5.8 g, about 6.0 g. The loading dose may include psilocybin or a derivative thereof in an amount from about 0.5 g mg to about 6 g, about 1 g to about 6 g, about 1 g to about 5 g, about 1 g to about 4 g, about 1 g to about 3 g, about 1 g to about 2 g, about 2 g to about 6 g, about 2 g to about 5 g, about 2 g to about 4 g, about 2 g to about 3 g, about 3 g to about 6 g, about 3 g to about 5 g, about 3 g to about 4 g, about 4 g to about 6 g, about 4 g to about 5 g. In some embodiments, the loading dose of psilocybin or derivative thereof or psilocin or derivative thereof is about 5 g of dried mushrooms. In some embodiments the dried mushrooms includes Psilocybe of Psilocybe cubensis.
The loading dose of natural psilocybin may include a dried mushroom, such as Psilocybe cubensis, which can be calculated based on the subject’s body weight. In some embodiments, the loading dose comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.11 mg/kg, about 0.12 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0. 19 mg/kg, or about 0.2 mg/kg of the subject’s body weight. In some embodiments the loading dose psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the loading dose comprises about 0.01 mg/kg to about 0.2 mg/kg, about 0.02 mg/kg to about 0.2 mg/kg, about 0.03 mg/kg to about 0.2 mg/kg, about 0.04 mg/kg to about 0.2 mg/kg, about 0.05 mg/kg to about 0.2 mg/kg, about 0.06 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.2 mg/kg, about 0.08 mg/kg to about 0.2 mg/kg, about 0.09 mg/kg to about 0.2 mg/kg, about 0.07 mg/kg to about 0.1 mg/kg, about 0.06 mg/kg to about 0.11 mg/kg, about 0.05 mg/kg to about 0. 13 mg/kg, about 0.4 mg/kg to about 0.13 mg/kg, about 0.4 mg/kg to about 0.14 mg/kg, about 0.4 mg/kg to about 0.14 mg/kg of the subject’s body weight.
In some embodiments, the loading dose is administered in conjunction with a psychological support session. In some embodiments, the loading dose is not administered in conjunction with a psychological support session. This could be because the loading dose selected may be low enough to not alter the subject’s state of consciousness.
Maintenance Dose(s)
In some embodiments, the subject is administered a maintenance dose either before or after receiving a loading dose. In some embodiments, the subject is administered a maintenance dose in the absence of a loading dose of psilocybin. In some embodiments, a maintenance dose includes psilocybin and/or psilocin or a derivative thereof. The maintenance dose can comprise a lower concentration of psilocybin or a derivative thereof than the loading dose. In some embodiments, the maintenance dose includes a cannabinoid, such as cannabidiol (CBD). In some embodiments, the maintenance dose includes a neurotransmitter activity modulator (e g , a tricyclic, SNRI, SSRI, or NRI antidepressant). In some embodiments, a maintenance dose includes one or more of a maintenance dose of psilocybin, CBD, a neurotransmitter activity modulator (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant).
A maintenance dose may include an amount of synthetic psilocybin or a derivative thereof that provides from about 0.01 mg/day up to about 10 mg/day of the psilocybin or the derivative thereof. This includes about 0.01 mg/day, about 0.02 mg/day, about 0.03 mg/day, about 0.04 mg/day, about 0.05 mg/day, about 0.06 mg/day, about 0.07 mg/day, about 0.08 mg/day, about 0.09 mg/day, about 0.1 mg/day, about 0.11 mg/day, about 0.12 mg/day, about 0.13 mg/day, about 0.14 mg/day, about 0.15 mg/day, about 0.16 mg/day, about 0.17 mg/day, about 0.18 mg/day, about 0.19 mg/day, about 0.2 mg/day, about 0.21 mg/day, about 0.22 mg/day, about 0.23 mg/day, about 0.24 mg/day, about 0.25 mg/day, about 0.26 mg/day, about 0.27 mg/day, about 0.28 mg/day, about 0.29 mg/day, about 0.3 mg/day, about 0.31 mg/day, about 0.32 mg/day, about 0.33 mg/day, about 0.34 mg/day, about 0.35 mg/day, about 0.36 mg/day, about 0.37 mg/day, about 0.38 mg/day, about 0.39 mg/day, about 0.4 mg/day, about 0.41 mg/day, about 0.42 mg/day, about 0.43 mg/day, about 0.44 mg/day, about 0.45 mg/day, about 0.46 mg/day, about 0.47 mg/day, about 0.48 mg/day, about 0.49 mg/day, about 0.5 mg/day, about 0.51 mg/day, about 0.52 mg/day, about 0.53 mg/day, about 0.54 mg/day, about 0.55 mg/day, about 0.56 mg/day, about 0.57 mg/day, about 0.58 mg/day, about 0.59 mg/day, about 0.6 mg/day, about 0.7 mg/day, about 0.8 mg/day, about 0.9 mg/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, or about 10 mg/day, and any amounts there between. For example, the dosage form may include an amount of psilocybin that provides from about 0.01 mg/day up to about 6 mg/day psilocybin. Other non-limiting ranges include about 0. 1 mg/day up to about 9 mg/day, about 0. 1 mg/day up to about 8 mg/day, about 0. 1 mg/day up to about 7 mg/day, about 0.1 mg/day up to about 6 mg/day, about 0.1 mg/day up to about 5 mg/day, about 0. 1 mg/day up to about 4 mg/day, about 0. 1 mg/day up to about 3 mg/day, about 0.1 mg/day up to about 2 mg/day, about 0. 1 mg/day up to about 1 mg/day, about 0. 1 mg/day up to about 0.9 mg/day, about 0. 1 mg/day up to about 0.8 mg/day, about 0.1 mg/day up to about 0.7 mg/day, about 0.1 mg/day up to about 0.6 mg/day, about 0.1 mg/day up to about 0.5 mg/day, about 0.1 mg/day up to about 0.4 mg/day, 0.2 mg/day up to about 9 mg/day, about 0.2 mg/day up to about 8 mg/day, about 0.2 mg/day up to about 7 mg/day, about 0.2 mg/day up to about 6 mg/day, about 0.2 mg/day up to about 5 mg/day, about 0.2 mg/day up to about 4 mg/day, about 0.2 mg/day up to about 3 mg/day, about 0.2 mg/day up to about 2.9 mg/day, about 0.2 mg/day up to about 2.8 mg/day, about 0.2 mg/day up to about 2.7 mg/day, about 0.2 mg/day up to about 2.6 mg/day, about 0.2 mg/day up to about 2.5 mg/day, about 0.2 mg/day up to about 2.4 mg/day, about 0.2 mg/day up to about 2.3 mg/day, about 0.2 mg/day up to about 2.2 mg/day, about 0.2 mg/day up to about 2.1 mg/day, about 0.2 mg/day up to about 2 mg/day, about 0.2 mg/day up to about 1.9 mg/day, about 0.2 mg/day up to about 1.8 mg/day, about 0.2 mg/day up to about 1.7 mg/day, about 0.2 mg/day up to about 1.6 mg/day, about 0.2 mg/day up to about 1.5 mg/day, about 0.2 mg/day up to about 1.4 mg/day, about 0.2 mg/day up to about 1.3 mg/day, about 0.2 mg/day up to about 1.2 mg/day, about 0.2 mg/day up to about 1.1 mg/day, about 0.2 mg/day up to about 1 mg/day, about 0.2 mg/day up to about 0.9 mg/day, about 0.2 mg/day up to about 0.8 mg/day, about 0.2 mg/day up to about 0.7 mg/day, about 0.2 mg/day up to about 0.6 mg/day, about 0.2 mg/day up to about 0.5 mg/day, about 0.2 mg/day up to about 0.4 mg/day, about 0.2 mg/day up to about 0.3 mg/day, about 0.2 mg/day up to about 2 mg/day, about 0.2 mg/day up to about 1 mg/day, about 0.2 mg/day up to about 0.9 mg/day, about 0.2 mg/day up to about 0.8 mg/day, about 0.2 mg/day up to about 0.7 mg/day, about 0.2 mg/day up to about 0.6 mg/day, about 0.2 mg/day up to about 0.5 mg/day, about 0.2 mg/day up to about 0.4 mg/day, about 0.2 mg/day up to about 0.3 mg/day, about 0.25 mg/day up to about 0.4 mg/day, about 0.3 mg/day up to about 0.4 mg/day, about 0.5 mg/day up to about 9 mg/day, about 0.5 mg/day up to about 8 mg/day, about 0.5 mg/day up to about 7 mg/day, about 0.5 mg/day up to about 6 mg/day, about 0.5 mg/day up to about 5 mg/day, about 0.5 mg/day up to about 4 mg/day, about 0.5 mg/day up to about 3 mg/day, about 0.5 mg/day up to about 2 mg/day, about 0.5 mg/day up to about 1 mg/day, about 1 mg/day up to about 9 mg/day, about 1 mg/day up to about 8 mg/day, about 1 mg/day up to about 7 mg/day, about 1 mg/day up to about 6 mg/day, about 1 mg/day up to about 5 mg/day, 1 mg/day up to about 4 mg/day, about 1 mg/day up to about 3 mg/day, about 1 mg/day up to about 2 mg/day of psilocybin.
In some embodiments, a maintenance dose of synthetic psilocybin or derivative thereof or psilocin or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, or about 0. 1 mg/kg of the subject’s body weight. In some embodiments, the maintenance dose of synthetic psilocybin or a derivative thereof, or psilocin or a derivative thereof can comprise about 0.01 mg/kg to about 0.1 mg/kg, about 0.02 mg/kg to about 0.1 mg/kg, about 0.03 mg/kg to about 0. 1 mg/kg, about 0.04 mg/kg to about 0. 1 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.08 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.06 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.01 mg/kg to about 0.04 mg/kg, about 0.02 mg/kg to about 0.08 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.06 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.03 mg/kg to about 0.045 mg/kg, or about 0.03 mg/kg to about 0.04 mg/kg of the subject’s body weight.
