Compositions and methods for treating patients with Alzheimer's dementia with a combination of THC and melatonin

Abstract

Compositions comprising tetrahydrocannabinol (THC) compounds and melatonin compounds and products incorporating the compositions (e.g., kits, medical devices, medicines) are provided. Also provided are methods for treating with the compositions and products, methods for diagnosing before or after treatment, and processes for formulating the compositions or processes for manufacturing the products. These address the need for new treatments for cognitive and sensory deficits, neuropsychiatric symptoms, neurodegenerative diseases, and neurological disorders. The inventors have discovered that therapeutically effective amounts of THC and melatonin can be administered to treat patients without the need for entourage effect or the need for cannabidiol (CBD) and other cannabinoid compounds.

Description

[Technical field]

[0001] The present invention relates to compositions, processes for formulating the compositions, methods for treatment and diagnosis, articles of manufacture (e.g., kits, medical devices, medicaments), and processes for manufacturing the articles of manufacture that address the need for treatment of cognitive and sensory deficits, neuropsychiatric conditions, neurodegenerative diseases, and neurological disorders. [Background technology]

[0002] Dementia represents a group of diseases characterized by profound cognitive decline that interferes with the physical activities of daily living, which are basic and essential tasks that healthy adults without physical or developmental disabilities routinely perform. The most common type of dementia (60%–80%) is Alzheimer's disease (AD). Less common are other neurodegenerative dementias (e.g., Parkinson's disease), vascular dementia, Lewy body dementia, frontotemporal dementia, and mixed dementia. Cognitive decline in mild cognitive impairment (MCI), as the name suggests, exceeds the cognitive decline expected with normal aging, but is less severe than that of dementia. MCI symptoms may remain stable or even improve for several years. On the other hand, cognitive decline in AD is progressive and irreversible. It is unclear whether MCI represents a transitional stage in the development of dementia and is a significant risk factor for dementia.

[0003] Although the prevalence of AD increases significantly in the elderly and the most important risk factor for late-onset AD is advanced age, dementia and AD are not inevitable consequences of normal aging. The hallmarks in the brains of AD patients include the deposition of insoluble amyloid plaques between cells and between the walls of cerebral arteries, hyperphosphorylation and aggregation of tau protein into insoluble neurofibrillary tangles, loss of neuronal and neural connectivity, disruption of the blood-brain barrier, and neuroinflammation. These may lead to the neurodegeneration, cognitive and functional impairment, and neuropsychiatric symptoms of AD.

[0004] Bilkei-Gorzo et al. (Nature Med, 2017 Jun, 23:782-787) reported that low doses of THC restore cognitive function in aged mice. Three cohorts (2-month-old "young" mice, 12-month-old "mature" mice, and 18-month-old "old" mice) received a continuous release of either THC (3 mg / kg body weight per day) for the treatment group, or vehicle only for the control group, for 4 weeks. When the three groups not treated with THC were tested, the mature and aged mice performed poorly on a variety of tasks compared to the young mice. In other words, this cohort was found to model age-related decline in cognitive function. In mice treated with THC, the young mice performed poorly compared to the young mice in the control group. This also reflects the observation that THC has deleterious effects on cognition in young animals and humans. Adult and aged mice treated with THC for four weeks lost their learning and memory deficits and performed similarly to young mice, and this reversal of age-related cognitive decline persisted long after treatment had ended.

[0005] Cao (Patent Document 1) provides a method for administering "ultra-low" amounts of THC to treat Alzheimer's disease. In one embodiment, THC is administered in an amount of at least 0.2 μg / kg of patient weight. THC is administered in an amount of about 0.2 μg / kg to about 0.16 mg / kg of patient weight, preferably about 0.2 μg / kg to about 0.02 mg / kg of patient weight. In another embodiment, THC in an amount of at least 0.2 μg / kg of patient weight is administered together with melatonin at about 0.11 mg / kg to about 1.1 mg / kg of patient weight. It is also taught that the ratio of THC to melatonin is about 1:400 to about 1:4000.

[0006] Mukunda et al. (Patent Document 2) provide methods and compositions for treating central nervous disorders such as Alzheimer's disease and Parkinson's disease using a composition having about 14 μg to about 10.0 mg (preferably about 14 μg to about 2.0 mg) of THC per 70 kg of body weight, about 1.4 mg to about 20.0 mg of melatonin per 70 kg of body weight, and about 0.35 mg to about 500 mg of curcumin per 70 kg of body weight. In a preferred embodiment, about 14 μg to about 200 mg of CBD per 70 kg of body weight is administered with a specific amount of THC and melatonin, with or without curcumin. In a further embodiment, the composition has about 14 μg to about 2.0 mg of THC per 70 kg of body weight, and about 14 μg to about 200 mg of CBD per 70 kg of body weight. Other compositions have about 14 μg to about 200 mg of CBD per 70 kg body weight, and about 1.4 mg to about 20.0 mg of melatonin per 70 kg body weight. Additional compositions include THC or CBD, without melatonin, and with the disclosed amounts of curcumin, respectively. Example 1 provides 45 mg of THC, 45 mg of melatonin, and 30 mg of curcumin as a grind to make a 30 ml formulation. Example 9 provides 45 mg of THC, 45 mg of melatonin, 30 mg of turmeric, and 33 mg of rutin in 30 ml. Example 10 provides 0.25% THC, 0.25% to 5% CBD, 0.15% melatonin, 0.05% curcumin, and 0.05% rutin in 30 ml. The effects of THC, melatonin, and curcumin on biomarkers and symptoms of AD were discussed.

[0007] Public interest in the beneficial effects of cannabis, the availability of hemp-derived products containing low amounts of THC, and caution about exposing already frail AD patients to the known risks of harm and intoxication from THC have focused attention on the study of cannabis-derived preparations in novel treatments. Of all the plant's cannabinoids, the use of THC to treat neuropsychiatric disorders may seem counterintuitive because "it is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and altered perception; THC can also produce moodiness, anxiety, and psychotic symptoms." See Dos Santos et al. (Adv Exp Med Biol, 2020 Dec, 1264:19-45). In controlled clinical trials, the efficacy of treatments with cannabis-derived products is supported by weak evidence at best. It is expected that such treatments will be rigorously reviewed by the U.S. Food and Drug Administration (FDA). See 85 FR 44305 (2020). According to www.fda.gov / news-events / public-health-focus / fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd, "The FDA has not approved any marketing applications for cannabis for the treatment of any disease or condition. However, the agency has approved one cannabis-derived product, Epidiolex (cannabidiol), and three synthetic cannabis-related products, Marinol (dronabinol), Syndros (dronabinol), and Cesamet (nabilone)." CBD has been approved for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. Dronabinol has been approved for use in nausea associated with cancer chemotherapy and for the treatment of anorexia associated with weight loss in AIDS patients.

[0008] Pauli et al. (Front Pharmacol, 2020 Feb, 11:63) reviewed 16 completed clinical trials involving CBD-based drugs and concluded that "CBD formulations have been tested in preclinical studies for diverse medicinal properties, such as antiemetic, antiemetic, antitumor, anti-inflammatory, antidepressant, antipsychotic, and anxiolytic properties. However, the variability of the formulations used and the limited number of cases reduce the usefulness of these studies for clinical application." Paunescu et al. (Am J Ther, 2020 May, 27:e249-e269) wrote after a meta-analysis of six clinical trials that "no clear conclusions can be drawn on the efficacy of psychoactive cannabinoids in treating psychiatric symptoms of AD, especially agitation and aggression." Velayudhan et al. (PLoS Med, 2021 Mar, 18:e1003524) reviewed 46 clinical trials on the safety and tolerability of cannabinoids in older adults.

[0009] van den Elsen et al. (Neurology, 2015 Jun,84:2338-2346) compared 4.5 mg / day THC with placebo. Neuropsychiatric symptoms improved in both treatment and placebo groups. No differences were noted in agitation or reduction from baseline in Neuropsychiatric Inventory (NPI) total scores. Forester et al. (Alzheimers Dement, 2017 Jul,13 Abstract Suppl:P3-026) and Rosenberg et al. (Am J Geriatric Psychiatry, 2020 Apr,28:S121-S122) described recruitment for a pilot clinical trial of dronabinol in AD patients with severe agitation. See also NCT02792257. Outen et al. (Am J Geriatric Psychiatry, 2021 Dec, 29:1253-1263) discussed possible mechanisms contributing to agitation in AD and the potential therapeutic relevance of cannabinoids.

[0010] In a case report, Defrancesco and Hofer (Front Psychiatry, 2020 May, 11:413) treated a patient with severe Alzheimer's disease with 4.9-6.7 mg dronabinol, 10 mg donepezil, and 50 mg sertraline per day, given the "known positive anxiolytic, pain-relieving, and sedative effects of cannabinoids." There was improvement in his emotional state and behavioral symptoms (i.e., disruptive behavior, aggression, and sedation). The patient's NPI total score decreased from 20 to 15.

[0011] In a meta-analysis, Ruthirakuhan et al. (J Clin Psychiatry, 2019 Jan, 80:18r12617) concluded that "the efficacy of cannabinoids for agitation and aggression in AD patients remains inconclusive, but there may be signals of possible benefit of synthetic cannabinoids." Compare Liu et al. (CNS Drugs, 2015 Aug, 29:615-623). Herrmann et al. (Am J Geriatric Psychiatry, 2019 Nov, 27:1161-1173) compared nabilone with placebo in patients with moderate to severe Alzheimer's disease (NCT02351882). Daily doses of nabilone were up to 2 mg. Nabilone may have benefits on neuropsychiatric symptoms and caregiver burden (NPI-NH total score and NPI-NH caregiver burden, respectively), suggesting that it may be an effective treatment for agitation. In a systematic review available online on the same day as the priority filing of this application, Bosnjak Kuharic et al. (Cochrane Database Syst Rev, 2021 Sep, 9:CD012820) concluded from a meta-analysis of randomized controlled trials (126 participants) of cannabinoids in the treatment of dementia that "it is uncertain whether cannabinoids [THC] have any beneficial or harmful effects on dementia."

[0012] The ability to identify small but clinically significant changes in patients with mild agnosia (e.g., MCI, amnesic MCI) or in the early stages of Alzheimer's disease (e.g., preclinical AD, prodromal AD, stage 1 or 2 AD, early AD, mild AD) is of critical importance. Common tests and assessment scales used to screen for cognitive decline and dementia include the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating Scale Total Score (CDR-SOB), General Practitioner Assessment of Cognition (GPCOG), Memory Impairment Screen (MIS), Mini-Cog, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Six Item Cognitive Impairment Test. High failure rates of new Alzheimer's treatments in Phase III clinical trials have led regulators to rethink the traditional drug approval process. See Riordan and Drosopoulou (J Clin Stud, 2018 Apr, 10:20-22) and Sabbagh et al. (Alzheimers Dement, 2019 Jan, 5:13-19).

[0013] In the above cited documents, the art has expressed skepticism about the efficacy of cannabinoids in the treatment of dementia, including mild cognitive impairment and early AD, and caution about the possible toxicity due to the psychoactive activity of THC, especially for frail elderly patients. Such toxicity has been addressed by reducing the dose of THC to ultra-low doses and / or specifying a high CBD:THC ratio (i.e., 1 or higher). Since the THC used herein is derived from cannabis plant material, there may be traces of CBD in our formulations, which may not substantially contribute to the treatment effect due to its extremely low concentration (i.e., less than 1% wt / vol).

[0014] Surprisingly, the inventors have found that intermediate doses of THC and melatonin are effective in treating multiple neuropsychiatric symptoms in AD without the need for entourage effect, CBD, and / or other non-THC cannabinoid compounds.This success may reflect the synergistic interaction of THC and melatonin compounds to treat these clinical indications.Herein, the efficacy of intermediate doses of THC and melatonin has been shown in clinical trials in AD patients to treat neurodegenerative diseases and neurological disorders, and to reduce or improve neuropsychiatric symptoms. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] U.S. Pat. No. 1,106,525 [Patent Document 2] International Publication No. 2019 / 190608 Summary of the Invention [Problem to be solved by the invention]

[0016] The objective is to treat at least dementia, Alzheimer's disease (AD), familial AD, late-onset AD, preclinical AD, prodromal AD, stage 1 AD, stage 2 AD, early AD, mild AD, mild cognitive impairment (MCI), amnesic MCI, severe neurocognitive disorder, mild cognitive disorder, HIV-associated dementia (HAD), amyloidosis, dementia-associated psychosis, depression, major depressive disorder, anxiety disorder, panic disorder, sleep disorder, neurodegenerative disease, or neurological disorder.

[0017] Another objective is to ameliorate at least one symptom selected from delusions, hallucinations, agitation, depression, anxiety, irritability, abnormal motor behavior, sleep disorders, or eating disorders. [Means for solving the problem]

[0018] In one embodiment, a product (e.g., a daily dose, medicament, medical device, or kit of parts) for treating a subject in need thereof is provided, comprising any effective amount of a tetrahydrocannabinol (THC) compound in the range of about 2.0 mg to about 7.0 mg (or in the range of about 0.0286 mg / kg to about 0.1000 mg / kg of the subject's body weight), and any effective amount of a melatonin compound in the range of about 1.0 mg to about 4.4 mg (or in the range of about 0.0143 mg / kg to about 0.0629 mg / kg of the subject's body weight). Cannabidiol (CBD), or other non-THC cannabinoid compounds, such as cannabichromene (CBC), cannabigerol (CBG), or cannabinol (CBN), may or may not be present in the product. Thus, the product may not include a mixture of cannabinoid compounds (e.g., nabiximols). Alternatively, the product may not contain more than about 2% (wt / vol) CBD and / or other non-THC cannabinoid compounds.

[0019] In another embodiment, a method for treating a subject in need of treatment is provided, comprising administering to a subject in need of treatment any effective amount of a tetrahydrocannabinol (THC) compound in the range of about 2.0 mg to about 7.0 mg (or in the range of about 0.0286 mg / kg to about 0.1000 mg / kg of the subject's body weight) and any effective amount of a melatonin compound in the range of about 1.0 mg to about 4.4 mg (or in the range of about 0.0143 mg / kg to about 0.0629 mg / kg of the subject's body weight) per day. The daily administration of the THC compound and the melatonin compound to the subject may continue for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, or at least 6 months, at least 9 months, or at least 1 year. Cannabidiol (CBD), or other non-THC cannabinoid compounds (CBC, CBG, CBN), may or may not be administered. Cannabis extracts containing a mixture of cannabinoid compounds, such as nabiximols, may or may not be administered. For example, less than about 2% (wt / vol) CBD and / or other non-THC cannabinoid compounds may be used in treatment.

[0020] The THC compound may be any amount in the range of about 2.25 mg to about 6.75 mg (or in the range of about 0.0321 mg / kg to about 0.0964 mg / kg of the subject's body weight). The THC compound may be any amount in the range of about 2.5 mg to about 6.5 mg (or in the range of about 0.0357 mg / kg to about 0.0929 mg / kg of the subject's body weight). The THC compound may be any amount in the range of about 2.75 mg to about 6.25 mg (or in the range of about 0.0393 mg / kg to about 0.0893 mg / kg of the subject's body weight). The THC compound may be any amount in the range of about 3.0 mg to about 6.0 mg (or in the range of about 0.0429 mg / kg to about 0.0857 mg / kg of the subject's body weight).

[0021] The THC compound can be dronabinol, nabilone, trans-delta-8-THC (Δ8-THC), cis-Δ8-THC, trans-delta-9-THC (Δ9-THC), cis-Δ9-THC, one or more Δ9-THC stereoisomers thereof (e.g., either or both of each enantiomeric pair), Δ9-THC carboxylic acid (THCA), Δ9-THC-4-oic acid (THCA-A), Δ9-THC-2-oic acid (THCA-B), 11-hydroxy-Δ9-THC (11-OH-THC), 11-nor-9-carboxy-Δ9-THC (11-COOH-THC), anandamide, 2-arachidonoyl-glycerol, 2-arachidonoyl-glyceryl ether, or any combination thereof. The THC compounds were 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ6a,10a-THC), (9R,10aR)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ6a,7-THC), (6aR,9R,10aR)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H The THC compound may be selected from any one, two, four, or all of the following: 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ7-THC), 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ10-THC), (6aR,10aR)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ9,11-THC). More generally, the THC compound may or may not be an endocannabinoid, a precursor of THC biosynthesis, a THC metabolite, or a synthetic agonist of a cannabinoid receptor (CB1 receptor or CB2 receptor). The molecular weight of the THC compound is Δ 9 If the amount of THC compound is significantly different from -THC, the amount of THC compound is Δ 9 -THC can be tailored for bioavailability and equivalent cannabinoid receptor signaling activity.

[0022] The melatonin compound may be any amount in the range of about 1.25 mg to about 4.20 mg (or in the range of about 0.0179 mg / kg to about 0.0600 mg / kg of the subject's body weight). The melatonin compound may be any amount in the range of about 1.5 mg to about 4.0 mg (or in the range of about 0.0215 mg / kg to about 0.0571 mg / kg of the subject's body weight). The melatonin compound may be any amount in the range of about 1.75 mg to about 3.75 mg (or in the range of about 0.0250 mg / kg to about 0.0536 mg / kg of the subject's body weight). The melatonin compound may be any amount in the range of about 2.0 mg to about 3.5 mg (or in the range of about 0.0286 mg / kg to about 0.0500 mg / kg of the subject's body weight).

[0023] The melatonin compound may be circadin, N-acetyl-5-methoxytryptamine, agomelatine, ramelteon, tasimelteon, 5-methoxytryptamine, N-acetyl-serotonin, or any combination thereof.More generally, the melatonin compound may or may not be a precursor of melatonin biosynthesis, a synthetic agonist of melatonin receptor (MT1 receptor or MT2 receptor), or a neurotransmitter.When the molecular weight of the melatonin compound is significantly different from that of N-acetyl-5-methoxytryptamine, the amount of the melatonin compound may be adjusted for bioavailability and equivalent melatonin receptor signaling activity compared to N-acetyl-5-methoxytryptamine.

[0024] The composition and / or product may further comprise a curcumin-related compound. Similarly, the method may further comprise administering any amount of a curcumin-related compound in the range of about 0.3 mg to about 1.5 mg (or in the range of about 0.0043 mg / kg to about 0.0215 mg / kg of the subject's body weight), or in the range of about 0.6 mg to about 1.2 mg (or in the range of about 0.0086 mg / kg to about 0.0171 mg / kg of the subject's body weight), or in the range of about 0.8 mg to about 1.0 mg (or in the range of about 0.0114 mg / kg to about 0.0143 mg / kg of the subject's body weight). The curcumin-related compound may be curcumin, and may further be or may not be turmeric, a curcuminoid other than curcumin, a structural derivative of curcumin, an analog of curcumin enhanced for at least better absorption, bioavailability, stability or taste, or any combination thereof.

[0025] The composition and / or product may further comprise a rutin-related compound. Similarly, the method may further comprise administering any amount of a rutin-related compound in the range of about 0.3 mg to about 1.5 mg (or in the range of about 0.0043 mg / kg to about 0.0215 mg / kg of the subject's body weight), or in the range of about 0.6 mg to about 1.2 mg (or in the range of about 0.0086 mg / kg to about 0.0171 mg / kg of the subject's body weight), or in the range of about 0.8 mg to about 1.0 mg (or in the range of about 0.0114 mg / kg to about 0.0143 mg / kg of the subject's body weight). The rutin-related compound may be rutin, and may further be or may not be a quercetin glycoside other than rutin (e.g., quercitrin), a rutinoside other than rutin (e.g., hesperidin), a structural derivative of rutin, an analog of rutin enhanced for at least better absorption, bioavailability, stability or taste, or any combination thereof.

[0026] The composition and / or product may further comprise one, two or more polyphenol compounds. Alternatively, one, two or more polyphenol compounds may be provided in a composition (e.g., two, three or four different compositions) or product (e.g., located in different locations in a device or kit of parts) separate from the THC compound and the melatonin compound. Similarly, the method may further comprise administering one, two or more polyphenol compounds. These may be administered simultaneously with at least the THC compound and / or the melatonin compound, or may be administered separately. The polyphenol compounds may be selected from turmeric, curcuminoids, curcumin, curcumin-related compounds, quercetin glycosides, rutin, rutinosides, rutin-related compounds, or any combination thereof. Vitamin E-related compounds may be included to enhance efficacy or stability.

[0027] The composition and / or product may further comprise a vitamin E related compound. Similarly, the method may further comprise administering any amount of a vitamin E related compound equivalent to an amount of alpha tocopherol in the range of about 20 mg to about 55 mg (or in the range of about 0.286 mg / kg to about 0.786 mg / kg of the subject's body weight), in the range of about 30 mg to about 45 mg (or in the range of about 0.429 mg / kg to about 0.643 mg / kg of the subject's body weight), or in the range of about 35 mg to about 40 mg (or in the range of about 0.500 mg / kg to about 0.571 mg / kg of the subject's body weight). The vitamin E related compound can be synthetic vitamin E (e.g., dl-α-tocopherol), natural vitamin E derived from vegetable oils (e.g., olive, sunflower, corn, soybean), tocopherol (E306), α-tocopherol (e.g., d-α-tocopherol), β-tocopherol, γ-tocopherol (e.g., d-γ-tocopherol), δ-tocopherol, α-tocopherol and β-tocopherol, α-tocopherol and γ-tocopherol, structural derivatives of tocopherol (e.g., salts, esters), analogs of tocopherol that have been enhanced for at least better absorption, bioavailability, stability, or palatability, or any combination thereof.

[0028] A vehicle and / or carrier may be present in the composition or product or may be administered in the method. At least a portion of the THC compound, at least a portion of the melatonin compound, or at least a portion of both may be solubilized in alcohol (e.g., ethanol), alcohol-water (e.g., about 5%-20% ethanol in water), oil (e.g., about 70% or more fatty acid), emulsion (e.g., nanoemulsion), lipid bilayer (e.g., liposome, nanoparticle), or any combination thereof, to enhance the stability and solubility of the compounds.

[0029] Also, excipients may be present in the composition or product or may be administered in the method. The excipients may be one or more selected from preservatives (e.g., ascorbic acid, ethanol, honey), emulsifiers (e.g., polysorbate 80, alpha-tocopherol PEG1000 succinate or TPGS1000), or any combination thereof. Other examples of excipients are provided elsewhere herein or known in the art.

