WO2020188551A1

WO2020188551A1 - Methods and compositions for treating autism spectrum disorder and associated disorders

Info

Publication number: WO2020188551A1
Application number: PCT/IL2019/050310
Authority: WO
Inventors: Tamir GEDO
Original assignee: Bol Pharma Ltd
Current assignee: Bol Pharma Ltd
Priority date: 2019-03-20
Filing date: 2019-03-20
Publication date: 2020-09-24
Anticipated expiration: 2021-09-20
Also published as: WO2020188568A1

Abstract

The present invention provides cannabinoid combinations comprising, as the only cannabinoids, cannabidiol (CBD) and optionally A9-tetrahydrocannabinol (A9-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A9-THC are at a weight ratio of about 20:1; pharmaceutical and nutraceutical compositions comprising the cannabinoid combination; and methods for treating autism spectrum disorder (ASD) or a disorder associated therewith, or for improving the efficacy of treatment of an ASD patient administered with a standard of care drug, by administering said cannabinoid combinations.

Description

METHODS AND COMPOSITIONS FOR TREATING AUTISM SPECTRUM

DISORDER AND ASSOCIATED DISORDERS

FIEUD OF INVENTION

[001] This invention is directed to combinations comprising cannabidiol (CBD) and D⁹- tetrahydrocannabinol (A⁹-THC), for use in treating autism spectrum disorder (ASD) or disorders associated with ASD.

BACKGROUND OF THE INVENTION

[002] Children, adolescents and young adults with autism spectrum disorder (ASD) have social and communication difficulties, stereotyped or repetitive behaviors and interests, sensory problems, and in many cases, cognitive impairment and disruptive behaviors. These deficits are present in early childhood, and lead to significant disabilities. ASD affects up to 15 per 1,000 children worldwide and it is a major public health challenge.

[003] About 50% of children and youth with ASD demonstrate behavioral difficulties, including tantrums, noncompliance, aggression, and self-injury, a rate higher than in any other neurodevelopmental disorder. Maladaptive behaviors in children with ASD can be divided to internalizing problems (e.g. emotionally reactive, depressed/anxious affect, somatic complaints and withdrawal) and externalizing problems (e.g. aggression, defiance and inattentive).

[004] The behavioral difficulties of children with ASD increase their social isolation and often cause more distress to caregivers than the core autistic symptoms. Maladaptive behaviors also limit the child’s ability to benefit from intervention efforts and thereby impact the long-term prognosis.

[005] The current treatment for behavioral problems in ASD is based on extensive behavioral interventions combined with medications, particularly atypical antipsychotics and mood stabilizers. However, both the efficacy and tolerability of pharmacotherapy in children with ASD are less favorable than data typically seen in non- ASD children with similar symptoms. Up to 40% of the children and youth with ASD suffer from refractory maladaptive behavior, despite extensive behavioral and medical treatment. Side effects of the medication are common and serious. Common side effects of medications used for disruptive behavior associated with ASD include weight gain and metabolic syndrome, somnolence, extrapyramidal symptoms, enuresis and hyperprolactinemia. [006] Refractory behavioral problems severely impact quality of life of individuals with ASD and take a heavy toll on their families. The frustration from current medical treatment leads to an exceptionally high percentage of parents seeking help from complementary and alternative medicine along with hectic efforts to find new pharmacotherapy options.

[007] Cannabis is known to have an effect on social behavior in humans. The main targets of cannabis in the brain are the CB1 cannabinoid receptors. CB1 is highly expressed in the frontal cortex and subcortical areas associated with social functioning. The CB 1 receptors and their endogenous ligands anandamide and 2-arachidonoil-glycerol (2-AG) regulate social play and social anxiety in animal models and in humans.

[008] A⁹-THC and CBD are the two main cannabinoids in the cannabis plant. Both A⁹-THC and CBD are neuroactive but only A⁹-THC is psychoactive (inducing the“high” feeling). CBD is not psychoactive and even attenuates the A⁹-THC-induced psychoactivity. As a result, in medical cannabis, strains with higher CBD concentrations are being used while in street cannabis the D⁹- A⁹-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 A⁹-THC and CBD concentrations in the strain used. The higher the A⁹-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

[009] In one aspect, the present invention provides a method for treating autism spectrum disorder (ASD) or a disorder associated therewith, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20: 1.

[010] In another aspect, the present invention provides a method for improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist, said method comprising further administering to said subject a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and D⁹ - tc t a h y droc a n n a b i n o 1 (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

[Oi l] In yet another aspect, the present invention provides a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (D⁹- THC), or an enantiomer, diastereomer, or racemate thereof, for use in treating autism spectrum disorder (ASD) or a disorder associated therewith, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

[012] In still another aspect, the present invention provides a cannabinoid combination for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an oc2 agonist, said cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (D⁹- THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

[013] In a further aspect, the present invention provides a kit for use in treating autism spectrum disorder (ASD) or a disorder associated therewith, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and A⁹-tetrahydrocannabinol (D⁹- THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC in the kit are the only cannabinoids, and are at weight ratio of about 20:1.

[014] In yet a further aspect, the present invention provides a kit for use in for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug for treating ASD such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and A⁹-tetrahydrocannabinol (D⁹- THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are the only cannabinoids in the kit, and are at weight ratio of about 20:1. BRIEF DESCRIPTION OF THE DRAWINGS

[015] Figs. 1A-1D show % of participants with a positive response as measured by various measures following treatment with a mixture of pure CBD and A⁹-THC (bars marked with C) compared to placebo (bars marked with P) during the first treatment period (left) and the second treatment period (right). A. Clinical global Impression - Improvement (CGI-I), positive response = much improved or very much improved on the CGI-I scale; B. Disruptive behavior - HSQ- ASD, positive response = 25% decrease in the Home Situations Questionnaire-ASD score; C. Core symptoms- Social Responsiveness Scale (SRS) -2nd edition, positive response = 15% decrease in the SRS-2 Total raw score; D. Autism Parenting Stress Index (APSI - disruptive behavior), positive response = 25% decrease in the APSI score. * Pearson Chi-Square between subjects analyses.

