WO2020188569A1 - Methods and compositions for preventing or treating weight gain caused by psychiatric drugs - Google Patents

Abstract

The present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, for use in preventing, inhibiting, or reducing weight gain resulting from treatment by at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer, wherein the CBD:THC weight ratio in the cannabinoid combination is about 20:1; pharmaceutical and nutraceutical compositions comprising the cannabinoid combinations; and methods for preventing, inhibiting, or reducing weight gain resulting from treatment by at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer, by administering the cannabinoid combination.

Description

METHODS AND COMPOSITIONS FOR PREVENTING OR TREATING WEIGHT

GAIN CAUSED BY PSYCHIATRIC DRUGS

FIEUD OF INVENTION

[001] This invention is directed to combinations comprising cannabidiol (CBD) and D⁹- tetrahydrocannabinol (THC), for use in preventing or treating weight gain caused by treatment with psychiatric drugs.

BACKGROUND OF THE INVENTION

[002] Antipsycho tics are drugs mainly used for treating psychiatric disorders involving psychosis, such as schizophrenia and manic episodes in bipolar disorder. However, one of the most common side effects of antipsycho tics is weight gain that may lead to obesity. People with schizophrenia are twice as likely to be obese than people in the general population, partly due to treatment with antipsycho tics. In a recent study by Scahill et al. 2016 (Journal of the American Academy of Child and Adolescent Psychiatry 55:415-423), 97 young children with autism spectrum disorder (ASD) were followed for six months after risperidone treatment onset suffered considerable adverse effects. The authors found an average weight gain of 5.4 ± 3.4 kg in six months, cutting the rate of“normal weight” classification in this population from 61% at base-line to 29%, after only 6 months. Accordingly, the incidence of metabolic syndrome was increased by 170% (from 7 to 19 patients) in only four months.

[003] Typically, the fastest weight gain occurs in the first six months after starting an antipsychotic, and further weight gain after that is usually slower. The highest risk of weight gain is associated with the atypical antipsycho tics olanzapine or clozapine, a somewhat lesser risk is associated with chlorpromazine, quetiapine, risperidone, and paliperidone, and still a lower risk is with asenapine, amisulpride, aripiprazole, lurasidone, ziprasidone, and haloperidol.

[004] Additional types of psychiatric drugs that may cause weight gain include certain types of antidepressants and mood stabilizers·

[005] THC and CBD are the two main cannabinoids in the cannabis plant. Both THC and CBD are neuroactive but only THC is psychoactive (inducing the “high” feeling). CBD is not psychoactive and even attenuates the THC-induced psychoactivity. As a result, in medical cannabis, strains with higher CBD concentrations are being used while in street cannabis the THC concentration is higher and the CBD concentration is lower. Current knowledge on long term side- effects of cannabinoids is typically based on longitudinal follow-up on recreational cannabis users. Several large studies demonstrated that the main risks, including decreased motivation, addiction, mild cognitive decline and schizophrenia - are all directly related to the THC and CBD concentrations in the strain used. The higher the THC and the lower the CBD levels - the greater the risk. The risk is also higher in younger onset of use (<18 years) and in the presence of other risk factors such as family history of schizophrenia and concomitant use of alcohol and tobacco.

SUMMARY OF THE INVENTION

[006] In one aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, for use in preventing, inhibiting, or reducing weight gain resulting from treatment by at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer in a subject, wherein CBD:THC weight ratio in the cannabinoid combination is about 20:1.

[007] In another aspect, the present invention provides a method for preventing, inhibiting, or reducing weight gain resulting from administration of at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, wherein CBD:THC weight ratio in the cannabinoid combination is about 20:1.

BRIEF DESCRIPTION OF THE DRAWINGS

[008] Fig. 1 shows the effect of treatment with a combination of CBD and THC on body mass index (BMI) in subjects with autism spectrum disorder (ASD). Left triad - first treatment period; right triad - second treatment period. P - placebo, W - whole plant extract, C - pure cannabinoids. The relative increase/decrease is indicated within the bars, statistics between bars is shown, n is the number of subjects.

[009] Fig. 2 shows the effect of treatment with the cannabinoids on weight by BMI class after the first treatment period. Left group: normal/thin, middle group: overweight, right group: obese. The empty bars represent treatment with cannabinoids (the whole plant extract and the pure cannabinoids treatments were grouped) and the filled bars represent placebo. DETAILED DESCRIPTION

[010] The inventors have inadvertently found that administering a cannabinoid combination having a ratio of CBD:THC of 20:1 to autistic patients treated with psychiatric drugs eliminated the weight gain that is a common side effect of these drugs. As can be seen from Fig. 1, patients not treated with the cannabinoid combination of the invention (the placebo group - P) gained weight, and their BMI increased between 0.22 and 0.59 kg/m². In contrast, patients treated with a cannabinoid combination having a CBD:THC ratio of 20: 1 exhibited a decrease in BMI of between 0.15 and 0.53 kg/m².

[Oi l] While a 99% pure cannabinoids mix is more reproducible than whole plant extract and is thus preferred as a treatment drug, several studies suggest that synergistic effects exist for numerous cannabis compounds in the whole plant extract ("entourage effect") (Ben-Shabat et ah, 1998, European journal of pharmacology 353:23-31; Russo and Taming, 2011, British journal of pharmacology 163: 1344-1364). In the present application, two preparations of cannabinoids were used: a botanical drug based on whole plant extract and a pure cannabinoid mix (both having a CBD:THC weight ratio of 20: 1).

[012] Surprisingly, and in contrast to the "entourage effect" theory, it was found that treatment with a combination of pure cannabinoids (C) had an effect similar to treatment with the whole extract (W).

[013] Accordingly, in one aspect, the present invention provides a method for preventing, inhibiting, or reducing weight gain resulting from administration of at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, wherein CBD:THC weight ratio in the cannabinoid combination is about 20: 1.

[014] In another aspect, the present application provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, for use in preventing, inhibiting, or reducing weight gain resulting from treatment by at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer in a subject, wherein CBD:THC weight ratio in the cannabinoid combination is about 20: 1.

