DISORDERS

FIELD OF INVENTION

[001] This invention is directed to combinations comprising cannabidiol (CBD), cannabidivarin (CBDV), and optionally D ⁹ - tc t a h y droc a n n a h i n o 1 (A ⁹ -THC) for use in treating epilepsy or disorders associated with epilepsy.

BACKGROUND OF THE INVENTION

[002] Epilepsy is the most common and serious central nervous system (CNS) disorder afflicting people of any age, ethnic, social, and geographic category, with an estimated prevalence of 0.5%- 1% .

[003] Epileptic seizures are the result of excessive and abnormal cortical nerve cell electrical activity in the brain. Despite the development of new anti-epileptic drugs (AEDs) since the early 2000s, approximately a third of people with epilepsy remain resistant to pharmacotherapy, even after polytherapy. It has been shown that 47% of patients with new-onset epilepsy can achieve complete seizure-freedom with the first AED, 13% of patients may become seizure-free using a second agent, and only 4% with a third or more agent. In 2010, the International League Against Epilepsy (ILAE) issued a consensus statement about the definition of drug resistant epilepsy (DRE). According to this definition, DRE is defined as failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. In children, refractory/intractable epilepsy is broadly defined as failure to achieve complete or at least acceptable control of seizures in response to AEDs or other treatment modalities. Refractory epilepsy has been reported in 9-23% of children with epilepsy. It can present significant treatment challenges and is associated with progressive cognitive impairment, depression, anxiety, developmental delay and impairment of executing activities of daily living. In general, epilepsy co-morbidities include cognitive decline, depressive disorders and schizophrenia, all of which are worsened by poorly controlled seizures.

[004] As mentioned above, most patients are treated with an AED as monotherapy or combinations of AEDs. However, failure of drug response is a major limitation in the treatment of epilepsy. Of those diagnosed with DRE, only 5% of patients per year will enter seizure remission as a result of medication changes. Surgery may be considered for lesional partial epilepsy, as this has the greatest chance of producing remission. Other treatment modalities include electrical nerve stimulation and diet therapies, but these are more likely to be palliative, rather than curative, treatment options.

[005] Cannabis sativa has a long history of use for the control of human seizures (Mechoulam 1986). The main targets of cannabis in the brain are the CB 1 cannabinoid receptors. CB 1 is highly expressed in the frontal cortex and subcortical areas associated with social functioning.

[006] Cannabidiol (CBD) and A ⁹ -tetrahydrocannabinol (A ⁹ -THC) are the two most well-known cannabinoids in the cannabis plant. Both A ⁹ -THC and CBD are neuroactive but only A ⁹ -THC is psychoactive (inducing the“high” feeling). CBD is not psychoactive and even attenuates the D ⁹ - THC-induced psychoactivity. As a result, in medical cannabis, strains with higher CBD concentrations are being used while in street cannabis the A ⁹ -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 of recreational cannabis users. Preclinical studies suggest that naturally-occurring cannabinoids (phytocannabinoids) have anticonvulsant effects which are mediated by the endocannabinoid system. CBD and CBDV have shown anti-seizure effects in both in-vivo and in-vitro models. In contrast to A ⁹ -THC, CBD does not produce euphoric or intrusive psychoactive side effects when used to treat seizures.

[007] Recently, cannabinoids reemerged as a therapeutic option for refractory epilepsy (Tzadok, 2016; Press, 2015; Devinsky, 2016) and a growing number of children and adolescent patients with epilepsy are treated with cannabinoids. A systematic review of controlled and observational evidence has concluded that pharmaceutical-grade CBD as adjuvant treatment in pediatric-onset DRE may reduce seizure frequency (Stockings 2017). Very recently, Epidiolex®, a purified CBD product, gained a unanimous positive result of FDA Advisory Committee Meeting as an add-on treatment of seizures associated with two rare forms of epilepsy: Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients two years of age and older.