[0030] In any of the above-mentioned methods, before treatment, subject may be diagnosed with at least dementia, Alzheimer's disease, severe neurocognitive disorder, mild cognitive impairment, mild neurocognitive disorder, dementia-related psychosis, depression, major depressive disorder, minor depressive disorder, anxiety disorder, panic disorder, sleep disorder or eating disorder.Diagnostic criteria are listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD).

[0031] In any of the above-mentioned methods, treatment can improve at least cognitive ability, including but not limited to memory, learning, attention, information processing speed, executive function, or any combination thereof.Cognitive impairment can be evaluated by art-recognized tests and assessment scales, namely, among others, Mini-Mental State Examination (MMSE), Mini-Cog test, Alzheimer's Disease Assessment Scale (ADAS-cog14), other tests that measure recent logical memory, including Wechsler Memory Scale-Revised (WMS-R), delayed logical memory, digit span, visual memory span test, cube combination, and digit-symbol coding test such as Wechsler Adult Intelligence Scale-3rd Edition (WAIS-III), Stroop test, Trail Making Test (TMT), Montreal Cognitive Assessment (MoCA), and Neuropsychological Test Battery (NTB) of cognitive function. See also Baldwin and Farias (Curr Protoc Neurosci, 2009 Oct, 49:20.3.1-20.3.8) and Robert et al. (Alzheimer Res Ther, 2010 Aug, 2:24).

[0032] In any of the above-mentioned methods, the subject may experience one or more symptoms of behavioral changes of Alzheimer's disease, including but not limited to delusions, hallucinations, agitation / aggression, depression, anxiety, elation / euphoria, apathy, disinhibition, irritability, abnormal motor behavior, sleep disorder, appetite / eating disorder, or any combination thereof. Behavioral changes can be evaluated by art-recognized tests and rating scales, such as behavioral rating scales for dementia, behavioral pathology rating scales for Alzheimer's disease, neurobehavioral rating scales, and neuropsychiatric symptom evaluation. Treatment may or may not reduce the severity of at least one, at least two, at least three, or at least four symptoms. The severity of at least one symptom may or may not reduce within one week, two weeks, three weeks, or one month of starting treatment.

[0033] In any of the above methods, the subject's caregiver may be burdened by at least one, at least two, at least three, or at least four of the subject's symptoms prior to treatment. The caregiver burden may or may not decrease within one week, two weeks, three weeks, or one month of initiating treatment.

[0034] In any of the above methods, the subject's ability to metabolize THC can be assayed prior to treatment by identifying genetic polymorphisms in at least CYP2C9, CYP3A4, CYP2C19, CYP1A1, CYP1A2, or any combination thereof. The effective amount of THC can be increased or decreased based on the subject's metabolism predicted from the expression of one or more of the above-mentioned cytochrome P450 isoenzymes.

[0035] In any of the above-mentioned methods, the subject may be medicated with one or more of the following drugs prior to treatment: antidepressants, antipsychotics, mood stabilizers, selective serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, or anti-anxiety drugs. The daily dosage of the drug may or may not be reduced within 1 week, 2 weeks, 3 weeks, or 1 month of starting treatment.

[0036] In any of the above methods, the subject may or may not have been medicated with at least aducanumab, donepezil, galantamine, memantine, rivastigmine, solanezumab, or any combination thereof prior to treatment. If so medicated, at least aducanumab, donepezil, galantamine, memantine, rivastigmine, or solanezumab may or may not be administered to the subject 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or 1 year after treatment. Alternatively, the effective amount of at least aducanumab, donepezil, galantamine, memantine, rivastigmine, or solanezumab may or may not be reduced from the amount the subject receives prior to treatment 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or 1 year after treatment.

[0037] In any of the above methods, the effective amounts of at least the THC compound and the melatonin compound may be administered only once per day. Alternatively, about 40%-60% (e.g., about half) of the effective amounts of at least the THC compound, at least the melatonin compound, or both, are administered twice per day (e.g., in the morning and in the evening).

[0038] In any of the above methods, the subject may be treated daily for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 1 year.

[0039] Examples of ranges of amounts or concentrations that may be administered in a daily dose are described herein. For convenience, the daily doses of the THC compound and the melatonin compound may be administered in one single dose per day, or the daily dose may be divided into multiple smaller doses that are all administered within about 24 hours (e.g., 22-26 hours). In the case of two doses per day, the complementary doses may include about 40%-60% (e.g., about half) of the daily dose of each compound, totaling 100% in both doses. Alternatively, the entire daily dose of the THC compound may be administered in one dose at a convenient time (e.g., in the morning), and the entire daily dose of the melatonin compound may be administered in one dose at a specific time (e.g., in the evening). In some cases, the two doses may be administered twice per day, at times separated by about 12 hours (e.g., 10-14 hours) or at least about 8 hours. Optionally, three doses may be administered three times per day, spaced apart by about 8 hours (eg, 7-9 hours) or at least about 6 hours.

[0040] The above-mentioned modifications and variations of the present invention are within the skill of a person skilled in the art. Therefore, obvious alternatives to the claimed invention are protected by the principle of equivalents. The following detailed description and examples are provided to aid the public in understanding the present invention. They are also not intended to limit the scope of the appended claims unless the claims expressly state limitations taken from the specification.

[0041] Specific embodiments are described below that are examples intended to apply one or more principles of the inventors' discoveries and inventions, but such examples are not necessary to practice the improvements discovered by the inventors. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Specific embodiments and examples that have been achieved by the inventors are described below, and although other embodiments and examples that apply aspects of the present invention are contemplated, it is not believed that the operability of every possible embodiment or example is necessary to benefit from any of the improvements discovered by the inventors.

[0043] Unless otherwise specified herein, technical terms have the same meaning as would be understood by a person skilled in the medical arts related to the present invention (i.e., a geriatrician, neurologist, or psychiatrist). Depending on the art, the person skilled in the art may also have the skills (i.e., knowledge, training, and experience) of chemistry, pharmacology, physiology, and biostatistics.

[0044] The terms "a" and "an" are defined as "at least one" and "one or more," and are described interchangeably herein. They include both the singular and plural forms of the article noun, unless either form is inconsistent with the context in which the noun is used. As used herein, they are equivalent to "one, more than one, either, or both" or "one, more than one, either, or both," and may be limited in amendment by substituting "only one" or "only one" to exclude a plurality (e.g., two or two, three or three, etc.), and "more than one" or "more than one" to exclude a singular. Similar recognized terms such as single, only, several, many, multiple, etc. have their ordinary meanings. Furthermore, references to pronouns herein include both the singular and plural forms of the pronoun (one and multiple persons), without necessarily indicating a limitation to "only one" or "more than one," unless inconsistent with the context in which the pronoun is used.

[0045] When describing ranges of functions or properties (e.g., age, amount, chemical formula, concentration, density, molecular weight, temperature) herein, all combinations of ranges (e.g., A-D and C-G refer to A-G), subcombinations of subranges (e.g., A-C, C-D, D-G), and specific embodiments therein (e.g., A, B, C, D, E, F, G) are also part of the following description of the invention. As used herein, when used in the context of a numerical value or numerical range, the term "about" means that the value or range may deviate by an amount that would be understood by one of ordinary skill in the art to be reasonable under the circumstances, such as within the variability of measurement and observation (random or systematic experimental error, respectively). Alternatively, the numerical value or numerical range may vary by 10% of the limits of the value or range. For example, "about 23°C" may mean a temperature in the range of 20.7°C to 25.3°C (or 23°C ±2.3°C) relative to the experimental error of the thermometer, while "about 21-25°C" may mean a temperature in the range of 18.9°C to 27.5°C.

[0046] The terms "comprising" and "comprised of" are defined as requiring at least the acts or elements listed thereafter, but other acts / elements not mentioned may or may not occur / be present. In other words, a process or product that includes A requires at least A, but the absence of B does not indicate the exclusion of B. Whenever "comprising" or "comprised of" is mentioned in this specification, it may be replaced with "containing" or "including", or "contained" or "included in" to support the amendment of the claims. Whenever "containing" or "including", or "contained in" or "included in" is mentioned in this specification, it may be replaced with "comprising" or "comprised of" to support the amendment of the claims attached. Depicting an act / element as "optionally" or "optional" means that it may occur / be present or it does not have to occur / be present.

[0047] Wherever the terms "comprising," "comprised of," "containing," or "including" appear in this specification, they may be replaced with the terms "consisting of" or "consists of" to support amendment of the accompanying claims. The terms "consisting of" and "consists of" are defined as requiring only the acts or objects listed thereafter and excluding the occurrence / presence of other acts or objects not recited.

[0048] Wherever the terms "comprising," "comprised of," "containing," or "including" appear in this specification, they may be substituted with the terms "consisting essentially of" or "consists essentially of" to support amendment of the accompanying claims. The terms "consisting essentially of" and "consists essentially of" with respect to a process or product are defined as requiring at least the recited acts or objects, and other acts or objects not recited may or may not occur / be present, if their occurrence / presence does not materially affect the basic and novel characteristics of the process or product.

[0049] A "device" is comprised of a physical structure (e.g., a dispenser) and a composition (e.g., a medicament) comprising at least two, three, four, five, or more compounds as described herein (e.g., a THC compound and a melatonin compound, optionally a polyphenolic compound, such as a curcumin-related compound and a rutin-related compound, optionally a vitamin E-related compound, and optionally at least one chemotherapeutic agent), such that it provides an effective amount of at least two, three, four, five, or more compounds to treat a subject. The process of making a "device" involves at least associating the composition with the physical structure, e.g., loading the composition into a reservoir of a dispenser. Examples of dispensers include, but are not limited to, bandages and patches, droppers and pipettes, enema bottles, hypodermic syringes, implantable depots and pumps, infusion pumps, inhalers, injection ampoules and vials, insufflators, intravenous (IV) drips via cannula / catheter, misters and sprayers, nebulizers, pill bottles, pill boxes, suppositories, and vaporizers.

[0050] A "dose" is the amount (e.g., amount by mass or amount within a range of mass) of a medicament, therapeutically active compound, or food ingredient that is at least given to or at least ingested by a subject in each administration step. A "unit dose" is a dose of a physical form (i.e., solid, semi-solid, or liquid) as described herein. A "dosage" is a dose (e.g., amount by mass or amount within a range of mass) of a medicament, therapeutically active compound, or food ingredient, or the number of doses administered over a given period of time (e.g., once per day or every day, twice per day, such as morning and evening, once per 8 hours or every 8 hours, once per 12 hours or every 12 hours). Alternatively, the frequency in a day can be once or twice per day (e.g., morning and evening with or without food). It can be equivalent to express a dose or dosage as a concentration (e.g., mass % or mass per volume) and volume, the product of which is equal to the amount and a concentration and a volume. A "single unit dose" is a dosage in a physical form (i.e., solid, semi-solid, or liquid), such as an ampoule, capsule, packet or sachet, chewable candy or gum, disintegrating strip or cap, lozenge or pastille, tablet, or vias, etc. The amount is for an adult human (male or female), adjusted for body weight (e.g., an adult human weighing 70 kg), or in some embodiments, regardless of body weight (e.g., any adult human).

[0051] A "medicament" is a pharmaceutical composition (more specifically, a unit dose, particularly a daily dose) that is composed of at least two, three, four, five, or more compounds as described herein, and a pharmaceutically acceptable excipient. A "medicament" includes a THC compound and a melatonin compound, optionally a polyphenolic compound, optionally a vitamin E-related compound, and optionally at least one chemotherapeutic agent. A "medicament" can be produced by formulating at least a THC compound and a melatonin compound as described herein, optionally at least a polyphenolic compound, optionally at least a vitamin E-related compound, at least a pharmaceutically acceptable excipient, optionally at least a vehicle, and optionally at least a carrier into the same formulation. Examples of suitable excipients include, but are not limited to, preservatives, antimicrobial agents, antioxidants, stabilizers, emulsifiers, surfactants, solubilizers, sweeteners and other flavors, food dyes and other colorants, essential oils and other odor masking agents.

[0052] The terms "effective amount" and "therapeutically effective amount" refer to an amount of at least two, three, four, five, or more compounds (individually or in total) that is sufficient to treat a subject with beneficial or therapeutic effects. The terms can refer to one or more doses (i.e., total doses) administered to a subject within a given period of time, particularly to doses administered only once per day (i.e., daily doses). The amount can be adjusted based on professional judgment, the current symptoms and severity of the disease, the route and type of administration, any other compounds administered together, and the characteristics of the subject, including but not limited to age, comorbidities and their current symptoms, family history, health status, sex at birth, genetic profile, racial background, and body weight. The total dose or daily dose is simply recalculated after adjustment.

[0053] The term "treatment" refers to treating a subject with cognitive or perceptual deficits, neuropsychiatric symptoms, neurodegenerative diseases, neurological disorders, or any combination thereof, for the benefit of the subject being treated. In general, administering one or a mixture of chemical or biological compounds to the subject is a feature of the method for treatment. Treatment encompasses "therapeutic" treatment, "prophylactic" treatment, "preventive" treatment, "palliative" treatment, or any combination thereof. The subject may or may not be diagnosed with at least dementia, mild cognitive impairment (MCI), amnesic MCI, Alzheimer's disease (AD), early-onset AD, late-onset AD, sporadic AD, familial AD, preclinical AD, prodromal AD, early AD, mild AD, stage 1 AD, stage 2 AD, or any combination thereof. The purpose of "therapeutic treatment" may be to promote health or wellness, promote at least cognitive or functional improvement, reduce at least the frequency or severity of symptoms caused by the disease, or any combination thereof, for the subject being treated. Treatment may continue until complete and sufficient recovery, but may not be achieved in chronic or fatal conditions. The purpose of "prophylactic treatment" may be to reduce the risk of at least occurrence of disease, at least future recurrence of disease, at least recurrence of symptoms caused by disease, or any combination thereof, for the subject being treated. The purpose of "preventive treatment" may be to at least prevent the deterioration of health or wellness caused by disease, at least delay the onset of disease, at least stop the deterioration of the frequency or severity of symptoms caused by disease, or any combination thereof, for the subject being treated. The purpose of "palliative treatment" may not be intended to cure, but may be to improve symptoms caused by disease, to distract from at least stress or pain caused by disease, to reduce at least discomfort or pain caused by disease, to promote well-being, to extend life expectancy, or any combination thereof, for the subject being treated. Achieving any one or more of these purposes may be considered the "therapeutic effect" of treatment.Those skilled in the art will appreciate that achieving a beneficial or therapeutic effect may be difficult to demonstrate in any particular subject, but may be statistically demonstrated in a cohort of similar subjects. As is known in the art, a beneficial or therapeutic effect of a treatment may be achieved without necessarily curing the disease or preventing the disease altogether.

[0054] Similarly, the term "treatment" refers to therapeutic, prophylactic, preventative, palliative, or any combination thereof, as described in the preceding paragraphs, incorporated herein by reference, for treating a subject in need of treatment and who may or may not have been diagnosed with at least dementia, severe neurocognitive disorder, mild cognitive impairment (MCI), amnestic MCI, mild cognitive disorder, Alzheimer's disease (AD), early-onset AD, late-onset AD, sporadic AD, familial AD, preclinical AD, prodromal AD, early AD, intermediate AD, late AD, mild AD, moderate AD, severe AD, stage 1 AD, stage 2 AD, stage 3 AD, stage 4 AD, HIV-associated dementia (HAD), amyloidosis, dementia-associated psychosis, depression, major depressive disorder, dysthymia or persistent depressive disorder, minor depressive disorder, anxiety disorder, panic disorder, sleep disorder, eating disorder, or any combination thereof, prior to treatment. Generally, "treatment" is a method that consists of at least administering an effective amount of one or a mixture of chemical or biological compounds to a subject in need of treatment. The purpose of "treatment" is to obtain any one or more of the beneficial or therapeutic effects as described in the above paragraphs, which are incorporated herein by reference. As is known in the art, beneficial or therapeutic effects can be obtained without necessarily curing the disease or preventing the disease altogether.

[0055] The term "diagnosis" refers to diagnosing a subject as having a cognitive or sensory deficit, a neuropsychiatric condition, a neurodegenerative disease, a neurological disorder, or any combination thereof. The diagnostician who determines (or exercises professional judgment) the subject's diagnosis may be a medical doctor, a psychiatrist, or a psychologist, and in some cases may be board certified in neurology, geriatric psychiatry, or neuropsychology. A diagnosis of dementia requires a comprehensive evaluation, such as, for example, a physical exam, a psychiatric evaluation, a psychological evaluation, brain imaging, or any combination thereof. A diagnosis may also include additional test assays, treatment suggestions, or recommendations of treatment options. A subject may consent to a physical exam, a psychiatric evaluation, a psychological evaluation, brain imaging, or any combination thereof, which are typically non-invasive and do not require the submission of a sample for a test assay. Alternatively, a subject may consent to providing a sample, typically a bodily fluid or tissue, which is taken and submitted for a test assay, such as a genetic test, a neuropathological test, a genetic test, a neuropathological test, a pathogen culture or detection, other clinical trial assays, or any combination thereof. Examples.

[0056] Generally, the test assay step is a feature of the method for diagnosis (possibly together with an optional analysis step, an optional comparison step, an optional determination step, or any combination thereof). The administration step of the method for treatment can be performed before or after the test assay (e.g., physical examination, psychiatric evaluation, psychological evaluation, brain imaging, genetic testing, neuropathological testing, pathogen culture or detection, other clinical testing assays, such as blood count and protein assay). Although a sample can be taken from the subject at the time of treatment, the taking of the sample can be considered as a step of the method for diagnosis that takes place before the test assay step. However, in many cases, the sample can be taken by the subject himself or his caregiver separately from the method for treatment or diagnosis, and the sample is then submitted for the test assay. However, simply "taking" or "obtaining" a sample from a subject, "providing" or "sending" a sample to diagnose a subject, or "requesting" or "submitting" a sample for a test assay may or may not be considered as any step of a method for treatment or diagnosis, especially in a combined method claim that includes both an administration step and a test assay step. The test assay of the subject's sample produces a result. Generally, the result is information about the characteristics of the subject. The information may be analyzed to determine a diagnosis, which may be used, without limitation, to make a decision about a treatment, to evaluate a treatment, to confirm the efficacy of a treatment, and to monitor changes in the disease due to treatment (e.g., remission, recurrence). A neurologist, psychiatrist, or psychologist may examine and analyze the subject to determine a diagnosis. However, the test assay step and the analysis step and / or the determination step may be performed by another person. A clinical laboratory or hospital facility (e.g., radiology) may perform the test assay steps, and the information obtained therefrom may be analyzed by another clinician (e.g., a pathologist reading the stained slides, a radiologist reading the PET-FDG images), who provides a report to and collaborates with the diagnostician or clinician treating the subject.

[0057] A "kit of parts" is comprised of a plurality of components, optionally a dispenser for at least one or more of the components, a package, optionally a seal that renders the components at least tamper-resistant, optionally a package insert, optionally an expiration date, and optionally a packaging. One or more of the components may be used to perform at least one step of a method for treatment (i.e., a "medical support kit"), at least one step of a method for diagnosis (i.e., a "test assay kit"), or at least one or two steps of a method for diagnosis and treatment (i.e., a "combined kit"). In general, with respect to the plurality of components, the medicament or pharmaceutical compound is characteristic of the medical support kit, while the diagnostic reagent is characteristic of the test assay kit. In a combined kit, the medicament and the diagnostic reagent may not be fixed in the same compartment of the kit.

[0058] The terms "protocol" and "system" refer broadly to the invention as a whole (e.g., methods for treatment or diagnosis, products used in the methods, and processes for making those products, all of which share an inventive concept and have the purpose of improving at least one behavioral or neuropsychiatric symptom, at least one cognitive or functional disorder, any combination thereof, or otherwise benefiting a subject in need of treatment). They are distinguished by the inventive concept of the protocol regarding possible principles of operation (e.g., coordinated signaling by cannabinoid receptors, melatonin receptors, and other signaling pathways with which they interact to maintain or restore homeostasis, synergistic action of any two or more therapeutically active compounds) and / or the inventive concept of the system regarding elements (e.g., combination of THC compounds and melatonin compounds that are ligands for at least cannabinoid receptors and melatonin receptors, synergistic action between THC compounds and melatonin compounds), even if the treatment does not require binding and signaling of cannabinoid receptors and melatonin receptors.

[0059] In this specification, the "subject" to be treated is a human patient, female or male, since clinical trials focus on functional and behavioral outcomes.Dementia-related animal models can only assess cognitive impairment or assay biomarker changes.Subjects can be adults (i.e., 18 years or older), young adults (i.e., 18 to 50 years old), middle-aged adults (i.e., over 50 years old), or elderly adults (i.e., 60 years or older).Subjects have early-onset Alzheimer's disease if diagnosed before 65 years old, or late-onset Alzheimer's disease if diagnosed at 65 years old or older.

[0060] Furthermore, while the patient is the subject to be treated, the patient's caregiver may be the recipient of the beneficial effects of the treatment. A "caregiver" may be related to the patient as a family member or friend before the onset of the disease or the treatment of the patient, especially in the early stages of mild cognitive impairment or disease, when the patient lives at home. In the later stages, the caregiver may be a professional who is skilled / experienced (or even certified) in providing care for dementia or psychiatric patients.

[0061] Drugs approved for the treatment of at least dementia, Alzheimer's disease, depression, anxiety disorders, panic disorders, or sleep disorders may or may not be used in combination with the protocols and systems described herein. Such drugs include selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, fluvoxamine, sertaline, vortioxetine), serotonin / norepinephrine reuptake inhibitors (e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine), antidepressants (e.g., mirtazapine, trazodone), mood stabilizers (e.g., carbamazepine, galanidine), and the like. bapentin, lamotrigine, oxcarbazepine, topiramate, valproic acid), antipsychotics (e.g., aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), anxiolytics (e.g., buspirone, gepirone, ipsapirone, tandospirone), and orexin receptor antagonists (e.g., lemborexant, suvorexant). Some drugs treat multiple symptoms. In compositions and methods for treating a subject, some drugs may or may not be avoided, including anticholinergics, benzodiazepines, and hypnotics (e.g., zolpidem, zopiclone, zaleplon).