[015] In some embodiments, the weight ratio of CBD:THC in the cannabinoid combination is about 10: 1 to about 40: 1. In some embodiments, the weight ratio of CBD:THC is about 15: 1 to about 25: 1, about 17: 1 to about 23: 1, about 20: 1 to about 30: 1, about 20: 1 to about 40: 1, or about 30: 1 to about 40: 1. In some embodiments, the weight ratio of CBD:THC is about 15: 1, about 16:1, about 17: 1, about 18: 1, about 19: 1, about 20: 1, about 21: 1, about 22:1, about 23: 1, about 24: 1, about 25: 1, about 26: 1, about 27: 1, about 28: 1, about 29:1, about 30: 1 or about 40: 1.

[016] The term "therapeutically effective amount" as used herein means an amount of the cannabinoid combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought. The amount must be effective to achieve the desired therapeutic effect as described above, depending inter alia on the type and severity of the condition to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person skilled in the art will know how to properly conduct such trials to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, and on factors such as age and gender, etc.

[017] The term "cannabinoid combination" as used herein refers to a combination of the cannabinoids CBD and THC, which are administered together or separately. The cannabinoid combination may be comprised in a single formulation or in two separate formulations, as further discussed below. The components of the cannabinoid combination must be administered at timing and dosages such that they are present in the circulation of the subject at the same time.

[018] The phrase "as the only cannabinoids" as used herein means that the only cannabinoids comprised in the cannabinoid combination are CBD and THC.

[019] In some embodiments, the cannabinoid combination of the invention is prepared from substantially pure preparations of CBD and/or THC.

[020] The term "substantially pure" means that the cannabinoid constitutes at least 95% of the weight of the preparation, and that no other active ingredient is present in the preparation in an amount detectable by HPLC.

[021] In some embodiments, the purity of the substantially pure CBD and/or THC preparations is at least 96%, at least 97%, at least 98%, or at least 99%.

[022] CBD (2-[6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol), has very low affinity for the cannabinoid CBi and CB2 receptors but is said to act as an indirect antagonist of these receptors. At the same time, it may potentiate the effects of THC by increasing CB i receptor density or through another CBi receptor-related mechanism. CBD has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., optical isomer, a racemate, i.e., an optically inactive mixture having equal amounts of two enantiomers, a diastereoisomer, or a mixture thereof. The present invention encompasses the use of all such enantiomers, isomers and mixtures thereof. CBD naturally exists as (2-[( li?,6i?)-6-isopropenyl-3 -methylcyclohex-2-en- 1 -yl] -5-pentylbenzene- 1 ,3-diol) .

[023] THC (6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6 -benzo[c]chromen-l-ol) is a partial agonist of the cannabinoid receptor CBi, located mainly in the central nervous system, and the CB2 receptor, mainly expressed in cells of the immune system. THC has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., an optical isomer, racemate, i.e., an optically inactive mixture having equal amounts of the two enantiomers, a diastereoisomer, or a mixture thereof. The present invention encompasses the use of all such enantiomers, isomers and mixtures thereof. THC naturally exists as (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6//-benzo[c]chromen-l-ol.

[024] For purposes of clarity, the terms CBD and THC as used throughout the description and the claims are intended to include enantiomer, diastereomer, or racemate thereof.

[025] In some embodiments, the CBD and/or THC are the naturally existing enantiomers, (2- [(liC6i?)-6-isopropenyl-3-methylcyclohex-2-en-l-yl] -5-pentylbenzene- 1,3-diol) and (6a/C 10a//)- 6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-67/-benzo[c]chromen-l-ol, respectively.

[026] Natural cannabinoids, including CBD and THC may be extracted from the cannabis plant using any suitable extraction or purification method known in the art, such as methods described, for example, in Gaoni and Mechoulam, J. Am. Chem. Soc. 93: 217-224 (1971), or by the method described below in the experimental section. A chemical signature may be made by a mass spectrometer so as to distinguish between a preparation made from an extract and a preparation made from the purified active ingredients.

[027] Alternatively, each of these cannabinoids may be synthesized following any one of the procedures disclosed in the literature. For example, CBD may be synthesized following any one of the procedures known in the art, e.g., by acid condensation of p-mentha-2,8-dien-l-ol with olivetol. Optically active forms of CBD or THC may be prepared using any one of the methods disclosed in the art, e.g., by resolution of the racemic form by recrystallization techniques; chiral synthesis; extraction with chiral solvents; or chromatographic separation using a chiral stationary phase. A non-limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including simulated moving bed chromatography, can also be used. A wide variety of chiral stationary phases are commercially available.

[028] In some embodiments, the cannabinoid combination does not comprise terpenes.

[029] In some embodiments, the cannabinoid combination consists essentially of CBD and THC.

[030] The phrase “consisting essentially of’ used herein with respect to the cannabinoid combination of the present invention means that the CBD and THC are the only active components of the cannabinoid combination. However, inactive agents such as those used in compositions and particularly in pharmaceutical compositions, including carriers, solvents, dispersion media, preservatives, antioxidants, coatings, and isotonic and absorption delaying agents, may be comprised in the cannabinoid combination of the invention. Additionally, it is clarified, that psychiatric drugs are not considered as part of the cannabinoid combination; however, they may be administered together therewith, as further discussed below.

[031] The CBD and THC of the cannabinoid combination of the invention may be formulated as separate pharmaceutical compositions for administration concurrently, or separately, at any order.

[032] When the cannabinoids of the cannabinoid combination are sequentially administered, the administration of the separate pharmaceutical composition may be separated by minutes, hours, or days.

[033] Accordingly, in some embodiments, the CBD and THC according to any of the above embodiments, are administered concomitantly or sequentially at any order.

[034] In some embodiments, the CBD and the THC are comprised in separate compositions and are administered concomitantly or sequentially at any order.

[035] In some embodiments, the CBD and the THC are comprised in separate compositions and are independently administered sublingually, orally, or by inhalation.

[036] In some embodiments, the CBD and the THC are comprised in separate compositions and are independently administered once, twice, or three times a day.

[037] When the CBD and the THC are not comprised in the same composition, the ratio of CBD:THC is calculated based on the daily amount of each cannabinoid.

[038] In some embodiments, the CBD and the THC comprised in the cannabinoid combination of the invention are formulated as a sole pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier.

[039] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein interchangeably refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. According to the present invention, the pharmaceutically acceptable carrier may further comprise ingredients aimed at enhancing the activity of the active agents or modulating the bioavailability thereof.