[016] Figs. 2A-2D show % of participants with a positive response as measured by various measures following treatment with a mixture of pure CBD and A⁹-THC (bars marked with C) compared to a whole cannabis extract (bars marked with W) during the first treatment period (left) and the second treatment period (right). A. CGI-I, positive response = much improved or very much improved on the CGI-I scale; B. Disruptive behavior - HSQ-ASD, positive response = 25% decrease in the Home Situations Questionnaire-ASD score; C. Core symptoms- SRS Scale -2nd edition, positive response = 15% decrease in the SRS-2 Total raw score; D. APSI (disruptive behavior), positive response = 25% decrease in the APSI score. * Pearson Chi-Square between subjects analyses.

DETAILED DESCRIPTION

[017] Preliminary data obtained by the inventors suggest high efficacy and tolerability for high cannabidiol (CBD) - low D⁹ - tc t ra h y droc a n n a b i n o 1 (A⁹-THC) whole plant extracts (having CBD: A⁹-THC ratios of 6:1 or 20: 1) in 36 children with autism spectrum disorder (ASD) and severe behavioral problems (unpublished data).

[018] 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; Russo and Taming, 2011). 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:A⁹-THC weight ratio of 20:1). Additionally, the maximal doses used are lower than those used in previous studies of same age groups (lOmg/kg/day CBD and 0.5 mg/kg/day A⁹-THC).

[019] As can be seen from Figs. 1A-1D, the pure cannabinoids mixture was more effective than placebo according to several measures for ASD, including Clinical Global Impression - Improvement (CGI-I) in which 56% of the treated patients showed positive result compared to 23% of the placebo -treated patients, Disruptive behavior - HSQ-ASD (48% vs. 34%), Core symptoms- Social Responsiveness Scale -2nd edition (30% vs. 7%), and Autism Parenting Stress Index (disruptive behavior) (38% vs. 16%).

[020] However, more surprising was the comparison between the whole plant extract and the pure cannabinoids. In contrast to the "entourage effect" theory described above, the inventors have found that the performance of the purified cannabinoids was very similar to that of the whole plant extract (Figs. 2A-2D), especially in the CGI-I measure (Fig. 2A).

[021] Accordingly, in one aspect, the present invention provides a method for treating autism spectrum disorder (ASD) or a disorder associated therewith, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (D⁹- THC), or an enantiomer, diastereomer, or racemate thereof.

[022] In some embodiments, the weight ratio of CBD: A⁹-THC is from about 10:1 to about 30:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 15:1 to about 25:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 17:1 to about 23:1. In some embodiments, the weight ratio of CBD: A⁹-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, or about 30: 1.

[023] In some embodiments the weight ratio of CBD to A⁹-THC in the cannabinoid combination of the invention is about 20:1.

[024] The term "therapeutically effective amount" as used herein means an amount of said 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.

[025] 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.

[026] The term "cannabinoid combination" as used herein refers to a combination of the cannabinoids CBD and A⁹-THC, which are administered together or separately for treating ASD or disorders associated thereof. 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.

[027] The phrase "as the only cannabinoids" as used herein means that the only cannabinoids comprised in the cannabinoid combination are CBD and A⁹-THC.

[028] In some embodiments, the cannabinoid combination of the invention is prepared from substantially pure preparations of CBD and/or A⁹-THC.

[029] 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.

[030] In some embodiments, the purity of the substantially pure CBD and/or A⁹-THC preparations is at least 96%, at least 97%, at least 98%, or at least 99%.

[031] 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 A⁹-THC by increasing CBi 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).

[032] A⁹-THC (6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-67/-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. A⁹-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. A⁹-THC naturally exists as (6a/?,10a/?)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6//- benzo[c]chromen- 1 -ol.

[033] For purposes of clarity, the terms CBD and A⁹-THC as used throughout the description and the claims are intended to include enantiomer, diastereomer, or racemate thereof.

[034] In some embodiments, the CBD and/or A⁹-THC are the naturally existing enantiomers, (2-[(li?,6i?)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol) and

(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6//-benzo[c]chromen-l-ol, respectively.

[035] Natural cannabinoids, including CBD and A⁹-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.

[036] 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 A⁹-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.

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

[038] In some embodiments, the cannabinoid combination consists essentially of CBD and D⁹-

THC. [039] The phrase“consisting essentially of’ used herein with respect to the cannabinoid combination of the present invention means that the CBD and A⁹-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 drugs used to treat ASD and disorders associated with ASD are not considered as part of the cannabinoid combination, however they may be administered together therewith, as further discussed below.

[040] The CBD and A⁹-THC of the cannabinoid combination according to any of the embodiments described above may be formulated as separate pharmaceutical compositions for administration concurrently, or separately, at any order.

[041] 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, provided that both cannabinoids comprised in the cannabinoid combination are present in the circulation of the subject at the same time. The relative timing of the sequential administrations therefore depends on the half-life of the cannabinoids in the circulation of the subject. For example, when orally taken, CBD has a half-life of 18-32 hours, and A⁹-THC has a half-life of about 1-13 days. However, the half-life may be affected by various factors, including other medications or substances taken, or whether the subject has been using cannabis before.

[042] Accordingly, in some embodiments, the CBD and A⁹-THC according to any of the above embodiments, are administered concomitantly or sequentially at any order.

[043] In some embodiments, the CBD and the A⁹-THC comprised in the cannabinoid combination at any of the ratios indicated above, are formulated as a sole pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.

[044] Each one of the pharmaceutical compositions mentioned above, which includes one or both of the CBD and the A⁹-THC, may be formulated for any suitable administration route as defined below, but is preferably formulated for oral, or sublingual administration, or for inhalation. In some specific embodiments, the pharmaceutical composition of the invention is administered by sublingual administration.