[0062] Tetrahydrocannabinol (THC) can be chemically synthesized (i.e., artificial or synthetic THC) or purified from the dried buds, flowers, seeds, leaves, etc. of plants such as Cannabis sativa, Cannabis indica, and hybrids of Cannabis sativa and Cannabis indica. Cannabis plants and plant parts with high THC content are preferred. As an alternative to chemical synthesis of pure THC, separation by chromatography, dehydration or distillation under vacuum, differential extraction, precipitation, recrystallization, solvent partitioning, or any combination thereof may be used to isolate THC from the plant material. THC-containing dried plant material from Cannabis may be extracted with a solvent (e.g., carbon dioxide, n-butane, ethanol). The extract and solvent may be separated under vacuum using a rotary evaporator, falling film evaporator, or reduced pressure distillation (e.g., short path distillation, fractional distillation, wiped film distillation). A THC-containing extract is recovered, and optionally the crude extract is defatted and dewaxed by dewaxing with cold ethanol to solidify fats and waxes, then filtered to remove solids from the extract, and then the residual solvent is removed by distillation. Tetrahydrocannabinolic acid (THCA) can be converted to THC by decarboxylation (e.g., heating the dried plant material or the dewaxed extract) to increase the final yield of THC. The THC distillate can be further purified to increase the purity of THC and remove contaminants.

[0063] THC can be purified from cannabis plant material using commercially available systems for extraction (e.g., closed loop extractors) and separation (e.g., vacuum distillation). The Transformer 1500-20L system from Apeks Supercritical (Johnstown, Ohio) uses subcritical or supercritical carbon dioxide as a solvent to extract the plant material. The extraction can be cycled between supercritical (higher temperature and pressure) and subcritical (lower temperature and pressure) conditions, and the extracts can be pooled as different compounds are extracted. The solvent is removed from the extract by releasing the pressure and evaporating the gas. The distillate is recovered in a cold separation. Delta Separations (Cotati, Calif.) offers CUP extraction units that use mechanical agitation and centrifugation to extract the plant material with chilled ethanol, FFE falling film evaporator units that remove ethanol from the extract, and RFD roll film distillation units that minimize contact with the hot evaporating surface and recover the distillate at a condensing surface. The IO Extractor 2.0, manufactured by Luna Technologies (Portland, Oregon), uses hydrocarbons (i.e., butane and / or propane) as solvents to extract plant material, producing hash oil or honey oil, which can be post-processed to remove residual solvent.

[0064] Artificial (pure) THC made by chemical synthesis and purified THC isolated from plants (i.e., THC isolate) can be in solid form (i.e., amorphous or crystalline), can be substantially free of cannabidiol (CBD), and can be suitable for administration to subjects in need of treatment.Thus, THC can be provided as THC crystals.In crude extracts or similar cannabis preparations with a mixture of cannabinoid compounds, THC can be purified by separating and isolating from each other, such as from other cannabinoid compounds (e.g., CBD), using chromatography, fractional distillation, recrystallization, or any combination thereof, to provide a THC distillate with a purity of more than 80%, more than 85%, more than 90%, more than 97%, more than 98%, or more than 99%. THC distillates, and THC concentrates, as described in the previous two paragraphs, may be in the form of, but are not limited to, amber glass or shatter (solid form), budder or wax (semi-solid form), diamond (i.e., crystals), dust (i.e., powder), and hash oil or honey oil (liquid form). Solid forms of THC can be ground into a powder and used in the anhydrous compositions.

[0065] "THC compounds" include, but are not limited to, dronabinol, nabilone, trans-delta-9-THC (Δ 9 -THC), its isomers (e.g., trans-delta-8-THC or Δ 8 -THC), Δ 9 -THC carboxylic acid (THCA), Δ 8 -THC carboxylic acid, Δ 9 -THC-4-oic acid (THCA-A), Δ 8 -THC-4-oic acid, Δ 9 -THC-2-oic acid (THCA-B), Δ 8 THC-2-oic acid, 11-hydroxy-Δ 9 -THC (11-OH-THC), 11-hydroxy-Δ 8 -THC, 11-nor-9-carboxy-Δ 9-THC (11-COOH-THC), 11-nor-9-carboxy-Δ 8 -THC, cannabinoid receptor agonists (e.g., Cambisol, Levonantradol, Arachidonyl-2'-chloroethylamide, AM-087, AM-411, AM-2389, CP47,497, CP55,940, HU-210, HU-308, JWH-018, JWH-048, JWH-133, O-1812, WIN55,212-2), endocannabinoids (e.g., N-arachidonoyl-ethanolamide, 2-arachidonoyl-glycerol, 2-arachidonoyl-glyceryl ether), or any combination thereof. The THC compounds were 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ6a,10a-THC), (9R,10aR)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ6a,7-THC), (6aR,9R,10aR)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H -dibenzo[b,d]pyran-1-ol (Δ7-THC), 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ10-THC), (6aR,10aR)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ9,11-THC). The THC compound may or may not be capable of substituting for endocannabinoids, THC precursors, THC metabolites, synthetic agonists of cannabinoid receptors (CB1 receptors or CB2 receptors, optionally specific for either CB1 or CB2), or orphan receptors (GPR3, GPR6, GPR12, GPR18, or GPR55), or any combination thereof. 9 If the amount of THC compound is significantly different from -THC, the amount of THC compound is Δ 9-THC can be tailored for bioavailability and equivalent cannabinoid receptor signaling activity.

[0066] In one embodiment, THC compounds may or may not be administered together with CBD or other non-THC cannabinoid compounds, and CBD and non-THC cannabinoid compounds may or may not be detectable in the composition administered, or at least they are not co-administered with THC compounds. For example, the weight or molar ratio of THC to CBD may be greater than 2:1, may be greater than 9:1, or may be greater than 99:1, or may not be greater than 2:1. In other embodiments, the weight or molar ratio of THC compounds to non-THC cannabinoid compounds (e.g., CBD, CBC, and CBG) may be greater than 2:1, may be greater than 9:1, or may be greater than 99:1, or may not be greater than 2:1. Crude extracts containing a mixture of cannabinoid compounds (e.g., nabiximols) may or may not be administered. Alternatively, less than about 1% (wt / vol) CBD may or may not be used in treatment. In other embodiments, the THC compound may be administered with undetectable or only trace amounts (e.g., less than about 1% wt / vol) of non-THC cannabinoid compounds (e.g., CBD, CBC, and CBG). CBN may be detectable because THCA is converted to cannabinolic acid (CBNA), which can be decarboxylated to form CBN.

[0067] Hydrophobic THC compounds are poorly soluble in water and other aqueous solutions. They can be dispersed or emulsified in a solvent. For example, 90% or more may or may not have a maximum dimension less than 500 nm (e.g., 50% or more may have a maximum dimension between about 10 nm and about 300 nm, or 50% or more may have a maximum dimension between about 50 nm and about 200 nm). See Heilscher (Dan Eur Nano Sys Workshop-ENS, 2005 Dec, 138-143). The conventional process described therein can be used to emulsify THC compounds and other hydrophobic compounds using ultrasonic cavitation to create stable oil-in-water emulsions. Other conventional processes for dissolving THC compounds (e.g., nano-THC compounds) in a solvent, dispersing them in a colloidal liquid or suspension, or emulsifying them are known in the art.

[0068] Melatonin is a dietary supplement and is related to the regulation of circadian rhythm and sleep-wake cycle.Melatonin is lipophilic, so it is typically insoluble in water.Solid form (i.e., amorphous or crystalline), artificial (pure) melatonin made by chemical synthesis and purified melatonin isolated from plants (melatonin isolate) can be suitable for treating subjects by administering melatonin crystals.Solid form melatonin can be ground into powder.

[0069] "Melatonin compound" may be one or more of, but not limited to, circadin, N-acetyl-5-methoxytryptamine, melatonin receptor agonist (e.g., agomelatine, ramelteon, tasimelteon), melatonin precursor (e.g., 5-methoxytryptamine, N-acetyl-serotonin), or any combination thereof. As a melatonin compound, it may or may not be possible to replace a precursor of melatonin biosynthesis, a synthetic agonist of melatonin receptor (MT1 receptor or MT2 receptor, in some cases MT2), a neurotransmitter, or any combination thereof. If the molecular weight of the melatonin compound is significantly different from melatonin, the amount of the melatonin compound may be adjusted for bioavailability and equivalent melatonin receptor signaling activity compared to melatonin. In this specification, the usefulness of a melatonin compound may not be the result of binding to its cognate receptor.

[0070] Hydrophobic melatonin compounds are poorly soluble in water and other aqueous solutions. They can be dispersed or emulsified in a solvent. For example, 90% or more may or may not have a maximum dimension less than 500 nm (e.g., 50% or more may have a maximum dimension between about 10 nm and about 300 nm, or 50% or more may have a maximum dimension between about 50 nm and about 200 nm). See Heilscher (Dan Eur Nano Sys Workshop-ENS, 2005 Dec, 138-143). The conventional process described therein can be used to emulsify melatonin compounds and other hydrophobic compounds using ultrasonic cavitation to create stable oil-in-water emulsions. Other conventional processes for dissolving melatonin compounds (e.g., nano melatonin compounds) in a solvent, dispersing them in a colloidal liquid or suspension, or emulsifying them are known in the art.

[0071] At least anhydrous or low moisture THC compound and at least anhydrous or low moisture melatonin compound may be suitable for manufacturing hard capsules or tablets (i.e., multiple unit doses).Alternatively, at least THC compound and at least melatonin compound may be dissolved in any of, but not limited to, alcohol, emulsions (e.g., nano THC compound, nano melatonin compound), glycerol, micelles and lipid vesicles, microspheres, nanoparticles, oils and waxes, water and other aqueous solutions, or any combination thereof (e.g., ethanol-water).The composition having at least THC compound and at least melatonin compound in solid, semi-solid, or liquid form may be encapsulated in soft gelatin capsules (i.e., multiple unit doses).

[0072] The THC compound and melatonin compound as described herein can be administered together at the same time or separately at different times.For example, one after the other consecutively (i.e. THC compound followed by melatonin compound, or melatonin compound followed by THC compound), or one immediately after waking up and the other immediately before going to sleep (i.e. THC compound in the morning and melatonin compound in the evening, or melatonin compound in the morning and THC compound in the evening).The THC compound and melatonin compound can be together in the same compartment of a kit of parts, or can be divided into different compartments.If the THC compound and melatonin compound are administered at different times of the day or more than once per day, split doses may be required.

[0073] Curcumin and rutin are plant-derived flavonoids with antibacterial activity and may be used as preservatives in the composition. They may also be included in the composition as preservatives due to their antioxidant activity. Like melatonin, curcumin and rutin are dietary supplements. Large amounts of each are generally recognized as safe (GRAS) in food and drugs. A rich source of curcumin is turmeric, which contains a few percent of curcuminoids (mainly curcumin and its derivatives). Rutin is a quercetin glycoside formed by linking quercetin with rutinose. Polyphenolic compounds such as curcumin and rutin are mostly poorly soluble in water and other aqueous solutions, but may be soluble in oils, alcoholic water (e.g., about 70% to 95% ethanol or isopropanol in water), emulsions (e.g., nanocurcumin, nanorutin), or lipids (e.g., micelles, vesicles). Vitamin E-related compounds may enhance the effectiveness of polyphenolic compounds.

[0074] Curcumin and / or rutin may be replaced by other polyphenolic compounds (e.g., flavonoids).Turmeric, curcuminoids other than curcumin, curcumin isomers, structural derivatives of curcumin, demethoxycurcumin, bisdemethoxycurcumin, dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, octahydrocurcumin, or cyclocurcumin may or may not replace curcumin.Therefore, the "curcumin-related compound" may be selected from at least curcumin, turmeric, curcuminoids, curcumin isomers, structural derivatives of curcumin, or any combination thereof. Quercetin glycosides other than rutin, quercitrin glycosides other than rutin, rutinosides other than rutin, rutin isomers, structural derivatives of rutin, avicularin, didymin, dihydroxyethyl rutoside, diosmin, eriocitrin, hesperidin, hyperoside, isorhamnetin, isoquercetin, monoxerutin, narcissine, narirutin, nicotiflorin, quercitrin, spireoside, tetrahydroxyethyl rutoside, or troxerutin may or may not replace rutin. Thus, the "rutin-related compound" may be selected from at least rutin, quercetin glycosides, rutinosides, rutin isomers, structural derivatives of rutin, or any combination thereof.

[0075] At least THC compound, at least melatonin compound, at least curcumin-related compound, at least rutin-related compound, and at least vitamin E-related compound can be administered together at the same time or separately at different times. For example, one after the other in succession (e.g., curcumin-related compound followed by rutin-related compound, rutin-related compound followed by curcumin-related compound), or one immediately after waking up and the other immediately before sleep (e.g., curcumin-related compound in the morning and rutin-related compound in the evening, rutin-related compound in the morning and curcumin-related compound in the evening). At least THC compound, at least melatonin compound, at least curcumin-related compound, at least rutin-related compound, and at least vitamin E-related compound can be provided in a device or kit of parts. For example, the compounds can be provided in the same location (e.g., reservoir) or different locations of the device. Alternatively, the compounds can be placed together in the same compartment of a kit of parts or separately in different compartments. Split doses may be necessary if the curcumin related compound and the rutin related compound are administered at different times per day or more than once per day.

[0076] At least the THC compound, at least the melatonin compound, at least the curcumin-related compound, at least the rutin-related compound, at least the vitamin E-related compound, and at least two or more pharma- ceutically acceptable excipients (which are anhydrous or low moisture, or can be easily made anhydrous or low moisture) may be suitable for the manufacture of hard capsules or tablets (i.e., multiple unit doses).Alternatively, at least the THC compound, at least the melatonin compound, at least the curcumin-related compound, at least the rutin-related compound, at least the vitamin E-related compound, and at least two or more pharma-ceutically acceptable excipients may be dissolved in any of, but not limited to, alcohol, emulsions (e.g., nanoemulsions), glycerol, micelles and lipid vesicles, microspheres, nanoparticles, oils and waxes, water and other aqueous solutions, or any combination thereof (e.g., ethanol-water). A composition comprising a THC compound, a melatonin compound, a curcumin-related compound, a rutin-related compound, a vitamin E-related compound, in solid, semi-solid, or liquid form, and two or more pharma- ceutically acceptable excipients may be encapsulated in a soft gelatin capsule (i.e., multiple unit doses).

[0077] Hydrophobic polyphenol compounds are poorly soluble in water and other aqueous solutions. They can be dispersed or emulsified in a solvent. For example, 90% or more may or may not have a maximum dimension less than 500 nm (e.g., 50% or more may have a maximum dimension between about 10 nm and about 300 nm, or 50% or more may have a maximum dimension between about 50 nm and about 200 nm). See Heilscher (Dan Eur Nano Sys Workshop-ENS, 2005 Dec, 138-143). The conventional process described therein can be used to emulsify polyphenol compounds and other hydrophobic compounds using ultrasonic cavitation to create stable oil-in-water emulsions. Other conventional processes are known in the art for dissolving, dispersing in a colloidal liquid or suspension, or emulsifying two or more polyphenol compounds (e.g., nanopolyphenol compounds) in a solvent. Vitamin E-related compounds can enhance the solubility of polyphenol compounds.

[0078] At least the THC compound, at least the melatonin compound, at least two or more polyphenolic compounds (e.g., curcumin-related compounds, rutin-related compounds), and at least the vitamin E-related compounds may be administered together at the same time or separately at different times. For example, they may be administered one after the other in any order in sequence. Alternatively, any one, two, three, four, five, or more compounds may be administered immediately after waking, and the remaining compounds may be administered just before sleep. At least the THC compound, at least the melatonin compound, at least two or more polyphenolic compounds (e.g., curcumin-related compounds, rutin-related compounds), and at least the vitamin E-related compounds may each be together in the same compartment of a kit of parts or separated into different compartments. If any one, two, three, four, five, or more compounds are administered at different times of the day or more than once per day, split doses may be required.

[0079] At least the THC compound, at least the melatonin compound, at least two or more polyphenol compounds (e.g., curcumin-related compounds, rutin-related compounds), at least the vitamin E-related compounds, and at least two or more pharma- ceutically acceptable excipients (all of which are anhydrous or low moisture, or can be easily made anhydrous or low moisture) may be suitable for the manufacture of hard capsules or tablets (i.e., multiple unit doses). Alternatively, at least the THC compound, at least the melatonin compound, at least two or more polyphenol compounds (e.g., curcumin-related compounds, rutin-related compounds), at least the vitamin E-related compounds (e.g., α-tocopherol), and at least two or more pharma-ceutically acceptable excipients may be dissolved in any of, but not limited to, alcohol, emulsions (e.g., nanoemulsions), glycerol, micelles and lipid vesicles, microspheres, nanoparticles, oils and waxes, water and other aqueous solutions, or any combination thereof (e.g., ethanol-water). The composition having the polyphenol compounds in solid, semi-solid, or liquid form may be encapsulated in a soft gelatin capsule. A composition comprising a THC compound, a melatonin compound, at least two or more polyphenol compounds (e.g., a curcumin-related compound, a rutin-related compound), a vitamin E-related compound, in solid, semi-solid, or liquid form, and two or more pharma- ceutically acceptable excipients, may be encapsulated in a soft gelatin capsule (i.e., multiple unit doses).

[0080] The carrier of the composition can be at least an emulsion (e.g., nanoemulsion), a polymeric micelle, a lipid vesicle, a solid or porous particle (e.g., nanoparticle), or any combination thereof. The THC compound, the melatonin compound, the curcumin-related compound, the rutin-related compound, and the vitamin E-related compound can all be associated with the same group of carriers. For example, a particulate carrier can be associated with any one, two, three, four, five, or more compounds. Alternatively, one or more of the THC compound, the melatonin compound, the curcumin-related compound, the rutin-related compound, or the vitamin E-related compound can be associated with different carriers. For example, a particulate carrier associated with any compound can only be associated with one compound. All the compounds can be mixed and the mixture can be incorporated or encapsulated in a carrier. Each compound can be incorporated or encapsulated separately in a carrier and then mixed together with the different carriers. Stable emulsions or lipid vesicles can be produced by processes such as ultra-high shear and ultrasonic cavitation. After dissolving one or more hydrophobic compounds in a solvent (e.g., oil), nanoparticles can be produced therefrom, such as nanoliposomes having a liquid core and a phospholipid bilayer membrane, nanolipospheres having a hydrophobic solid core and a phospholipid monolayer membrane, nanoemulsions having a liquid lipid core and a phospholipid monolayer membrane, solid lipid nanoparticles having a solid lipid core and a phospholipid monolayer membrane, nanostructured lipid carriers having a liquid / solid lipid core and a phospholipid monolayer membrane, polymeric nanoparticles having a hydrophilic polymer shell, and metal nanoparticles having a surface coated with a nanoemulsion. See Vegallo (Nanomaterials. 2020 Jun, 10:1232), which is incorporated herein by reference.

[0081] Examples of emulsifiers include, but are not limited to, cyclodextrins, fatty alcohols, lecithin or phospholipids, poloxamers, polyethylene glycols (e.g., PEG 1000), polyglycerol fatty acid esters, polysorbates (e.g., polysorbate 80 or Tween 80), saponins, and sorbitan fatty acid esters (e.g., sorbitan oleate or Span 80). Surfactants are often emulsifiers, and emulsifiers and surfactants can also be considered solubilizers.

[0082] The vehicle of the composition may be an aqueous or non-aqueous solution, or a mixture of two or more solvents (e.g., H2O+DMSO). Water, saline, buffered aqueous solution (optionally hypotonic or isotonic), and dimethyl sulfoxide may be used as a solvent for water-soluble (preferably hydrophilic) compounds. Alcohol (optionally diluted to about 5%-20% or about 10%-15% ethanol in water as a final concentration for administration), N,N-dimethylacetamide, glycerol, hydrogenated vegetable oil, mineral oil, vegetable oil, PEG1000, polysorbate 80, propylene glycol, medium chain triglycerides (MCT may be caprylic acid, capric acid, or both), and dimethyl sulfoxide may be used as a solvent for one or more hydrophobic compounds.

[0083] Compositions (medicines, medical devices, and kits of parts) The compositions may include (i) a THC compound as described herein and (ii) a melatonin compound (or a salt of either or both compounds, or a solvate such as a hydrate of either or both compounds, or an analog of either or both compounds sharing the same or similar therapeutic properties, or a structural derivative of either or both compounds having the same or similar therapeutic effect, or a stereoisomer of either or both compounds, or a polymorph of either or both compounds, or a metabolite of either or both compounds, or a prodrug of either or both compounds), (iii) optionally a polyphenol compound as described herein (e.g., curcumin and rutin, compounds related thereto), (iv) optionally a vitamin E related compound as described herein (e.g., α-tocopherol), (v) optionally at least one chemotherapeutic agent (see example agents below), (vi) a plurality of pharmaceutically acceptable excipients, (vii) optionally a pharmaceutically acceptable vehicle, and (viii) optionally a pharmaceutically acceptable carrier.

[0084] The composition comprises a therapeutically effective amount of (i) a THC compound as described herein and (ii) a melatonin compound (or a salt of either or both compounds, or a solvate such as a hydrate of either or both compounds, or an analog of either or both compounds sharing the same or similar therapeutic properties, or a structural derivative of either or both compounds having the same or similar therapeutic effect, or a stereoisomer of either or both compounds, or a polymorph of either or both compounds, or a metabolite of either or both compounds, or any (iii) optionally, an effective amount of a polyphenolic compound as described herein (e.g., curcumin and rutin and related compounds); (iv) optionally, an effective amount of a vitamin E related compound as described herein (e.g., α-tocopherol); (v) optionally, an effective amount of at least one chemotherapeutic agent (example agents are provided in the next two paragraphs); (vi) a plurality of pharmaceutical acceptable excipients; (vii) optionally, a pharmaceutical acceptable vehicle; and (viii) optionally, a pharmaceutical acceptable carrier.

[0085] In some embodiments, at least one chemotherapeutic agent can be combined with at least two compounds as described herein (i.e., a THC compound and a melatonin compound) or at least five compounds as described herein (i.e., in addition to polyphenolic compounds such as curcumin and rutin, vitamin E, and related compounds) to treat neuropsychiatric symptoms or disorders. The chemotherapeutic agent can be selected from, but is not limited to, antidepressants, antipsychotics, mood stabilizers, selective serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, and anti-anxiety agents. For example, the chemotherapeutic agent can be a selective serotonin reuptake inhibitor (e.g., citalopram, escitalopram, fluvoxamine, sertaline, vortioxetine), a serotonin / norepinephrine reuptake inhibitor (e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine), an antidepressant (e.g., mirtazapine, trazodone), a mood stabilizer (e.g., carbamazepine, gabapentin, lamotrigine, oxcarbazepine, topiramate, valproic acid), an antipsychotic (e.g., aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), an anxiolytic (e.g., buspirone, gepirone, ipsapirone, tandospirone), and an orexin receptor antagonist (e.g., lemborexant, suvorexant). Chemotherapeutic agents may be co-administered with the THC and melatonin compounds as described herein (at least two, three, four, five, or more compounds together in the same composition only once per day, simultaneously in the same divided composition more than once per day, separately in their own composition only once per day, or separately in their own composition at two different times per day).