A maintenance dose may include natural psilocy bin or a derivative thereof in the form of a dried mushroom, such as Psilocybe cubensis may include an amount of from about 0.05 g to about 0.6 g. This includes about 0.05 g, about 0.06 g, about 0.07 g, about 0.08 g, about 0.09 g, about 0.1 g, about 0.12 g, about 0.14 g, about 0.16 g, about 0.18 g, about 0.2 g, about 0.22 g, about 0.24 g, about 0.26 g, about 0.28 g, about 0.30 g, about 0.32 g, about 0.34 g, about 0.36 g, about 0.38 g, about 0.4 g, about 0.42 g, about 0.44 g, about 0.46 g, about 0.48 g, about 0.5 g, about 0.52 g, about 0.54 g, about 0.56 g, about 0.58 g, about 0.6 g. A maintenance dose of natural psilocybin or a derivative thereof may include psilocybin or a derivative thereof in an amount from about 0.05 g mg to about 0.6 g, about 0. 1 g to about 0.6 g, about 0.1 g to about 0.5 g, about 0. 1 g to about 0.4 g, about 0.1 g to about 0.3 g, about 0. 1 g to about 0.2 g, about 0.2 g to about 0.6 g, about 0.2 g to about 0.5 g, about 0.2 g to about 0.4 g, about 0.2 g to about 0.3 g, about 0.3 g to about 0.6 g, about 0.3 g to about 0.5 g, about 0.3 g to about 0.4 g, about 0.4 g to about 0.6 g, about 0.4 g to about 0.5 g. In some embodiments, the maintenance dose of natural psilocybin or derivative thereof or psilocin or derivative thereof is about 0.25 g to about 0.5 g of dried mushrooms.
A maintenance dose of natural psilocybin or a derivative thereof, or psilocin or a derivative thereof in the form of a dried mushroom, such as Psilocybe cubensis can be determined based on the subject’s body weight. In some embodiments, the natural psilocybin comprises about 0.001 mg/kg, about 0.002 mg/kg, about 0.003 mg/kg, about 0.004 mg/kg, about 0.005 mg/kg, about 0.006 mg/kg, about 0.007 mg/kg, about 0.008 mg/kg, about 0.009 mg/kg, about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.017 mg/kg, about 0.018 mg/kg, about 0.019 mg/kg, or about 0.02 mg/kg of the subject’s body weight. In some embodiments the natural psilocybin or a derivative thereof, or psilocin or a derivative thereof is in the form of a dried mushroom, wherein the composition comprises about 0.001 mg/kg to about 0.02 mg/kg, about 0.002 mg/kg to about 0.02 mg/kg, about 0.003 mg/kg to about 0.02 mg/kg, about 0.004 mg/kg to about 0.02 mg/kg, about 0.005 mg/kg to about 0.02 mg/kg, about 0.006 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.02 mg/kg, about 0.008 mg/kg to about 0.02 mg/kg, about 0.009 mg/kg to about 0.02 mg/kg, about 0.007 mg/kg to about 0.01 mg/kg, about 0.006 mg/kg to about 0.011 mg/kg, about 0.005 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.013 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg, about 0.04 mg/kg to about 0.014 mg/kg of the subject’s body weight.
A maintenance dose may include from about 1 mg to about 1000 mg of a cannabinoid. The cannabinoid in various embodiments is cannabidiol (CBD). In some embodiments, the cannabinoid is synthetic CBD. The maintenance dose may include, e.g., about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675, about 700, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg cannabinoid (e.g., CBD), or any amount there between.
Thus, a maintenance dose may include a synthetic cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about 300 mg to about 1000 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg, about 300 mg to about 700 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 350 mg to about 700 mg, about 350 mg to about 650 mg, about 350 mg to about 600 mg. In some embodiments, a maintenance dose may include a synthetic cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about
I mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg.
In some embodiments, a maintenance dose of synthetic cannabidiol or derivative thereof, can be calculated based on the subject’s body weight. In some embodiments, the composition comprises about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about
I I mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, or about 15 mg/kg of the subject’s body weight. In some embodiments, the maintenance dose of synthetic cannabidiol or a derivative thereof can comprise about 1 mg/kg to about 15 mg/kg, about 1 mg/kg to about 13 mg/kg, about 1 mg/kg to about 11 mg/kg, about 2 mg/kg to about 11 mg/kg, about 3 mg/kg to about 10 mg/kg, about 4 mg/kg to about 9 mg/kg of the subject’s body weight.
In some embodiments, a maintenance dose cannabidiol or derivative thereof can be a natural cannabidiol, for example in the form of a full kief. In some embodiments, a maintenance dose of natural cannabidiol comprises about 1 to about 2000 mg of natural cannabidiol, for example, about 1 mg, about 50, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1003 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290, about 1300 mg, about 1310 mg, about 13200 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 137 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg cannabinoid (e.g., CBD), or any amount there between.
In some embodiments, a maintenance dose may include a natural cannabinoid in an amount from about 1 mg to about 1000 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 1000 mg, about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 300 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 100 mg to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 250 mg to about 1000 mg, about 250 mg to about 900 mg, about 250 mg to about 800 mg, about 250 mg to about 700 mg, about 250 mg to about 600 mg, about 300 mg to about 1000 mg, about 300 mg to about 900 mg, about 300 mg to about 800 mg, about 300 mg to about 700 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 800 mg, about 350 mg to about 700 mg, about 350 mg to about 650 mg, about 350 mg to about 600 mg. In some embodiments, a maintenance dose may include a natural cannabinoid in an amount from about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg. about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg.
In some embodiments, a maintenance dose of natural cannabidiol, can be calculated based on the subject’s body weight. In some embodiments, a maintenance dose of natural cannabidiol comprises about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2. 1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, or about 3.0 mg/kg of the subject’s body weight. In some embodiments, a maintenance dose natural cannabidiol can comprise about 0.1 mg/kg to about 3 mg/kg, about 0.2 mg/kg to about 3 mg/kg, about 0.3 mg/kg to about 3 mg/kg, about 0.4 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 3 mg/kg, about 0.6 mg/kg to about 3 mg/kg, about 0.7 mg/kg to about 3 mg/kg, about 0.5 mg/kg to about 2.9 mg/kg, about 0.5 mg/kg to about 2.8 mg/kg, about 0.5 mg/kg to about 2.7 mg/kg, about 0.5 mg/kg to about 2.6 mg/kg, about 0.5 mg/kg to about 2.5 mg/kg, about 0.7 mg/kg to about 2.9 mg/kg, about 0.7 mg/kg to about 2.8 mg/kg, about 0.7 mg/kg to about 2.7 mg/kg, about 0.7 mg/kg to about 2.6 mg/kg, or about 0.7 mg/kg to about 2.5 mg/kg of the subject’s body weight.
A maintenance dose may include an amount of a neurotransmitter activity modulator or a derivative thereof (e.g., a tricyclic, SSRI, SNRI, or NRI antidepressant) that provides from about 1 mg to about 600 mg of the neurotransmitter activity modulator. In some embodiments the neurotransmitter activity modulator or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 1 3 mg, about 164 mg, about 165 mg, about 166 mg, about 1 7 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the amount of neurotransmitter activity modulator can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, about 1 mg to about 300 mg, about 1 mg to about 305 mg, about 1 mg to about 310 mg, about 1 mg to about 315 mg, about 1 mg to about 320 mg, about 1 mg to about 325 mg, about 1 mg to about 330 mg, about 1 mg to about 335 mg, about 1 mg to about 340 mg, about 1 mg to about 345 mg, about 1 mg to about 350 mg, about 1 mg to about 355 mg, about 1 mg to about 360 mg, about 1 mg to about 365 mg, about 1 mg to about 370 mg, about 1 mg to about 375 mg, about 1 mg to about 380 mg, about 1 mg to about 385 mg, about 1 mg to about 390 mg, about 1 mg to about 395 mg, about 1 mg to about 400 mg, about 1 mg to about 405 mg, about 1 mg to about 410 mg, about 1 mg to about 415 mg, about 1 mg to about 420 mg, about 1 mg to about 425 mg, about 1 mg to about 430 mg, about 1 mg to about 435 mg, about 1 mg to about 440 mg, about 1 mg to about 445 mg, about 1 mg to about 450 mg, about 1 mg to about 455 mg, about 1 mg to about 460 mg, about 1 mg to about 465 mg, about 1 mg to about 470 mg, about 1 mg to about 475 mg, about 1 mg to about 480 mg, about 1 mg to about 485 mg, about 1 mg to about 490 mg, about 1 mg to about 495 mg, about 1 mg to about 500 mg, about 1 mg to about 505 mg, about 1 mg to about 510 mg, about 1 mg to about 515 mg, about 1 mg to about 520 mg, about 1 mg to about 525 mg, about 1 mg to about 530 mg, about 1 mg to about 535 mg, about 1 mg to about 540 mg, about 1 mg to about 545 mg, about 1 mg to about 550 mg, about 1 mg to about 555 mg, about 1 mg to about 560 mg, about 1 mg to about 565 mg, about 1 mg to about 570 mg, about 1 mg to about 575 mg, about 1 mg to about 580 mg, about 1 mg to about 585 mg, about 1 mg to about 590 mg, about 1 mg to about 595 mg, or about 1 mg to about 600 mg.
Specifically, a maintenance dose may include about 1 mg to about 500 mg of a tricyclic antidepressant. In some embodiments, the neurotransmitter activity modulator or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the amount of tricyclic antidepressant or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, about 1 mg to about 300 mg, about 1 mg to about 305 mg, about 1 mg to about 310 mg, about 1 mg to about 315 mg, about 1 mg to about 320 mg, about 1 mg to about 325 mg, about 1 mg to about 330 mg, about 1 mg to about 335 mg, about 1 mg to about 340 mg, about 1 mg to about 345 mg, about 1 mg to about 350 mg, about 1 mg to about 355 mg, about 1 mg to about 360 mg, about 1 mg to about 365 mg, about 1 mg to about 370 mg, about 1 mg to about 375 mg, about 1 mg to about 380 mg, about 1 mg to about 385 mg, about 1 mg to about 390 mg, about 1 mg to about 395 mg, about 1 mg to about 400 mg, about 1 mg to about 405 mg, about 1 mg to about 410 mg, about 1 mg to about 415 mg, about 1 mg to about 420 mg, about 1 mg to about 425 mg, about 1 mg to about 430 mg, about 1 mg to about 435 mg, about 1 mg to about 440 mg, about 1 mg to about 445 mg, about 1 mg to about 450 mg, about 1 mg to about 455 mg, about 1 mg to about 460 mg, about 1 mg to about 465 mg, about 1 mg to about 470 mg, about 1 mg to about 475 mg, about 1 mg to about 480 mg, about 1 mg to about 485 mg, about 1 mg to about 490 mg, about 1 mg to about 495 mg, about 1 mg to about 500 mg, about 1 mg to about 505 mg, about 1 mg to about 510 mg, about 1 mg to about 515 mg, about 1 mg to about 520 mg, about 1 mg to about 525 mg, about 1 mg to about 530 mg, about 1 mg to about 535 mg, about 1 mg to about 540 mg, about 1 mg to about 545 mg, about 1 mg to about 550 mg, about 1 mg to about 555 mg, about 1 mg to about 560 mg, about 1 mg to about 565 mg, about 1 mg to about 570 mg, about 1 mg to about 575 mg, about 1 mg to about 580 mg, about 1 mg to about 585 mg, about 1 mg to about 590 mg, about 1 mg to about 595 mg, or about 1 mg to about 600 mg.