[045] 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.

[046] 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).

[047] 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.

[048] 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.

[049] 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, said 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.

[050] 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.

[051] 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.

[052] 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).

[053] 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., corn 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.

[054] 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.

[055] 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.

[056] 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 - h y d o x y p o p y 1 - b - c y c 1 o dc x t i n (HPCD), a surfactant such as Tween-80, and isotonic sodium chloride solution.

[057] 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. [058] 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.

[059] CBD and A⁹-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.

[060] In some embodiments, the daily dose of CBD for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about 150mg to about 600mg, from about 200mg to about 500mg, from about 200mg to about 400mg, from about 5mg/kg to about 15mg/kg, or about lOmg/kg.

[061] In some embodiments, the daily dose of A⁹-THC for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments, is from about 7.5mg to about 30mg, from about lOmg to about 25mg, from about lOmg to about 20mg, from about 0.25mg/kg to about 0.75mg/kg, or about 0.5 mg/kg.

[062] 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 cure is effected or diminution of the disease state or symptoms is achieved.

[063] Accordingly, in some embodiments, each of the pharmaceutical compositions defined above, comprising one or both CBD and A⁹-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.

[064] 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.

[065] Autism spectrum disorder encompasses a range of conditions classified as neurodevelopmental disorders in the DSM-5, published in 2013. Individuals diagnosed with ASD must present two types of symptoms: deficits in social communication and social interaction; and restricted, repetitive patterns of behavior, interests or activities.

[066] The DSM-5 redefined the autism spectrum disorders to encompass the previous (DSM- IV-TR) diagnoses of autism, Asperger syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), and childhood disintegrative disorder. Features of these disorders include social deficits, communication difficulties, stereotyped or repetitive behaviors and interests, sensory issues, and in some cases, cognitive delays.

[067] Accordingly, in some embodiments, the ASD is selected from autistic disorder, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PDD- NOS).

[068] ASD may be syndromic of 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. A further distinction may be made for non-syndromic patients without a significant perinatal complication (such as prematurity, SGA (small for gestational age), neonatal intensive care of 8 or more days, or severe neonatal seizures), which is referred to as idiopathic ASD.

[069] In some embodiments, the ASD treated according to any of the above embodiments is non- syndromic ASD. In some embodiments, the ASD is idiopathic ASD. In some embodiments, the ASD is syndromic ASD.

[070] Several standardized assessment tools are used to evaluate the severity of symptoms in ASD patients. These tests include Autism diagnostic observation schedule (ADOS), the parent rated - Social Communication Questionnaire (SCQ), the parent interview based - Vineland™-II and the behavioral observation based - Childhood Autism Rating Scale (CARS -2).

[071] It appears that the lower the ADOS score are, indicating less severe core symptoms (which belong either to the repetitive restrictive behavior (RRB) or the social communication (SC)), the higher the effect of the cannabinoid combination. It also appears that the cannabinoid treatment is more effective for males and there is a positive correlation with age.

[072] Accordingly, in some embodiments, the subject has a low score in the ADOS questionnaire. In some embodiments, the core symptoms of the subject are not severe.

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

[074] In some embodiments, the ASD subject treated according to any of the above embodiments is a male and the ASD is idiopathic ASD. In more specific embodiments, the subject is a male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe. In still more specific embodiments, the subject is an adult male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe.

[075] Symptoms of ASD include behavioral problems that may be internalizing problems such as being emotionally reactive, depressed/anxious affect, expressing somatic complaints and withdrawal, or externalizing problems such as aggression, defiance and inattentiveness, tantrums and self-injury. Additionally, symptoms include restrictive/repetitive behavior and deficit in social communication/interaction behaviors (https://www.autismspeaks.org/what- autism/symptoms) .

[076] Accordingly, in some embodiments, treating ASD is treating symptoms of ASD selected from internalizing behavioral problems and externalizing behavioral problems.

[077] In some embodiments, treating ASD is treating symptoms of ASD selected from repetitive behavior, language impairment, and deficit in social interaction.

[078] In some embodiments, treating ASD is treating symptoms of ASD selected from acute anxiety and physical aggression.

[079] In some embodiments, the method according to any of the above embodiments is for treating a symptom of ASD that is a behavioral problem, such as tantrums, noncompliance, aggression, self-injury, repetitive behavior, or deficit in social interaction. [080] In some embodiments, the behavioral problem is an internalizing behavioral problem such as emotional reactivity, depressed/anxious affect, somatic complaints, or withdrawal; or an externalizing behavioral problem such as aggression, defiance, or inattentive.

[081] Up to 40% of the children and youth with ASD suffer from drug -refractory maladaptive behavior, despite extensive behavioral and medical treatment. Drug -refractory behavioral problems are defined as symptoms of aggression, self-injury, and tantrums requiring medication adjustment despite previous trials of risperidone and aripiprazole or previous trials of three psychotropic drugs targeting the symptom cluster, one of which was risperidone or aripiprazole.

[082] Accordingly, in some embodiments, the behavioral problems are drug -refractory.

[083] In some embodiments, treating ASD according to any of the above embodiments results in improvement in at least one of the measures used to evaluate success in treatment, which are Clinical Global Impression - Improvement (CGI-I), Disruptive behavior - HSQ-ASD, Core symptoms - Social Responsiveness Scale (SRS) and Autism Parenting Stress Index (disruptive behavior). In some embodiments, treating ASD according to any of the above embodiments results in improvement in the CGI-I measure.

[084] In some embodiments, the method according to any of the above embodiments is for treating a communication problem. In some embodiments, the method of any of the above embodiments is directed to treating a subject suffering from non-syndromic ASD and having a communication problem. In some specific embodiments, the subject is a male subject, suffering from non-syndromic ASD, and having a communication problem. In some more specific embodiments, the subject is a male adult subject, suffering from non-syndromic ASD, and having a communication problem. In some specific embodiments, the non-syndromic ASD is idiopathic ASD.