[0086] In other embodiments, at least one chemotherapeutic agent can be combined with at least two compounds as described herein (i.e., a THC compound and a melatonin compound) or at least five compounds as described herein (i.e., in addition, polyphenolic compounds such as curcumin and rutin, vitamin E, and compounds related thereto) to treat dementia or Alzheimer's disease. The chemotherapeutic agent can be selected from, but is not limited to, acetylcholinesterase inhibitors, antibodies that bind to β-amyloid, antibodies that bind to tau protein, β-amyloid aggregation inhibitors, β-secretase inhibitors, γ-secretase inhibitors, kinase inhibitors, receptor antagonists, tau phosphorylation inhibitors, and tau protein aggregation inhibitors. The chemotherapeutic agent can be aducanumab, amantadine, bepranemab, brexpiprazole, bryostatin, colostrinin, donanemab, donepezil, ginkgo extract EGb761, galantamine, gantesnerumab, goslanemab, lanabecestat, lecanemab, leucomethylthioninium, levetiracetam, memantine, methylphenidate, neflamapimod, prasinezumab, rivastigmine, semolinemab, solanezumab, tirabonemab, tramiprosate, tricaprylin, zagotenemab, or any combination thereof. Chemotherapeutic agents may be co-administered with at least two, three, four, five, or more compounds together in the same composition only once per day, simultaneously in the same divided composition more than once per day, separately in their own composition only once per day, or separately in their own composition at different times two times per day.

[0087] The medicaments are pharma- ceutically acceptable and may include any of the compositions as described herein. The medicaments may be, but are not limited to, aerosols, capsules, packets and sachets, chewable candies and gums, colloids, disintegrating strips and tabs, drops, elixirs, foams and mousses, hydrogels, lozenges and pastilles, mouthwashes and oral rinses, solutions, suspensions, tablets, and tonics, the contents of a sealed container, such as, but not limited to, an ampoule, a blister pack (i.e., a blister card or a blister pouch), a pill bottle, a pill box, or a vial, or the contents of a device, such as, but not limited to, an inhaler, an insufflator, an atomizer or sprayer, a nebulizer, a suppository, a syringe, or a vaporizer. The pharmaceutical use can be the administration of a THC compound and a melatonin compound as described herein, optionally an optional polyphenolic compound as described herein (e.g., curcumin and rutin, and related compounds), optionally at least one chemotherapeutic agent as described herein, optionally a pharmaceutical excipient, optionally a pharmaceutical vehicle, and optionally a pharmaceutical carrier, by any route, including but not limited to, at least enteral administration, parenteral administration, transmucosal administration, pulmonary administration, or any combination thereof.

[0088] The at least one chemotherapeutic agent may be administered together with or separately from two or more compounds as described herein (e.g., THC compound, melatonin compound, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E, and compounds related thereto). The at least one chemotherapeutic agent may be administered enterally (i.e., digested and absorbed in the digestive tract, likely oral) or parenterally (i.e., all other routes) for systemic action after entering the circulation. Enteral administration of the at least one chemotherapeutic agent may use capsules, chewable candies or gums, disintegrating strips or tabs, elixirs, lozenges or troches, tablets, or tinctures. Parenteral administration of the at least one chemotherapeutic agent may use subcutaneous syringes (e.g., intramuscular, intravenous, subcutaneous), implantable depots, implantable pumps, infusion pumps, or intravenous infusions via cannula / catheter.

[0089] Pulmonary administration (e.g., inhalation, insufflation) of at least one chemotherapeutic agent can achieve local action in the lungs or systemic action by absorbing directly into the circulation through the alveolar epithelium and bypassing first-pass hepatic metabolism. Examples of other routes of administration include, but are not limited to, the ear for ear drops, the eye for eye drops, the nose for nose drops and sprays, the rectum for rectal enemas and suppositories, and the vagina for vaginal enemas and suppositories.

[0090] In particular, excipients of interest may have desirable properties for formulating compositions and manufacturing products, such as preservatives (e.g., antimicrobials, antioxidants, stabilizers), emulsifiers, solubilizers, surfactants, and other food ingredients that are generally recognized as safe (GRAS).Examples of chemicals that may be suitable for use in the compositions and products as pharma- ceutically acceptable excipients include, but are not limited to, one or more of acetate, alcohol (e.g., benzyl alcohol, ethanol, isopropanol), aluminum silicate, aluminum stearate, amino acids (e.g., arginine, aspartic acid, glutamic acid, glycine, histidine, methionine), ascorbic acid (vitamin C), beta-carotene, carbomer, dendrimers, fatty acid esters (e.g., cetyl palmitate, methyl linoleate, myristyl esters, glyceryl stearate ... isopropyl phosphate, isopropyl palmitate), fatty alcohols (e.g., cetyl alcohol, octyldodecanol, oleyl alcohol, stearyl alcohol), format, free fatty acids (e.g., caprylic acid, capric acid, myristic acid, oleic acid, palmitic acid, stearic acid), gelatin, hydrogenated vegetable oils, magnesium silicate, magnesium stearate, medium chain triglycerides (MCT), non-reducing sugars (e.g., raffinose, sucrose, trehalose), phospholipids (e.g., phosphatidic acid, phosphatidic acid, Alcohol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine), polyacrylates, polyethylene glycol, polyethylene oxide, polyglycerol esters, polylactic-glycolic acid copolymers, polymethacrylates, poloxamers, polypropylene glycol, polysorbates, polyvinyl alcohol, polyvinylpolypyrrolidone, polyvinylpyrrolidone, propylene glycol, reducing sugars (e.g., fructose, galactose, lactose, maltose), retinal (vitamin A ), sugars (e.g., agar, alginate, alginic acid, carboxymethylcellulose, carrageenan, cellulose acetate, chitosan, chondroitin sulfate, cyclodextrin, dextran, dextrin, ethylcellulose, guar gum, tragacanth gum, hyaluronic acid, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sodium hyaluronate, starch, xanthan gum), salts (e.g., cation Ca. 2+ , K + , Mg 2+ , Na+ , or NH4 + , and the anion C2H3O2 - , HCO3 - , Cl - , NO2 - , or PO4 3- Any combination of), saponin, silicone oil, sodium benzoate, sugar alcohol (e.g., erythritol, glycerol, isomalt, lactitol, maltitol, mannitol, sorbitol, xylitol), syrup (e.g., agave, corn, date palm, honey, malt extract, tallow), titanium dioxide, tocopherol, vegetable oil, white petrolatum, zinc stearate, or any combination thereof. It should be noted that chemicals suitable for use as pharma-ceutically acceptable excipients may have multiple (and sometimes overlapping) properties that are desirable for formulating compositions and manufacturing products. See Sheskey et al. (Handbook of Pharmaceutical Excipients, Ninth Ed, 2020 Oct, Pharmaceutical Press), which is incorporated herein by reference for its indicated excipients and description thereof.

[0091] In some embodiments, the composition may further comprise one or more vehicles, such as aqueous solvents, non-aqueous solvents, and mixtures thereof (e.g., alcohol water, alcohol, buffer, preferably hypotonic or isotonic solution, N,N-dimethylacetamide, dimethylsulfoxide, fat, glycerol, mineral oil, vegetable butter, saline, silicone oil, vegetable oil, white petrolatum, water), and / or one or more types of carriers (e.g., emulsions, micelles, particles, vesicles). For example, the THC and melatonin compounds as described herein may be formulated in at least polymeric micelles, nanoparticles, oil-in-water nanoemulsions, or lipid vesicles to enhance the solubility, stability, bioavailability, or any combination thereof, of at least the THC and melatonin compounds.

[0092] Sterile compositions can be prepared by dissolving an effective amount of a compound as described herein in a suitable solvent, optionally with other vehicles, carriers, and / or excipients, followed by filter sterilization. Alternatively, a solution can be prepared by dissolving a sterile compound as described herein in a sterile vehicle that is a dissolution medium. A colloid liquid can be prepared by dispersing a sterile compound as described herein in a sterile vehicle that is a colloid medium. A suspension can be prepared by dispersing a sterile compound as described herein in a sterile vehicle that is a suspension medium. For solid forms of compounds used to prepare sterile infusion or injection solutions, evaporation or freeze-drying can produce solid forms (e.g., granules) that contain a compound as described herein with any excipients, which can be reconstituted with a sterile vehicle, all under sterile conditions. Systemic action can be obtained thereby.

[0093] The "finished" composition is formulated into a solid, semi-solid, or liquid form before being transported to the location where the subject is to be treated. The finished composition is preferably compatible with the selected mode and route of administration, is substantially stable at physiological levels of pH and osmolality, and is confirmed to be free of detectable pathogens and pyrogens.

[0094] formulation The composition may be in any form selected from, but not limited to, any aerosol, capsule, sachet or packet, chewable candy or gum, colloid, cream, disintegrating strip or tab, drop, elixir, foam or mousse, hydrogel, lozenge or troche, mouthwash or oral rinse, ointment, suspension, tablet, or tincture, and may be administered by a route selected from, but not limited to, at least oral, enteral, mucosal (e.g., buccal, sublabial, sublingual), or pulmonary (i.e., inhalation, insufflation, drops), or delivered by a dispenser selected from, but not limited to, any bandage or patch, dropper or pipette, enema bottle, implantable depot or pump, infusion pump, inhaler, insufflator, intravenous (IV) bag or bottle, mister and sprayer, nebulizer, pill bottle, pill box, suppository, syringe, or vaporizer, thereby providing a systemic or localized effect.

[0095] Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous solutions (e.g., saline, water for injection), alcohol (e.g., ethanol), glycerol, polyethylene glycol, polypropylene glycol, propylene glycol, vegetable oil, and mixtures thereof (e.g., alcohol-water). Examples of pharmaceutically acceptable carriers include, but are not limited to, cyclodextrins, dendrimers, lipid vesicles, microspheres, nanoparticles, nanofibers, polymeric micelles, and stable emulsions. It should be noted that some vehicles and some carriers can also be considered as excipients.

[0096] The composition may further comprise at least two, three, four, or more pharma- ceutically acceptable excipients, including, but not limited to, preservatives (e.g., ascorbic acid, ethanol, glycerol, sodium benzoate), emulsifiers (e.g., glycerol, polysorbate 80, PEG1000), binders, diluents or fillers, disintegrants, glidants or lubricants, buffers (e.g., sodium citrate), and isotonicity agents (e.g., dextrose, potassium salts, sodium salts). It should be noted that some excipients may have multiple, and sometimes overlapping, functions, for example, an emulsifier may function as both a surfactant and a solubilizer.

[0097] The method of formulating the composition may include one or more steps of associating (i.e., directly or indirectly contacting) two or more compounds as described herein (e.g., THC compound and melatonin compound, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E and compounds related thereto, and optionally at least one chemotherapeutic agent), and one or more pharmaceutically acceptable excipients. In some embodiments, the composition may be formulated by one or more steps of associating a therapeutically effective amount of a THC compound and melatonin compound as described herein, optionally an effective amount of two or more polyphenolic compounds, optionally an effective amount of a vitamin E related compound, one or more pharmaceutically acceptable excipients, and optionally at least a vehicle and / or carrier. The liquid form may be dispensed aseptically into a sterile container with or without an intervening process of drying the composition by conventional processes (e.g., evaporation, lyophilization) as known in the art. Alternatively, the solid form may be dispensed aseptically into a sterile container with or without an intervening process of forming the composition into a plurality of unit doses.

[0098] As described in the paragraph above, compounds in liquid form can be dried or compounds in solid form can be combined to provide an anhydrous composition. In other embodiments, a composition can be anhydrous when substantial contact with moisture and / or humidity is expected or likely to occur at least during manufacture, finishing, storage, or combinations thereof. Thus, anhydrous compositions can be formulated in low humidity conditions from low moisture compounds and then gently heated under vacuum to ensure that residual moisture and volatiles are driven off. Anhydrous compositions can be formulated, transported, and stored such that their anhydrous properties are maintained. Similarly, the composition can be "finished" using barrier materials to prevent exposure to air and moisture. If the anhydrous composition is in solid form, the composition can be administered in solid form or in liquid form after reconstitution with a sterile vehicle under aseptic conditions. Ampoules, blister cards, sachets or packets, pill bottles, pill boxes, and vials can hold anhydrous compositions.

[0099] Water can be added to anhydrous formulations as a means of simulating long-term storage to test their stability, effectiveness after shipping and / or storage, and shelf life. Contact with and oxygenation can be avoided by filling or purging with inert gas during filling and other processes. Lot testing can be performed to ensure the absence of viruses, pyrogens, or other contaminants.

[0100] Anhydrous compositions may contain two or more compounds as described herein (e.g., a THC compound and a melatonin compound, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E and related compounds, and optionally at least one chemotherapeutic agent). Anhydrous compositions may be held in a sealed container, such as, but not limited to, an ampoule or vial, an intravenous (IV) bag or bottle, or the like, that can be reconstituted under aseptic conditions with a sterile vehicle and then delivered by gravity drip, pump, or syringe.

[0101] The process of formulating a pharmaceutical product, or by further processing, manufacturing of the downstream product, includes unit doses in solid forms including, but not limited to, blister cards, packets or sachets, chewable candies or gums, coated or uncoated tablets, disintegrating strips or tabs, hard or soft capsules, or lozenges or pastilles.

[0102] Capsules or tablets can be manufactured by conventional machines as known in the art. Capsules can be hard or soft. Capsules and tablets can be coated or uncoated. Coatings can include at least resinous or polymeric materials and can control the release of the THC and melatonin compounds as described herein. Compositions for enteral administration can be provided as enteric coated capsules or tablets containing the THC and melatonin compounds as described herein mixed with a diluent or filler (e.g., calcium carbonate) or as enteric coated capsules containing the THC and melatonin compounds as described herein mixed with a vehicle (e.g., alcohol, alcohol-water, oil, water). The coating on the capsules or tablets can largely determine their release characteristics and bioavailability. Preferably, the capsule or tablet has an enteric coating to bypass the stomach (and its digestive fluids) and target delivery of the THC and melatonin compounds as described herein to the proximal end of the small intestine (e.g., the duodenum) where the THC and melatonin compounds as described herein will be absorbed.

[0103] Dosage Two or more compounds as described herein (e.g., a THC compound, a melatonin compound, optionally a polyphenol compound such as curcumin and rutin, optionally vitamin E and compounds related thereto, and optionally at least one chemotherapeutic agent) can be delivered in the form of a composition comprising a predetermined amount of each compound, two or more pharma- ceutically acceptable excipients, and optionally a pharma-ceutically acceptable vehicle and / or carrier.

[0104] The THC and melatonin compounds as described herein can be delivered in the form of a composition comprising a therapeutically effective amount of the THC and melatonin compounds, optionally an effective amount of two or more polyphenolic compounds (e.g., curcumin and rutin and related compounds), optionally an effective amount of a vitamin E related compound, and optionally an effective amount of at least one chemotherapeutic agent, formulated together with one or more pharma- ceutically acceptable vehicles, carriers, and / or excipients.

[0105] In some embodiments, the THC compound and melatonin compound, polyphenol compound, vitamin E-related compound, and at least one chemotherapeutic agent as described herein are administered in separate compositions and can be administered in different modes and / or routes due to the different physical and / or chemical properties of the compounds (e.g., one compound is administered enterally while the other compound is administered parenterally). In other embodiments, the THC compound and melatonin compound, polyphenol compound, and at least one chemotherapeutic agent as described herein are administered separately but can be administered by the same route (e.g., both enterally, both by inhalation, both parenterally). For convenience, it is expected that the THC compound and melatonin compound, two or more polyphenol compounds, and at least one chemotherapeutic agent as described herein can be administered in the same composition by oral and / or nasal routes.

[0106] The selected dosage level can depend on a variety of factors, including, for example, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound, its rate and extent of absorption, the duration of treatment, other compounds and / or materials used in combination with the particular compound, the age, sex, weight, disease state, general health, and prior medical history of the subject being treated, and similar factors well known in the medical art.

[0107] A suitable amount of tetrahydrocannabinol (THC) compound may be about 2.0 mg to about 7.0 mg per day, or the amount may be a daily dose of about 0.0286 mg / kg to about 0.1000 mg / kg of the subject's body weight. A suitable amount of THC compound may be about 2.25 mg to about 6.75 mg per day, or the amount may be a daily dose of about 0.0321 mg / kg to about 0.0964 mg / kg of the subject's body weight. A suitable amount of THC compound may be about 2.5 mg to about 6.5 mg per day, or the amount may be a daily dose of about 0.0357 mg / kg to about 0.0929 mg / kg of the subject's body weight. A suitable amount of THC compound may be about 2.75 mg to about 6.25 mg per day, or the amount may be a daily dose of about 0.0393 mg / kg to about 0.0893 mg / kg of the subject's body weight. A suitable amount of the THC compound may be from about 3.0 mg to about 6.0 mg per day, or the amount may be a daily dosage of from about 0.0429 mg / kg to about 0.0857 mg / kg of the subject's body weight.

[0108] A suitable amount of the melatonin compound may be about 1.0 mg to about 4.4 mg per day, or the amount may be a daily dose of about 0.0143 mg / kg to about 0.0629 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.6 mg to about 4.4 mg per day, or the amount may be a daily dose of about 0.0229 mg / kg to about 0.0629 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.25 mg to about 4.2 mg per day, or the amount may be a daily dose of about 0.0179 mg / kg to about 0.0600 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.6 mg to about 4.2 mg per day, or the amount may be a daily dose of about 0.0229 mg / kg to about 0.0600 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.0 mg to about 4.2 mg per day, or the amount may be a daily dose of about 0.0143 mg / kg to about 0.0600 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.25 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0179 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.6 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0229 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.5 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0215 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.75 mg to about 3.75 mg per day, or the amount may be a daily dose of about 0.0250 mg / kg to about 0.0536 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 1.75 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0250 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the melatonin compound may be about 2.0 mg to about 3.5 mg per day, or the amount may be a daily dose of about 0.0286 mg / kg to about 0.0500 mg / kg of the subject's body weight.

[0109] A suitable amount of the curcumin-related compound may be about 0.3 mg to about 1.5 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0215 mg / kg of the subject's body weight. A suitable amount of the curcumin-related compound may be about 0.3 mg to about 1.2 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0171 mg / kg of the subject's body weight. A suitable amount of the curcumin-related compound may be about 0.6 mg to about 1.2 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0171 mg / kg of the subject's body weight. A suitable amount of the curcumin-related compound may be about 0.6 mg to about 1.5 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0215 mg / kg of the subject's body weight.

[0110] A suitable amount of the rutin-related compound may be about 0.3 mg to about 1.5 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0215 mg / kg of the subject's body weight. A suitable amount of the rutin-related compound may be about 0.3 mg to about 1.2 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0171 mg / kg of the subject's body weight. A suitable amount of the rutin-related compound may be about 0.6 mg to about 1.2 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0171 mg / kg of the subject's body weight. A suitable amount of the rutin-related compound may be about 0.6 mg to about 1.5 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0215 mg / kg of the subject's body weight.

[0111] A suitable amount of the two or more polyphenol compounds may be about 0.1 mg to about 5.0 mg per day, or the amount may be a daily dose of about 0.0014 mg / kg to about 0.0714 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.3 mg to about 5.0 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0714 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.1 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0014 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.3 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.3 mg to about 3.0 mg per day, or the amount may be a daily dose of about 0.0043 mg / kg to about 0.0429 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.6 mg to about 5.0 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0714 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.6 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.6 mg to about 3.0 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0429 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.6 mg to about 2.4 mg per day, or the amount may be a daily dose of about 0.0086 mg / kg to about 0.0343 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.9 mg to about 5.0 mg per day, or the amount may be a daily dose of about 0.0129 mg / kg to about 0.0714 mg / kg of the subject's body weight.A suitable amount of the two or more polyphenol compounds may be about 0.9 mg to about 4.0 mg per day, or the amount may be a daily dose of about 0.0129 mg / kg to about 0.0571 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 0.9 mg to about 3.0 mg per day, or the amount may be a daily dose of about 0.0129 mg / kg to about 0.0429 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 1.2 mg to about 2.4 mg per day, or the amount may be a daily dose of about 0.0171 mg / kg to about 0.0343 mg / kg of the subject's body weight. A suitable amount of the two or more polyphenol compounds may be about 1.2 mg to about 3.0 mg per day, or the amount may be a daily dose of about 0.0171 mg / kg to about 0.0429 mg / kg of the subject's body weight. The polyphenolic compounds may be only one curcumin-related compound and only one rutin-related compound in approximately equal amounts (e.g., 1.1:1, 1.2:1, 1.5:1, 1.7:1, 1.8:1, 1:1, 1:1.8, 1:1.7, 1:1.5, 1:1.2, 1:1.1, 1-1.8:1-1.8, or 1.8:1-1:1.8, 1.9:1-1:1.9, 1.7:1-1:1.7, 1.5:1-1:1.5, 1.2:1-1:1.2, 1.1:1-1:1.1).

[0112] Any suitable amount of vitamin E related compound may be equivalent to about 20mg to about 55mg of α-tocopherol per day, or the amount may be equivalent to a daily dose of about 0.286mg / kg to about 0.786mg / kg of α-tocopherol per subject's body weight. A suitable amount of vitamin E related compound may be equivalent to about 30mg to about 45mg of α-tocopherol per day, or the amount may be equivalent to a daily dose of about 0.429mg / kg to about 0.643mg / kg of α-tocopherol per subject's body weight. A suitable amount of vitamin E related compound may be equivalent to about 35mg to about 40mg of α-tocopherol per day, or the amount may be equivalent to a daily dose of about 0.500mg / kg to about 0.571mg / kg of α-tocopherol per subject's body weight.