[040] The term "acceptable" with respect to the pharmaceutically acceptable carrier denotes a carrier, excipient, or non-active ingredient that does not produce an adverse, allergic, or other untoward reaction when administered to a mammal or human as appropriate. For human administration, compositions should meet sterility, pyrogenicity, and general safety and purity standards as required by, e.g., the U.S. FDA or the European Medicines Agency (EMA).

[041] The pharmaceutical compositions disclosed herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19^th Ed., 1995. The compositions can be prepared, e.g., by uniformly and intimately bringing the active agents into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The compositions may be in the form of a liquid (e.g., solution, emulsion, or suspension), gel, cream, solid, semisolid, film, lyophilisate, or aerosol, and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients. In one embodiment, the pharmaceutical composition of the present invention is formulated as nanoparticles.

[042] The pharmaceutical compositions of the present invention may be formulated for any suitable route of administration, e.g., for oral, buccal, sublingual, or parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, or topical, administration, as well as for inhalation, but is preferably formulated for oral or sublingual administration, or for inhalation.

[043] The pharmaceutical compositions of the invention, when formulated for oral administration, may be in any suitable form, e.g., tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In certain embodiments, the tablets are in the form of matrix tablets in which the release of a soluble active is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid {in vitro) or gastro intestinal fluid {in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other embodiments, the tablets are formulated as bi- or multi-layer tablets, made up of two or more distinct layers of granulation compressed together with the individual layers lying one on top of another, with each separate layer containing a different active agent. Bilayer tablets have the appearance of a sandwich since the edge of each layer or zone is exposed.

[044] Pharmaceutical compositions for oral administration might be formulated so as to inhibit the release of one or both of the active agents in the stomach, i.e., delay the release of one or both of the active agents until at least a portion of the dosage form has traversed the stomach, in order to avoid the acidity of the gastric contents from hydrolyzing the active agent. Particular such compositions are those wherein the active agent is coated by a pH-dependent enteric-coating polymer. Examples of pH-dependent enteric-coating polymer include, without being limited to, Eudragit^® S (poly(methacrylicacid, methylmethacrylate), 1:2), Eudragit^® L 55 (poly (methacrylicacid, ethylacrylate), 1: 1), Kollicoat^® (poly(methacrylicacid, ethylacrylate), 1: 1), hydroxypropyl methylcellulose phthalate (HPMCP), alginates, carboxymethylcellulose, and combinations thereof. The pH-dependent enteric-coating polymer may be present in the composition in an amount from about 10% to about 95% by weight of the entire composition.

[045] In certain embodiments, the invention provides pharmaceutical compositions for oral administration, which is solid and may be in the form of granulate, granules, grains, beads or pellets, mixed and filled into capsules or sachets, or compressed to tablets by conventional methods. In some particular embodiments, the pharmaceutical composition is in the form of a bi- or multilayer tablet, in which each one of the layers comprise one of the active agents, and the layers are optionally separated by an intermediate, inactive layer, e.g., a layer comprising one or more disintegrants.

[046] Another contemplated formulation is depot systems, based on biodegradable polymers. As the polymer degrades, the active agent(s) is slowly released. The most common class of biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules. Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide- co-glycolide) (PLG).

[047] Pharmaceutical compositions for oral administration may be prepared according to any method known to the art and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active agents in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., com starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc. The tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.

[048] Useful dosage forms of the pharmaceutical compositions include orally disintegrating systems including, but not limited to, solid, semi-solid and liquid systems including disintegrating or dissolving tablets, soft or hard capsules, gels, fast dispersing dosage forms, controlled dispersing dosage forms, caplets, films, wafers, ovules, granules, buccal/mucoadhesive patches, powders, freeze dried (lyophilized) wafers, chewable tablets which disintegrate with saliva in the buccal/mouth cavity and combinations thereof. Useful films include, but are not limited to, single layer stand-alone films and dry multiple layer stand-alone films.

[049] The pharmaceutical composition of the invention may comprise one or more pharmaceutically acceptable excipients. For example, a tablet may comprise at least one filler, e.g., lactose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose; at least one disintegrant, e.g., cross-linked polyvinylpyrrolidinone; at least one binder, e.g., polyvinylpyridone, hydroxypropylmethyl cellulose; at least one surfactant, e.g., sodium laurylsulfate; at least one glidant, e.g., colloidal silicon dioxide; and at least one lubricant, e.g., magnesium stearate.

[050] The pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleagenous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents. The sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include, without limiting, water, Ringer's solution, polyethylene glycol (PEG), 2-hydroxypropyl- -cyclodextrin (HPCD), a surfactant such as Tween-80, and isotonic sodium chloride solution.

[051] Pharmaceutical compositions according to the invention, when formulated for inhalation, may be in any suitable form, e.g., liquid or fine powder, and may be administered utilizing any suitable device known in the art, such as pressurized metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.

[052] The pharmaceutical compositions of the invention may be formulated for controlled release of one or more of the active agents. Such compositions may be formulated as controlled-release matrix, e.g., as controlled-release matrix tablets in which the release of a soluble active agent is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid {in vitro ) or gastro-intestinal fluid {in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other configurations, the compositions comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters.

[053] CBD and THC are insoluble in water but soluble in organic solvents, such as oil. Accordingly, they may be formulated for use in the described methods through use of any organic solvent known to the pharmaceutical arts, including, but not limited to edible oils. When formulated for oral administration, any edible oil can be used in the cannabinoid formulation, including olive oil.

[054] In some embodiments, the daily dose of CBD according to the invention is about 50 mg to about 600 mg, about 100 mg to about 600 mg, about 150mg to about 600mg, about 200mg to about 600mg, about 300mg to about 600mg, about 200mg to about 500mg, about 200mg to about 450mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 450 mg, about 500 mg, about 550, about 600 mg, from about 5mg/kg to about 15mg/kg, or about lOmg/kg.

[055] In some embodiments, the daily dose of THC according to the invention, is about 2.5 mg to about 30 mg, about 5 mg to about 30 mg, about 7.5mg to about 30mg, about lOmg to about 25mg, about 10 mg to about 20mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, from about 0.25mg/kg to about 0.75mg/kg, or about 0.5 mg/kg.