[085] In some embodiments, the method of any of the above embodiments is directed to treating an ASD-associated disorder, or co-morbidity, such as obesity, insomnia, depression, allergies, or an immune-mediated disorder.

[086] In some embodiments, the patient has epilepsy.

[087] In some embodiments, the patient does not have epilepsy.

[088] Patients treated with the cannabinoid combination of the invention may further be treated with a standard of care (SOC) drug).

[089] The term "standard of care" (SOC) drug as used herein relates to any drug that is used by standard practice for treating ASD or any symptom thereof. [090] The SOC drug may be an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor (SSRI, for treating depression), a benzodiazepine, a stimulant, an a.2 agonist, or another such as enalapril, stratera X2, circadin, deralin, dekinet, L-thyroxine, valcyclovir, norditropin (somatropin- GH), singular X2, decapeptyl, xenazine, cyproheptadine (antihistamine), or zeto.

[091] Accordingly, in some embodiments, the method according to any of the embodiments defined above comprises administering the cannabinoid combination further in combination with standard of care (SOC) drug, or at least one (i.e., one, two, three, or more) SOC drugs, such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, an a.2 agonist, or another type of drug. The cannabinoid combination adds value by improving the efficacy of the drug, by providing relief from symptoms not addressed by the drug, or by alleviating side effects of the drug.

[092] The cannabinoid combination of the invention may be used for alleviating adverse events related to ASD or treatment of ASD such as disturbed sleep, nervousness, and confusion.

[093] In some embodiments, the antipsychotic drug is aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; the AED is carbamazepine, lamotrigine, topiramate, or valproic acid; the selective serotonin reuptake inhibitor is clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; the stimulant is an amphetamine, an ephedrine, or ritalin; the a2 agonist is clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine; and/or the another type of drug is enalapril, stratera X2, circadin, deralin, dekinet, L-thyroxine, valcyclovir, norditropin (somatropin- GH), singular X2, decapeptyl, xenazine, cyproheptadine (antihistamine), or zeto.

[094] The medications used for treating various symptoms of autism may cause severe adverse effect, including somnolence, extrapyramidal symptoms, enuresis and hyperprolactinemia, weight gain and even obesity.

[095] In some embodiments, administering the cannabinoid combination of the invention enables using lower doses of the drug, thereby reducing side-effects.

[096] In some embodiments, administration of the cannabinoid combination of the invention for treating ASD facilitates using sub -therapeutic doses of the presently used drugs, or even eliminates the need for the presently used drugs altogether. [097] 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 ASD.

[098] In some embodiments, the SOC drug is administered at a sub-therapeutic dose.

[099] In an additional aspect, the present invention provides a method for improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug, or at least one SOC drug (such as one, two, three or more SOC drugs) selected from the group consisting of an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, an a.2 agonist, or another type of drug, said method comprising further administering to said subject a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof.

[0100] The phrase "improving the efficacy" as used herein means that the combined administration of the cannabinoid combination and the treatment results in an improved response to the combined treatment compared with the response to the treatment alone, such as improvement in any of the parameters measured as indication for a successful treatment, or any positive effect on symptoms related to the ASD or to disorders associated therewith as described herein. Improved efficacy may also mean that the SOC drug administered as part of the treatment may be administered at a lower dose or at a lower frequency.

[0101] In some embodiments, the weight ratio of CBD: A⁹-THC is from about 10:1 to about 30:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 15:1 to about 25:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 17:1 to about 23:1. In some embodiments, the weight ratio of CBD: A⁹-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, or about 30: 1.

[0102] In some embodiments, the CBD and A⁹-THC are at weight ratio of about 20:1.

[0103] The CBD and A⁹-THC of the cannabinoid combination according to any of the embodiments described above may be formulated as separate pharmaceutical compositions for administration concurrently, or separately, at any order.

[0104] In some embodiments, the CBD and the A⁹-THC comprised in the cannabinoid combination at any of the ratios indicated above, are formulated as a sole pharmaceutical composition, further comprising a pharmaceutically acceptable carrier. [0105] Each one of the pharmaceutical compositions mentioned above, which includes one or both of the CBD and the A⁹-THC, may be formulated for any suitable administration route as defined below, but is preferably formulated for oral, or sublingual administration, or for inhalation. In some specific embodiments, the pharmaceutical composition of the invention is administered by sublingual administration.

[0106] In some embodiments, the daily dose of CBD for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about 150mg to about 600mg, from about 200mg to about 500mg, from about 200mg to about 400mg, from about 5mg/kg to about 15mg/kg, or about lOmg/kg.

[0107] In some embodiments, the daily dose of A⁹-THC for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments, is from about 7.5mg to about 30mg, from about lOmg to about 25mg, from about lOmg to about 20mg, from about 0.25mg/kg to about 0.75mg/kg, or about 0.5 mg/kg.

[0108] 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 cure is effected or diminution of the disease state or symptoms is achieved.

[0109] Accordingly, in some embodiments, each of the pharmaceutical compositions defined above, comprising one or both CBD and A⁹-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.

[0110] Accordingly, in some embodiments, the ASD is selected from autistic disorder, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PDD- NOS).

[0111] In some embodiments, the ASD subject treated according to any of the above embodiments is non-syndromic ASD. In some embodiments, the ASD is idiopathic ASD. In some embodiments, the ASD is syndromic ASD.

[0112] Accordingly, in some embodiments, the subject has a low score in the ADOS questionnaire. In some embodiments, the core symptoms of the subject are less severe.

[0113] In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject. 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.

[0114] In some embodiments, the ASD subject treated according to any of the above embodiments is a male and the ASD is idiopathic ASD. In more specific embodiments, the subject is a male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe. In still more specific embodiments, the subject is an adult male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe.