[0113] The effective amount of the compounds as described herein (e.g., THC compounds, melatonin compounds, optionally polyphenolic compounds such as curcumin and rutin, and compounds related thereto, and optionally at least one chemotherapeutic agent) can be varied to obtain an amount of compound that is effective for achieving the desired therapeutic response for a particular subject and mode of administration without toxicity or harm. In some embodiments, a dosage below the lower limit of the above range is sufficient to be therapeutically effective, but a dosage above the upper limit can be administered without adverse effects, for example, by dividing a large dosage into many smaller doses and administering them more frequently over a period of time.

[0114] Compounds as described herein (e.g., THC compounds, melatonin compounds, optionally polyphenolic compounds such as curcumin and rutin, and compounds related thereto, and optionally at least one chemotherapeutic agent) may be administered enterally (digestion and absorption in the digestive tract, likely orally) or parenterally (all other routes) as one or more compositions for systemic action after entering the circulation. In particular, capsules, chewable candies or gums, disintegrating strips or tabs, elixirs, tablets, or tinctures may be administered enterally. Alternatively, subcutaneous syringes (e.g., intramuscular, intravenous, subcutaneous), implantable depots or pumps, infusion pumps, intravenous (IV) drips, or the like, may be used for parenteral administration.

[0115] In general, an appropriate amount of a chemotherapeutic agent may be the minimum amount effective to produce the desired therapeutic effect. The appropriate amount will generally depend on factors such as those described above. The daily dosage of a chemotherapeutic agent for a 70 kg subject may be about 0.0001 mg to about 1000 mg, or about 0.01 mg to about 1000 mg, or about 1 mg to about 1000 mg, or about 0.001 mg to about 500 mg, or about 0.01 mg to about 500 mg, or about 0.1 mg to about 500 mg, or about 1 mg to about 500 mg, or about 0.01 mg to about 100 mg, or or about 0.1 mg to about 100 mg, or about 1 mg to about 100 mg, or about 0.001 mg to about 50 mg, or about 0.01 mg to about 50 mg, or about 0.1 mg to about 50 mg, or about 1 mg to about 50 mg, or about 0.001 mg to about 10 mg, or about 0.01 mg to about 10 mg, or about 0.1 mg to about 10 mg, or about 1 mg to about 10 mg.

[0116] Chemotherapeutic agents may be administered daily (preferably only once), every other day, weekly, biweekly, or monthly. The dosing schedule may include a "drug holiday", for example, the chemotherapeutic agent may be administered 2 weeks on, 1 week off, or 3 weeks on, 1 week off, or 4 weeks on, 1 week off, etc., or continuously without a drug holiday. In some embodiments, the therapeutically effective amount of the chemotherapeutic agent may be reduced when administered in a combination therapy.

[0117] The chemotherapeutic agent is administered in a single unit dose or multiple unit doses within a given period of time. Generally, the dose is at least the daily amount given to or taken by the subject. For example, once, twice, three times, four times, or six times per day. The dosage can be about once a month, about once every two weeks, about once a week, or about once every other day. The chemotherapeutic agent can be co-administered with the THC compound and melatonin compound as described herein at a frequency ranging from once per day (every day) to six times per day. In other embodiments, they can be co-administered simultaneously for less than about 7 days, more than about 6 days, less than about 10 days, more than about 2 weeks, less than about 15 days, more than about 3 weeks, less than about 30 days, more than about 1 month, less than about 60 days, more than about 2 months, less than about 90 days, more than about 3 months, less than about 120 days, more than about 6 months, less than about 360 days, or more than about 1 year. In some cases, dosing is continued for as long as necessary to obtain beneficial effects, in other cases, dosing is tapered after a systemic therapeutically effective amount or therapeutic benefit is obtained.

[0118] The administration of the composition as provided herein can continue as long as necessary.In some embodiments, the chemotherapeutic agent is administered for more than about 1 day, more than about 1 week, more than about 2 weeks, more than about 3 weeks, more than about 1 month, more than about 2 months, more than about 3 months, more than about 6 months, or more than about 1 year.In some embodiments, the composition is administered for less than about 28 days, less than about 30 days, less than about 60 days, less than about 120 days, or less than about 360 days.In some embodiments, the chemotherapeutic agent is administered for about 1 day, about 1 week, about 2 weeks, about 1 month, about 2 months, about 3 months, about 6 months, or about 1 year.In some embodiments, the chemotherapeutic agent is administered continuously and chronically, for example, for the treatment of chronic effects.

[0119] The THC and melatonin compounds as described herein can be administered in combination with other treatments (e.g., psychological counseling, psychotherapy, surgical procedures, co-administration of additional chemotherapeutic agents), so that the dose of each compound or the frequency of treatment can be lower than that of the corresponding single agent treatment. Alternatively, the daily dose of the chemotherapeutic agent can be in an amount of about 0.0001 mg to about 200 mg, or about 0.001 mg to about 100 mg, or about 0.01 mg to about 100 mg, or about 0.1 mg to about 100 mg, or about 1 mg to about 50 mg per kilogram of subject body weight.

[0120] Parts Kit Compositions, components thereof, formulations thereof, and dosage amounts thereof as described elsewhere herein are incorporated by reference and may be used to further describe the contents of the kits below.

[0121] A kit may use at least some of its contents in a method (e.g., a method for treatment and / or diagnosis) as described herein. A kit may be comprised of multiple components, optionally a dispenser for one or more components, a package, optionally a package insert describing the components and their use, optionally a seal that renders the components at least tamper-resistant, optionally an expiration date, and optionally a packaging. A package includes any case (e.g., carton, bag) that limits access to its contents (e.g., one or more components) before opening. The case may be crush-resistant. After opening, the case may be closed to limit access to any remaining contents. It may or may not be possible to open and close the case multiple times. A package may optionally include a dispenser. The optional package insert may include information such as, for example, how to use the medicine, dosage and route of administration, risks and benefits of the treatment, citations to medical literature and discussion of clinical studies, any drug interactions or other adverse effects, instructions for companion diagnostic tests, how to select treatment subjects according to analysis of test assay results, or any combination thereof approved by and / or meeting the requirements of a regulatory agency (e.g., U.S. FDA, European Medicines Agency). The optional seal may include a tamper-resistant adhesive label and / or hologram attached to the package itself or to a portion of the kit. When the package is opened to access its contents, this will break the seal, and the broken seal may be evidence of tampering. If the seal is intact, the user will be assured that no one has tampered with the ingredients. The optional expiration date may include a future date that is printed on a label attached to the kit or the package itself, and is preferably not printed on any part of the optional packaging that is disposed of after opening the package and before using its contents.

[0122] The kit can be manufactured by enclosing at least a number of components, optionally a dispenser, and optionally a package insert. They can be inserted into an open case, or they can be placed in the case and the case assembled. At least one component (or at least one dispenser holding one or more components) can be fixed in a compartment of the package during manufacture. In a kit usable for treatment and / or companion diagnostic test over several days, the multiple daily doses of the medicament and / or at least one diagnostic reagent can be fixed in separate compartments such that at least one component is fixed separately from another fixed copy of the component. Alternatively, a dispenser with multiple daily doses of the medicament can be fixed in its own compartment. In any order, an optional seal can be applied, an optional expiration date can be added, and the package can be wrapped. Preferably, the package is transparent, and the package (and possibly the seal and / or the optional expiration date) is visible from the outside. The optional seal may be affixed to a portion of the optional dispenser, case, package, and / or optional wrapping (which may itself include or consist of a seal). The package may be optionally wrapped to protect at least from the environment during storage, rough handling or shipping, or any combination thereof. The package and / or its wrapping may have printing that at least identifies the kit, its origin (e.g., manufacturer or its country of manufacture), contents (e.g., pharmaceutical or diagnostic reagents), other information (e.g., manufacturer's URL or TCP / IP address), or any combination thereof. The optional seal and / or optional expiration date may be visible to an outside observer when holding the wrapped package.

[0123] In some embodiments, the kit includes (i) a THC compound (e.g., isolated THC or pure THC) and a melatonin compound (e.g., melatonin), optionally a polyphenol compound, such as a curcumin-related compound (e.g., curcumin, turmeric) and a rutin-related compound (e.g., rutin), in solid, semi-solid, or liquid form, in at least two different, separate pharmaceutical compositions, in at least three different, separate pharmaceutical compositions, in at least four different, separate pharmaceutical compositions, or in at least five different, separate pharmaceutical compositions, that can be administered in one or more doses in a daily dosage amount (e.g., a single unit dose or multiple unit doses). (ii) optionally a dispenser of one or more of the medicaments; (iii) a sealed package; (iv) a package insert containing prescribing information (e.g., how to use the medicament, dosage and route of administration, benefits and risks of the treatment, citations to medical literature and discussion of clinical studies, any drug interactions or other adverse effects) approved by and / or meeting the requirements of a regulatory agency (e.g., FDA, EMA); (v) a tamper-evident seal; (vi) an expiration date for the medicament; and (vii) optionally packaging. The optional dispenser may be, but is not limited to, a sealed blister pack (e.g., a blister card with capsules or tablets, a blister pouch with cream or ointment, a strip of peelable blister pouches with cream or ointment), a container with sealed ampoules or vials, a sealed container with capsules or tablets (e.g., pill bottle, pill box), or the like. The optional dispenser (e.g., a bottle with a lid) containing multiple unit doses in liquid form may optionally further include a tool (e.g., a dropper, a pipette) for measuring the volume of one or more unit doses. The sealed package may optionally include a dispenser. The description of the kit and its manufacture in the above two paragraphs is incorporated herein by reference.

[0124] In other embodiments, the kit can be a medicament that includes (i) a plurality of compounds as described herein (e.g., a THC compound and a melatonin compound, optionally a polyphenolic compound, such as a curcumin-related compound and a rutin-related compound, optionally a vitamin E-related compound, optionally at least one chemotherapeutic agent, a pharma- ceutical acceptable excipient, optionally a pharma-ceutical acceptable vehicle, and optionally a pharma-ceutical acceptable carrier), formulated as a pharmaceutical composition (e.g., a single unit dose or multiple unit doses) in solid, semi-solid, or liquid form, as described herein. The device is comprised of a plurality of compounds, (ii) optionally a dispenser of one or more compounds or medicaments, (iii) at least one diagnostic reagent (e.g., a set of test assay reagents) and optionally a container for collecting a sample (e.g., biological fluid, tissue), (iv) a sealed package, (v) a package insert containing prescription information for the medicament and, optionally, a package insert for a test assay, including use as a companion diagnostic device, (vi) a tamper-resistant seal, (vii) an expiration date for the medicament and, optionally, an expiration date for at least one diagnostic reagent, and (viii) optional packaging. The plurality of unit doses may be provided in an optional dispenser selected from, but not limited to, a sealed blister pack (e.g., a blister card with capsules or tablets, a blister pouch with a cream or ointment, a strip of peelable blister pouches with a cream or ointment), a container with sealed ampoules or sealed vials, a sealed container with capsules or tablets (e.g., a pill bottle, a pill box), or the like. The sealed package may include an optional dispenser, a container with sealed ampoules or vials, a sealed container with capsules or tablets (e.g., pill bottles, pill boxes), or the like. An optional dispenser (e.g., a bottle with a lid) containing multiple unit doses in liquid form may optionally further include a tool (e.g., a dropper, a pipette) for measuring the volume of one or more unit doses. When the pharmaceutical and diagnostic reagents are fixed in a compartment of the package, they are preferably in separate compartments.The kits and the description of their manufacture incorporated in the paragraphs above are also incorporated herein by reference.

[0125] In kits containing medicaments, the warning or instructions can be provided as printed markings (e.g., letters, numbers, pictograms, or logograms) on the medicament itself or adjacent to an optional compartment that secures the medicament. The warning or instructions can correspond to a dosing schedule, such as the number and / or order of doses to be administered within a given period (e.g., per day), the time of day or day of the week the doses should be administered, and the like. The dosages can be provided in the kit as a single unit dose, multiple unit doses all at once (e.g., a first unit dose containing a THC compound and a second unit dose containing a melatonin compound), or multiple unit doses at different times (e.g., a first unit dose containing a THC compound in the morning and a second unit dose containing a melatonin compound in the evening) for administration within a given period (e.g., every day). All unit doses administered within a 24-hour period can constitute a daily dosage.

[0126] The optional at least one chemotherapeutic agent can be an agent used to treat dementia or Alzheimer's disease (e.g., aducanumab, amantadine, bepranemab, brexpiprazole, bryostatin, colostrinin, donanemab, donepezil, ginkgo extract EGb761, galantamine, gantesnerumab, goslanemab, lanabecestat, lecanemab, leucomethylthioninium, levetiracetam, memantine, methylphenidate, neflamapimod, prasinezumab, rivastigmine, semolinemab, solanezumab, tirabonemab, tramiprosate, tricaprylin, zagotenemab, or any combination thereof). The optional at least one chemotherapeutic agent may be selected from, but is not limited to, an acetylcholinesterase inhibitor, an antibody that binds to β-amyloid, an antibody that binds to tau protein, a β-amyloid aggregation inhibitor, a β-secretase inhibitor, a γ-secretase inhibitor, a kinase inhibitor, a receptor antagonist, a tau phosphorylation inhibitor, a tau protein aggregation inhibitor, or any combination thereof.

[0127] The THC compound and melatonin compound as described herein, optionally two or more polyphenol compounds (e.g., curcumin and rutin, compounds related thereto), optionally vitamin E-related compounds, and optionally at least one chemotherapeutic agent may be provided in two or more separate compartments of the kit. Alternatively, they may be provided together in the same compartment of the kit. Additional items for suitable packaging and use (e.g., pre-measured vehicles and / or carriers for semi-solid or liquid forms, foil packaging to minimize exposure to air and moisture) are known in the art and may be further included in the kit. The kit may include a blister pack containing multiple unit doses as a blister card or a strip of separable blister pouches. The kit may include a container in which multiple unit doses are each in a sealed ampoule or sealed vial, a leak-proof bag or bottle with liquid contents (e.g., colloids, elixirs, hydrogels, tinctures), a sealed container with capsules or tablets (e.g., pill bottle, pill box), or the like. The kit may further comprise at least a THC compound and a melatonin compound as described herein, optionally two or more polyphenol compounds (e.g., curcumin and rutin, and related compounds thereof), optionally a vitamin E related compound, and optionally a dispenser used to administer at least one chemotherapeutic agent. Examples of dispensers include, but are not limited to, dressings and patches, droppers and pipettes, inhalers, insufflators, intravenous (IV) drips, misters and sprayers, nebulizers, suppositories, and vaporizers. The kit may be provided to health care providers (e.g., pharmacists, doctors, nurses) and caregivers.

[0128] A blister card for solid forms (e.g., capsules, tablets) may include a sheet of a rigid but deformable, preferably transparent, material in which recesses formed therein have the size and shape of the solid form to be placed in the recess. The blister card may also include a sheet of a tearable material, preferably coated paper or metal foil. Both sheets have substantially the same size and shape. They are aligned, pressed together, and sealed around the edges of each recess to form the opposing top and bottom surfaces of the blister card such that a single solid form is fixed in each recess. As a result, the solid form is encapsulated in the blister card. Any recess in the first sheet is manually pressed until the recess is flattened and the solid form meets the resistance of the second sheet, which tears the opening in the second sheet and the solid form is removed through the opening without disturbing the solid forms in the other recesses.

[0129] Blister pouches for semi-solid or liquid forms (e.g., colloids, creams, hydrogels, suspensions) may comprise a tearable material, preferably coated paper or metal foil, which may be one of a number of pouches arranged in a strip. For example, each pouch may be filled with a unit dose and then sealed. As a result, a strip of blister pouches may contain a single unit dose of semi-solid or liquid in each blister pouch. Packets in a strip may be separated from the next by tearing through a tear line. Each packet has a cut that can be torn to open the packet. The composition may be delivered by tearing the packet open at the cut, flattening the packet, and releasing the semi-solid or liquid from the opening.

[0130] The kit may further comprise a pharma- ceutically acceptable vehicle and / or a pharma- ceutically acceptable carrier that can be used to administer the THC and melatonin compounds as described herein. For example, when the THC and melatonin compounds as described herein are provided in solid form, they need to be reconstituted with a sterile vehicle and / or a sterile carrier before administration. The kit may further comprise a sealed container into which the THC and melatonin compounds as described herein can be transferred and, optionally, reconstituted with a suitable sterile vehicle for administration. Examples of pharma- ceutically acceptable vehicles include, but are not limited to, water for injection and other aqueous solutions (e.g., sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection). Examples of sealed containers include, but are not limited to, ampoules, bags, blister cards, blister pouches, bottles, pill boxes, and vials.

[0131] The inheritance of genetic markers associated with increased risk of disease can be determined as a step of a method for diagnosis or treatment.The genes of interest include, but are not limited to, APOE, APP, PSEN1, PSEN2, ABCA7, ADAM10, AKAP9, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, CYP2C9, CYP3A4, DSG2, EPHA1, FERMT2, HLA-DRB5-HLA-DRB1, INPP5D, MAPT, MEF2C, MS4A6A / MS4A4E, NME8, PICALM, PLD3, PTK2B, SLC24A4, SORL1, TREM2, UNC5C, ZCWPW1, or any combination thereof.In particular, early-onset Alzheimer's disease can be caused by rare mutations in the above-mentioned genes or other newly discovered genes. Subjects may be selected for treatment by the presence or absence of a genetic mutation that is associated with an increased or decreased risk of developing Alzheimer's disease.

[0132] Testing for target genes, such as but not limited to those listed in the above paragraph, can be preferably performed in an AABB-accredited or CLIA-certified genetic testing laboratory. Genetic testing can be selected from but not limited to detection of mutations or polymorphisms, epigenomics, gene expression, gene profile or genotyping, pharmacogenomics or precision medicine, and transcriptomics, using diagnostic reagents (e.g., CRISPR nuclease and its RNA guide, nucleic acid primers flanking the target region and probes for detecting the target region, nucleic acid polymerase) and equipment (e.g., nucleic acid synthesizers, fluorometers or spectrophotometers, microarray scanners, NGS or DNA sequencing systems, nucleic acid amplifiers, nucleic acid extraction systems). For example, patients suspected of having late-onset disease can be tested for APOE alleles, while patients suspected of having early-onset disease can be tested for APP, PSEN1, or PSEN2 mutations. The presence or absence of APOE4 alleles or mutations in one or more target genes can be used to select patients who are likely to benefit from treatment. Expression of CYP2C9, CYP3A4, CYP2C19, CYP1A1, CYP1A2, or any combination thereof may be tested. The effective amount of THC may be increased or decreased based on the expression of the above-mentioned cytochrome P450 isoenzymes. Gene editing can be used to introduce human mutations associated with increased risk or protection from the development of neurodegenerative diseases or neurological disorders into model organisms to study the effects of the mutations or treatments. In addition to detecting APOE alleles by genotyping, they can also be identified as different protein isoforms.

[0133] Neuropathological testing of central nervous system (CNS) tissues may include, but is not limited to, histopathological examination (e.g., dyes, stains), immunoassays (e.g., analytes or antigens, antibodies), and immunohistochemical examination. Although biological fluids and biopsies from living patients may be examined, many tissues are obtained postmortem at autopsy to confirm clinical diagnosis. The results may guide the treatment of the biopsied patient or future treatment of the patient. Testing may be preferably performed in an AABB-accredited or CLIA-certified neuropathology laboratory. Pathological testing may at least identify, at least localize in tissue, or at least quantify any of, but is not limited to, diffuse or dense core plaques, granulovacuolar degeneration, Hirano bodies, insoluble amyloid fibrils, neuritic plaques, synaptic loss, tau neurofibrillary tangles, tau paired helical fibrils, or any combination thereof. The test assay kit may include a resealable, leak-proof container with a fixative (e.g., formaldehyde) for preserving tissue samples for pathological examination. Staining or dyes (e.g., Bodian protargol, Congo red, Galliasbraak silver, thioflavin), and antibodies that specifically bind to Aβ or tau can be used to visualize amyloid plaques and neurofibrillary tangles. The histological process, staining, and immunohistochemistry may be automated to at least some steps. In parallel, slides with abnormal structures may be analyzed, nucleic acids may be prepared from areas with abnormal structures and controls, and genetic tests may be performed on the nucleic acids. In the test assay kit, at least one or more copies of diagnostic reagents may be selected from, but are not limited to, Bodian protargol stain, Congo red dye, Galliasbraak silver stain, thioflavin T dye, anti-Aβ antibodies, anti-tau antibodies, and a leak-proof container containing a preservative for taking the subject's tissue sample. The efficacy of a treatment to modify the disease and / or disease development can be determined by changes in the histological characteristics of Alzheimer's disease.

[0134] Clinical laboratories may use tests and assays known in the art to at least detect (e.g., presence or absence) or at least measure (e.g., amount, concentration, level) one or more biomarkers in a patient's biological fluid sample (e.g., plasma, serum, whole blood, urine, cerebrospinal fluid or CSF). Ruan et al. (Mol Med Rep, 2016 Oct, 14:3184-3198) and McGrowder et al. (Brain Sci, 2021 Feb, 11:215) are referenced and are incorporated herein by reference for their lists of biomarkers and their use to monitor disease onset and the ability of treatments to mutually modify disease processes. Beta amyloid peptide (Aβ42), phosphorylated tau protein (P-tau), total tau protein (T-tau), neurofibrillary light chain (NfL), ratio of Aβ42 / P-tau, ratio of Aβ42 / T-tau, or ratio of Aβ42 / Aβ40 in blood, urine, or CSF can be assayed. Reduction in the level of at least one or more of, but not limited to, Aβ40 / Aβ42 in plasma, Aβ40, Aβ42, P-tau, T-tau, Aβ42 / P-tau, or Aβ42 / T-tau in CSF can be used as a surrogate biomarker to determine whether the treatment at least delays, stops, or reverses the onset of the disease. Proteins can be at least identified, isolated, quantified, or separated using competition with specific antibodies or, optionally, their cognate antigens, bead or plate immunoassays, high performance liquid chromatography (HPLC), mass spectrometry (MS), or any combination thereof (e.g., HPLC-MS, HPLC-MS / MS). In addition to quantifying biomarkers (e.g., Aβ40, Aβ42, APOE4) by immunoassays, HPLC-tandem MS can be used for quantification. See, for example, West et al. (Mol Neurodegener, 2021 May, 16:30), which is incorporated herein by reference. The effect of treatments that modify disease and / or disease development can be determined by quantifying biomarkers (e.g., Aβ42 / Aβ40), particularly changes therein associated with increased or decreased risk of developing Alzheimer's disease.In the test assay kit, at least one or more copies of a diagnostic reagent may be selected from, but are not limited to, an anti-Aβ antibody, an anti-tau antibody, an anti-NfL antibody, an anti-APOE antibody, or any combination thereof, a leak-proof container for collecting a sample from blood (with or without an anticoagulant), urine, or CSF, a known amount of Aβ40, Aβ42, P-tau, T-tau, NfL, APOE isoforms, or any combination thereof.