[056] Dosing of the pharmaceutical compositions of the invention according to any one of the above embodiments, may be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until the desired effect is achieved.

[057] Accordingly, in some embodiments, each of the pharmaceutical compositions defined above, comprising one or both CBD and THC, is independently administered to the subject as needed. Administration of each of these pharmaceutical compositions may be once per day, once every several days, such as once every two or three days, twice per day, or three times per day, more than three times per day, such as 4, 5, 6 or more times per day as needed, provided that both cannabinoids comprised in the cannabinoid combination are present in the circulation of the subject at the same time.

[058] In some specific embodiments, the cannabinoid combination of the invention, when comprised in a sole pharmaceutical composition, is administered once per day. In some embodiments the cannabinoid combination is administered once every several days, such as once every two or three days. In some embodiments, the cannabinoid combination is administered twice daily. In some embodiments, the cannabinoid combination is administered three times daily. In some embodiments, the cannabinoid combination is administered more than three times per day, such as 4, 5, 6 or more times per day, as needed.

[059] Psychiatric drugs are drugs used in psychiatry, including antipsycho tics, antidepressants, and mood stabilizers·

[060] Antipsycho tics, also known as neuroleptics or major tranquilizers, are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. They are increasingly being used in the management of non-psychotic disorders but with serious side effects. Antipsycho tics are usually effective in relieving symptoms of psychosis in the short term.

[061] Antidepressants are drugs used for the treatment of major depressive disorder and of other conditions, including anxiety disorders, chronic pain conditions, and to help manage addictions.

[062] Mood stabilizers are psychiatric drugs used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder type I or type II, borderline personality disorder (BPD) and schizoaffective disorder.

[063] The terms "preventing", "inhibiting", and "reducing", as used herein refer to means of eliminating altogether or partially an undesired physiological effect, such as weight gain, as a side effect of a psychiatric treatment. Weight gain is prevented if the subject does not gain weight during treatment with the cannabinoid combination and the psychiatric drug, in spite of weight gain being a side effect of the psychiatric drug. Weight gain is inhibited if it is delayed, e.g., appears later during treatment with the psychiatric drug and the cannabinoid combination, or at a higher dose of the psychiatric drug that without treatment with the cannabinoid combination. Weight gain is reduced if the extent of weight gain is less following treatment with the cannabinoid combination and the psychiatric drug compared to the expected weight gain for the same psychiatric drug at the same dose. [064] The term "treating", or "treatment", as used herein refers to means of obtaining a desired physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease and/or symptoms attributed to the disease. The term refers to inhibiting the disease, i.e. arresting its development; or ameliorating the disease, i.e. causing regression of the disease.

[065] Antipsychotic drugs related to the present invention are atypical antipsychotic including amisulpride, aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone, or typical antipsycho tics such as chlorpromazine or haloperidol.

[066] Antidepressant related to the present invention may be selective serotonin reuptake inhibitors (SSRI) such as paroxetine or fluoxetine, tricyclic antidepressants such as amitriptyline, or tetracyclic antidepressants such as mirtazapine.

[067] Mood stabilizers related to the present invention are carbamazepine, lithium, or valproic acid.

[068] Treatment of a subject with the above psychiatric drugs may be needed in various circumstances. For example, antipsycho tics may be administered for treating psychosis which may appear in schizophrenia and bipolar disorder, but also in various medical conditions including postpartum psychosis, sleep deprivation, neurodevelopmental disorders, autism spectrum disorder (ASD), Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, stroke, brain tumors, multiple sclerosis, epilepsy, certain infections, endocrine diseases such as hypothyroidism, hyperthyroidism, Cushing's syndrome, inborn errors of metabolism such as porphyria, metachromatic leukodystrophy, metabolic disorders, etc. Alternatively, antipsycho tics may be administered in cases of psychiatric disorders such as bipolar disorder and schizophrenia.

[069] Antidepressants may be administered in disorders such as anxiety disorder, ASD, a chronic pain condition, dementia, depression, dysthymia, obsessive -compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and Tourette syndrome.

[070] Mood stabilizers may be administered for treating mood disorders such as bipolar disorder, borderline personality disorder, and schizoaffective disorder.

[071] Accordingly, in some embodiments, the subject is suffering from psychosis or a disorder selected from anxiety disorder, bipolar disorder, borderline personality disorder, a chronic pain condition, dementia, depression, dysthymia, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), schizoaffective disorder, schizophrenia, and Tourette syndrome.

[072] In some embodiments, the subject does not have autistic spectrum disorder (ASD).

[073] The term "weight gain" as used herein means an increase in weight, or body mass index (BMI). The increase may be mild, moderate or severe, and the level of weight gain may cause obesity in the subject. [074] The cannabinoid combination may be administered to the subject concomitantly or sequentially at any order with the psychiatric drug. In some embodiments, the cannabinoid combination is administered to the subject prior to treatment with the psychiatric drug.

[075] In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.

[076] In some embodiments, the subject according to any of the above embodiments is a child. In some embodiments, the subject is adolescent. In some embodiments, the subject is an adult. In some embodiments, the age of the subject is between 5 and 12 years old. In some embodiments, the age of the subject is between 12 and 21 years old. In some embodiments, the age of the subject is between 5 and 21 years old. In some embodiments, the subject is older than 21 years old. In some embodiments, the subject is older than 25, 30, or 40 years old.

[077] In some embodiments, the subject is overweight prior to the treatment with the psychiatric drug. In some embodiments, the subject is obese prior to the treatment with the psychiatric drug. In some embodiments, the body mass index (BMI) of the subject prior to the treatment with the psychiatric drug is at least 25, at least 30, at least 35, or at least 40.

[078] As can be seen from Fig. 2, the obese group of patients had the largest decrease in weight following treatment with the cannabinoid combination compared to placebo.

[079] In some embodiments, the subject is overweight prior to administration of the cannabinoid combination. In some embodiments, the subject is obese prior to administration of the cannabinoid combination. In some embodiments, the body mass index (BMI) of the subject prior to administration of the cannabinoid combination is at least 25, at least 30, at least 35, or at least 40.

[080] The definitions of overweight and obese are according to the World Health Organization (WHO) BMI-for-age growth reference standards from 2007. In general, overweight is equivalent to BMI of above 25/kg/m2 at 19 years of age, and obese is equivalent to BMI of above 30/kg/m2 at 19 years of age.