[0115] Accordingly, in some embodiments, the ASD treatment is directed to treating symptoms of ASD selected from internalizing behavioral problems and externalizing behavioral problems.

[0116] In some embodiments, the ASD treatment is directed to treating symptoms of ASD selected from repetitive behavior, language impairment, and deficit in social interaction.

[0117] In some embodiments, the ASD treatment is directed to treating symptoms of ASD selected from acute anxiety and physical aggression.

[0118] In some embodiments, the ASD treatment is directed to treating a symptom of ASD that is a behavioral problem, such as tantrums, noncompliance, aggression, self-injury, repetitive behavior, or deficit in social interaction.

[0119] In some embodiments, the behavioral problem is an internalizing behavioral problem such as emotional reactivity, depressed/anxious affect, somatic complaints, or withdrawal; or an externalizing behavioral problem such as aggression, defiance, or inattentive.

[0120] In some embodiments, the ASD treatment according to any of the above embodiments results in improvement in at least one of the measures used to evaluate success in treatment, which are Clinical Global Impression - Improvement (CGI-I), Disruptive behavior - HSQ-ASD, Core symptoms - Social Responsiveness Scale (SRS) and Autism Parenting Stress Index (disruptive behavior).

[0121] In some embodiments, the ASD treatment is directed to treating a communication problem. In some embodiments, the ASD treatment is directed to treating a subject suffering from non- syndromic ASD and having a communication problem.

[0122] In some embodiments, the ASD treatment is directed to treating an ASD-associated disorder, or co-morbidity, such as obesity, insomnia, depression, allergies, or an immune -mediated disorder.

[0123] In some embodiments, the antipsychotic drug is aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; the AED is carbamazepine, lamotrigine, topiramate, or valproic acid; the selective serotonin reuptake inhibitor is clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; the stimulant is an amphetamine, an ephedrine, or ritalin; the a.2 agonist is clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine; and/or the another type of drug is enalapril, stratera X2, circadin, deralin, dekinet, L-thyroxine, valcyclovir, norditropin (somatropin- GH), singular X2, decapeptyl, xenazine, cyproheptadine (antihistamine), or zeto.

[0124] According to an additional aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, for use in treating autism spectrum disorder (ASD) or a disorder associated therewith.

[0125] In some embodiments, the weight ratio of CBD: A⁹-THC is from about 10:1 to about 30:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 15:1 to about 25:1. In some embodiments, the weight ratio of CBD: A⁹-THC is from about 17:1 to about 23:1. In some embodiments, the weight ratio of CBD: A⁹-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, or about 30:1.

[0126] In some embodiments, the CBD and A⁹-THC are at weight ratio of about 20:1.

[0127] The CBD and A⁹-THC of the cannabinoid combination according to any of the embodiments described above may be formulated as separate pharmaceutical compositions for administration concurrently, or separately, at any order.

[0128] In some embodiments, the CBD and the A⁹-THC comprised in the cannabinoid combination at any of the ratios indicated above, are formulated as a sole pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.

[0129] Each one of the pharmaceutical compositions mentioned above, which includes one or both of the CBD and the A⁹-THC, may be formulated for any suitable administration route as defined below, but is preferably formulated for oral, or sublingual administration, or for inhalation. In some specific embodiments, the pharmaceutical composition of the invention is administered by sublingual administration.

[0130] In some embodiments, the daily dose of CBD for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about 150mg to about 600mg, from about 200mg to about 500mg, from about 200mg to about 400mg, from about 5mg/kg to about 15mg/kg, or about lOmg/kg.

[0131] In some embodiments, the daily dose of A⁹-THC for treating ASD or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments, is from about 7.5mg to about 30mg, from about lOmg to about 25mg, from about lOmg to about 20mg, from about 0.25mg/kg to about 0.75mg/kg, or about 0.5 mg/kg.

[0132] 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 cure is effected or diminution of the disease state or symptoms is achieved.

[0133] Accordingly, in some embodiments, each of the pharmaceutical compositions defined above, comprising one or both CBD and A⁹-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.

[0134] Accordingly, in some embodiments, the ASD is selected from autistic disorder, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PDD- NOS).

[0135] In some embodiments, the ASD treated according to any of the above embodiments is non- syndromic ASD. In some embodiments, the ASD is idiopathic ASD. In some embodiments, the ASD is syndromic ASD.

[0136] Accordingly, in some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD in a subject having a low score in the ADOS questionnaire. In some embodiments, the core symptoms of the subject are less severe.

[0137] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD in a male subject. In some embodiments, the subject is a female subject. In some embodiments, the subject is a child. In some embodiments, the subject is adolescent. In some embodiments, the subject is an adult.

[0138] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD in a male and the ASD is idiopathic ASD. In more specific embodiments, the subject is a male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe. In still more specific embodiments, the subject is an adult male, the ASD is idiopathic ASD, and the ADOS assessment score at baseline was low, indicating that the core symptoms were not severe.

[0139] Accordingly, in some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD symptoms selected from internalizing behavioral problems and externalizing behavioral problems.

[0140] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD symptoms selected from repetitive behavior, language impairment, and deficit in social interaction.

[0141] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating ASD symptoms selected from acute anxiety and physical aggression.

[0142] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating an ASD symptom that is a behavioral problem, such as tantrums, noncompliance, aggression, self-injury, repetitive behavior, or deficit in social interaction.

[0143] In some embodiments, the behavioral problem is an internalizing behavioral problem such as emotional reactivity, depressed/anxious affect, somatic complaints, or withdrawal; or an externalizing behavioral problem such as aggression, defiance, or inattentive.

[0144] In some embodiments, the cannabinoid combination of any of the above embodiments when used for treating ASD results in improvement in at least one of the measures used to evaluate success in treatment, which are Clinical Global Impression - Improvement (CGI-I), Disruptive behavior - HSQ-ASD, Core symptoms - Social Responsiveness Scale (SRS) and Autism Parenting Stress Index (disruptive behavior).