[0135] Brain imaging (or scanning) is a radiological testing assay that includes, but is not limited to, computed tomography, magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). Brain atrophy, cerebral amyloid angiopathy, ventricular enlargement, and diffusion tensor imaging of white matter can be seen with structural MRI to monitor neurodegeneration. Synaptic activity in the brain (reduced in disease) can be visualized using PET and fluorodeoxyglucose (FDG), which responds to glucose metabolism (hypometabolism). Of further interest, brain circuitry and brain network activity can be assessed using functional MRI (fMRI), which measures changes in blood oxygen level-dependent (BOLD) contrast at rest. Probes for amyloid (e.g., florbetaben F-18, florbetapir F-18, flutemetamol F-18) and tau (e.g., flortaucipir F-18) can be used with PET to detect amyloid and tau pathology (e.g., cortical amyloid or tau PET). Changes in brain imaging can be used to select patients for treatment (e.g., the absence or presence of changes indicates or is associated with an increased risk of Alzheimer's disease) or disease modification by treatment, using at least one or more copies of diagnostic reagents, such as FDG, PET, and SPECT probes for amyloid and / or tau.

[0136] A test assay kit may include one or more diagnostic reagents (e.g., a set of test assay reagents) for use in one or more test assay steps of a diagnostic method, including, optionally, an enzyme, optionally a plurality of standards for the test assay, optionally at least one or two controls (e.g., positive and / or negative controls that produce or do not produce a signal, respectively, in the test assay), or any combination thereof. Standards may include known amounts of analyte and / or label to at least calibrate, confirm, or verify the ability of the test assay to quantify the analyte. The test assay steps of the diagnostic method may be performed separately from the method of treatment, without administering a pharmaceutical composition or medicament to the subject (i.e., administration of the claimed methods of treatment and the claimed products), and by a person who, to the extent of contacting the subject to obtain a sample therefrom, or by the subject providing the same. The results of the test assay step, or optionally information relating to the sample (or the subject from which the sample was obtained), may be used in an analysis and / or decision step to diagnose the subject, to select the subject for treatment, to determine or evaluate the outcome of the treatment (e.g., reduction, inhibition, worsening, or amelioration of a biomarker), or any combination thereof.

[0137] Formulations for enteral administration The composition for enteral administration may comprise a THC compound and a melatonin compound as described herein, optionally a polyphenol compound, and one or more pharma- ceutically acceptable excipients suitable for enteral administration.In some embodiments, the composition for enteral administration may comprise a therapeutically effective amount of a THC compound and a melatonin compound as described herein, optionally an effective amount of two or more polyphenol compounds, one or more pharma-ceutically acceptable excipients, and optionally a pharma-ceutically acceptable vehicle and / or carrier suitable for enteral administration.Examples of suitable excipients include, but are not limited to, antibacterial agents, antioxidants, emulsifiers, solubilizers, stabilizers, and surfactants.In other embodiments, the composition for enteral administration may further comprise an effective amount of at least one chemotherapeutic agent.

[0138] Compositions for enteral administration include a predetermined amount of two or more compounds as described herein (e.g., a THC compound, a melatonin compound, optionally a polyphenolic compound such as curcumin and rutin, optionally vitamin E and related compounds, and optionally at least one chemotherapeutic agent). These may be provided in the form of individual unit doses, such as, but not limited to, capsules, packets or sachets, chewable candies or gums, disintegrating strips or tabs, lozenges or pastilles, or tablets. A plurality of unit doses may be held in dispensers, such as, but not limited to, sealed blister cards containing medicaments (e.g., capsules, tablets), sealed containers containing medicaments (e.g., chewable candies or gums, disintegrating strips or tabs, lozenges or pastilles), and sealed pill bottles or pill boxes containing medicaments (e.g., capsules, tablets). Other enteral compositions may be provided in solid form (e.g., powder), semi-solid form (e.g., paste, slurry), or liquid form, such as, but not limited to, aerosols, colloids, drops or other orally ingestible solutions, elixirs, mouthwashes or oral rinses, suspensions, tinctures, etc. For enteral administration, the route of administration is usually oral or esophageal, although other routes are possible, provided that the composition is ingested and at least a portion of the compound is adsorbed in the digestive tract.

[0139] The composition can be formulated by conventional process as known in the art.For example, THC compound and melatonin compound as described herein, optionally two or more polyphenol compounds, optionally vitamin E related compound, optionally at least one chemotherapeutic agent, and one or more pharma-ceutically acceptable excipients are mixed together uniformly and intimately in the intermediate state of matter, which can be in solid form (e.g., granules), semi-solid form (e.g., paste, slurry), or liquid form.The composition can further comprise vehicle and / or carrier.Formulation can further comprise mixing with at least vehicle and / or carrier, dispersing in colloidal liquid or suspension, encapsulating in particles, incorporating in micelles or lipid vesicles, solubilizing in emulsion or solution, or any combination thereof.

[0140] If desired, the unfinished compositions can be formulated into unit doses by filling the compounds as described herein into capsules or compressing them into tablets.For example, capsules or tablets can be produced by feeding a free-flowing granule or fine powder (e.g., about 40-200 mesh) containing a mixture of THC compounds and melatonin compounds as described herein, optionally a polyphenol compound, optionally a vitamin E related compound, optionally at least one chemotherapeutic agent, and one or more pharma-ceutically acceptable excipients (e.g., preservatives, disintegrants, diluents or fillers) into an encapsulating machine or tableting machine, respectively, to fill empty capsules or form into tablets. Alternatively, empty capsules (e.g., gelatin or hydroxypropylmethylcellulose shells) can be filled with semi-solid or liquid forms (e.g., alcohol water, glycerol, honey, oil) of compositions comprising THC and melatonin compounds as described herein, optionally polyphenol compounds, optionally vitamin E related compounds, optionally at least one chemotherapeutic agent, and one or more pharma- ceutically acceptable vehicles, carriers, and / or excipients (e.g., preservatives, emulsifiers, diluents, or fillers) by providing a fluid solution, oil, or syrup. Capsule sizes are preferably 000 (1.4 ml), 00 (0.9 ml), or 0 (0.7 ml). Optional excipients can be added to capsules or tablets to chemically stabilize at least THC and melatonin compounds as described herein during formulation and / or to physically stabilize the "finished" composition prior to its delivery and use in treatment. For example, at least a THC compound and a melatonin compound as described herein can be uniformly and intimately admixed with a finely divided solid carrier.

[0141] Capsules can be manufactured in solid or semi-solid form by filling the empty shells with a mixture comprising THC compounds and melatonin compounds as described herein, optionally polyphenolic compounds (e.g., curcumin and rutin, compounds related thereto), optionally vitamin E-related compounds, optionally at least one chemotherapeutic agent, two or more pharma- ceutically acceptable excipients, and optionally pharma-ceutically acceptable carriers in an encapsulation machine. Glidants and lubricants can be used to aid in the manufacturing process. If improved storage or drug delivery is desired, the capsules can be coated with one or more coatings to provide controlled, delayed, or sustained release. Glidants and lubricants can be used to aid in the manufacturing process. Enteral compositions in liquid form can be encapsulated as soft gelatin capsules in semi-solid form. Capsules can include hard or soft shells, shells made of gelatin or hydroxypropylmethylcellulose, enteric coatings, or any combination thereof.

[0142] Tablets can be manufactured in solid form by compressing or molding a composition comprising a THC compound and a melatonin compound as described herein, optionally a polyphenolic compound (e.g., curcumin and rutin, and related compounds), optionally a vitamin E related compound, optionally at least one chemotherapeutic agent, two or more pharma- ceutically acceptable excipients, and optionally a pharma-ceutically acceptable carrier, in a tableting machine. Glidants and lubricants can be used to aid the manufacturing process. Disintegrants (e.g., crospovidone, hydroxypropyl methylcellulose) and solubilizers (e.g., cyclodextrin, polypropylene glycol) can be added to enhance drug delivery. When improved storage or drug delivery is desired, multi-layer tablets and / or multi-coated tablets can be manufactured for controlled, delayed, or sustained release. Matrix tablets or enteric coated tablets can be intended for drug delivery.

[0143] The compounds as described herein can be combined with one or more pharma- ceutically acceptable vehicles, carriers, and / or excipients and then formulated using conventional processes known in the art. Carriers can take a wide variety of forms, depending on the form of the composition desired for administration. When formulating enteral compositions for oral use, any of the usual pharma- ceutical acceptable media can be utilized as vehicles and / or carriers, such as alcohol, emulsions, glycerol, lipid vesicles, micelles, oils, microparticles, or water in the case of enteral compositions in liquid form (e.g., colloids, elixirs, orally ingestible solutions, suspensions, tinctures). Excipients such as cellulose derivatives, microcrystalline or powdered cellulose, pregelatinized starch, starch, sugar, syrups, binders, diluents or fillers, and disintegrants can be used in the case of enteral compositions in solid form. For example, solid forms suitable for enteral administration include, but are not limited to, capsules and tablets. In some embodiments, the solid forms can be coated or uncoated, encapsulated in gelatin or other polymers, or distributed non-uniformly (e.g., embedded in multiple layers, each with different release characteristics, or in a tablet matrix) by conventional processes as known in the art. The capsules or tablets are preferably enteric coated.

[0144] For enteral administration, when colloids, elixirs, orally ingestible solutions, suspensions, tinctures, or the like are desired, the THC and melatonin compounds as described herein can be mixed with, optionally, polyphenol compounds (e.g., curcumin and rutin, and related compounds), optionally vitamin E related compounds, optionally at least one chemotherapeutic agent, optionally vehicles (e.g., ethanol, glycerol, water), optionally carriers (e.g., lipid vesicles, micelles, nanoemulsions, nanoparticles), and excipients (e.g., preservatives, emulsifiers). Enteral compositions in semi-solid form (e.g., pastes, slurries) or liquid form can be encapsulated in soft gelatin capsules.

[0145] The compositions can be formulated for enteral administration by combining a THC compound, a melatonin compound, a curcumin-related compound, a rutin-related compound, a vitamin E-related compound, optionally a pharma- ceutically acceptable vehicle (e.g., alcohol water, alcohol, glycerol, vegetable oil), optionally a pharma- ceutically acceptable carrier (e.g., a nanoemulsion), and pharma- ceutically acceptable excipients, including, but not limited to, preservatives (e.g., ascorbic acid, glycerol, sodium benzoate), emulsifiers (e.g., glycerol, polysorbate 80, propylene glycol), diluents or fillers (e.g., calcium carbonate), colorants (e.g., brown E150, titanium dioxide, yellow E110), flavors (e.g., honey, menthol, sorbitol), and buffers (e.g., sodium citrate). The capsules and tablets can be coated by conventional processes as known in the art to at least enhance bioavailability and stabilize the THC and melatonin compounds as described herein, avoiding degradation in stomach acid and delaying release until passing through the stomach. The capsules can include a shell of cellulose (e.g., hydroxypropylmethylcellulose), gelatin, shellac, or the like. Alternatively, the capsules and tablets can include a coating of cationic polymethacrylate (e.g., Eudragit®), cellulose acetate phthalate (e.g., Aquateric®), polyvinyl acetate phthalate (e.g., Coaterir), glyceryl monostearate, glyceryl distearate, or the like. The coating of the capsule or tablet can be the main determinant of its release characteristics and bioavailability. Preferably, the capsule or tablet includes an enteric coating to deliver the THC and melatonin compounds as described herein to the digestive tract where they are absorbed. They are metabolized by liver enzymes before entering the systemic circulation.

[0146] The preservative may be one or more of an antimicrobial agent, an antioxidant, and a stabilizer. Suitable antimicrobial agents include, but are not limited to, benzalkonium salts, benzoic acid, benzyl alcohol, boric acid, chloroxylenol, ethanol, glycerol, sodium benzoate, and sorbic acid. Suitable antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, β-carotene, monothioglycerol, potassium bisulfite, potassium metabisulfite, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, and tocopherol. Stabilizers include, but are not limited to, cellulose, citric acid, cyclodextrin, disodium edetate, ethylenediaminetetraacetic acid, polyethylene glycol, polyols, propylene glycol, starch, and trehalose.

[0147] Emulsifiers can be used to form the composition.Suitable emulsifiers are selected from, but not limited to, hydrophilic surfactants and lipophilic surfactants.A mixture of hydrophilic surfactants can be utilized, a mixture of lipophilic surfactants can be utilized, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant can be utilized.Hydrophilic surfactants can be ionic or non-ionic.

[0148] Suitable ionic surfactants include, but are not limited to, acylactylates, alkyl ammonium salts, alkyl sulfate salts, carnitine fatty acid ester salts, citrate esters of mono- and di-glycerides, fatty acid salts and fatty acid derivatives of amino acids, oligopeptides, and polypeptides, fusidate salts and glyceride derivatives of amino acids, oligopeptides, and polypeptides, lactyl esters of fatty acids, lysophospholipids and derivatives thereof, mono- and di-acetyltartaric acid esters of mono- and di-glycerides, phospholipids and derivatives thereof, and succinylated mono- and di-glycerides. In particular, the ionic surfactant may be cholyl sarcosine, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, or a salt thereof, caprate, caproate, caprylate, laurate, linoleate, myristate, oleate, palmitate, or a salt thereof, PEG- or PVP-phosphatidylethanolamine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, or lysophosphatidylserine, sodium docusate, and stearoyl-2-lactylate or stearoyl lactylate.

[0149] Hydrophilic nonionic surfactants include polyethylene glycol alkyl ethers, polyethylene glycol alkyl phenols, polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, polyethylene glycol glycerin fatty acid esters, polyglycerin fatty acid esters (e.g., polyglyceryl-3 oleate, polyglyceryl-10 laurate, polyglyceryl-10 oleate), polyethylene glycols (e.g., PEG 200, PEG 400, PEG 600, PEG 1000), polyoxyethylated vitamins (e.g., α-tocopherol P EG1000 succinate), polyoxyethylene sterols, polyoxyethylene-polyoxypropylene block copolymers (e.g., poloxamer 188, poloxamer 238), polyethylene glycol sorbitan fatty acid esters, polysorbates (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80), sorbitan fatty acid esters (e.g., sorbitan monolaurate, sorbitan monooleate), sucrose monostearate, sucrose monolaurate, and sucrose monopalmitate.

[0150] Suitable lipophilic surfactants include, but are not limited to, fatty alcohols, glycerol fatty acid esters, acetyl glycerol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and their derivatives, polyoxyethylated sterols and their derivatives, polyethylene glycol alkyl ethers, and oil-soluble vitamins and their derivatives.Other examples of lipophilic surfactants include, but are not limited to, glycerol fatty acid esters, propylene glycol fatty acid esters, and the hydrophobic transesterification products of polyols and vegetable oils or triglycerides (e.g., Cremophor® or Kolliphor®).

[0151] Binder can be used to formulate solid form composition by binding different components together.The examples of suitable excipients that can be used as binder include, but are not limited to, alginate, alginic acid, carrageenan, cellulose and its derivatives (carboxymethylcellulose, cellulose acetate, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, powdered cellulose, microcrystalline cellulose), cross-linked polyvinylpyrrolidone, gelatin, guar gum, gum tragacanth, polyvinylpyrrolidone, pregelatinized starch, starch, and xanthum gum.

[0152] Diluent or filler can be used to formulate the solid form composition to obtain appropriate size.This excipient can be considered as a filler, since it increases a small amount of therapeutically active compound during formulation and mainly contributes to the volume of the finished unit dose.The examples of suitable excipients that can be used as diluent or filler include, but are not limited to, aluminum silicate, calcium carbonate, calcium hydrogen phosphate dihydrate, dextrate, lactose, magnesium silicate, magnesium stearate, mannitol, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sorbitol, sucrose, and starch.

[0153] Disintegrants can be used to promote the disintegration of solid forms of the composition (e.g., capsules, tablets) when exposed to the digestive tract. Too much disintegrant can create a fragile solid form during transportation, while too little can be insufficient to cause disintegration. Thus, using an amount of disintegrant outside the working range can change the release rate and extent of one or more of the compounds as described herein. Assuming that enteral administration is oral administration, the amount of disintegrant is sufficient to allow the production of solid forms of the composition and to be substantially digestible, which may depend on the chemical nature of other excipients and any coatings. Examples of suitable excipients that can be used as disintegrants include, but are not limited to, alginic acid, calcium carbonate, calcium hydrogen phosphate dihydrate, carboxymethylcellulose, cross-linked polyvinylpyrrolidone, guar gum, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, polyvinylpyrrolidone, sodium starch glycolate, and starch.

[0154] Glidants and lubricants are used during the manufacture of solid forms of compositions (e.g., capsules, tablets) to facilitate the flow of anhydrous or low moisture ingredients in machines or to prevent capsules and tablets from sticking to the machine surfaces, respectively. Glidants reduce friction between particles to smooth and even the filling of empty shells (where the contents are then sealed to form capsules) and die cavities (where the contents are then compressed to form tablets). Suitable lubricants can be selected from, but are not limited to, ascorbyl palmitate, ascorbyl stearate, calcium palmitate, colloidal silica, magnesium carbonate, magnesium silicate, magnesium stearate, starch, and talc. Lubricants reduce friction between newly manufactured capsules and tablets and the machine surfaces to facilitate the removal of the capsules and tablets from where they are held in the machine. Suitable lubricants can be selected from, but are not limited to, calcium stearate, glyceryl behenate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, stearic acid, and zinc stearate. Glidants and lubricants, along with anti-adherent excipients, may be considered lubricating substances. Generally, glidants and lubricants are only used in small amounts in the manufacture of solid forms of the composition and may not carry over to the final product.

[0155] The composition may include a solubilizer to ensure proper dispersion and dissolution of two or more compounds as described herein (e.g., THC compound, melatonin compound, polyphenolic compounds such as curcumin and rutin, vitamin E and related compounds, at least one chemotherapeutic agent) and minimize precipitation of any compound. This may be particularly important in compositions for parenteral use (e.g., compositions for injection). Solubilizers may also be added to increase the solubility of hydrophilic compounds and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution.

[0156] Suitable solubilizers may be selected from alcohols and polyols (e.g., benzyl alcohol, cyclodextrin, diethylene glycol monoethyl ether, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, propylene glycol), amides and other nitrogen-containing compounds (e.g., N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, 2-pyrrolidone, 2-piperidone, polyvinylpyrrolidone), and esters (e.g., acetyl tributyl citrate, acetyl triethyl citrate, β-butyrolactone, δ-valerolactone, ethyl butyrate, ethyl caprylate, ethyl oleate, ethyl propionate, glycerol triacetate, N-2-hydroxyethyl-2-pyrrolidone, N-methyl-2-pyrrolidone, propylene glycol diacetate, propylene glycol monoacetate, tributyl citrate, triethyl citrate). Further examples of suitable solubilizers include, but are not limited to, benzyl alcohol, diethylene glycol monoethyl ether, glycerol, glycerol triacetate, PEG400, polysorbate 80, and propylene glycol.The amount of suitable solubilizer can be easily ascertained by those skilled in the art.In some situations, it may be advantageous to include solubilizer in an amount far greater than pharma- ceutically acceptable, for example, to maximize the concentration of drug, and excess solubilizer is removed before providing the composition to subject by using conventional processes (e.g., distillation, evaporation) as known in the art.

[0157] Solvents for hydrophobic compounds include, but are not limited to, alcohol, fatty acid ester, fatty alcohol, glycerol, mineral oil, silicone oil, and vegetable oil.Vegetable oils are made from plants, for example, but are not limited to, avocado, babassu, cacao, candlenut, castor, coconut, corn, hazelnut, macadamia, olive, palm, palm kernel, peanut, rapeseed, rice bran, safflower, sesame, soybean, sunflower, sweet almond, walnut, wheat germ, etc.Carnauba wax, cacao butter, jojoba wax, mango butter, paraffin wax, shea butter, silicone wax, soybean wax, stearyl alcohol, and white petrolatum can be used to formulate ointments, suspensions, and the like.

[0158] Additionally, bases and / or acids can be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharma-ceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)-aminomethane, and the like. Other suitable bases are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid. Also usable are salts of polybasic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. When the base is a salt, its cation can be any pharmaceutically acceptable cation, such as ammonium, an alkali metal (e.g., lithium, potassium, sodium), or an alkaline earth metal (e.g., calcium, magnesium).

[0159] The acid may be an organic acid or an inorganic acid. Examples of pharmaceutically acceptable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of pharmaceutically acceptable organic acids include, for example, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like.

[0160] Formulations for parenteral administration Compositions for parenteral administration may include THC compounds and melatonin compounds as described herein, optionally polyphenol compounds, optionally vitamin E-related compounds, and one or more pharma- ceutically acceptable excipients suitable for parenteral administration. In some embodiments, compositions for parenteral administration may include a therapeutically effective amount of THC compounds and melatonin compounds as described herein, optionally an effective amount of two or more polyphenol compounds, optionally an effective amount of vitamin E-related compounds, and one or more pharma- ceutically acceptable vehicles, carriers, and / or excipients suitable for parenteral administration. Examples of excipients include, but are not limited to, preservatives (e.g., antibacterial agents, antioxidants, stabilizers), emulsifiers, solubilizers, and surfactants. In other embodiments, compositions for parenteral administration may further include an effective amount of at least one chemotherapeutic agent.

[0161] Liquid form parenteral composition (e.g. infusion or injection) can be administered by infusion or injection.When parenteral composition is in solid form, it can be reconstituted under aseptic conditions with a preferably sterile, pharma- ceutically acceptable vehicle as aerosol, colloid, cream, foam or mousse, hydrogel, solution or suspension.Excipients such as emulsifiers, solubilizers, surfactants, antifoaming agents, and wetting agents can be included when formulating parenteral compositions.