[081] In some embodiments, administration of the cannabinoid combination of the invention facilitates using lower doses of one or more of the at least one psychiatric drug, thereby causing a reduction or elimination of the side effects of the psychiatric drug, including weight gain.

[082] In some embodiments, one or more of the at least one psychiatric drug is administered according to the invention at a daily dose lower than the daily dose recommended by the manufacturer. [083] In some embodiments, one or more of the at least one psychiatric drug is administered according to the invention at a daily dose lower than the daily dose previously taken by the subject.

[084] In some embodiments, the daily dose of one or more of the at least one psychiatric drug is at least 10%, 20%, 30%, 40%, 50%, 60%, 70% lower than lowest daily dose recommended by the Manufacturer.

[085] In some embodiments, the daily dose of one or more of the at least one psychiatric drug is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70% lower than daily dose recommended for the subject.

[086] In some embodiments, the daily dose of one or more of the at least one psychiatric drug is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70% lower than the daily dose which the subject was taking before commencement of treatment with the cannabinoid combination.

[087] In some embodiments, administration of the cannabinoid combination of the invention facilitates using sub-therapeutic doses of one or more of the at least one psychiatric drug, thereby causing a reduction or elimination of the side effects of the psychiatric drug, including weight gain.

[088] Accordingly, in some embodiments, one or more of the at least one psychiatric drug is administered at a sub-therapeutic dose.

[089] The term "sub-therapeutic dose" as used herein means less than the therapeutic dose of the drug that is needed to produce a therapeutic effect when the drug is used to treat the disease or condition it is administered for. In some embodiments, the SoC drug is administered at a sub- therapeutic dose.

[090]

[091] In some embodiments, the CBD and the THC comprised in the cannabinoid combination at any of the ratios indicated above, are formulated as a sole pharmaceutical composition, further optionally comprising a pharmaceutically acceptable carrier, or a sole nutraceutical composition, optionally further comprising a nutraceutically acceptable carrier.

[092] The nutraceutical composition may be formulated as a tablet, capsule, pill and powder, or as a liquid such as syrup, or elixir, drink or beverage, and may be prepared by conventional techniques known in the art. Particular such nutraceutical compositions are formulated for oral, buccal or sublingual administration, or for inhalation.

[093] It is conceivable that the cannabinoid combination of the invention, including CBD, and THC will be provided as a kit. Such a kit includes two compositions, each comprising one of the two cannabinoids. The kit may further include the psychiatric drug. [094] Unless otherwise indicated, all numbers expressing, e.g., weight ratios or doses of the two cannabinoids defined above, used in this specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

[095] The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Example 1: The effect of a combination of CBD and THC on weight gain in ASD patients treated with psychiatric drugs

Study design

[096] Participants ages 5-21 years, with ASD and moderate to severe refractory behavioral problems, were randomized for treatment with oral pure cannabinoids, whole plant extract or a placebo. The treatment plan (Tr.) included 12 weeks of a first treatment period and four weeks of washout, then another 12 weeks of a second treatment period with one of the two remaining compositions (altogether three treatment plans each having two treatment periods, as detailed below). Each treatment period was followed by gradual dose decrease for two weeks and a washout period of another two weeks (weeks 13-16 and 29-32 for the first and the second treatment period, respectively).

Participants

[097] Inclusion criteria were: ages 5-21 years; established ASD diagnosis [DSM-5 criteria] based on clinical assessment; moderate or greater behavioral problems as assessed by the Clinical Global Impression - Severity (CGI-S) score; and documented failure of at least two medications prescribed for the behavioral problems (at least one antipsychotic medication). Failure is defined as persistence of moderate or greater behavioral problems despite proper use or discontinuation of the treatment by the prescribing physician due to intolerable side effects.

[098] Participants were clinically evaluated by the site’s primary investigator. Participants with clinical diagnosis of ASD [DSM-5] and a rating of moderate or higher behavioral problems (CGI- S score > 4) were recruited. To assign the CGI-S score, the sites’ primary investigators were trained to consider disruptive behavior, the child’s overall clinical presentation, and the effect of the child’s behavior on the family.

[099] Patients could be separated into two group, syndromic and non-syndromic. Syndromic ASD is a disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype. Examples include fragile X syndrome, Rett syndrome, Dravet syndrome, Phelan- McDermid syndrome, Angelman syndrome, trisomy 21, Cornelia de Lange syndrome, tuberous sclerosis complex, or any defined genetic syndrome. Non-syndromic ASD is not associated with a known disorder.

[0100] Most patients were also treated with at least one of the following medications during the study: antipsycho tics - aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; anti-epileptics (AED) - carbamazepine, lamotrigine, topiramate, or valproic acid; a selective serotonin reuptake inhibitor (SSRI) - clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; a stimulant - an amphetamine, an ephedrine, or ritalin; an a.2 agonist - clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine; and/or the another type of drug - enalapril, stratera X2, circadin, deralin, dekinet, L-thyroxine, valcyclovir, norditropin (somatropin- GH), singular X2, decapeptyl, xenazine, cyproheptadine (antihistamine), or zeto.

[0101] Exclusion criteria were: planned changes in existing interventions for the duration of the trial or such a change in the last four weeks of current treatment with cannabis -based therapy; heart, liver, renal or hematological disorders; history of psychotic disorder in a first degree relative; or anxiety disorder in the participant.

Baseline assessments

[0102] Throughout the study, various tests were administered and parameters were measured, including a complete physical examination (including height and weight measurements). Weight was measured 4 times during the study (Period 1: baseline and end of period 1 and Period 2: baseline and end of period 2).

[0103] ASD adaptive functioning at baseline was measured using several well established tools: the standardized assessment - Autism Diagnostic Observation Schedule™ (ADOS-2), the parent rated - Social Communication Questionnaire (SCQ) Lifetime Form (Rutter et ah, 2003), the parent interview based - Vineland™-II (Sparrow et ah, 1984) and the behavioral observation based - Childhood Autism Rating Scale (CARS-2, Schopler et ah, 1980). A short medical history questionnaire with emphasis on etiological evaluations (genetic, imaging) and comorbidities (epilepsy, allergies, immune mediated disorders and sleep disorders) is completed.