[0145] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating an ASD symptom that is a communication problem. In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating a subject suffering from non-syndromic ASD and having a communication problem.

[0146] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating an ASD-associated disorder, or co-morbidity, such as obesity, insomnia, depression, allergies, or an immune-mediated disorder.

[0147] In some embodiments, the antipsychotic drug is aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; the AED is carbamazepine, lamotrigine, topiramate, or valproic acid; the selective serotonin reuptake inhibitor is clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; the stimulant is an amphetamine, an ephedrine, or ritalin; the a.2 agonist is clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine; and/or the another type of drug is enalapril, stratera X2, circadin, deralin, dekinet, L-thyroxine, valcyclovir, norditropin (somatropin- GH), singular X2, decapeptyl, xenazine, cyproheptadine (antihistamine), or zeto.

[0148] According to yet a further aspect, the present invention provides a cannabinoid combination for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug, or at least one SOC drug (such as one, two, or three SOC drugs) for treating ASD selected from the group consisting of an antipsychotic drug, a selective serotonin reuptake inhibitor, an anticonvulsant, and a stimulant drug, said cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof.

[0149] In some embodiments, the CBD and A⁹-THC are at weight ratio of about 20:1.

[0150] In some embodiments, the cannabinoid combination for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith, comprises, as the only cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof. In some embodiments, the CBD and A⁹-THC are at weight ratio of from about 20:1, formulated as a sole pharmaceutical or nutraceutical composition.

[0151] 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.

[0152] According to yet another aspect, the present invention is directed to the use of cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, as the only cannabinoids, in the preparation of a pharmaceutical composition for treating autism spectrum disorder (ASD) or a disorder associated therewith. In some embodiments, the CBD and the A⁹-tetrahydrocannabinol (A⁹-THC) are at a ratio of 20:1.

[0153] According to still another aspect, the present invention is directed to the use of cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, as the only cannabinoids, in the preparation of a pharmaceutical composition for improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug, or at least one SOC drug (such as one, two, or three SOC drugs) for treating ASD selected from the group consisting of an antipsychotic drug, a selective serotonin reuptake inhibitor, an anticonvulsant, and a stimulant drug. In some embodiments, the CBD and the D⁹- tetrahydrocannabinol (A⁹-THC) are at a ratio of 20:1.

[0154] It is conceivable that the cannabinoid combination of the invention, including CBD, and A⁹-THC will be provided as a kit. Such a kit includes two compositions, each comprising one of the two cannabinoids.

[0155] Accordingly, in a further aspect, the present invention provides a kit for use in treating autism spectrum disorder (ASD) or a disorder associated therewith, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and D⁹- tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC in the kit are the only cannabinoids, and are at weight ratio of about 20:1.

[0156] In yet a further aspect, the present invention provides a kit for use in for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug for treating ASD selected from the group consisting of an antipsychotic drug, a selective serotonin reuptake inhibitor, an anticonvulsant, and a stimulant drug, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are the only cannabinoids in the kit, and are at weight ratio of about 20: 1.

[0157] Unless otherwise indicated, all numbers expressing, e.g., weight ratios 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.

[0158] The invention will now be illustrated by the following non-limiting Examples. EXAMPLES

Example 1: The effect of a combination of CBD and A⁹-THC on patients with ASD and behavioral problems

Study design

[0159] Participants ages 5-29 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).

[0160] Primary outcome measures: for each month of the study, parents or primary caregivers rated disruptive behavior and noncompliance on co-primary outcomes: The Home Situations Questionnaire-Autism Spectrum Disorder (HSQ-ASD), the Child Behavior Checklist (CBCL; externalizing scale), and the Autism Parenting Stress Index (APSI). Secondary outcome measures: Clinical Global Impression (CGI, improvement and efficacy index items, clinician rated) and Social Responsiveness Scale (SRS, parent and teacher rated) were assessed at baseline and termination of each treatment period. Adverse events were documented every 4 weeks.

Participants

[0161] Inclusion criteria were: ages 5-29 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 .

[0162] 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.

[0163] 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.

[0164] Most patients were also treated with at least one of the following medications during the study: antipsychotics - 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.

[0165] 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

[0166] 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.

[0167] 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 .

[0168] 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)

[0169] Social Communication Questionnaire (SCO) Lifetime Form {Flutter 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.

[0170] Vineland Adaptive Behavior Scales (Vineland™, 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.

[0171] 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.

[0172] 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

[0173] 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

[0174] Cannabis sativa flowers were dried and ground. The ground plant material contained CBD, and A⁹-THC in their acidic forms - CBDa and A⁹-THCa. Decarboxylation process performed at 140°C turned the CBDa and A⁹-THCa to CBD and A⁹-THC, while releasing CO2 gas. CBD and A⁹-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.

[0175] 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.

[0176] For A⁹-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 A⁹-THC. A⁹-THC was stored at 4°C under nitrogen in glass containers, protected from light.

[0177] The cannabinoids were >99 pure.

Cannabinoids in oil

[0178] Cannabinoids were added to olive oil in a beaker to concentration of 295 mg/ml CBD and 14.7 mg/ml A⁹-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 A⁹-THC. Treatment

[0179] Cannabinoid treatments included sublingual administration of a composition comprising cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-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 A⁹-THC at a weight ratio of 20: 1; a 99% pure CBD and A⁹-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.

[0180] 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 A⁹-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.

[0181] For subjects weighting 20-40 kgs: maximal CBD dose was 10 mg/kg/day; up to 200 mg/day, and maximal A⁹-THC dose was 0.5mg/kg/day up to 10 mg/day.

[0182] For subjects weighting 40-80 kgs: maximal CBD dose is 7.5 mg/kg/day; up to 300 mg/day, and maximal A⁹-THC dose was 0.33 mg/kg/day up to 15 mg/day.