[0162] The composition may comprise at least one surfactant selected from polysorbates, sorbitan esters, polyoxyl stearates, and polyoxyethylene-polyoxypropylene block copolymers.Surfactants also include polyoxyethylene esters of sorbitan fatty acids (e.g., PEG sorbitan monooleate) and polyoxyethylated vitamins (e.g., α-tocopherol PEG1000 succinate), sorbitan fatty acid esters (e.g., sorbitan monooleate), or any combination thereof.Other suitable excipients (e.g., preservatives, antimicrobial agents, antioxidants, stabilizers, emulsifiers, solubilizers, surfactants, diluents, or fillers) are as described above for enteral compositions.These excipients and their descriptions are incorporated herein by reference.

[0163] Pharmaceutically acceptable vehicles for parenteral administration can be sterile aqueous solutions such as Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection, although other saline or buffered isotonic solutions may also be suitable. Parenteral compositions may contain excipients such as, but not limited to, albumin, gelatin, cellulose and its derivatives (e.g., carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, microcrystalline cellulose, powdered cellulose), buffers (e.g., sodium acetate, sodium citrate, sodium phosphate), isotonicity agents (e.g., dextrose, potassium salts, sodium salts), polyols (e.g., cross-linked polyacrylates, glycerol, polyethylene glycol, polypropylene glycol, ... , sodium polyacrylate), polysaccharides (e.g., chitosan, chondroitin sulfate, hyaluronic acid, lactose, maltose, mannitol, sodium hyaluronate, sorbitol, trehalose), polyvinyls (e.g., carboxyvinyl polymers, cross-linked polyvinylpyrrolidone, polyvinyl alcohol, polyvinylpyrrolidone), preservatives (e.g., benzalkonium chloride, benzethonium chloride, benzyl alcohol, chloroxylenol, ethanol, sodium benzoate), emulsifiers (e.g., glycerol, polysorbate 80, propylene glycol), or any combination thereof.

[0164] Parenteral compositions may be provided as single unit doses in ampoules, blister pouches, dropper bottles, vials, or the like, each containing a predetermined amount of two, three, four, five, six, or more compounds as described herein (e.g., a THC compound, a melatonin compound, a polyphenolic compound such as curcumin and rutin, vitamin E and related compounds, at least one chemotherapeutic agent). Alternatively, parenteral compositions comprising two or more compounds as described herein (e.g., a THC compound, a melatonin compound, optionally a polyphenolic compound such as curcumin and rutin, optionally vitamin E and compounds related thereto, and optionally at least one chemotherapeutic agent) can be formulated into semi-solid or liquid forms, such as, but not limited to, aerosols, colloids, creams, foams or mousses, hydrogels, solutions, and suspensions. Parenteral compositions can be dispersed in colloidal liquids or suspensions, encapsulated in particles, incorporated into micelles or lipid vesicles, or solubilized in emulsions or solutions. Formulation can further include mixing with at least a vehicle and / or carrier, dispersion in colloidal liquids or suspensions, encapsulation in particles, incorporation into micelles or lipid vesicles, solubilization in emulsions or solutions, or any combination thereof.

[0165] The route of parenteral administration may be mucosal (e.g., oral, nasopharyngeal, sublabial, sublingual), pulmonary (e.g., inhalation, insufflation, drops), or any combination thereof. A plurality of unit doses may be held in a dispenser, such as, but not limited to, a sealed ampoule or sealed vial containing a medicament (e.g., an injection solution), a sealed bag or bottle containing a medicament (e.g., a colloid, drops, infusion solution, suspension), and a sealed tub or tube containing a medicament. Parenteral administration may be performed by a dispenser, such as, but not limited to, an inhaler, an insufflator, an atomizer or sprayer, a nebulizer, and a vaporizer.

[0166] Formulations for pulmonary administration The composition for pulmonary administration may comprise a THC compound and a melatonin compound as described herein, optionally a polyphenol compound, optionally a vitamin E-related compound, optionally at least one chemotherapeutic agent, and one or more pharmaceutically acceptable excipients suitable for pulmonary administration. In some embodiments, the pulmonary composition may comprise a therapeutically effective amount of a THC compound and a melatonin compound as described herein, optionally an effective amount of two or more polyphenol compounds, such as curcumin and rutin, vitamin E, and related compounds, optionally an effective amount of at least one chemotherapeutic agent, and one or more pharmaceutically acceptable vehicles, carriers, and / or excipients suitable for pulmonary administration. Examples of excipients include, but are not limited to, preservatives, antimicrobial agents, antioxidants, and stabilizers, as well as emulsifiers, solubilizers, and surfactants. Other suitable excipients are as described above for enteral and parenteral compositions. These excipients and their descriptions are incorporated herein by reference.

[0167] Pulmonary compositions may be in solid form (e.g., granules) or liquid form. If in solid form, they may or may not be reconstituted as a liquid before administration. In some embodiments, they may be aerosols, colloids, droplets, or suspensions in which the THC and melatonin compounds as described herein are formulated (e.g., dissolved, dispersed, emulsified, encapsulated, suspended) in a pharma- ceutically acceptable vehicle (e.g., aqueous solution, organic solvent). Compositions in liquid form, or as a solution reconstituted from a solid form with a sterile vehicle, may further comprise a pharma- ceutically acceptable carrier selected from emulsions (e.g., nanoemulsions), micelles or lipid vesicles, porous or solid particles (e.g., nanoparticles), or any combination thereof. Pulmonary compositions may be administered by inhalation or insufflation via the oral or nasal route for systemic effect.

[0168] Pulmonary administration of the composition may be inhalation or insufflation through the mouth and / or nose. In particular, a delivery device can be used to generate aerosol from an inhaler, mist or sprayer, nebulizer, or vaporizer. The "finished" composition can be provided in solid form (e.g., granules) or liquid form, which is aerosolized during pulmonary administration so that aerosol particles or droplets are administered to the mouth and / or nose, respectively. The goal of pulmonary administration is to deliver the composition from the upper to the lower respiratory tract so that the THC compound and melatonin compound as described herein, optionally a polyphenol compound, optionally a vitamin E related compound, two or more pharma- ceutically acceptable excipients, optionally at least one chemotherapeutic agent, and optionally a vehicle and / or carrier, are absorbed by the alveolar epithelium for the unique physiological benefits of the lung. Alternatively, liquid compositions can be delivered more efficiently by instilling the composition directly into the trachea. Pulmonary administration can provide local effect in the lungs or systemic effect by absorption directly into the circulation via the respiratory mucosa, bypassing first-pass hepatic metabolism.

[0169] Formulations for controlled release administration Compositions for controlled release administration (e.g., delayed, sustained, sustained) may include a THC compound and a melatonin compound as described herein, optionally a polyphenol compound, optionally a vitamin E related compound, and one or more pharma- ceutically acceptable excipients suitable for controlled release administration. In some embodiments, compositions for controlled release may include a therapeutically effective amount of a THC compound and a melatonin compound as described herein, optionally an effective amount of two or more polyphenol compounds, optionally an effective amount of a vitamin E related compound, and one or more pharma- ceutically acceptable vehicles, carriers, or excipients suitable for controlled release administration. Examples of excipients include, but are not limited to, preservatives, antimicrobials, antioxidants, and stabilizers, as well as emulsifiers, solubilizers, and surfactants. In other embodiments, the compositions for controlled release administration may further comprise an effective amount of at least one chemotherapeutic agent, which may be an agent used to treat dementia or Alzheimer's disease (e.g., aducanumab, amantadine, bepranemab, brexpiprazole, bryostatin, colostrinin, donanemab, donepezil, ginkgo biloba extract EGb761, galantamine, gantesnerumab, goslanemab, lanabecestat, lecanemab, leucomethylthioninium, levetiracetam, memantine, methylphenidate, neflamapimod, prasinezumab, rivastigmine, semolinemab, solanezumab, tirabonemab, tramiprosate, tricaprylin, zagotenemab, or any combination thereof). This may be selected from, but is not limited to, acetylcholinesterase inhibitors, antibodies that bind to β-amyloid, antibodies that bind to tau protein, β-amyloid aggregation inhibitors, β-secretase inhibitors, γ-secretase inhibitors, kinase inhibitors, receptor antagonists, tau phosphorylation inhibitors, and tau protein aggregation inhibitors, which may have a systemic effect.

[0170] The controlled release composition may be administered by delayed, sustained, extended or other controlled release using carriers such as, but not limited to, emulsions, micelles or lipid vesicles, nanoemulsions, nanoparticles, solid or porous particles, or other conventional means for controlled release as known in the art (e.g., enteric coating of a solid form of the composition). Absorption of infused or injected compositions may be controlled by including excipients that delay absorption. Controlled release may use a dispenser, such as, for example, an infusion pump. Suitable controlled release formulations, including those described herein, are known in the art to provide the desired release profile of the compound by using unit doses suitable for enteral administration, such as, but not limited to, capsules and tablets adapted for controlled release by coating or multilayer structure.

[0171] A controlled release composition may improve treatment over that obtained by a non-controlled release composition. In some embodiments, the use of a controlled release formulation in treatment is characterized in that a minimum amount of the THC compound and melatonin compound as described herein is administered to treat a neurodegenerative disease or neurological disorder in a minimum time. The advantages of a controlled release composition include at least an increase in the bioactivity or bioavailability of the compound, a reduction in the frequency of administration, or an improvement in patient compliance with the treatment protocol. In addition, a controlled release composition may be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus affect the occurrence of adverse side effects.

[0172] The controlled release composition can be designed to initially release an effective amount of a compound as described herein (e.g., THC compound, melatonin compound, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E and related compounds, and optionally at least one chemotherapeutic agent) that immediately produces at least the desired therapeutic, preventative, preventative, palliative, or other beneficial effect in a loading phase, and gradually release a lower amount of the compound as described herein to maintain this level of beneficial effect over time in a maintenance phase. To maintain effective levels of the THC compound and melatonin compound as described herein, optionally polyphenolic compounds, optionally vitamin E related compounds, and optionally at least one chemotherapeutic agent in the body, they can be released at a rate that can replace the amount metabolized and excreted from the body. The controlled release of the compound as described herein can be altered by various conditions, including but not limited to pH, salt, temperature, and other physiological conditions. For example, enteric capsules or tablets have a polymeric coating that degrades in response to the pH of the digestive tract. Alternatively, rather than enteric coated capsules, the capsule shell itself may be made from an enteric material, or the capsule contents may be particulate, with the particles having an enteric coating.

[0173] The composition can be administered using an infusion pump, a transdermal patch with a penetration enhancer, a nanoemulsion, a polymeric or metal nanoparticle, a micelle or lipid vesicle, or other means for controlled release administration. See Pons-Faudoa et al., Biomed Microdevices, May 2019, 21:47; Rahnfeid and Luciani, Pharmaceutics, June 2020, 12:0567; Nkanga et al., Adv Drug Deliv Rev, December 2020, 167:19-46. In other embodiments, an implantable polymeric material or an injectable depot can be placed at the appropriate site of the subject to deliver the composition. The THC and melatonin compounds as described herein can diffuse out of the solid matrix and enter the systemic circulation in a controlled release step.

[0174] Also, reduced degradation and / or increased intestinal absorption of compounds as described herein (e.g., THC compounds, melatonin compounds, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E and compounds related thereto, optionally at least one chemotherapeutic agent) can be obtained by encapsulating them in fat vesicles. In the size distribution within the population, 90% or more of the fat vesicles may or may not have a diameter less than 500 nm (e.g., more than 50% may have a diameter between about 10 nm and about 300 nm, or more than 50% may have a diameter between about 50 nm and about 200 nm). The fat vesicles can be coated or stabilized.

[0175] Lipid vesicles are used for drug delivery due to the properties of their lipid bilayer. Dissolved hydrophilic solutes cannot easily pass through lipids. Hydrophobic chemicals can be dissolved in the lipid bilayer, and thus lipid vesicles can carry both hydrophobic and hydrophilic molecules. To deliver THC and melatonin compounds as described herein to body sites, lipid bilayers can fuse with cell membranes to deliver the contents of lipid vesicles. By preparing lipid vesicles in a solution containing THC and melatonin compounds as described herein, they can be delivered to cells lining the digestive system.

[0176] Lipid vesicles can also be designed to deliver compounds as described herein in other ways. Because the pH is neutral within lipid vesicles (protons can pass through the lipid bilayer), compounds can be neutralized and can freely pass through the lipid bilayer. These lipid vesicles act to deliver compounds as described herein by diffusion rather than direct fusion. Another strategy for drug delivery is to target endocytosis events. Lipid vesicles can be made in a specific size range that is a viable target for natural phagocytosis by macrophages. These lipid vesicles can be digested while inside the phagosome of the cell, releasing THC and / or melatonin compounds as described herein. Lipid vesicles can also be decorated with opsonins and ligands to activate endocytosis in other cell types.

[0177] The lipid vesicles may be prepared using conventional processes as known in the art. The lipid vesicles may be prepared by dissolving lipids in a solvent in a container. The container may have a volume of more than 10 times the volume of the expected suspension of lipid vesicles. The solvent is removed using a rotary evaporator under negative pressure at about 40° C. The solvent is usually removed within about 5 minutes to 2 hours, depending on the desired volume of lipid vesicles. The composition may be further dried under vacuum in a desiccator. The dried lipid may be hydrated at about 25 mM to 50 mM phospholipid in sterile pyrogen-free water by shaking until the lipid film is substantially resuspended. The lipid vesicles in the aqueous solution may then be divided into aliquots, each of which may be placed in a vial, lyophilized, and sealed under vacuum.

[0178] Micelles and lipid vesicles are in contact with aqueous solutions on both sides of their phospholipid bilayer, so that their amphiphilic phospholipids have their hydrophobic tails facing each other and their hydrophilic polar heads in contact with water. The lipids can be selected from sterol lipids, fatty acids, fatty alcohols, glycerolipids (e.g., monoglycerides, diglycerides, and triglycerides), phospholipids, glycerophospholipids, sphingolipids, prenol lipids, glycolipids, polyketides, or any combination thereof. The lipids can be polyunsaturated fatty acids or alcohols. The terms polyunsaturated fatty acids and polyunsaturated fatty alcohols refer to fatty acids or alcohols, respectively, that have two or more carbon-carbon double bonds in the hydrocarbon chain. The lipids can also be highly unsaturated fatty acids or alcohols. The terms highly polyunsaturated fatty acids and highly polyunsaturated fatty alcohols refer to fatty acids or alcohols, respectively, that have at least 18 carbon atoms and at least three double bonds. The lipids or phospholipids can be conjugated with polyethylene glycol (PEG). The lipid moiety of the PEG conjugate can be a diacylglycerol, a dialkylamine, a dialkylglycerol, phosphatidic acid, or a phosphatidylethanolamine.

[0179] Specific examples of lipids include 1,3-propanediol dicaprylate / dicaprate, 10-undecenoic acid, 1-dotriacontanol, 1-heptacosanol, 1-nonacosanol, 2-ethylhexanol, androstane, arachidic acid, arachidonic acid, arachidyl alcohol, behenic acid, behenyl alcohol, capric acid, capric alcohol, capryl alcohol, caprylic acid, saturated fatty alcohol C 12 -C 18Caprylic / Capric Acid Ester, Caprylic / Capric Triglyceride, Caprylic / Capric Triglyceride, Ceramide Phosphorylcholine, Ceramide Phosphorylethanolamine, Ceramide Phosphorylglycerol, Ceroplastinic Acid, Cerotic Acid, Ceryl Alcohol, Cetearyl Alcohol, Cetyl Alcohol, Cholane, Cholestane, Cholesterol, cis-11-Eicosenoic Acid, cis-11-Octadecenoic Acid, cis-13-Docosenoic Acid, Docosahexaenoic Acid, Eicosapentaenoic Acid, Eicosenoic Acid, Elaid ... Drinolenyl Alcohol, Elaidolinoleyl Alcohol, Elaidyl Alcohol, Erucic Acid, Erucyl Alcohol, Estran, Distearate, Gedetic Acid, Gedyl Alcohol, Glycerol Tricaprylate / Caprate, Glycerol Tricaprylate / Caprate, Glyceryl Monocaprylate, Glyceryl Triacetate, Glyceryl Tricaprylate, Glyceryl Tricaprylate / Caprate / Glyceryl Laurate, Glyceryl Tricaprylate / Glyceryl Tricaprate, Glyceryl Tripalmitate, Henatea Triacylcos ... Heptacosyl alcohol, henicosyl acid, heptacosyl acid, heptadecanoic acid, heptadecyl alcohol, hexatriacontylic acid, isostearic acid, isostearyl alcohol, russellic acid, lauric acid, lauryl alcohol, lignoceric acid, lignoceryl alcohol, linoelaidic acid, linoleic acid, linolenyl alcohol, linoleyl alcohol, margaric acid, melissic acid, melissyl alcohol, montanic acid, montanyl alcohol, myricyl alcohol, myristic acid, myristoleic acid, myristyl alcohol, neodecane Acid, Neoheptanoic Acid, Neonanoic Acid, Nervonic Acid, Nonacosylic Acid, Nonadecylic Alcohol, Nonadecylic Acid, Nonadecylic Acid, Oleic Acid, Oleyl Alcohol, Palmitic Acid, Palmitoleic Acid, Palmitoleic Alcohol, Pelargonic Acid, Pentacosylic Acid, Pentadecyl Alcohol, Pentadecylic Acid, Phosphatidic Acid, Phosphatidylcholine, Phosphatidylethanolamine, Phosphatidylglycerol, Phosphatidylserine, Polyglyceryl-6-distearate, Pregnane, Propylene Glycol Dicaprate,Examples of suitable oleic acid include, but are not limited to, propylene glycol dicaprylocaprate, propylene glycol dicaprylocaprate, psyllic acid, recinoleaic acid, recinoleyl alcohol, sapienic acid, stearic acid, stearidonic acid, stearyl alcohol, tricosylic acid, tridecyl alcohol, tridecylic acid, undecyl alcohol, undecylenic acid, undecylic acid, alpha-linolenic acid, gamma-linolenic acid, or any combination thereof.

[0180] Specific examples of phospholipids include phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, lysophosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidylserine, sphingomyelin, dimyristoylphosphatidylglycerol, dimyristoylphosphatidylcholine, dimyristoylphosphatidylethanolamine, dimyristoylphosphatidylserine, dioleoylphosphatidylglycerol, including, but not limited to, dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, dioleoylphosphatidylserine, dipalmitoylphosphatidylglycerol, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, distearoylphosphatidylglycerol, distearoylphosphatidylcholine, distearoylphosphatidylethanolamine, palmitoyloleoylphosphatidylcholine, stearoylpalmitoylphosphatidylcholine, or any combination thereof.

[0181] Combination Therapy THC compound and melatonin compound as described herein can be administered in combination with one or more other treatments or therapies.For example, a method for combination therapy is provided herein, in which at least one chemotherapeutic agent known to regulate at least signaling pathways other than those related to cannabinoid receptors and melatonin receptors, or even components of cannabinoid or melatonin signaling pathways, is used in combination therapy with THC compound and melatonin compound as described herein, or pharmacologic acceptable forms of either compound or both compounds (e.g., one or more pharmacologic acceptable salts of THC compound and / or melatonin compound as described herein, one or more pharmacologic acceptable solvates of THC compound and / or melatonin compound, such as hydrates of THC compound and / or melatonin compound, one or more pharmacologic acceptable isomers of THC compound and / or melatonin compound, one or more pharmacologic acceptable prodrugs of THC compound and / or melatonin compound). The systems and protocols of the present invention include, but are not limited to, the use of combinations of THC and melatonin compounds (and optionally polyphenolic compounds) as described herein with at least one chemotherapeutic agent (including, but not limited to, small molecule drugs, antibodies, other biologics) to provide at least a therapeutic, prophylactic, preventative, palliative, or other therapeutic effect.

[0182] The terms "combination therapy" and "administration of a combination" are used interchangeably. They include administering to a subject in need of treatment at least THC compounds and melatonin compounds as described herein, optionally polyphenolic compounds (e.g., curcumin and rutin, compounds related thereto), optionally vitamin E-related compounds, and at least one chemotherapeutic agent, either together, simultaneously, not simultaneously, or sequentially. THC compounds and melatonin compounds as described herein, and at least one chemotherapeutic agent are therapeutically active compounds. Polyphenolic compounds and vitamin E-related compounds may also be considered therapeutically active compounds, but do not necessarily function effectively in such capacity. In certain embodiments, combination therapy includes administering to a subject in need of treatment therapeutically active compounds in at least two, three, or four separate compositions, administering them at two, three, or four different times in two, three, or four separate compositions, or administering them at two, three, or four different times, each at least one or two hours apart.

[0183] "In combination" is not intended to mean that at least one chemotherapeutic agent must be administered simultaneously with the THC compound and melatonin compound as described herein and / or formulated for delivery with the THC compound and melatonin compound as described herein, although these methods of delivery are within the scope of combination therapy. The THC compound and melatonin compound as described herein can be administered simultaneously with, before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, or 12 hours) other treatments with one or more additional chemotherapeutic agents. In general, each chemotherapeutic agent can be administered at a daily dosage and dosing schedule determined for that particular chemotherapeutic agent prior to treatment. The at least one chemotherapeutic agent can be administered separately with the THC compound and melatonin compound as described herein in the same composition or in a different composition.

[0184] In general, it is expected that any additional chemotherapeutic agents used in combination with the protocols as described herein will be utilized at levels that do not exceed the levels utilized by themselves. In some embodiments, the levels utilized in combination may be lower than those utilized by themselves.

[0185] In other embodiments, the composition for treating a disease comprises a therapeutically effective amount of at least one chemotherapeutic agent used to treat dementia or Alzheimer's disease (e.g., aducanumab, amantadine, bepraneumab, brexpiprazole, bryostatin, colostrinin, donanemab, donepezil, ginkgo biloba extract EGb761, galantamine, gantesnerumab, goslanemab, lanabecestat, lecanemab, leucomethylthiouracil, leucine ... The therapeutically effective amount of THC compounds and melatonin compounds as described herein may be combined with THC compounds such as ninium, levetiracetam, memantine, methylphenidate, neflamapimod, prasinezumab, rivastigmine, semolinemab, solanezumab, tirabonemab, tramiprosate, tricaprylin, zagotenemab, or any combination thereof, or their pharmaceutically acceptable forms (e.g., salts, solvates, hydrates, solvates or salts of hydrates). Alternative chemotherapeutic agents are any of the chemical and biological compounds known in the art for off-label use or approved by medical regulatory authorities for treatment, for treating dementia, Alzheimer's disease, depression, anxiety disorder, panic disorder, or sleep disorder. Chemotherapeutic agents may or may not be used in combination with THC compounds and melatonin compounds as described herein.