[008] Several studies were conducted in children with refractory epilepsy treated with a whole plant extract or with a formulation of purified cannabinoids in olive oil, in which CBD and D ⁹ - THC were at a 20: 1 ratio (Tzadok, 2016). Results indicated reduced seizure frequency with some adverse effects.

[009] Cannabidivarin (CBDV) is a propyl cannabinoid found in cannabis. It is a homolog of CBD, and has a side chain shorter by two CH ₂ units. CBD and its propyl counterpart CBDV appear to have broadly similar applications in medicine. CBDV is non-psychoactive, and like CBD, it appears to have strong effectiveness as an anti-epileptic agent.

[010] CBDV-rich botanical extracts have been shown to possess strongly anticonvulsant properties in mice and rats (Hill et ah, 2013), as well as suppressing the expression of certain genes related to epilepsy. US publication no. 2014/0243405 discloses a whole-plant extract rich in CBDV and CBD, which is intended for treating neurological conditions including epilepsy. The ratios of CBDV to CBD presented in this publication are between 7: 1 and 1:2, with CBDV being the main cannabinoid.

SUMMARY OF THE INVENTION

[011] According to one aspect, the present application provides a method for treating epilepsy or a disorder associated therewith comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally D ⁹ - tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at a weight ratio of from about 20: 1 to about 30: 1.

[012] According to another aspect, the present application provides a method for improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith being treated by an anti-epileptic drug (AED), said method comprising further administering to said subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and D ⁹ - THC, when present, are at weight ratio of from about 20: 1 to about 30: 1.

[013] According to a further aspect, the present application provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, for use in treating epilepsy or a disorder associated therewith, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20: 1 to about 30: 1.

[014] According to yet another aspect, the present application provides a cannabinoid combination for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith being treated by an anti-epileptic drug (AED), said cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, respectively, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20: 1 to about 30: 1.

[015] According still another aspect, the present application provides a kit for use in treating epilepsy or a disorder associated therewith, comprising two or three composition, each composition comprising one or two of cannabidiol (CBD), cannabidivarin (CBDV), and D ⁹ - tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the kit includes, as the only cannabinoids, CBD and CBDV, or CBD, CBDV, and A ⁹ -THC, and the CBD and CBDV in the kit are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, in the kit are at weight ratio of from about 20: 1 to about 30: 1.

[016] According to yet an additional aspect, the present application provides a kit for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith being treated by an anti-epileptic drug (AED), comprising two or three composition, each composition comprising one or two of cannabidiol (CBD), cannabidivarin (CBDV), and A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the kit includes, as the only cannabinoids, CBD and CBDV, or CBD, CBDV, and A ⁹ -THC, and the CBD and CBDV in the kit are at a weight ratio of from about 20:1 to about 10: 1, and the CBD and A ⁹ -THC, when present, in the kit are at weight ratio of from about 30: 1 to about 20: 1.

BRIEF DESCRIPTION OF THE DRAWINGS

[017] Figs. 1A-1C show anticonvulsant properties of cannabis strain extracts containing high CBD content. 1A. Topaz extract reduced Pentylenetetrazole (PTZ)-induced mortality. Lined bars: alive (lower part of bars), filled bars: dead (upper part of bar in control), Chi-square test, P < 0.0007). IB. Topaz extract significantly increased latency to first tonic-clonic seizures (F _{2, 54} =8.64, P=0.0005). 1C. Treatment with extracts from Topaz and Turkiz lowered development of tonic- clonic seizures. Filled bars: percentage of mice not expressing seizures (upper part of bars); lined bars: percentage of mice expressing seizures (lower part of bars), (Chi-square test, P = 0.0007). Results are expressed as mean (± S.E.M.).