In some embodiments, the tricyclic antidepressant can include between about 1 mg and about 300 mg imipramine. In some embodiments, the imipramine or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In some embodiments, the amount of imipramine or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 1 10 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, or about 1 mg to about 300 mg. A maintenance dose may include about 1 mg to about 600 mg of an SSRI. In some embodiments, the SSRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the amount of SSRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, about 1 mg to about 300 mg, about 1 mg to about 305 mg, about 1 mg to about 310 mg, about 1 mg to about 315 mg, about 1 mg to about 320 mg, about 1 mg to about 325 mg, about 1 mg to about 330 mg, about 1 mg to about 335 mg, about 1 mg to about 340 mg, about 1 mg to about 345 mg, about 1 mg to about 350 mg, about 1 mg to about 355 mg, about 1 mg to about 360 mg, about 1 mg to about 365 mg, about 1 mg to about 370 mg, about 1 mg to about 375 mg, about 1 mg to about 380 mg, about 1 mg to about 385 mg, about 1 mg to about 390 mg, about 1 mg to about 395 mg, about 1 mg to about 400 mg, about 1 mg to about 405 mg, about 1 mg to about 410 mg, about 1 mg to about 415 mg, about 1 mg to about 420 mg, about 1 mg to about 425 mg, about 1 mg to about 430 mg, about 1 mg to about 435 mg, about 1 mg to about 440 mg, about 1 mg to about 445 mg, about 1 mg to about 450 mg, about 1 mg to about 455 mg, about 1 mg to about 460 mg, about 1 mg to about 465 mg, about 1 mg to about 470 mg, about 1 mg to about 475 mg, about 1 mg to about 480 mg, about 1 mg to about 485 mg, about 1 mg to about 490 mg, about 1 mg to about 495 mg, about 1 mg to about 500 mg, about 1 mg to about 505 mg, about 1 mg to about 510 mg, about 1 mg to about 515 mg, about 1 mg to about 520 mg, about 1 mg to about 525 mg, about 1 mg to about 530 mg, about 1 mg to about 535 mg, about 1 mg to about 540 mg, about 1 mg to about 545 mg, about 1 mg to about 550 mg, about 1 mg to about 555 mg, about 1 mg to about 560 mg, about 1 mg to about 565 mg, about 1 mg to about 570 mg, about 1 mg to about 575 mg, about 1 mg to about 580 mg, about 1 mg to about 585 mg, about 1 mg to about 590 mg, about 1 mg to about 595 mg, or about 1 mg to about 600 mg.
A maintenance dose may include about 1 mg to about 600 mg of an SNRI. In some embodiments, the SNRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 1 5 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the amount of SNRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg, about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, about 1 mg to about 300 mg, about 1 mg to about 305 mg, about 1 mg to about 310 mg, about 1 mg to about 315 mg, about 1 mg to about 320 mg, about 1 mg to about 325 mg, about 1 mg to about 330 mg, about 1 mg to about 335 mg, about 1 mg to about 340 mg, about 1 mg to about 345 mg, about 1 mg to about 350 mg, about 1 mg to about 355 mg, about 1 mg to about 360 mg, about 1 mg to about 365 mg, about 1 mg to about 370 mg, about 1 mg to about 375 mg, about 1 mg to about 380 mg, about 1 mg to about 385 mg, about 1 mg to about 390 mg, about 1 mg to about 395 mg, about 1 mg to about 400 mg, about 1 mg to about 405 mg, about 1 mg to about 410 mg, about 1 mg to about 415 mg, about 1 mg to about 420 mg, about 1 mg to about 425 mg, about 1 mg to about 430 mg, about 1 mg to about 435 mg, about 1 mg to about 440 mg, about 1 mg to about 445 mg, about 1 mg to about 450 mg, about 1 mg to about 455 mg, about 1 mg to about 460 mg, about 1 mg to about 465 mg, about 1 mg to about 470 mg, about 1 mg to about 475 mg, about 1 mg to about 480 mg, about 1 mg to about 485 mg, about 1 mg to about 490 mg, about 1 mg to about 495 mg, about 1 mg to about 500 mg, about 1 mg to about 505 mg, about 1 mg to about 510 mg, about 1 mg to about 515 mg, about 1 mg to about 520 mg, about 1 mg to about 525 mg, about 1 mg to about 530 mg, about 1 mg to about 535 mg, about 1 mg to about 540 mg, about 1 mg to about 545 mg, about 1 mg to about 550 mg, about 1 mg to about 555 mg, about 1 mg to about 560 mg, about 1 mg to about 565 mg, about 1 mg to about 570 mg, about 1 mg to about 575 mg, about 1 mg to about 580 mg, about 1 mg to about 585 mg, about 1 mg to about 590 mg, about 1 mg to about 595 mg, or about 1 mg to about 600 mg.
A maintenance dose may include about 1 mg to about 600 mg of an NRI. In some embodiments, the NRI or derivative thereof comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg. In some embodiments, the amount of NRI or derivative thereof can comprise about 1 mg to about 5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 1 mg to about 35 mg, about 1 mg to about 40 mg, about 1 mg to about 45 mg, about 1 mg to about 50 mg, about 1 mg to about 55 mg, about 1 mg to about 60 mg, about 1 mg to about 65 mg, about 1 mg to about 70 mg, about 1 mg to about 75 mg, about 1 mg to about 80 mg, about 1 mg to about 85 mg, about 1 mg to about 90 mg, about 1 mg to about 95 mg, about 1 mg to about 100 mg, about 1 mg to about 105 mg, about 1 mg to about 110 mg, about 1 mg to about 115 mg, about 1 mg to about 120 mg, about 1 mg to about 125 mg, about 1 mg to about 130 mg, about 1 mg to about 135 mg, about 1 mg to about 140 mg, about 1 mg to about 145 mg, about 1 mg to about 150 mg, about 1 mg to about 155 mg, about 1 mg to about 160 mg, about 1 mg to about 165 mg, about 1 mg to about 170 mg, about 1 mg to about 175 mg, about 1 mg to about 180 mg, about 1 mg to about 185 mg, about 1 mg to about 190 mg, about 1 mg to about 195 mg, about 1 mg to about 200 mg, about 1 mg to about 205 mg, about 1 mg to about 210 mg, about 1 mg to about 215 mg, about 1 mg to about 220 mg, about 1 mg to about 225 mg, about 1 mg to about 230 mg, about 1 mg to about 235 mg, about 1 mg to about 240 mg, about 1 mg to about 245 mg, about 1 mg to about 250 mg, about 1 mg to about 255 mg, about 1 mg to about 260 mg, about 1 mg to about 265 mg, about 1 mg to about 270 mg, about 1 mg to about 275 mg, about 1 mg to about 280 mg. about 1 mg to about 285 mg, about 1 mg to about 290 mg, about 1 mg to about 295 mg, about 1 mg to about 300 mg, about 1 mg to about 305 mg, about 1 mg to about 310 mg, about 1 mg to about 315 mg, about 1 mg to about 320 mg, about 1 mg to about 325 mg, about 1 mg to about 330 mg, about 1 mg to about 335 mg, about 1 mg to about 340 mg, about 1 mg to about 345 mg, about 1 mg to about 350 mg, about 1 mg to about 355 mg, about 1 mg to about 360 mg, about 1 mg to about 365 mg, about 1 mg to about 370 mg, about 1 mg to about 375 mg, about 1 mg to about 380 mg, about 1 mg to about 385 mg, about 1 mg to about 390 mg, about 1 mg to about 395 mg, about 1 mg to about 400 mg, about 1 mg to about 405 mg, about 1 mg to about 410 mg, about 1 mg to about 415 mg, about 1 mg to about 420 mg, about 1 mg to about 425 mg, about 1 mg to about 430 mg, about 1 mg to about 435 mg, about 1 mg to about 440 mg, about 1 mg to about 445 mg, about 1 mg to about 450 mg, about 1 mg to about 455 mg, about 1 mg to about 460 mg, about 1 mg to about 465 mg, about 1 mg to about 470 mg, about 1 mg to about 475 mg, about 1 mg to about 480 mg, about 1 mg to about 485 mg, about 1 mg to about 490 mg, about 1 mg to about 495 mg, about 1 mg to about 500 mg, about 1 mg to about 505 mg, about 1 mg to about 510 mg, about 1 mg to about 515 mg, about 1 mg to about 520 mg, about 1 mg to about 525 mg, about 1 mg to about 530 mg, about 1 mg to about 535 mg, about 1 mg to about 540 mg, about 1 mg to about 545 mg, about 1 mg to about 550 mg, about 1 mg to about 555 mg, about 1 mg to about 560 mg, about 1 mg to about 565 mg, about 1 mg to about 570 mg, about 1 mg to about 575 mg, about 1 mg to about 580 mg, about 1 mg to about 585 mg, about 1 mg to about 590 mg, about 1 mg to about 595 mg, or about 1 mg to about 600 mg. In some embodiments, the NR1 or derivative thereof can comprise about 5 mg to about 600 mg, about 10 mg to about 600 mg, about 15 mg to about 600 mg, about 20 mg to about 600 mg, about 25 mg to about 600 mg, about 30 mg to about 600 mg, about 35 mg to about 600 mg, about 40 mg to about 600 mg, about 45 mg to about 600 mg, about 50 mg to about 600 mg, about 55 mg to about 600 mg, about 60 mg to about 600 mg, about 65 mg to about 600 mg, about 70 mg to about 600 mg, about 75 mg to about 600 mg, about 80 mg to about 600 mg, about 85 mg to about 600 mg, about 90 mg to about 600 mg, about 95 mg to about 600 mg, about 100 mg to about 600 mg, about 105 mg to about 600 mg, about 110 mg to about 600 mg, about 115 mg to about 600 mg, about 120 mg to about 600 mg, about 125 mg to about 600 mg, about 130 mg to about 600 mg, about 135 mg to about 600 mg, about 140 mg to about 600 mg, about 145 mg to about 600 mg, or about 150 mg to about 600 mg. Schedules
In various embodiments, the loading dose is administered once about every 1 week, 2 weeks, 3 weeks 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, or 35 weeks. In various embodiments, the loading dose is administered once about every 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In various embodiments, the loading dose is administered only once during an indicated time period. In some embodiments, the loading dose is administered more than once during an indicated time period.
In some embodiments of the methods of the disclosure, a subject is administered a loading dose of psilocybin or a denvative thereof and is not administered any further psilocybin until a subsequent loading dose after one of the time periods specified above. In some embodiments of the disclosure, a subject is administered a loading dose of psilocybin or a derivative thereof and is not administered any further psilocybin or a derivative thereof until
I day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days have passed. In some embodiments a subject is administered a loading dose of psilocybin or a derivative thereof and is not administered any further psilocybin or derivative thereof until 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months,
I I months, or 12 months have passed.