[0104] High-functioning participants also underwent in the first, second and fourth meetings: electroencephalogram (EEG) during sleep, a computerized continuous performance task - TOVA (Test of variables of attention) and the parental questionnaire: Attention Deficit Hyperactivity Disorder- Rating Scale- ADHD-RS .

[0105] Autism diagnostic observation schedule, second edition (ADOS-2™, Lord et al, 2000), is a standardized, play-based assessment of communication, social interaction, play, and imaginary use of materials. It consists of four modules, each designed to be administered to different individuals according to their level of expressive language. Scoring of the ADOS-G involves diagnostic algorithms for four domains: communication, social interaction, play /creativity, and restricted/repetitive behaviors or interests. Cut-off scores are in the domains of communication, social interaction, and combined (communication + social interaction)

[0106] Social Communication Questionnaire (SCQ) Lifetime Form (Rutter et al, 2003) is a 40- item, parent report-based screening measure used to assess ASD symptoms. The SCQ total score comprises items assessing reciprocal social interaction, communication, and restricted, repetitive and stereotypical patterns of behavior. SCQ items score 0 or 1 and having a cut-off of > 15 is recommended for identifying potential ASD cases. This measure corresponds well with the gold standard ASD measures and has high discriminant validity.

[0107] Vineland Adaptive Behavior Scales (Vinelandⁱ , Sparrow et al, 1984) is a semi- structured caregiver interview designed to assess functional skills in three domains: communication, socialization, and daily living skills. The adaptive composite score estimates overall adaptive behavior. Vineland items are scored based on open-ended questions such as 0 (behavior not performed), 1 (performed sometimes) or 2 (performed on a regular basis). The instrument provides standard scores (mean = 100, SD = 15) and age equivalent scores. To measure changes, the age equivalent score provides an estimate of improvement (in months) against the passage of time.

[0108] Childhood Autism Rating Scale, second edition (CARS2-ST, Schopler et al, 1980), is a well-established scale for the screening and classification of ASD. It is a quantitative measure of direct behavioral observations consisting of 15 scales of which 14 cover various aspects of interactive behavior - communication, body use, the child’s response to stimuli, and activity level. The last scale is a general impression of the degree of autism in the child. All scales are rated from 1 (normal) to 4 (severely abnormal and/or inappropriate). Total scores of 30-36.5 indicate mild to moderate ASD (30-36.5) and scores above 36.5 are indicative of severe ASD.

[0109] Test of Variables of Attention (TOVA, Llorente et al, 2001 ) is a computerized continuous performance task that incorporates standardized two-second inter- stimulus intervals during a 21.6 minute test. The test presents stimuli over a consistent 3.5: 1 ratio. There are two target paradigms: target infrequent and target frequent. In the first part of the test, a 3.5: 1 ratio of non-targets to targets is presented while in the second part the ratio is reversed. The participant is instructed to press the micro-switch as quickly as possible when the target appears on the computer screen. The stimulus is a single square within a square. The results are expressed as Z scores, calculated based on established norms for gender and age group. Z-score < -1.8 is suggestive for attention deficit and/or impulsivity.

Biological samples

[0110] Blood samples for serum markers of the endocannabinoid system activity [2- Arachidonoylglycerol (2- AG), Anandamide (AEA), Arachidonic Acid, Palmitoylethanolamide (PEA), Oloeylethanolamide (OEA)] along with markers of immune system activity and autoimmunity were taken at the baseline and at the end of each treatment period from a subset of patients that will consent for these tests. Urine samples were taken at the end of each treatment period to assess cannabinoid levels.

Preparation of purified cannabinoids

[0111] Cannabis sativa flowers were dried and ground. The ground plant material contained CBD, and THC in their acidic forms - CBDa and THCa. Decarboxylation process performed at 140°C turned the CBDa and A⁹-THCa to CBD and THC, while releasing CO2 gas. CBD and THC were extracted from the decarboxylated material via supercritical CO2 extraction. The extract was dissolved in ethanol following winterization step at -20°C for 48 hours. The ethanolic winterized extract was filtered to remove waxy constitutes, and the ethanol was evaporated.

[0112] For CBD (cannabidiol, CAS Number: 13956-29-1) preparation, the dried extract was dissolved in pentane under heat to achieve super saturation and cooled to room temperature. Crystallization took place in two stages: first stage: -20°C, second stage: 4°c. After crystallization, the CBD was dried and milled, and stored in air-tight containers, protected from air and light at room temperature.

[0113] For THC (CAS Number: 1972-08-3) preparation, the dried extract was dissolved in cyclohexane and separated in a normal phase column with cyclohexane/ethyl acetate. The clean fractions were dried and dissolved in methanol: water 70:30 for reverse phase chromatography. The reverse phase clean fractions were dried and washed twice with ethanol. The ethanol solution was evaporated to receive neat THC. THC was stored at 4°C under nitrogen in glass containers, protected from light.

[0114] The cannabinoids were >99% pure.

Cannabinoids in oil

[0115] Cannabinoids were added to olive oil in a beaker to concentration of 295 mg/ml CBD and 14.7 mg/ml THC. The beaker was closed with a glass cover, and the mixture was stirred with magnetic stirrer for 60 minutes. The solution was then tested for Cannabinoids concentration via HPLC. Each drop has a volume of 0.034 ml and contains 10 mg CBD and 0.5 mg THC.

Treatment

[0116] Cannabinoid treatments included sublingual administration of a composition comprising cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC) at a weight ratio of 20:1, in olive oil by drops of 0.034 each. Three different groups were: a whole plant extract including CBD, and THC at a weight ratio of 20: 1; a 99% pure CBD and THC mix at a weight ratio of 20: 1 in olive oil (B.O.L pharma, Israel, FDA global G.A.P. approved, GMP condition); and placebo.

[0117] The initial administered dose was 0.1 drop/kg/day divided into three daily doses equal to lmg/kg/day for CBD and 0.05 mg/kg/day for THC, or a placebo (made before addition of the active ingredients to the olive oil). The dose was up-titrated by 0.1 drop/kg/day every other day until intolerance or the maximal dose was reached.

[0118] For subjects weighting 20-40 kgs: maximal CBD dose was 10 mg/kg/day; up to 300 mg/day, and maximal THC dose was 0.5mg/kg/day up to 15 mg/day.