[0186] At least one chemotherapeutic agent can be combined with two or more compounds as described herein (e.g., THC compounds, melatonin compounds, optionally polyphenolic compounds such as curcumin and rutin, optionally vitamin E, and compounds related thereto). The chemotherapeutic agent can be selected from one or more of antidepressants, antipsychotics, mood stabilizers, selective serotonin reuptake inhibitors, serotonin / norepinephrine reuptake inhibitors, and anti-anxiety agents. For example, the chemotherapeutic agent can be selected from, but is not limited to, selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, fluvoxamine, sertaline, vortioxetine), serotonin / norepinephrine reuptake inhibitors (e.g., desvenlafaxine, duloxetine, levomilnacipran, venlafaxine), antidepressants (e.g., mirtazapine, trazodone), mood stabilizers (e.g., camlafaxine, cefotaxime ... The chemotherapeutic agent may be selected from THC compounds and melatonin compounds as described herein, such as levamazepine, gabapentin, lamotrigine, oxcarbazepine, topiramate, valproic acid, antipsychotics (e.g., aripiprazole, haloperidol, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), anxiolytics (e.g., buspirone, gepirone, ipsapirone, tandospirone), and orexin receptor antagonists (e.g., lemborexant, suvorexant). Chemotherapeutic agents may or may not be used in combination with the THC compounds and melatonin compounds as described herein.

[0187] We demonstrate below that administration of THC and melatonin in intermediate doses improves certain symptoms of neurological disorders. EXAMPLES

[0188] Non-limiting examples According to npiTEST.net, the Neuropsychiatric Inventory (NPI) is the most widely used assessment criterion in clinical trials of drugs to treat dementia. Patient behaviors related to dementia and Alzheimer's disease can be assessed by NPI and similar tests, and changes can be quantified using these assessment scales. In clinical trials, the NPI was employed to evaluate the efficacy of anti-dementia drug treatments by their ability to improve Alzheimer's symptoms in the behavioral domain, which are 10 neuropsychiatric symptoms (i.e., delusions, hallucinations, agitation / aggression, depression, anxiety, elation / euphoria, apathy, disinhibition, irritability, and abnormal motor behavior) and two autonomic symptoms (i.e., sleep disorder and appetite / eating disorder).

[0189] Cummings states that the NPI provides a comprehensive assessment of psychopathology in patients with dementia. Neuropsychiatric disorders can be diagnosed from characteristic symptoms, such as behavioral changes, and specific NPI profiles. The reliability, reproducibility, and validity of the NPI for assessing behavioral symptoms indicative of dementia and Alzheimer's disease have been independently confirmed. There is no cut-off score that indicates an abnormal NPI.

[0190] The Neuropsychiatric Inventory-Questionnaire (NPI-Q), adapted from the Neuropsychiatric Inventory, provides a brief assessment of the patient through an interview with an informant who cares for the patient and is familiar with his or her behavior during the past month. The NPI-Q includes questions about Alzheimer's symptoms in the 12 behavioral domains listed above. The frequency and severity of each behavior is graded by the patient's caregiver. The caregiver also grades their own burden caused by the patient's behavior. Survey responses were tallied to produce scores: a patient total score, a caregiver burden score, and a score for each of the 12 problem behaviors. The NPI is a reliable, reproducible, and valid assessment instrument for studying the neuropsychiatric signs and symptoms of dementia syndromes, diagnosing and differentiating among dementia syndromes, and evaluating the effectiveness of investigational treatments on the natural history of Alzheimer's disease. It is sensitive to treatment effects and has demonstrated in clinical trials that cholinergic agents can improve behavioral symptoms in patients with Alzheimer's disease.

[0191] First results were obtained from a randomized, triple-blind, crossover clinical trial (NCT04749563) with an escalating daily dose and a placebo control. In this phase 1 study, safety and tolerability were evaluated in three dose-escalation cohorts in the same group of 12 patients with dementia due to Alzheimer's disease. Given the fragility of the study population, the safety cohort (2 active and 1 placebo patients) started each dose 1 day earlier than the other patients for early detection of adverse events. Safety and tolerability at the three doses were selected as primary outcome measures. Change in NPI score from baseline was selected as secondary outcome measure. Change in patient total score or caregiver burden score in the NPI was used as a sensitive measure of patient outcome in clinical trials of anti-dementia drugs (e.g., acetylcholinesterase inhibitors).

[0192] The caregiver was read each question exactly as written. If the caregiver did not understand a question, it was repeated or asked in a different word. After reading the screening question, the caregiver was asked if the behavior described was present. If the answer was "no," the clinician proceeded to the next section and read the next screening question. However, if the answer was "yes," further questions were read and a "yes" or "no" response was obtained. The caregiver was asked to rate the frequency (i.e., sometimes, often, frequently, or very frequently) and severity (i.e., mild, moderate, or severe) of the patient's most abnormal behavior. After the frequency and severity of each behavior was determined, the caregiver was asked to rate their own burden associated with that behavior (i.e., no burden, minimal, mild, moderate, moderate to severe, or very severe or extreme) before the clinician proceeded to the next behavior domain.

[0193] The frequency of the patient's behavior 1 = Occasionally (less than once a week) 2 = Often (about once a week) 3 = Frequently (not daily but several times a week) 4 = Very frequently (every day or virtually continuously) The severity of the patient's behavior 1 = Mild (noticeable, but no major changes in behavior) 2 = Moderate (noticeable, but not a dramatic change in behavior) 3 = Severe (very noticeable or prominent, dramatic change) Caregiver burden (Responses to "How mentally stressful do you find this behavior?") 0 = no burden 1=min 2=Mild 3=moderate 4 = moderate to severe 5 = Very severe or extreme Frequency, severity, and caregiver burden were scored according to the rating scales described above. NPI scores were calculated as the product of frequency and severity for each symptom (i.e., delusions, hallucinations, agitation / aggression, depression, anxiety, elation / euphoria, apathy, disinhibition, irritability, abnormal motor behavior, sleep disturbance, and appetite / eating disorder). Total patient score was calculated as the sum of the frequency x severity products for the 12 behavioral domains.

[0194] Patients were administered one, two, or three capsules per day enterally. Each 1 ml capsule consisted of 2.5 mg THC, 1.5 mg melatonin, 0.5 mg curcumin, 0.5 mg rutin, 10 mg ascorbic acid, 0.025 ml vitamin E TPGS (approximately 18.75 mg d-α-tocopherol), 0.01 ml Tween 80 (polysorbate 80), 0.12 ml ethanol, 0.2 ml honey, and water to a total volume of 1 ml. A cohort of 12 patients with Alzheimer's disease was treated with a low dose of 1 × daily dose for 2 weeks, followed by a 4-day washout period. The same cohort was then administered a medium dose of 2 × daily dose for 2 weeks, followed by a new 4-day washout period. Finally, the cohort was administered a high dose of 3 × daily dose for 2 weeks. Of the cohort of 12 patients, two received a placebo.

[0195] I. The low dose was one dose of 2.5 mg THC and 1.5 mg melatonin per day for two weeks.

[0196] II. The medium dose was one dose of 5 mg THC and 3 mg melatonin per day for two weeks.

[0197] III. The high dose was one dose of 7.5 mg THC and 4.5 mg melatonin per day for two weeks.

[0198] A patient's neuropsychiatric symptoms were considered to have improved if there was a statistically significant difference (reduction) in the change from baseline in the mean NPI score in the corresponding behavioral domain. Secondary evaluation criteria were considered to have been met if there was a statistically significant decrease in either the mean patient total change score and / or the mean caregiver burden change score. NPI scores for each behavioral domain were obtained at interviews on days 1 (pretreatment or baseline), 10 (on treatment), and 15 (end of treatment). Change scores were calculated for each patient after 1 week and 2 weeks of treatment, and the mean change score for the treatment group was calculated. A statistically significant difference (i.e., change from baseline) in the mean NPI scores led to the rejection of the null hypothesis. If there was a significant decrease in the mean NPI change score of the treatment group, the symptoms were considered to have improved with the treatment. A significant increase in the mean NPI change score of the treatment group could be considered as a worsening of symptoms.

[0199] Because NPI scores could change in either direction with treatment (i.e., symptoms improved or worsened), two-tailed tests were used. Two-tailed tests compared change scores on "day 1 vs. day 10" and "day 1 vs. day 15" with the null hypothesis being no difference with treatment. At a significance level of 0.05 (5%), two-tailed tests allocate half (i.e., 0.025 or 2.5%) to tests of significance in one direction (symptoms improved) and half to tests of significance in the other direction (symptoms worsened). A p-value <0.025 rejects the null hypothesis. The p-values ​​for treatment with the low daily dose are shown in Table 1, the p-values ​​for treatment with the medium daily dose are shown in Table 2, and the p-values ​​for treatment with the high daily dose are shown in Table 3.

[0200] The null hypotheses were rejected in 2 of 12 behavioral domains after 1 week of treatment with the low daily dose of 2.5 mg THC and 1.5 mg melatonin. There was a significant improvement in depression and anxiety. The null hypotheses were also rejected after 2 weeks of treatment with the low daily dose for depression. The change in mean patient total score from baseline (i.e., patient total score) also improved after 1 week of treatment with the low daily dose and remained improved at the end of treatment. The same pattern was seen in the change in mean caregiver burden score from baseline score (i.e., caregiver burden score).

[0201] The null hypothesis was rejected in 3 of 12 behavioral domains after 1 week of treatment with a medium daily dose of 5.0 mg THC and 3.0 mg melatonin. The null hypothesis was also rejected after 2 weeks of treatment with a medium daily dose for depression. Patient total scores improved after 1 week of treatment with the medium daily dose and remained improved at the end of treatment. The same pattern of improvement was seen in caregiver burden scores. In general, treatment with the medium daily dose was more beneficial for Alzheimer's disease than the low daily dose.

[0202] At the high daily dose of 7.5 mg THC and 4.5 mg melatonin, the null hypothesis was not rejected for any of the 12 behaviors after 1 or 2 weeks of treatment. Surprisingly, increasing the amount of THC and melatonin did not increase the benefits to Alzheimer's patients seen with the two lower doses. Patient total scores improved only after 2 weeks of treatment with the high daily dose. Caregiver burden scores did not improve.

[0203] Table 4 summarizes the change from baseline in mean patient total score and mean caregiver burden score at 1 week (day 1 minus day 10) and 2 weeks (day 1 minus day 15) after each treatment. For convenience, the p values ​​from Tables 1-3 are repeated in Table 4 for a head-to-head comparison of treatments with low, medium, and high daily doses. As noted above, there was a significant improvement in patient total score and caregiver burden score for treatments with low and medium daily doses. Improvement in patient total score was seen as quickly as one week of treatment and continued after the second week of treatment. Similarly, caregiver burden score improved for treatments with low and medium daily doses. However, at the high daily dose, patient total score did not improve until two weeks after treatment, and caregiver burden score did not improve.

[0204] We conclude that the most dramatic effects on patient outcomes were obtained with treatment at daily doses lower than the maximum level reached in this study. The improvements were rapid and sustained. It is also noteworthy that the changes in mean scores in the treatment groups did not go in the other direction (i.e., worsening). Thus, treatment, even at the high daily doses, did not worsen any of the 12 neuropsychiatric symptoms assessed in this study.

[0205] Howard et al. (Int J Geriatric Psychiatry, 2011 Aug, 26:812-817) listed the minimal clinically important difference in patient total scores as 8 (i.e., 0.4 standard deviations in change from baseline). In Table 4, the statistically significant differences in change scores met Howard's criteria.

[0206] npiTEST.net stated that the clinical significance of the drug-placebo difference will vary according to the severity of baseline behavioral changes and the behavioral domains affected. According to npiTEST.net, "As a general rule, a 4-point or 30% reduction in baseline scores can be considered clinically significant." "However, smaller changes in some symptoms, such as agitation, may be considered important to caregivers or indicate important drug effects. This needs to be considered on an individual basis and is pre-specified as appropriate in the analysis." No statistically significant differences were calculated between the treatment and placebo groups herein. The small number of patients and the large variance of their NPI scores may have prevented the changes due to treatment from reaching statistical significance. Are there patient characteristics that can be used to predict who will benefit from treatment? Recruiting patients using such criteria may reduce the variance of their baseline and change scores. By recruiting more patients and increasing the number of cases (e.g., both placebo and treatment groups), the width of the confidence interval should be narrower. Therefore, by recruiting patients with late-onset Alzheimer's disease who are younger, have no serious comorbidities, are otherwise healthy and well, or any combination thereof, or whose symptoms, cognitive deficits, functional impairment, or any combination thereof are mild, and by expanding both the treatment and placebo groups, minimal important differences may be discernible.

[0207] Table 1 shows improvement with low doses of 2.5 mg THC and 1.5 mg melatonin (p<0.025).

[0208] [Table 1]

[0209] Table 2 shows improvement with medium doses of 5 mg THC and 3 mg melatonin (p<0.025).

[0210] [Table 2]

[0211] Table 3 shows improvement with higher doses of 7.5 mg THC and 4.5 mg melatonin (p<0.025).

[0212] [Table 3]

[0213] Table 4 shows a comparison of improved patient total scores and caregiver burden scores.

[0214] [Table 4]

[0215] Table 5 shows a comparison of the claimed daily dosages with the examples of WO 2019 / 190608.

[0216] [Table 5]

[0217] References 1.CANEVELLI et al. “Behavioral and psychological subsyndromes in Alzheimer's disease using the Neuropsychiatric Inventory” Intl J Geriat Psychiatry, 2013 Aug, 28: 795-803. 2.CONNORS et al. “The stability of neuropsychiatric subsyndromes in Alzheimer's disease” Alzheimers Dement, 2018 Jul, 14: 880-888. 3. CUMMINGS et al. “The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia” Neurology, 1994 Dec, 44: 2308-2314. 4. CUMMINGS “The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients” Neurology, 1997 May, 48: S10-S16. 5. CUMMINGS & McPHERSON “Neuropsychiatric assessment of Alzheimer’s disease and related dementias” Aging, 2001 Jun, 13: 240-246. 6. CUMMINGS & ZHONG “Trial design innovations: Clinical trials for treatment of neuropsychiatric symptoms in Alzheimer’s disease” Clin Pharmacol Ther, 2015 Nov, 98: 483-485. 7. CUMMINGS “The Neuropsychiatric Inventory: Development and applications” J Geriatr Psychiatry Neurol, 2020 Mar, 33: 73-84. 8. EIKELBOOM et al. “Neuropsychiatric and cognitive symptoms across the Alzheimer disease clinical spectrum: Cross-sectional and longitudinal associations” Neurology, 2021 Aug, 97: e1276-e1287, doi: 10.1212 / WNL.0000000000012598. 9. FRISONI et al. “Behavioral syndromes in Alzheimer’s disease: Description and correlates” Dement Geriatr Cogn Disord, 1999 Mar, 10: 130-138. 10. KAUFER et al. “Assessing the impact of neuropsychiatric symptoms in Alzheimer’s disease: The Neuropsychiatric Inventory Caregiver Distress Scale” J Am Geriatr Soc, 1998 Feb, 46: 210-215. 11. KAUFER et al. “Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory” J Neuropsychiatry Clin Neurosci, 2000 Spring, 12: 233-239. 12. LAI “The merits and problems of Neuropsychiatric Inventory and an assessment tool in people with dementia and other neurological disorders” Clin Interv Aging, 2014 Jul, 9: 1051-1061. 13. LANCTOT et al. “Neuropsychiatric signs and symptoms of Alzheimer’s disease: New treatment paradigms” Alzheimers Dement, 2017 Aug, 3: 440-449. 14. de MEDEIROS et al. “The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): Reliability and validity of a revised assessment of neuropsychiatric symp-toms in dementia” Int Psychgeriatr, 2010 Sep, 22: 984-994. 15. SAARI et al. “Psychometric properties of the Neuropsychiatric Inventory” J Alzheimer Dis, 2020 Aug, 86: 1485-1499, doi: 10.3233 / JAD-200739. The publications cited above describe various versions of the NPI, its validation, and its use in assessing symptoms in patients with Alzheimer's disease. All of the publications cited, as well as U.S. Patent Application No. 63 / 245,799, are incorporated herein by reference.

[0218] Table 5 compares the daily dosages of claims 1, 18, and 48 below with the compositions in the examples of our WO 2019 / 190608. The claimed daily dosages include low and medium daily dosages, but not high dosages. As a result, the claimed THC range excludes the amounts of THC disclosed in WO 2019 / 190608. In other words, "about 2 mg (or more) to about 7 mg (or less)" of THC excludes about 1.5 mg and about 7.5 mg of THC. Similarly, "from about 1.6 mg (or more)" of melatonin excludes about 1.5 mg of melatonin, and "to about 4.4 mg (or less)" of melatonin excludes about 4.5 mg of melatonin.

[0219] The inventors' discoveries and speculations as to aspects of the invention, principles of operation, and features not yet claimed are set forth above. Although specific embodiments applying aspects of the invention are contemplated, it is not necessary to fully implement all of the embodiments contemplated in order to benefit from the inventors' discoveries. Similarly, the inventors' speculations as to principles of operation, whether or not they are demonstrated, do not in any way defeat the utility and practice of the claimed invention.

[0220] Although this description may refer to specific alternative elements or materials, design choices or ornamental designs, functional limitations, goals or objectives, means or steps, optionally arrangements or configurations, priorities, relative or subjective terms, perceptions (e.g., color, flavor, odor, sound, texture), shape or size, or the like, it will be understood that the inventors' discoveries and inventions generally follow their operating principles and may be applied to the core features described hereinabove as being conventional practice or known in the art to which the invention pertains, and may be adapted or modified by including departures from this description as falling within the scope of the invention and within the limits of the claims appended hereto or hereinafter. Thus, the claims should not limit their scope of protection to the specific embodiments and examples described herein.

Claims

1. 1. A medicament for treating one or more behavioral and psychological symptoms in a human patient in need thereof, comprising: Daily dosage: (i) 2.0 mg to 7.0 mg of a tetrahydrocannabinol (THC) compound; (ii) 1.0 mg to about 4.4 mg of a melatonin compound; Pharmaceuticals, including

2. the daily dose of the THC compound is 2.25 mg to 6.75 mg; The pharmaceutical composition according to claim 1.

3. the daily dose of the THC compound is 2.5 mg to 6.5 mg; The pharmaceutical composition according to claim 1.

4. The THC compounds include dronabinol, nabilone, trans-delta-8-THC (Δ8-THC), trans-delta-9-THC (Δ9-THC), Δ9-THC stereoisomers, Δ9-THC carboxylic acid (THCA), Δ9-THC-4-oic acid (THCA-A), Δ9-THC-2-oic acid (THCA-B), 11-hydroxy-Δ9-THC (11-OH-THC), ), 11-nor-9-carboxy-Δ9-THC (11-COOH-THC), 7,8,9,10-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ6a,10a-THC), (9R,10aR)-8,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1 -ol (Δ6a,7-THC), (6aR,9R,10aR)-6a,9,10,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ7-THC), 6a,7,8,9-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ10-THC), and (6 aR,10aR)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-9-methylene-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (Δ9,11-THC), ananamide, 2-arachidonoyl-glycerol, 2-arachidonoyl-glyceryl ether, and all combinations thereof; The pharmaceutical composition according to claim 1.

5. the daily dosage of the melatonin compound is 1.25 mg to 4.2 mg; The pharmaceutical composition according to claim 1.

6. the daily dosage of the melatonin compound is 1.5 mg to 4.0 mg; The pharmaceutical composition according to claim 1.

7. The melatonin compound is selected from the group consisting of circadin, N-acetyl-5-methoxytryptamine, agomelatine, ramelteon, tasimelteon, 5-methoxytryptamine, N-acetyl-serotonin, and all combinations thereof. The pharmaceutical composition according to claim 1.

8. Further comprising a curcumin-related compound in an amount of 0.3 mg to 1.5 mg. The pharmaceutical composition according to claim 1.

9. Further comprising a curcumin-related compound in an amount of 0.6 mg to 1.2 mg. The pharmaceutical composition according to claim 1.

10. The curcumin-related compound is selected from the group consisting of curcumin, turmeric, curcuminoids other than curcumin, structural derivatives of curcumin, and all combinations thereof. The pharmaceutical composition according to claim 8 or 9.

11. Further comprising a rutin-related compound in an amount of 0.3 mg to 1.5 mg. The pharmaceutical composition according to claim 1.

12. Further comprising a rutin-related compound in an amount of 0.6 mg to 1.2 mg. The pharmaceutical composition according to claim 1.

13. The rutin-related compound is selected from the group consisting of rutin, quercetin glycosides other than rutin, quercitrin, rutinosides other than rutin, hesperidin, structural derivatives of rutin, and any combination thereof. The pharmaceutical composition according to claim 11 or 12.

14. further comprising one or more polyphenol compounds, The pharmaceutical composition according to claim 1.

15. The polyphenolic compound is selected from the group consisting of turmeric, curcuminoids, curcumin, curcumin-related compounds, quercetin glycosides, rutin, rutinosides, rutin-related compounds, and any combination thereof. The pharmaceutical composition according to claim 14.

16. To enhance the stability and solubility of THC, at least a portion of the THC is formulated in an emulsion containing alcohol, water, oil, surfactant, or a phospholipid bilayer; The medicament of claim 1 in a liquid carrier.

17. The surfactant is selected from the group consisting of polysorbate 80 and polyethylene glycol 1000 ester of vitamin E succinate (TPGS). The pharmaceutical composition of claim 16.

18. Contains less than 2% (wt / vol) cannabidiol (CBD), The pharmaceutical composition according to claim 1.

19. A kit or medical device comprising: (a) one or more unit doses of a medicament, each unit dose comprising: (i) an effective amount of a tetrahydrocannabinol (THC) compound, wherein the amount is between 2.0 mg and 7.0 mg; (ii) a pharmaceutical comprising an effective amount of a melatonin compound, the amount of which is 1.6 mg to 4.4 mg; (b) a package or optionally a dispenser for multiple unit doses; (c) a package insert containing prescription information for said drug; (d) the expiration date of the medicament; (e) a seal that renders the medication at least tamper-resistant; 20. A kit or medical device comprising:

20. The medicament contains less than 2% (wt / vol) cannabidiol (CBD), 20. The kit or medical device of claim 19.