Administration of the loading dose of psilocybin or a derivative thereof may occur one day or more before commencing the maintenance dose, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, or more days, before commencing the maintenance dose. For example, administration of the loading dose of psilocybin or a derivative thereof may occur 1 to 28 days before commencing the maintenance dose, 1 to 14 days before commencing the maintenance dose, 1 to 7 days before commencing the maintenance dose, 1 to 3 days before commencing the maintenance dose, or 1 day before commencing the maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 7 days to about 21 days before commencing an initial maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 10 days to about 15 days before commencing the initial maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 12 days to about 15 days before commencing an initial maintenance dose. In some embodiments, the loading dose of psilocybin is administered about 14 days before commencing an initial maintenance dose.
In specific examples, administration of the loading dose of psilocybin or a derivative thereof occurs about two weeks before commencing the maintenance dose. Additionally, or alternatively, the methods described herein may comprise administering one or more loading dose(s) of psilocybin or a derivative thereof (as described above) after commencing a maintenance dose. Administration of one or more loading dose(s) of psilocybin or a derivative thereof may occur one day or more after commencing the maintenance dose, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, or more days, after commencing the maintenance protocol. For example, administration of the loading dose of psilocybin or a derivative thereof may occur 1 to 28 days after commencing the maintenance dose, 1 to 14 days after commencing the maintenance dose, 1 to 7 days after commencing the maintenance dose, 1 to 3 days after commencing the maintenance dose, or 1 day after commencing the maintenance dose. In specific examples, administration of the loading dose of psilocybin or a derivative thereof occurs about two weeks after commencing the maintenance dose. In some embodiments, two or more loading doses are administered after beginning administration of a maintenance dose. In some embodiments, the two or more loading doses are on a predetermined schedule (e.g., to be administered at months 1 and 3 after beginning administration of a maintenance dose). In some embodiments, the two or more loading doses are administered on an ad hoc basis, based on patient symptoms during the course of treatment of the maintenance dose.
The maintenance dose of psilocybin can be administered on administered on a daily basis or on a scheduled basis. Non-limiting examples of a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week. Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six out of every seven days. The method may comprise administering the composition by a weekly protocol consisting of daily administration of a maintenance dose composition for 3-5 consecutive days followed by no administration for 1-3 consecutive days. A weekly protocol or schedule is sometimes referred herein as a “maintenance therapy.” In some embodiments, the maintenance dose is administered according to a weekly regimen.
The maintenance dose of cannabinoid can be administered on administered on a daily basis or on a scheduled basis. Non-limiting examples of a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week. Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six days out of every seven days. Additional schedules are within the scope of the disclosure.
The maintenance dose of a neurotransmitter activity modulator (e.g., a tricyclic, SNRI, SSRI, or NRI antidepressant) can be administered on administered on a daily basis or on a scheduled basis. Non-limiting examples of a scheduled basis include every other day, every two days, every three days, every four days, every five days, every six days, or once a week. Other non-limiting examples of a scheduled basis include one day on - six days off, two days on - five days off, three days on - four days off, four days on - three days off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include two days on - one day off, two days on - two days off, two days on - three days off, two days on - four days off, two days on - five days off, three days on - one day off, three days on - two days off, three days on - three days off, three days on - four days off, four days on - one day off, four days on - two days off, four days on - three days off, five days on - one day off, five days on - two days off, six days on - one day off. Yet further non-limiting examples of a scheduled basis include one day out of every seven days, two days out of every seven days, three days out of every seven days, four days out of every seven days, five days out of every seven days, or six days out of every seven days. Additional schedules are within the scope of the disclosure.
Administration of psilocybin or a derivative thereof and/or a cannabidiol or a derivative thereof may be continued on an as-needed basis, including for about or at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months. For example, administering the composition as a maintenance dose as outlined above may be continued for consecutive weeks, including for 2, 3, 4, or more consecutive weeks, or for consecutive months, including for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more consecutive months, including for 1-12 months, for 1-24 months, or longer.
Additional Methods of Treating Cluster -Tic Syndrome in Combination with Other Therapies
In some embodiments, the compositions described herein (e.g., of psilocybin, cannabidiol, neurotransmitter activity modulator, and combinations thereof) can be administered in conjunction with other therapies used to treat cluster-tic syndrome or symptoms thereof.
For example, the compositions described herein can be administered for the treatment of symptoms associated with cluster-tic syndrome, or conditions associated with cluster-tic syndrome (e.g. cluster-tic syndrome-associated depression) with one or more other therapies selected from the group consisting of carbamazepine, oxcarbazepine, gabapentin, lamotrigine, baclofen, botulinum toxin inj ections, pregabalin, phenytoin, topiramate, tizanidine, levetiracetam, misoprostol, topiramate, tocainide, pimozide, duloxetine, eslicarbazepin, vixotngine, opioids, lidocaine, fosphenytoin, sumatriptan, and combinations thereof. In some embodiments, the compositions described herein can be administered with one or more other therapies selected from the group consisting of carbamazepine, oxcarbazepine, and combinations thereof. In some embodiments, the compositions described herein can be administered with one or more other therapies selected from the group consisting of gabapentin, lamotrigine, baclofen, topiramate, tizanidine, and combinations thereof.
Additionally, the compositions described herein can be administered for the treatment of symptoms associated with cluster-tic syndrome, or conditions associated with cluster-tic syndrome (e.g., cluster-tic syndrome-associated depression) with one or more other therapies selected from the group consisting of 100% oxygen, triptans (e.g., sumatriptan, zolmitriptan), lidocaine, ergotamine, dihydroergotamine, octreotide, or combinations thereof. In some embodiments, the compositions described herein can be administered for the treatment of cluster-tic syndrome with one or more other therapies selected from the group consisting of verapamil, glucocorticoids, dihydroergotamine, prednisone, topiramate, lithium, triptans, CGRP targeted medication (e.g., galcanezumab), topiramate, melatonin, valproate, capsaicin, baclofen, indomethacin, ketamine, pasireotide, nasal carbon dioxide, lysergic acid diethylamide (LSD), botox, civamide, suboccipital steroid injection, warfarin, prednisone, or combinations thereof.
In some embodiments, the compositions of the disclosure may be provided as separate compositions and/or in separate or multiple dosage forms, including divided doses, from the other therapies. In some embodiments, the compositions of the disclosure may be formulated with one or more of the other therapies in the same dosage form. In some embodiments, the methods of the disclosure can still be practiced when the compositions of the disclosure and/or the other therapies are administered in a dosage form different from the previous administration of that particular composition or other therapy.
In some embodiments, the compositions of the disclosure may be administered before, concurrent with, or after the other therapies. In some embodiments, the methods of the disclosure include administering one or more other therapies on the same schedule as the compositions of the disclosure. In some embodiments, the methods of the disclosure include administering one or more other therapies on a different schedule as the compositions of the disclosure. In a non-limiting example, a subject with cluster-tic syndrome may be treated with a low/maintenance dose of psilocybin and CBD, every other day. The subject may be treated with one or more of the other therapies on one or more “off days” of the psilocybin + CBD treatment.
In some embodiments, a subject with cluster-tic syndrome may have been treated with one or more of the other therapies before beginning treatment with one or more of the compositions of the disclosure. In some embodiments, a subject with cluster-tic syndrome may have been treated with one or more of the other therapies before beginning treatment with one of the methods of the disclosure. In some embodiments, a subject may have experienced refractory symptoms after treatment with one or more of the other therapies. In some embodiments, a subject may not have been previously administered a therapy to treat cluster-tic syndrome or symptoms thereof prior to administration of the compositions described herein.
In some embodiments, the compositions described herein (e.g., of psilocybin, cannabidiol, neurotransmitter activity modulator, and combinations thereof) can be used in conjunction with neurostimulation or surgical treatment to treat cluster-tic syndrome or symptoms thereof.
For example, in some embodiments, the neurostimulation treatment may include, but is not limited to noninvasive vagus nerve stimulation, deep brain stimulation, sphenopalatine ganglion stimulation, occipital nerve stimulation, and combinations thereof. Additionally, in some embodiments, the surgical treatment may include, but is not limited to microvascular decompression, gamma knife surgery, controlled lesioning of the trigeminal ganglion or root by mechanical compression (e.g., balloon compression), peripheral neurectomy (e.g., incision, alcohol injection, radiofrequency lesioning, cryotherapy), radiofrequency thermocoagulation, glycerol rhizolysis, internal neurolysis, stereotactic radiosurgery. In other non-limiting embodiments, the surgical treatment may include radiofrequency thermocoagulation, glycerol ganglio-rhizolysis, microvascular decompression, alcohol injection, gamma knife radiosurgery, nerve sectioning, and combinations thereof.
In some embodiments a subject with cluster-tic syndrome may have been treated with one or more neurostimulation protocols and/or one or more surgical therapies before beginning treatment with one or more of the compositions of the disclosure. In some embodiments, a subject may have experienced refractory symptoms after treatment with one or more of the surgical therapies. In some embodiments, a subject may not have previously undergone surgical therapy before beginning treatment with one or more of the compositions and/or methods of the disclosure. In some embodiments, a subject may be treated with one or more compositions of the disclosure before the subject undergoes surgical treatment for cluster-tic syndrome or symptoms thereof.
Psychological Support
The methods of the present disclosure may comprise having a subject participate in one or more pre- and/or post-administration psychological support session(s). In various embodiments, the methods of the present disclosure involve administering psychotherapy to a patient. Pre-Administration Psychological Support Sessions
In some embodiments, the subject participates in at least one psychological support session before administration of a composition of the present disclosure (“pre-administration psychological support session”). Administration of the composition may be referred to as an “administration session”. In various embodiments the composition administered during the administration session comprises psilocybin or a derivative thereof. In some embodiments, a pre-administration psychological support session may be held about 1 month prior to the administration session. In some embodiments, a pre-administration psychological support session may be held about 2 weeks prior to the administration. In some embodiments, a pre- administration psychological support session may be held about 1 week prior to the administration. In some embodiments, a pre-administration psychological support session may be held about 3 days prior to the administration. In some embodiments, a pre- administration psychological support session may be held about 1 day prior to the administration. In some embodiments, a pre-administration psychological support session may be held on the same day as and prior to administration.