[0183] For subjects weighting more than 80 kgs: maximal CBD dose was 5 mg/kg/day up to 400 mg/day (for 80 kilo already 400 mg), and maximal A⁹-THC dose was 0.25 mg/kg/day up to 20 mg/day.

Outcome measures

[0184] 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 (CBCL) and the Autism Parenting Stress Index (APSI). Adverse events are assessed using a modified version of the Liverpool Adverse Events Profile (LAEP). 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.

[0185] The HSQ-ASD and CBCL 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 CBCL 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).

[0186] 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.

[0187] 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

[0188] 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.

[0189] 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.

[0190] 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

[0191] 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 A⁹-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

[0192] 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.

[0193] 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

Terms:

WP: whole plant extract;

PU: purified CBD + A⁹-THC;

PL: placebo

Tr. - treatment plan - comprising two treatment periods (first and second);

Tr. 1: 1st period: PL; 2nd period: WP

Tr. 2: 1st period: PU; 2nd period: PL

Tr. 3: 1st period: WP; 2nd period: PU

PR: positive response, defined as follows: CGI: Improvement, positive response = much improved or very much improved on the CGI-I scale. HSQ-ASD: Disruptive behavior, positive response = 25% decrease in the Home Situations Questionnaire-ASD score; SRSt: Severity of social deficit, positive response = 15% decrease in the SRS-2 total raw score; APSI: Disruptive behavior Positive response = 25% decrease in the APSI score [0194] Fifty participants were randomly assigned to each the three treatments plans as explained above. As seen from Table 1, 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%.

Table 1: demographic and baseline characteristics

[0195] "Perinatal" means at least one of perinatal complications such as prematurity, SGA (small for gestational age), neonatal intensive care of 8 or more days, or severe neonatal seizures.

Analysis of differences between treatments

1. Comparison of treatment ( whole extract or purified CBD and D⁹ -THC) vs. placebo

[0196] In the first treatment period, the rates of a positive response to the cannabis treatments (whole plant + pure cannabinoids) vs. placebo were: 43% and 21% on the CGI-scale (p=0.0089, see Table 2) and 43% and 19% (p=0.0132, Table 2) on the on the SRSt. Similar results were seen on the same comparison on the second treatment period on CGI-I and SRSt, in addition, there was a significant difference 44% vs. 22% (p=0.0244) on the HSQ-ASD as well (Table 3). Table 2: WP + PU vs. PL (treatment period 1)

Table 3: WP + PU vs. PL (treatment period 2)

[0197] In the cannabis treatments vs. placebo there was a positive response on the CGI-I in the younger age group 5-12 years on the first and second treatment period (Tables 4 and 6) but in the older group, a significant difference was seen only on the teacher SRS assessment (p=0.0113) on the first treatment period (Table 5).

Table 4: WP+PU vs. PL at treatment period 1, Age 5-12 years old

Table 5: WP+PU vs. PL at treatment period 1, Age >12-21 years old

Table 6: WP+PU vs. PL at treatment period 2, Age 5-12 years old

Table 7: WP+PU vs. PL at treatment period 2, Age >12-21 years old

2. Comparison of whole extract vs. placebo

[0198] In the comparison of the whole plant extract to the placebo, the rates of a positive response to the active treatment on CGI-I was 53% and 23% in the placebo (p=0.0027, Table 8). When we have analyzed the same aspect in the different age groups the significance was seen in the younger age group 5-12 years on the first and second treatment period (Tables 9 and 11) but not in the older group (Tables 10 and 12). In the older age group, we did see a difference in the SRSt assessment 61% positive responses on the whole plant extract treatment and 13% on the placebo (p=0.0037, Table 10).

Table 8: WP vs. PL at treatment period 2

Table 9: WP vs. PL at treatment period 1, Age 5-12 years old

Table 10: WP vs. PL at treatment period 1, Age >12-21 years old

Table 11: WP vs. PL at treatment period 2, Age 5-12 years old

Table 12: WP vs. PL at treatment period 2, Age >12-21 years old

3. Comparison of purified CBD and D⁹ -THC to placebo

[0199] In the comparison of the pure cannabinoids to the placebo on the second period, the rates of a positive response to the active treatment were 55% and 23% in the placebo on CGI-I (p=0.0013, Table 13). Different rates of positive response to the active treatment were 30% and 7% in the placebo on SRSt (p=0.013). In the younger age group 5-12 years on the second treatment period we did see a difference in the CGI-I 62% and 20% (p=0.0033, Table 16).

Table 13: PU vs. PL at treatment period 2 (Fig. 1)

Table 14: PU vs. PL at treatment period 1, Age 5-12 years old

Table 15: PU vs. PL at treatment period 1, Age >12-21 years old

Table 16: PU vs. PL at treatment period 2, Age 5-12 years old

Table 17: PU vs. PL at treatment period 2, Age >12-21 years old

4. Comparison of treatments : whole extract vs. purified CBD and D⁹ -THC

[0200] Surprisingly, the comparison of the whole plant extract arm to the pure cannabinoids arm did not raise any significant differences, implying that the treatment by the complete extract does not provide significantly better results than treating with pure CBD and A⁹-THC. This is surprising since the complete extract was expected to perform better due to the "entourage effect". Table 18: WP vs. PU at treatment period 2

Table 19: WP vs. PU at treatment period 1, Age 5-12 years old

Table 20: WP vs. PU at treatment period 1, Age >12-21 years old

Table 21: WP vs. PU at treatment period 2, Age 5-12 years old

Table 22: WP vs. PU at treatment period 2, Age >12-21 years old

[0201] Adverse events that were more prevalent in the active treatment groups included: somnolence, decreased appetite, and disturbed sleep. There were no treatment-related severe adverse events. The average number of adverse events during a 3-month period was 4.28, 5.02 and 4.87 for participants in the placebo, pure cannabinoids, and cannabis extract groups, respectively.