[0119] For subjects weighting 40kgs or more: maximal CBD dose is 7.5 mg/kg/day; up to 420 mg/day, and maximal THC dose was 0.375 mg/kg/day up to 21 mg/day.

[0120] .

Outcome measures

[0121] Participants were assessed every four weeks through the 32-week trial. The first primary outcome measure is the per-item mean scores on the parent-rated Home Situations Questionnaire -Autism Spectrum Disorder (HSQ-ASD). The second and third primary outcome measures are based on the normalized T-scores from the externalizing section of the parent-rated Child Behavior Checklist (CBCF) and the Autism Parenting Stress Index (APSI). Adverse events are assessed using a modified version of the Fiverpool Adverse Events Profile (FAEP). The caregivers complete these outcome questionnaires every four weeks. Secondary outcome measures were based on the global improvement and efficacy index items of the clinician-rated CGI and the parent and teacher rated Social Responsiveness Scale (SRS). These outcome questionnaires were completed at the beginning and end of each treatment period.

[0122] The HSQ-ASD and CBCF are common well-standardized tools to measure behavioral problems in children with ASD. In a systematic review of tools used to measure behavioral problems in children with ASD by Hanratty et ah, 2015, the authors conclude that in terms of strength of measurement properties the overall preferred choice appears to fall between the HSQ- ASD and CBCF tests. The APSI was chosen as the third primary outcome measure as it incorporates the subjective impact of the behavioral changes on parents. As secondary outcome measures we chose to use the clinician impression of the treatment response (CGI-I, CGI-D) - an indirect but more comparative assessment and the parents and teachers ratings of social deficits that are not necessarily related to behavioral problems (SRS).

[0123] HSQ-ASD (Chowdhury et ah, 2015)- This is a 24-item parent-rated measure of noncompliant behavior in children with ASD. The scale yields per-item mean scores of 0 to 9 (higher scores indicating greater noncompliance) for the total score and on each of two, 12-item subscales (Demand- specific, Socially Inflexible). Internal consistency, measured using Cronbach’s a, is 0.84 for Socially Inflexible and 0.89 for Demand Specific. Test-retest reliability for the subscale totals are considered significant with r=0.57 for Socially Inflexible, r=0.58 for Demand Specific, and r=0.57 for the combined total. Validity analyses using the per-item mean HSQ-ASD score and the two subscale scores provide evidence of good convergent and divergent validity.

[0124] CBCL- validated Hebrew version (Achenbach 1991), is a questionnaire used as an instrument for screening emotional and behavioral problems in children aged 4-18 years old. The 120 CBCL items are rated on a three-point Likert scale: 0 (not true), 1 (somewhat or sometimes true) or 2 (very true or often true). The CBCL generates three broad band results: an internalizing score (summing up anxious/depressed scale, somatic complaints scale and withdrawn scale) an externalizing score (summing up non-compliant scale and aggressive behavior scale) and a total score. These three composite scores are converted to T-scores (M = 50, SD = 10). A T-score of 70 and above (at least two standard deviations above the mean for the general population) is generally considered to be clinically significant. For this study we will use the externalizing section only. Numerous studies have supported the reliability and validity of CBCL across many different clinical samples. In a sample of ASD-affected youths, the internal consistency was good with r = 0.92 on the aggressive behavior scale. Structural validity for the complete measure was good.132 [0125] Autism Parenting Stress Index (APSI, Silva, 2012) is a 13-item parent-rated test designed to assess parental stress from interventions to control disruptive behavior in children with ASD. Items fall into three categories: the core social disability, difficult-to-manage behavior, and physical issues. Each item is ranked from‘Not stressful’, ‘Sometimes creates stress’, Often creates stress’,‘Very stressful on a daily basis’, to‘So stressful that sometimes we feel we cannot cope’. Internal consistency is 0.83 (Cronbach’s alpha) and test-retest coefficient is 0.88.

[0126] Clinical Global Impressions Scale (CGI, Guy, 1976) is a seven-point scale designed to measure severity of illness (CGI-S), overall improvement from baseline (CGI-I) and drug effects (both therapeutic effect and side effects, CGI-D). This measure has been used in several ASD clinical trials. Scores in the severity scale range from 1 (normal) through 7 (amongst the most severely-ill patients). In the improvement scale, scores range from 1 (very much improved) to 4 (unchanged), and then up to 7 (very much-worse). Scores of much improved or very much improved are used to define positive responses; all other scores indicate negative responses. Treatment response ratings takes into account both therapeutic efficacy and treatment-related adverse events and range from 0 (marked improvement and no side-effects) to 4 (unchanged or worse and side-effects outweigh the therapeutic effects). Each component of the CGI is rated separately. At each clinic visit, the CGI-I and CGI-D will be rated by the clinician. At baseline, the clinician will ask parents to identify the child’ s three most pressing problems and the clinician will document the frequency (e.g., tantrums per day), duration, and intensity of episodes and effect of the behavior on the family. This baseline evaluation will be reviewed and revised in subsequent visits and used to score the CGI-I and CGI-D.

[0127] Social Responsiveness Scale (SRS - Hebrew version, Constantino and Gruber, 2005), is a 70/71 -item, caregiver (pSRS) or teacher (tSRS) questionnaire used to determine the severity of social deficit exhibited by participants with ASD. The SRS contains five subscales: social awareness, social cognition, social communication, social motivation, and autistic mannerisms. These subscales measure the following abilities: to recognize social cues; to interpret social cues; to use expressive verbal and nonverbal language skills; to engage in social-interpersonal behaviors; and to display stereotypical behaviors and restricted interests which are characteristic of autism. Each item is rated on a four-point Likert scale, (0 to 3, total scores range from 0 to 195) with a higher score indicating greater impairment. Each subscale can be converted into a T-score. The SRS Total T-score reflects the sum of the T-scores for the five scales. SRS T-scores between 60 and 75 indicate a level of autistic social impairment that is“mild to moderate,” whereas scores above 75 indicate a“severe” level. The caregivers and teachers will complete the SRS based on the patient's behavior over the previous six weeks at the beginning of the study (baseline), week 12, week 28 and week 44. The SRS has been used extensively to assess behavioral problems in ASD research 136-141 with evidence for high levels of internal reliability, a = 0.97; test-retest reliability, a = 0.85; and inter-rater reliability coefficients ranging from 0.75 to 0.91 across the different pairs of raters.