In some embodiments, the subject may participate in one, two, three, four, five, six, seven, or eight pre-administration psychological support sessions. In some embodiments, the subject may participate in at least two pre-administration psychological support sessions. In some embodiments, the subject may participate in at least three pre-administration psychological support sessions. In some embodiments, the subject may participate in pre- administration psychological support sessions at least once per week, for at least two or three weeks prior to the administration. In some embodiments, the subject may additionally participate in a pre-administration psychological support session the day before the administration. The pre-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a person administering the psychological support. In some embodiments, the psychological support sessions may be group sessions, wherein more than one subject meets with a single person administering the psychological support, or more than one person administering the psychological support. In some embodiments, one or more of the subject’s family members or friends may be present at the pre-administration psychological support session(s)
In some embodiments, the goals of the pre-administration session may include (i) establishing therapeutic alliance between subject and person administering the psychological support; (ii) answering the subject’s questions and addressing any concerns; and/or (iii) demonstrating and practicing the skills of self- directed inquiry and experiential processing. In some embodiments, the pre-administration psychological support sessions focus on discussion of possible effects, and/or preparing subjects for a dosing session by practicing relevant therapeutic techniques to reduce avoidance and anxiety, eliciting relevant therapeutic goals, building rapport, and/or establishing therapeutic alliance. During the psychological support session, skills of self-directed inquiry and experiential processing may be demonstrated and/or practiced.
Psychological Support During Administration
During the treatment session, the subject may be supervised by one or more trained person administering the psychological supports. The person administering the psychological support supervising the subject during the administration may be the same person administering the psychological support from the subject’s pre-administration psychological support session(s), or may be a different person administering the psychological support. The person administering the psychological support(s) may provide psychological support to the subject as necessary. As used herein, the term “psychological support” refers to any measure(s) taken by the person administering the psychological support during the administration to ensure the safety of the subject and maximize the clinical effectiveness of the administration. For example, the psychological support may be anything done by the person administering the psychological support to (1) to ensure psychological safety of the subject; (2) to allow the subject’s subjective experience to unfold naturally within the boundaries of the therapeutic intention set at the preparation; (3) to maintain participant’s attention and awareness on the experience of the present moment thus allowing exposure and processing of the challenging emotional states and personal memories; and/or (4) to generate insights and solutions for the resolution of challenging personal situations, conflicts and traumatic experiences.
In some embodiments, the main therapeutic goals of the person administering the psychological support during the administration are to (i) minimize extreme anxiety, and (ii) provide appropriate support that enables the skills and processes of self-directed inquiry and experiential processing.
In some embodiments, the level of psychological support will vary during the various stages of the subject’s experience during an administration session (e.g., the initial stage, the early stage, the peak stage, and the late stage). In some embodiments, the type of psychological support will vary during the various stages of the subject’s experience (e.g., the initial stage, the early stage, the peak stage, and the late stage). Because non-dual, ego- dissolution or “unitive” experiences have been shown to positively correlate with the magnitude and durability of the clinical response, the person administering the psychological support will, in some embodiments, attend to such states with particular care.
In some embodiments, a subj ect may experience of a compromised sense of self during the subject’s experience. In some embodiments, an ego dissolution experience is a spontaneously occurring state of consciousness where there is a reduction in the self- referential awareness that defines normal waking consciousness, resulting in a compromised sense of “self . In some embodiments, a unitive experience is an experience characterized by a sense of unity or “oneness” that exceeds sensory or cognitive apprehension.
At the initial and early stage of the administration session, psychological support may be used to reduce severe and/or prolonged anxiety. Anxiety prior to or during the onset of psilocybin effects is not uncommon, and the person administering the psychological supports may be specially trained to recognize and actively manage subjects through such periods of anxiety until the subject is comfortable enough to continue on their own. At the initial and early stage of the administration session, the person administering the psychological support may encourage the subject to lie down, practice relaxation and breathing exercises, and/or listen to calming music. In some embodiments, the person administering the psychological support may remind the subject that their primary task during this session is to simply collect new and interesting experiences which can then be discussed with the person administering the psychological support after the session. The person administering the psychological support may remind the participant of the purpose of the therapy and the role of experiential processing, namely allowing the participant to be open and curious to whatever arises and encountering thoughts and feelings previously unknown to them. In some embodiments, the person administering the psychological support emphasizes that this process inherently requires letting go and a willing passivity to the psychedelic experience.
In some embodiments, the person administering the psychological support may encourage the subject to put on an eye mask, such as a Mindfold eyeshade. In some embodiments, the person administering the psychological support encourages the subject to put on the eye mask before, during, or after the onset of the psilocybin’s active metabolite, psilocin’s effects.
In some embodiments, the person administering the psychological support may encourage the subject to put on headphones and listen to music. In some embodiments, the headphones reduce outside noise (e.g., “noise cancelling” headphones). In case of prolonged anxiety or distress, person administering the psychological supports may, in some embodiments, actively guide participants through such experiences without interpreting or judging the experiences or giving advice. Once participants are comfortable, the person administering the psychological support may encourage them to again engage in introspection.
In some embodiments, the psychological support comprises mindfulness-based therapy or CBT cognitive behavioral therapy (CBT). In some embodiments, the psychological support is informed by a functional theory of human behavior called Perceptual Control Theory.
In some embodiments, a person administering the psychological support provides psychological support for approximately 4-8 hours immediately after administration of the loading composition.
Post-Administration Psychological Support Session
In some embodiments, subjects may be encouraged to engage in post-administration integration sessions with their person administering the psychological support. Integration is a process that involves processing, or embodying, a psychedelic experience within a therapeutic context. The process initially begins by the subject verbalizing and reflecting upon any experience from the administration session and discussing it openly with their person administering the psychological support. Successful integration of an experience accommodates for emotional changes and comprises of translating experiences into new insights, perspectives, and subsequently new behaviors that can be used to benefit the subject’s quality of life. New perspectives might in turn influence the participant’s current knowledge or values and lead to new ways of relating to cognitions, emotions, behaviors, and physical experiences. In some embodiments, the goals and supportive methods used by the person administering the psychological support throughout integration sessions should remain consistent, regardless of the intensity or content of the subjective experience explored by the subject.
In some embodiments, the subject participates in at least one psychological support session after administration (“post-administration psychological support session”). In some embodiments, a post-administration psychological support session may be held on the same day as the administration session, after the effects of the psilocin have substantially worn off. In some embodiments, a post-administration psychological support session may be held the day after, two days after, three days after, four days after, five days after, six days after, one week after, two weeks after, three weeks after one month after, two months after, three months after, six months after, or twelve months after the administration session.
In some embodiments, the subject may participate in one, two, three, four, five, six, seven, or eight post-administration psychological support sessions. In some embodiments, the subject may participate in at least two, or at least three post-administration psychological support sessions. The post-administration psychological support sessions may be individual sessions, wherein a subject meets one-on-one with a person administering the psychological support. In some embodiments, the psychological support sessions may be group sessions, wherein more than one subject meets with a single person administering the psychological support, or more than one person administering the psychological support. In some embodiments, one or more of the subject’s family members or friends may be present at the post-administration psychological support session(s).
Psychological Support Provided Remotely
In some embodiments, psychological support may be provided remotely to a subject. For example, a person administering the psychological support providing psy chological support may not be in the same room, the same building, or in the same facility as a subject. Remote psychological support may be provided, for example by telephone (i.e., by voice call), by video call or video conference, by text, or by email.
In some embodiments, a pre-admimstration therapy session is conducted remotely. In some embodiments, a post-administration therapy session (e.g., an integration session) is conducted remotely.
Subject Evaluation
Various methods are available to one of skill in the art to select a subject for treatment. Such methods include assessing the physical, psychological, and/or neurological state of a subject. The methods can be used to select a subject for receiving a composition of the present disclosure and/or to monitor the subject’s psychological and/or neurological condition after or while being treated for a neurological or psychological condition by one of the methods of the disclosure.
In various embodiments, improvement of cluster-tic syndrome (e.g., lower intensity and/or frequency of an episode(s)) or cluster-tic syndrome-associated symptoms and improved quality of life measures (e.g., improved problem solving, improved concentration. improving thinking, and improved general well-being) for a subject is achieved through various embodiments of the methods of the present disclosure.
Efficacy of treatment, as described further below, can be confirmed by clinical evaluation using means known in the art, such as, but not limited to, assessing functional improvement (e.g., reduction of one or more of irritability , anxiety and/or light/noise sensitivity, and/or improvement in one or more of appetite, concentration, memory, sleep, overall well-being, problem-solving, and multitasking ability), as may be measured using validated subjective quality of life assessments, for example.
In some embodiments, assessments may be used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome. In some embodiments, the assessments can be used to assess, monitor, or otherwise evaluate physical function, functional disability, global function, safety, and tolerability of treatment, and/or patient satisfaction with treatment. In some embodiments, the evaluation is the Spatial Working Memory (SWM) test. In some embodiments, the subject is evaluated using the spatial working memory between errors (SWMBE) score. In some embodiments, the subject is evaluated using the spatial working memory strategy (SWMS) score. In some embodiments, the subject is evaluated using the Rapid Visual Information Processing (RVP) test is utilized to evaluate the safety and efficacy of a composition. In some embodiments, the subject is evaluated using the Paired Associates Learning (PAL). In some embodiments, the subject is evaluated using the Emotion Recognition Task (ERT) test. In some embodiments, the subject is evaluated using the Intra- Extra Dimensional Set Shift (IED) test. In some embodiments, the subject is evaluated using the One Touch Stockings (OTS) of Cambridge test. In some embodiments, the subject is evaluated using the Digit Span Forward (DSF) test. In some embodiments, the subject is evaluated using the Five Dimension Altered States of Consciousness questionnaire (5D- ASC). In some embodiments, the subject is evaluated using the Positive and Negative Affect Schedule (PANAS). In some embodiments, the subject is evaluated using the NEO-Five Factor Inventory (NEO-FFI) test. In some embodiments, the subject is evaluated using the Symptom Checklist-90 item (SCL-90) questionnaire. In some embodiments, the subject is evaluated using the Life Changes Inventory (LCI) questionnaire. In some embodiments, the subject is evaluated using the Social Cognition Panel scales. In some embodiments, the subject is evaluated using the HIT-6. In some embodiments, the subject is evaluated using the Cluster Headache Quality of life scale (CHQ). In some embodiments, the subject is evaluated using the Cluster Headache Scales (CHS). In some embodiments, the assessment used may be, but is not limited to, the Penn Facial Pain Scale, Pain Disability Index, Patient Global Impression of Change Scale.