Table 23: syndromic vs. non-syndromic SRS responders

Syndromic ASD is a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype. "Syndromic" means that there is genetic confirmation or a classic syndrome (e.g. Cornelia de Lange), and "Suspected syndromic" means that the genetic workup is negative or incomplete.

Table 23 shows response as defined by Social Responsiveness Scale (SRS) questionnaire to treatment with purified cannabinoids. The patients were divided into two groups - syndromic and non-syndromic (as defined above). Positive response in the SRS questionnaire (measuring severity of social deficit) was defined as 15% decrease in the SRS -2 total raw score.

As can be seen from the Table 23, all the responders were in the non-syndromic group of patients.

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Claims

1. A method for treating autism spectrum disorder (ASD) or a disorder associated therewith, comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

2. The method of claim 1, wherein the CBD and the A⁹-THC are administered concomitantly or sequentially at any order.

3. The method of claim 1, wherein the CBD and the A⁹-THC are independently administered sublingually, orally, or by inhalation.

4. The method of claim 1, wherein each of the CBD and the A⁹-THC are independently administered once, twice, or three times a day.

5. The method of claim 1, wherein the daily dose of the CBD is from about 200 mg to about 400 mg; and/or the daily dose of the A⁹-THC is from about 10 mg to about 20 mg.

6. The method of claim 1, wherein the CBD and the A⁹-THC are formulated as a sole pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.

7. The method of claim 6, wherein said pharmaceutical composition is formulated for sublingual or oral administration, or for inhalation.

8. The method of claim 1, wherein said ASD is selected from Asperger’s syndrome, autistic disorder, and pervasive developmental disorder not otherwise specified.

9. The method of claim 1, wherein said ASD is syndromic ASD.

10. The method of claim 1, wherein said ASD is non-syndromic ASD.

11. The method of claim 1, for treating a symptom of ASD which is a behavioral problem such as tantrums, noncompliance, aggression, self-injury, repetitive behavior, or deficit in social interaction.

12. The method of claim 11, wherein said behavioral problem is drug-refractory.

13. The method of claim 11, wherein said behavioral problem is an internalizing behavioral problem such as emotional reactivity, depressed/anxious affect, somatic complaints, or withdrawal; or an externalizing behavioral problem such as aggression, defiance, or inattentive.

14. The method of claim 1, wherein said treating ASD results in an improvement in at least one measure selected from the group consisting of Clinical Global Impression - Improvement (CGI-I), Home Situations Questionnaire (HSQ-ASD), Social Responsiveness Scale (SRS) and Autism Parenting Stress Index (disruptive behavior).

15. The method of claim 1, for treating a symptom of ASD which is a communication problem.

16. The method of claim 15, wherein said subject is suffering from non-syndromic ASD.

17. The method of claim 1, wherein said disorder associated with ASD is obesity, insomnia, depression, allergy, or an immune-mediated disorder.

18. The method of claim 1, wherein said subject is further being treated with a SOC drug, such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist.

19. The method of claim 18, wherein the antipsychotic drug is aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; the AED is carbamazepine, lamotrigine, topiramate, or valproic acid; the selective serotonin reuptake inhibitor is clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; the stimulant is an amphetamine, an ephedrine, or ritalin; and/or the a.2 agonist is clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine.

20. The method of claim 18, wherein said SOC drug is administered at a sub-therapeutic dose.

21. A method for improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist, said method comprising further administering to said subject a therapeutically effective amount of a cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and D⁹- tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

22. A cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, for use in treating autism spectrum disorder (ASD) or a disorder associated therewith, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

23. The cannabinoid combination for use in treating autism spectrum disorder (ASD) or a disorder associated therewith of claim 22, wherein the CBD and A⁹-THC are formulated as a sole pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

24. The cannabinoid combination for use in treating ASD or a disorder associated therewith of claim 22, wherein said cannabinoid combination is used further in combination with a standard of care (SOC) drug such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist.

25. The cannabinoid combination for use in treating ASD or a disorder associated therewith of claim 24, wherein the antipsychotic drug is aripiprazole, chlorpromazine, clonidine, fluphenazine, geodon, haloperidol, risperidone, thioridazine, or zyprexa; the AED is carbamazepine, lamotrigine, topiramate, or valproic acid; the selective serotonin reuptake inhibitor is clomipramine, fluoxetine, fluvoxamine, or sertraline; the benzodiazepine is alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam, or triazolam; the stimulant is an amphetamine, an ephedrine, or ritalin; and/or the a2 agonist is clonidine, dexmedetomidine, fadolmidine, guanabenz, guanethidine, guanfacine, guanoxabenz, medetomidine, methyldopa, methylnorepinephrine, tizanidine, or xylazine.

26. A cannabinoid combination for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a2 agonist, said cannabinoid combination comprising, as the sole cannabinoids, cannabidiol (CBD) and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are at weight ratio of about 20:1.

27. The cannabinoid combination for use in improving the efficacy of a treatment in a subject suffering from ASD or a disorder associated therewith of claim 26, wherein the cannabinoid combination is formulated as a sole pharmaceutical or nutraceutical composition.

28. A kit for use in treating autism spectrum disorder (ASD) or a disorder associated therewith, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC in the kit are the only cannabinoids, and are at weight ratio of about 20:1.

29. A kit for use in for use in improving the efficacy of a treatment in a subject suffering from autism spectrum disorder (ASD) or a disorder associated therewith and administered with a standard of care (SOC) drug for treating ASD such as an antipsychotic drug, an anti-epileptic drug (AED), a selective serotonin reuptake inhibitor, a benzodiazepine, a stimulant, or an a.2 agonist, the kit including a composition comprising cannabidiol (CBD), and a composition comprising and A⁹-tetrahydrocannabinol (A⁹-THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and A⁹-THC are the only cannabinoids in the kit, and are at weight ratio of about 20:1.