Adverse Events

[0128] Tolerability and adverse effects were assessed using a modified Liverpool Adverse Events Profile (LAEP) that includes all 19 items of the original LAEP and another 15 items to cover all reported significant side effects of CBD and THC in former studies. Parents or caregivers complete the modified LAEP every four weeks. Additionally, adverse events were monitored and documented at each assessment visit whether considered related to study treatments or not. At each assessment visit the following was recorded: recent health concerns, use of medical services, concomitant medications, and change in ongoing medications. Reports of new adverse events or worsening of previously reported events were rated mild (present, but not a problem), moderate (present, posing a problem or intervention required to prevent a problem), or severe (present, posing a problem and needing intervention). Hospitalization was documented as a serious adverse event.

Statistical Plan and Data Analyses

[0129] The primary endpoint in this study was a non-compliant behavior as best measured by the Home Situations Questionnaire - Autism Spectrum Disorder (HSQ-ASD). Based on previous large studies in children with ASD and moderate or greater behavioral problems (same target population as current study), a mean total score of 4.0 ± 1.5 was expected without treatment and 25% decrease in the total score reflected meaningful improvement. The study was designed as a three-arm semi-crossover study. Participants were randomized to receive one treatment option in period one and then crossover to one of the other options in the second period. This design allowed a within subject comparison of each of the three treatment options. Assuming a moderate correlation of 0.3 between observations for the same subject and 10% attrition.

[0130] The study data was analyzed by means of a mixed linear model, where the child’s ID was treated as a random effect. Tukey's correction will be used for the three multiple comparisons. Results

[0131] Fifty participants were randomly assigned to each the three treatments plans as explained above. 46, 45 and 46 subjects in the different treatment groups (respectively) crossed-over to the second treatment period and 44 in each group completed the study (12% attrition; a total of 150 children; 120 boys; mean age, 11.71+4.05 years). The ASD symptoms severity were in the high range in 78.7% of the children according to the Autism Diagnostic Observation Schedule (ADOS- 2, Comparison score = 8-10) and adaptive level in the Vineland behavior scales was "low" (standard score <70) in 88%.

[0132] As can be seen from Fig. 1, patients not treated with the cannabinoid combination (the placebo group - P) exhibited an average BMI increase of 0.22 kg/m² (first treatment duration) or 0.59 kg/m² (second treatment duration). However, treating with CBD and THC at a ratio of 20: 1 resulted in a decrease in BMI of between 0.15 kg/m² and 0.53 kg/m² kg/m². Specifically, Treatment by a combination of pure cannabinoids (C) resulted in an average decrease in BMI of 0.46 kg/m² in the first treatment period and 0.15 kg/m² in the second, while treatment with the whole extract (W) resulted in an average decrease in BMI of 0.53 kg/m² in the first treatment period and 0.25 kg/m² in the second. Statistics of the results following the first treatment period showed that the increase in BMI in the placebo group was significantly greater (P=0.0001) than the weight change observed in the active-treatment arms.

[0133] Fig. 2 further shows the effect of treatment with cannabinoids on weight, in correlation with the subject’s initial weight before treatment with the cannabinoids. As can be seen from this figure, the group of obese people showed the largest decrease in weight from baseline after treatment with cannabinoids, and even a larger difference between the placebo and the cannabinoid treatment. The difference for obese individuals between placebo and cannabis treatment was significant (p-value = 0.0008). The definitions of normal, overweight, and obese are according to the World Health Organization (WHO) BMI-for-age growth reference standards from 2007. In general, overweight is equivalent to BMI of above 25/kg/m2 at 19 years of age, and obese is equivalent to BMI of above 30/kg/m2 at 19 years of age.

Claims

1. A cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, for use in preventing, inhibiting, or reducing weight gain resulting from treatment by at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer in a subject, wherein CBD:THC weight ratio in the cannabinoid combination is about 20: 1.

2. The cannabinoid combination of claim 1, formulated as a sole pharmaceutical composition, optionally further comprising a pharmaceutically acceptable carrier.

3. The cannabinoid combination of claim 1 or claim 2, wherein the CBD is formulated for administration at a daily dose of about 200 mg to about 500 mg, and the THC is formulated for administration at a daily dose of about 10 mg to about 25 mg.

4. The cannabinoid combination of any one of claims 1-3, wherein the cannabinoid combination is formulated for administration once, twice, or three times a day.

5. The cannabinoid combination of any one of claims 1-4, wherein the cannabinoid combination is formulated for administration sublingually, orally, or by inhalation.

6. The cannabinoid combination of any one of claims 1-5, wherein the antipsychotic drug is an atypical antipsychotic such as amisulpride, aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, or ziprasidone, or a typical antipsychotic such as chlorpromazine or haloperidol.

7. The cannabinoid combination of any one of claims 1-5, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI) such as paroxetine or fluoxetine, a tricyclic antidepressant such as amitriptyline, or a tetracyclic antidepressant such as mirtazapine.

8. The cannabinoid combination of any one of claims 1-5, wherein the mood stabilizer is carbamazepine, lithium, or valproic acid.

9. The cannabinoid combination of any one of claims 1-8, wherein the subject suffers from psychosis or a disorder selected from anxiety disorder, bipolar disorder, borderline personality disorder, a chronic pain condition, dementia, depression, dysthymia, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), schizoaffective disorder, schizophrenia, and Tourette syndrome.

10. The cannabinoid combination of any one of claims 1-9, wherein the subject does not have autistic spectrum disorder (ASD).

11. The cannabinoid combination of any one of claims 1-10, wherein the subject is obese prior to administration of the cannabinoid combination.

12. The cannabinoid combination of any one of claims 1-11, wherein the cannabinoid combination is administered to the subject prior to treatment with the at least one psychiatric drug.

13. A method for preventing, inhibiting, or reducing weight gain resulting from administration of at least one psychiatric drug selected from an antipsychotic drug, an antidepressant, and a mood stabilizer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC), or an enantiomer, diastereomer, or racemate thereof, wherein CBD:THC weight ratio in the cannabinoid combination is about 20:1.