In some embodiments, pain thresholds, reports of pain relief, or pain management is used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome. In some embodiments, the pain thresholds, reports of pain relief, or pain management may be evaluated by using a pain diary or tracking application. In some embodiments, the pain diary or tracking application may track attack frequency, pain intensity or severity, duration or refractory period of pain, pain-free time, remission time, trigger sensitivity, and/or the use of rescue medication/use of acute pain management treatments. In addition, there are a number of pain scales that can be used to assess pain intensity, including but not limited to visual analogue scales (VAS), numerical rating scales, facial pain scales, and verbal ratings of pain. In some embodiments, the scales are multidimensional questionnaires designed to assess pain, such as the McGill Pain Questionnaire and Brief Pain Ivenoriscual Analogue Score (VAS) to assess pain or other pain scale.
In some embodiments, the subject is evaluated using the Reading the Mind in the Eyes Test (RMET). In some embodiments, after treating according to the methods of the disclosure, one or more of the subject’s Social Cognition Panel Scales Score, i.e. , PET, RMET, SVO, TEQ, and/or SSR score), improves by about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, about 1 10 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
In some embodiments, the subject is evaluated using the Toronto Empathy Questionnaire (TEQ). In some embodiments, the subject is evaluated using the Scale of Social Responsibility (SSR). In some embodiments, the subject is evaluated using the Sheehan Suicidality Tracking Scale (SSTS). In some embodiments, the subject is evaluated using the Tellegen Absorption Scale.
In some embodiments, the subject is physically examined. A physical examination, includes, but is not limited to, an examination of the subject’s general appearance, including an examination of the skin, neck, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities and musculoskeletal system. In some embodiments, body weight and height of a subject are assessed. In some embodiments, body mass index is considered. In some embodiments, the subject is evaluated using an electrocardiogram (ECG) is utilized to evaluate the safety and/or efficacy of a composition. In some embodiments, a Standard 12- lead ECG is obtained. In some embodiments, vital signs of a subject are used to evaluate safety and/or efficacy of a composition. Vital signs include, but are not limited to, blood pressure (BP), respiratory rate, oral body temperature, and pulse. In some embodiments, blood pressure is taken after a subject has been sitting down for at least three minutes.
In some embodiments, clinical laboratory tests are utilized to evaluate the safety and/or efficacy of a composition. In some embodiments, the clinical laboratory tests include blood samples and/or urine samples. In some embodiments, hemoglobin, hematocrit, red blood cell count, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count (with differential) and platelet count are measured to evaluate safety and/or efficacy of a composition. In some embodiments, albumin, alkaline phosphatase, alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), bicarbonate, bilirubin (direct, indirect and total), calcium, chloride, creatine kinase, creatinine, y- glutamyl transferase, glucose, lactate dehydrogenase, lipase, magnesium, phosphate, potassium, protein-total, sodium, blood urea nitrogen and/or uric acid are measured to evaluate the safety and/or efficacy of a composition. In some embodiments, urine is tested for pregnancy and/or illicit drugs.
In some embodiments, the subject is monitored by monitoring the signs or symptoms of depression in a subject before, during, and/or after treatment with a composition of the present disclosure. In some embodiments, the sign or symptom of depression is measured according to a diary assessment, an assessment by clinician or caregiver, a clinical rating scale, an imaging test, or a blood or CSF test.
In some embodiments, the sign or symptom of depression in a subject is measured using a neuropsychological assessment or clinical rating scale. In some embodiments, the neuropsychological assessment or clinical rating scale is the Hamilton Depression Rating Scale, the Clinical Global Impression (CGI) Scale, the Montgomery -Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory' (BDI), the Zung Self-Rating Depression Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology (IDS), the Quick Inventory of Depressive Symptomatology (QIDS), the Columbia-Suicide Severity' Rating Scale, or the Suicidal Ideation Attributes Scale.
In some embodiments, the sign or symptom of depression in a subject is measured using the Hamilton Depression Rating (HAM-D) scale. The HAM-D scale is a 17-item scale that measures depression severity before, during, or after treatment. The scoring is based on 17 items and generally takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored on a 3-point scale, ranging from 0 = not present to 2 = severe. A score of 10- 13 indicates mild depression, a score of 14-17 indicates mild to moderate depression, and a score over 17 indicates moderate to severe depression. In some embodiments, after treatment with the methods described herein, the subject’s HAM-D score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Clinical Global Impression (CGI) scale. The CGI scale is a 3-item scale that measures illness severity, global improvement or change, and therapeutic response. The CGI is rated on a 7-point scale, with the severity of illness measured using a range of responses from 1 (normal) through 7 (amongst the most severely ill subjects). In some embodiments, after treatment with the methods described herein, the subject’s CGI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Montgomery- Asberg Depression Rating Scale (MADRS). The MADRS scale is a 10-item scale that measures the core symptoms of depression. Nine of the items are based upon patient report, and 1 item is on the rater’s observation during the rating interview. A score of 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, and over 34 indicates severe depression. MADRS items are rated on a 0-6 continuum with 0 = no abnormality and 6 = severe abnormality. In some embodiments, after treatment with the methods described herein, the subject’s MADRS score decreases by betw een about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment. In some embodiments, the sign or symptom of depression in a subject is measured using the Beck Depression Inventory (BDI). The BDI is a 21 -item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. The items are rated on 0-3 continuum with 0 = no abnormality and 3 = severe abnormality. A score of 17-20 indicates borderline clinical depression, a score of 21 -30 indicates moderate depression, a score of 31 - 40 indicates severe depression, and over 40 indicates extreme depression. In some embodiments, after treatment with the methods described herein, the subject’s BDI score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Zung Self-Rating Depression Scale. The Zung Self-Rating Depression Scale is a 20-item self- report questionnaire that measures the psychological and somatic symptoms associated with depression. The questionnaire takes about 10 minutes to complete, and items are framed in terms of positive and negative statements. Each item is scored on a Likert scale ranging from 1 to 4. A total score is derived by summing the individual item scores, and ranges from 20 to 80. Most people with depression score between 50 and 69, while a score of 70 and above indicates severe depression. In some embodiments, after treatment with the methods described herein, the subject’s Zung Self-Rating Depression score decreases by between about 5 % and about 1 0 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Raskin Depression Rating Scale. The Raskin Depression Rating Scale measures baseline levels of depression and change in depression severity overtime. Each item is scored on a scale ranging from 1 to 5 with 1 = not at all and 5 = very much. A total score is derived by summing the individual item scores, and scores of 9 or greater represents moderate depression. In some embodiments, after treatment with the methods described herein, the subject’s Raskin Depression Rating Scale score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Inventory' of Depressive Symptomatology (IDS). The IDS is a 30-item inventory that measures depressive signs and symptoms. Each item is scored on a scale of 0 to 3 with 0 = absence of pathology' and 3 = severe pathology. A total score is derived by summing the individual item scores; scores between 26-38 indicates mild depression, scores between 39-48 indicate moderate depression, and scores 49 or greater indicate severe depression. In some embodiments, after treatment with the methods described herein, the subject’s IDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Quick Inventory of Depressive Symptomatology (QIDS). The QIDS is a 16-item inventory that measures depressive signs and symptoms. Each item is scored on a scale of 0 to 3 with 0 = absence of pathology and 3 = severe pathology. A total score is derived by summing the individual item scores; scores between 11-15 indicate moderate depression, scores between 16- 20 indicate severe depression, and scores 21 or greater indicate very severe depression. In some embodiments, after treatment with the methods described herein, the subject’s QIDS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Young Mania Rating Scale (YMRS). The YMRS is an 11 -item inventory that measures manic signs and symptoms. There are 4 items that are graded on a 0 to 8 scale, ranging from 0 = absent to 8 = severe. The remaining 7 items are graded on a 0 to 4 scale, ranging from 0 = absent to 4 = severe. A total score is derived by summing the individual item scores; scores between 9-15 indicate mild mania, scores between 16-25 indicate moderate mania, and scores 26 or greater indicate severe mania. In some embodiments, after treatment with the methods described herein, the subject’s YMRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Columbia-Suicide Severity Rating Scale (C-SSRS). The C-SSRS measures the severity of suicidal ideation and behavior. The scale contains 10 binary questions (no = 0 points and yes = 1 point) and each question addresses a different component of the subject’s suicidal ideation severity and behavior. A subject is considered to have suicidal ideation and/or behavior if they answer “yes” to any of the 10 questions. In some embodiments, after treatment with the methods described herein, the subject’s C-SSRS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression in a subject is measured using the Suicidal Ideation Attributes Scale (SID AS). The SID AS measures the presence and severity of suicidal thoughts. The scale contains 5 questions measured on a 10-point scale with 0 = never and 10 = always. Total scores are calculated as the sum of the 5 items and range from 0 to 50. Scores of 21 or greater indicate high risk of suicidal behavior. In some embodiments, after treatment with the methods described herein, the subject’s SID AS score decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, cluster-tic syndrome or a sign or symptom of cluster-tic syndrome (e.g., attack) in a subject is evaluated for secondary causes using an imaging test before, during, or after treatment with the methods described herein. In some embodiments, the imaging test is a CT scan. In some embodiments, the imaging test is a functional MRI scan. In some embodiments, the functional MRI scan measures the blood oxygen leveldependent (BOLD) response as an indicator of brain activity and/or functional connectivity. In some embodiments, the BOLD response is measured in the subject at resting state, in response to emotional faces, or in response to music. In some embodiments, after treatment with the methods described herein, the BOLD response in a region of the brain increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment. In some embodiments, after treatment with the methods described herein, the BOLD response in the amygdala increases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment. In other embodiments, after treatment with the methods described herein, the BOLD response in a region of the brain decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment. In some embodiments, after treatment with the methods described herein, the BOLD response in the amygdala decreases by between about 5 % and about 100 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, or about 100 %, or more, compared to prior to treatment.
In some embodiments, the sign or symptom of depression associated with cluster-tic syndrome is measured using a marker for depression in the blood or cerebral spinal fluid. In some embodiments, the marker for depression is measured in the subject before, during, or after treatment with the methods or compositions described herein. In some embodiments, the marker for depression is red blood cell folate, serum folate, vitamin Bl 2, plasma homocysteine, serum methylfolate, and/or testing for one or more of brain-derived neurotrophic factor (BDNF) Val66Met, bone morphogenetic protein rs41271330, and/or 5- HTTLPR polymorphisms. In some embodiments, the marker for depression decreases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 110 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment. In other embodiments, the marker for depression increases by between about 5 % and about 300 %, for example, about 5 %, about 10 %, about 15 %, about 20 %, about 25 %, about 30 %, about 35 %, about 40 %, about 45 %, about 50 %, about 55 %, about 60 %, about 65 %, about 70 %, about 75 %, about 80 %, about 85 %, about 90 %, about 95 %, about 100 %, about 110 %, about 120 %, about 130 %, about 140 %, about 150 %, about 160 %, about 170 %, about 180 %, about 190 %, about 200 %, about 210 %, about 220 %, about 230 %, about 240 %, about 250 %, about 260 %, about 270 %, about 280 %, about 290 %, or about 300 %, or more, compared to prior to treatment.
In addition to the above clinical assessments, there are validated animal models of cluster-tic syndrome, as well as validated animal models that assess the animal’s response to pain. In some embodiments, sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome. In some embodiments, the sensory testing is quantitative sensory testing (QST). In some embodiments, QST monitors and evaluates the patient’s sensory thresholds of vibration, cold, warmth, heat pain, and cold pain. In some embodiments, the sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome is somatosensory evoked potentials (SEPs) or far-field potentials (FFPs), including but not limited to nerve, root, brainstem, subcortical FFPs. In some embodiments, the sensory testing used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome is assessment of trigeminal reflexes. In some embodiments, the trigeminal reflexes that could be assessed include comeal reflex, blink reflex, masseter inhibitory periods, and jaw-jerk.
In some embodiments, pain thresholds, reports of pain relief, or pain management is used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome. In some embodiments, the pain thresholds, reports of pain relief, or pain management may be evaluated by using a pain diary or tracking application. In some embodiments, the pain diary or tracking application may track attack frequency, pain intensity or severity, duration or refractory period of pain, pain-free time, remission time, trigger sensitivity, and/or the use of rescue medication/use of acute pain management treatments. In addition, there are a number of pain scales that can be used to assess pain intensity, including but not limited to visual analogue scales (VAS), numerical rating scales, facial pain scales, and verbal ratings of pain. In some embodiments, the scales are multidimensional questionnaires designed to assess pain, such as the McGill Pain Questionnaire and Brief Pain Ivenoriscual Analogue Score (VAS) to assess pain or other pain scale.
In some embodiments, assessments may be used to assess, monitor, or otherwise evaluate symptoms of cluster-tic syndrome and/or efficacy of treatment of cluster-tic syndrome. In some embodiments, the assessments can be used to assess, monitor, or otherwise evaluate physical function, functional disability, global function, safety, and tolerability of treatment, and/or patient satisfaction with treatment. In some embodiments, the assessment used may be, but is not limited to, the Penn Facial Pain Scale, Pain Disability Index, Patient Global Impression of Change Scale.
In addition to the above, there are validated animal models of cluster-tic syndrome, as well as validated animal models that assess the animal’s response to pain. In some embodiments, cluster -tic syndrome can be studied in the superior salivatory nucleus stimulation model. In this model, trigeminal distribution of pain is determined by dural meningeal artery vasodilation and neuronal firing in the trigeminocervical complex and cranial autonomic symptoms such as lacrimation or tearing is measured by changes in blood flow in the lacrimal gland/duct. In some embodiments, nitroglycerin can induce cluster-tic syndrome symptoms such as decreased food consumption, increased facial signs of discomfort, hypersensitivity to touch, cold, and heat, anxiety -like behaviors and some lightaversion.
Inflammatory Soup (IS) model can also be used to assess symptoms and treatments of cluster-tic syndrome. For example, Inflammatory Soup (IS) or the use of Complete Freund’s Adjuvant (CFA) are often used to mimic neurogenic inflammation in rodents that can result cluster-tic syndrome type symptoms. The IS model is based on the fact that natural behaviors in rodents, such as exploratory behavior, locomotor activity, rearing, or even food and water consumption, can be decreased during a painful event. Some animal behaviors, however, are exacerbated in response to nociception, such as grooming, freezing, head twitch response (wet dog shake/head shake), eye closure or eye blinking. All of these spontaneous behaviors can be assessed in preclinical research as indirect markers for noxious experience. A pain state (e.g., cluster-tic syndrome) can be elicited by administering to the animal a mixture of histamine, serotonin, bradykinin, and PGE2. Pharmacological interventions can also be administered to the animal in order to evaluate whether the pharmacological interventions ameliorate the pain associated with cluster-tic syndrome.
Another animal model that may be used to assess cluster-tic syndrome is a spontaneous trigeminal allodynia model. The spontaneous trigeminal allodynia model is a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment. This model system is a genetic model in which a Sprague-Dawley rat was discovered with a changing periorbital pain threshold. Subsequent breeding demonstrated that the trait is inherited. Pharmacologic interventions can be administered to the rats and evaluated to determine whether the pharmacologic interventions ameliorated the pain.
The Chronic Constriction Injury (CCI) model is induced by ligation of the infraorbital nerve (loN) this model was improved by litation of a segment of the distal loN (dlon) used validated animal model. The model is used to identify experimental compounds with analgesic properties that are palliative for cluster-tic syndrome pain.
Neuropathic Pain Models can be assessed for multiple behaviors including allodynia (mechanical, heal or cold) using von Frey test, plantar test, or acetone test.
Electrophysiology can be assessed using compound muscle action potential (CMAP), Nerve conduction velocity, and sensory nerve action potential. Imaging is also often used similar to that used to evaluate cluster-tic syndrome in humans including PET/ SPECT CT, functional ultrasound, MRI, and functional MRI (fMRI). The von Frey task is a measure of pain tolerance. The test involves gradual increases in the size of filaments that poke the center of the rat’s hind paw, with larger filament size being indicative of higher mechanical nociceptive (or pain) thresholds. When referring to animal models of pain, including forms of headache (e.g., cluster-tic syndrome), testing is highly dependent upon measurements of nociception. Both acute and chronic pain assessments assist in the translational value pharmacologic agents used to treat cluster-tic syndrome. Other tests of pain include the acetone evaporation test, Hargreaves’ test, and testing with a dynamic plantar aesthesiometer.
In some embodiments, animal models of cognitive impairment may be examined in addition to animal models of pain, as pam can interfere with normal cognitive functions. Spatial learning and memory are the most studied aspects of cognition in animal model studies, the Morris water maze (MWM), is among the tasks most frequently used. The MWM consists of a circular pool of water that contains an escape platform and is surrounded by visual spatial cues that the rodent can use to assist it in locating the escape platform. Measures that assess ability to locate the platform, including search latency, swim path, distance traveled, time spent in the platform quadrant, and search strategy/efficiency (e.g., direct and circle swims) can be used to assess spatial learning and memory. The Novel Object Recognition (NOR) test evaluates recognition memory' and involves placing a rodent in an open field that contains familiar and/or novel objects. The animal will be familiarized with two objects, and following an intertrial time interval, one of these original/familiar objects will be replaced with a novel object. The novel object is typically recognized and preferred by healthy rodents.
In some embodiments, the animal models of anxiety and depression may be examined in addition to animal models of pain, as chronic pain may lead to these secondary conditions. Depression and anxiety assessments assist in the translational value of pharmacologic agents used to treat cluster-tic syndrome as well as cluster-tic syndrome associated anxiety and/or depression. Animal models of anxiety and depression can include, but are not limited to, elevated plus maze (EPM), open field test (OFT), forced swim test (FST), or tail suspension test (TST). Many cluster-tic syndrome subjects experience a psychiatric illness in connection to cluster-tic syndrome, with depression and anxiety the most common presentations.
Many tasks have been designed to measure anxiety in rodents, using the animal’s natural conflicts of fear of open spaces against the desire to explore its environment to search for food. The Elevated Plus Maze (EPM) is a behavioral task assessment that uses this strategy and is used to explore anxiety -like behaviors. The EPM test is widely used to study anxiety and has been used to identify deficits in regions such as the limbic regions, hippocampus, amygdala, and dorsal raphe. The animal is placed at the junction of the four arms of the maze, two of which are closed by walls and two are open. The animal is placed facing an open arm and the time spent or number of entries in the open or closed arms of the maze is recorded. The time spent in the closed arms correlates to anxiety, since the animal lacks the drive to explore the open arm that is less safe.
The Open Field Test (OFT) assesses the animal’s locomotor activity, exploratory behavior, and anxiety. The test places the animal in a square, rectangle, or circular box with set spacing requirements and the animal’s exploratory behavior is monitored. Two factors are known to influence anxiety-like behavior in the open field. The first is social isolation and the second is stress/aversion created by the brightly lit, unprotected, novel test environment. Rodents exposed to the novel experimental arena typically spend greater time exploring the periphery rather than the center area. In addition to exploratory activity other anxiety behaviors such as grooming, rearing, and defecation are typically recorded.
The Forced Swim Test (FST) is one of the most frequently used behavior tasks used to assess depression behaviors. Rodents are placed in an inescapable transparent tank filled with water and their escape related mobility behavior is measured to evaluate depression. Increased time spent immobile in the tank correlates with depression traits such as despair and disengagement from stress coping. The Tail Suspension Test (TST) is another frequently used test used to assess depression behaviors. Rodents are suspended by their tails and monitored for the amount of time the rodent exhibits escape behaviors. As with the FST, increased time spent immobile correlates with depression traits such as despair and disengagement from stress coping.
In some embodiments, the animal model of anxiety, and/or depression is a social interactions test. Many tests may be used to support the potential social function benefits associated with the combination(s) (psilocybin, CBD, psilocybin + CBD, and/or psilocybin + neurotransmitter activity modulator) including but not limited to the social interactions test. The Social Interactions Test includes the introduction of an unfamiliar animal to the test animal as a social stimulus and the degree of social interest is quantified at various time points.
In some embodiments, the animal model is a motor test. Cluster-tic syndrome may affect the mechanical aspects of motor behavior, balance disturbances, and social interactions. Balance requires complex interactions and integration of many neural and musculoskeletal systems. Beam walking tasks are specifically advantageous for testing motor impairments in animals given that they are not subject to practice effects and do not have any memory or learning components. Animals are evaluated for beam-balance latency by placing the animal on a narrow beam and measuring the duration of the time that the animal can remain on the beam. In some embodiments, the animal is evaluated using a social interactions test. The Social Interactions Test includes the introduction of an unfamiliar animal to the test animal as a social stimulus and the degree of social interest is quantified at various time points.
In addition to animal models, there are also in vitro models that can be used to assess the benefits of the compositions described herein. In some embodiments, neurite outgrowth may be assessed utilizing primary rat cortical cultures. In some embodiments, various cell lines and tissue analysis may be used to assess the pathophysiological indicators, pathways, and markers associated with cluster-tic syndrome, such as, but not limited to, human potassium ion channel expressing cell lines, rat CB2 cannabinoid GPCR expressing cell lines, human NMDA receptor cell lines, and/or human sodium ion channel expressing cell lines.
Kits
The present disclosure contemplates kits for the treatment and/or prevention of cluster-tic syndrome, and/or symptoms thereof. In some embodiments, the kit comprises a composition of the present disclosure. In some embodiments, the composition comprises psilocybin or a derivative thereof, and/or cannabidiol (CBD), and/or a neurotransmiter activity modulator, or combinations thereof. The kit can include instructions for a treatment regimen. The instructions provided in a kit according to the present disclosure may be directed to suitable dosages and administration frequencies. The kit may comprise safety information relating to components of compositions contained within the kit. The kit may contain a survey for assessing safety and/or efficacy of the composition(s) or information directing a subject to a website or smartphone/tablet application for assessing safety and/or efficacy of the compositions(s). In some embodiments, the kit may contain separate compartments or containers for storing different compositions and/or compositions to be administered to a subject. The containers can be boxes, ampoules, botles, vials, tubes, bags, pouches, blister-packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
If desired, an agent of the disclosure is provided together with instructions for administering the agent to a subject presently experiencing or at risk of suffering cluster-tic syndrome. The instructions will generally include information about the use of the composition(s) for the treatment of the injury or syndrome. In other embodiments, the instructions include at least one of the following: description of the therapeutic agent; dosage schedule and administration for treatment; precautions; warnings; indications; counterindications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. The instructions may be provided on a portable electronic storage medium (e.g., a DVD, a CD, or a USB drive) or the instructions may be stored on a remote server and accessible through the use of a smart phone or tablet application or a web browser.
Other Embodiments
From the foregoing description, it will be apparent that variations and modifications may be made to the disclosure described herein to adapt it to various usages and conditions. Such embodiments are also within the scope of the following claims.
The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or sub-combination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

Claims

What is claimed is:
1. A method for reducing a symptom of cluster-tic syndrome in a subject in need thereof, the method comprising:
(i) administering to the subject at least one loading dose comprising between about 5 mg and 30 mg of psilocybin, inclusive; and
(ii) administering to the subject at least one maintenance dose comprising between about 0.25 mg to about 3 mg of psilocybin and between about 50 mg to about 600 mg of cannabidiol (CBD), inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome.
2. The method of claim 1, wherein the symptom of cluster-tic syndrome comprises at least one of unilateral attacks of facial pain, paroxysms, autonomic features, a sense of restlessness, agiation, and combinations thereof.
3. The method of any of claims 1-2, wherein the autonomic features comprise at least one of lacrimation, conjunctival injection, nasal congestion rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof.
4. The method of any of claims 1-3, wherein at least one loading dose is administered prior to the at least one maintenance dose.
5. The method of any of claims 1-4, wherein at least one maintenance dose is administered prior to the at least one leading dose.
6. The method of any of claims 1-5, wherein the loading dose comprises about 10 mg psilocybin.
7. The method of any of claims 1-5, wherein the loading dose comprises about 25 mg psilocybin.
8. The method of any of claims 1-5, wherein the loading dose comprises about 30 mg psilocybin.
9. The method of any of claims 1-8, wherein the psilocybin is amorphous psilocybin.
10. The method of any of claims 1-9, wherein the CBD comprises synthetic CBD.
11. The method of claim 10, wherein the CBD comprises between about 400 mg and 600 mg CBD.
12. The method of claim 11, wherein the CBD comprises between about 500 mg and 600 mg CBD.
13. The method of claim 12, wherein the CBD comprises about 600 mg CBD.
14. The method of any of claims 1-13, wherein the loading dose is administered prior to an initial maintenance dose by at least seven days.
15. The method of any of claims 1-14, wherein two or more loading doses are administered over a 6 month time period.
16. The method of any of claims 1-15, wherein the maintenance dose is administered every day.
17. The method of any of claims 1-16, wherein the maintenance dose is not administered every day.
18. The method of any of claims 1-17, wherein the maintenance dose is administered according to a predetermined schedule.
19. The method of any of claims 1-18, wherein the maintenance dose is administered for five out of every seven days. 0. The method of any of claims 1-19, wherein the maintenance dose is fomiulated in a single dosage form.
21. The method of any of claims 1-20, wherein the maintenance dose is formulated in multiple dosage forms.
22. A method for reducing a symptom of cluster-tic syndrome in a subject, the method comprising:
(i) administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and
(ii) administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome.
23. The method of claim 22, wherein the symptom of cluster-tic syndrome comprises at least one of unilateral attacks of facial pain, paroxysms, autonomic features, and combinations thereof.
24. The method of any of claims 22-23, wherein the autonomic features comprise at least one of lacrimation, conjunctival injection, nasal congestion, rhinorrhea, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, rhinorrhea, and combinations thereof.
25. The method of any of claims 22-24, wherein the psilocybin is synthetic psilocybin.
26. The method of claim 25, wherein the synthetic psilocybin is amorphous psilocybin.
27. The method of any of claims 22-26, wherein the CBD is synthetic CBD.
28. The method of any of claims 22-27, wherein the CBD comprises between about 400 mg and 600 mg CBD.
29. The method of claim 28, wherein the CBD comprises between about 500 mg and 600 mg CBD.
30. The method of claim 29, wherein the CBD comprises about 600 mg CBD. The method of any of claims 22-30, wherein the maintenance dose is administered every day. The method of any of claims 22-30, wherein the maintenance dose is administered according to a predetermined schedule. The method of any of claims 22-30, wherein the maintenance dose is not administered every day. The method of any of claims 22-30, wherein the maintenance dose is administered for five out of every seven days. The method of any of claims 22-24, wherein the maintenance dose is formulated in a single dosage form. The method of any of claims 22-34, wherein the maintenance dose is formulated in multiple dosage forms. A method for reducing a symptom of cluster-tic syndrome in a subject suspected or diagnosed as having cluster-tic syndrome, the method comprising:
(i) administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and
(ii) administering to the subject at least one maintenance dose comprising between about 50 mg to about 600 mg of CBD, inclusive, wherein the subject has received a loading dose of about 25 mg to about 30 mg of psilocybin. The method of claim 37, wherein the symptom of cluster-tic syndrome comprises at least one of unilateral attacks of facial pain, autonomic features, restlessness, and combinations thereof. The method of claim 37, wherein the autonomic features comprise at least one of ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea, nasal congestion, eyelid edema, forehead sweating, facial sweating, miosis, ptosis, and combinations thereof.
40. The method of any of claims 37-39, wherein the psilocybin is synthetic psilocybin.
41. The method of claim 40, wherein the synthetic psilocybin is amorphous psilocybin.
42. The method of any of claims 37-41, wherein the CBD is synthetic CBD.
43. The method of any of claims 37-42, wherein the CBD comprises between about 400 mg and 600 mg CBD.
44. The method of claim 43, wherein the CBD comprises between about 500 mg and 600 mg CBD.
45. The method of claim 44, wherein the CBD comprises about 600 mg CBD.
46. The method of any of claims 37-45, wherein the maintenance dose is administered every day.
47. The method of any of claims 37-45, wherein the maintenance dose is administered according to a predetermined schedule.
48. The method of any of claims 37-45, wherein the maintenance dose is not administered every day.
49. The method of any of claims 37-45, wherein the maintenance dose is administered for five out of every seven days.
50. The method of any of claims 37-49, wherein the maintenance dose is formulated in a single dosage form.
51. The method of any of claims 37-49, wherein the maintenance dose is formulated in multiple dosage forms.
52. A method of reducing a symptom of cluster-tic syndrome in a subject, comprising: administering to a subject in need thereof and having received a loading dose of about 25 mg to about 30 mg of psilocybin, at least one maintenance dose of a combination of about 0.25 mg to about 3.0 mg of synthetic psilocybin and about 50 mg to about 600 mg of synthetic cannabidiol, wherein the at least one maintenance dose is administered to the subject about 1 to about 28 days after the subject received the loading dose, to thereby reduce the symptom of cluster-tic syndrome in the subject.
53. The method of claim 52, wherein the synthetic psilocybin is amorphous psilocybin.
54. The method of any of claims 52-53, wherein the CBD comprises between about 400 mg and 600 mg CBD.
55. The method of claim 54, wherein the CBD comprises between about 500 mg and 600 mg CBD.
56. The method of claim 55, wherein the CBD comprises about 600 mg CBD.
57. The method of any of claims 52-56, wherein the maintenance dose is administered every day.
58. The method of any of claims 52-56, wherein the maintenance dose is administered according to a predetermined schedule.
59. The method of any of claims 52-56, wherein the maintenance dose is not administered every day.
60. The method of any of claims 52-56, wherein the maintenance dose is administered for five out of every seven days.
61. The method of any of claims 52-60, wherein the dose of psilocybin comprises between about 10 mg and 30 mg.
62. The method of claim 61, wherein the loading dose of psilocybin comprises about 10 mg.
63. The method of claim 61, wherein the loading dose of psilocybin comprises about 20 mg.
64. The method of claim 61, wherein the loading dose of psilocybin comprises about 25 mg.
65. The method of claim 61, wherein the loading dose of psilocybin comprises about 30 mg.
66. The method of any of claim 52-65, wherein the loading dose is administered prior to an initial maintenance dose by at least seven days.
67. The method of any of claims 52-66, wherein two or more loading doses are administered over a 6 month time period.
68. A method of treating cluster-tic syndrome-associated depression in a subject, the method comprising:
(i) administering to the subject at least one maintenance dose comprising between about 0.25 mg and about 3.0 mg psilocybin, inclusive; and
(n) administering to the subject at least one maintenance dose comprising between about 1 mg to about 600 mg of a neurotransmitter activity modulator, inclusive, wherein the subject has been suspected or diagnosed as having cluster-tic syndrome-associated depression.
69. The method of claim 68, wherein the neurotransmitter activity modulator is selected from the group consisting of a tricyclic antidepressant, an SSRI, and SNRI, and an NRI.
70. The method of claim 69, wherein the neurotransmitter activity modulator comprises a tricyclic antidepressant.
71. The method of claim 69, wherein the neurotransmitter activity modulator comprises an SSRI.
72. The method of claim 69, wherein the neurotransmitter activity modulator comprises an SNRI.
73. The method of claim 69, wherein the neurotransmitter activity modulator comprises an NRI.
74. The method of claim 68, wherein the neurotransmitter activity modulator comprises about 1 mg to 00 mg of the neurotransmitter activity modulator.
75. The method of claim 68, wherein the neurotransmitter activity modulator comprises about 1 mg to 400 mg of the neurotransmitter activity modulator.
76. The method of claim 68, wherein the neurotransmitter activity modulator comprises about 1 mg to 300 mg of the neurotransmitter activity modulator.
77. The method of claim 68, wherein the neurotransmitter activity modulator comprises about 1 mg to 200 mg of the neurotransmitter activity modulator.
78. The method of claim 68, wherein the neurotransmitter activity modulator comprises about 1 mg to 100 mg of the neurotransmitter activity modulator.
79. The method of claim 68, wherein the subject has received a loading dose of between 25 mg and 30 mg psilocybin.
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