DETAILED DESCRIPTION

[018] The inventors of the present application have found that a cannabis extract from the cannabis strain Topaz had an anti-convulsive effect, manifested in reducing pentylenetetrazole (PTZ)-induced mortality, significantly increasing latency to first tonic-clonic seizures, and lowering the % of mice developing tonic-clonic seizures, as can be seen from Fig. 1. The extract of this strain of cannabis has a weight ratio of cannabidiol (CBD) to cannabidivarin (CBDV) to D ⁹ - 1 c t a h y d o c a n n a b i n o 1 (A ⁹ -THC), of about 30:2: 1, respectively. Surprisingly, the Topaz extract was more effective than an extract from a different cannabis strain, Turkiz, which has a ratio of CBD: CBDV: A ⁹ -THC of about 40: 1: 1, respectively.

[019] Most reports of the therapeutic value of cannabinoids are based on treatment with whole plant extracts. Several studies suggest that synergistic effects exist for numerous cannabis compounds in the whole plant extract (this is termed "entourage effect", Ben-Shabat, 1998; Russo, 2011). For this reason, the difference in performance between the two cannabis strains was surprising, and may indicate that the difference in the ratio of the three cannabinoids between the two strains was the reason for the different effect. Accordingly, the inventors continued to examine the effect of this ratio in clinical trials with isolated CBD, CBDV, and A ⁹ -THC. The advantage of using isolated cannabinoids as opposed to a whole plant extract is that mixtures of highly pure cannabinoids provide a more reproducible and reliable drug compared to a whole plant extract. However, the notion of the "entourage effect" implies that purified cannabinoids may behave in the same way as the complete extract.

[020] In one aspect, the present invention provides a method for treating epilepsy or a disorder associated therewith comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomers, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at a weight ratio of from about 20: 1 to about 30:1.

[021] 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.

[022] 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.

[023] The term "cannabinoid combination" as used herein refers to a combination of the cannabinoids CBD, CBDV, and optionally A ⁹ -THC, which are administered together or separately for treating epilepsy or disorders associated therewith. The cannabinoid combination may be comprised in a single formulation or in two or three separate formulations, as further discussed below. All components of the cannabinoid combination must be administered so that they are present in the circulation of the subject at the same time.

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

[025] In some embodiments, the cannabinoid combination of the invention is prepared from substantially pure preparations of CBD, CBDV, and A ⁹ -THC.

[026] 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.

[027] In some embodiments, the purity of the substantially pure CBD, CBDV, and A ⁹ -THC is at least 96%, at least 97%, at least 98%, or at least 99%.

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

[029] A ⁹ -THC (6,6,9-trimethyl-3-pentyl-6a,7,8,l0a-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 CB ₂ receptor, mainly expressed in cells of the immune system. A ⁹ -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. A ⁹ -THC naturally exists as (6a/?,l0a/?)-6,6,9-trimethyl-3-pentyl-6a,7,8,l0a-tetrahydro- 67/-benzo[c]chromen-l-ol. [030] CBDV (2-(3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5-propylbenz ene-l,3-diol), has been shown to act as an agonist of human transient receptor potential (TRP) channels of the ankyrin type-l (TRPA1), TRP channels of vanilloid type-l and type-2 agonist, but as a TRP channel of melastatin type-8 antagonist. CBDV has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring , and accordingly exists 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. CBDV naturally exists as (2-((iR,6R)-3-methyl-6- (prop-l-en-2-yl)cyclohex-2-enyl)-5-propylbenzene-l,3-diol).

[031] For purposes of clarity, the terms CBD, CBDV, and A ⁹ -THC as used throughout the description and the claims are intended to include enantiomer, diastereomer, or racemate thereof.

[032] In some embodiments, the CBD, CBDV, and/or A ⁹ -THC are the naturally existing enantiomers, (2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pent ylbenzene-l,3- diol), (2-((iR,6R)-3-methyl-6-(prop-l-en-2-yl)cyclohex-2-enyl)-5-pr opylbenzene-l,3-diol), and (6aR,l0aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,l0a-tetrahydro-6/ /-benzo[c]chromen-l-ol, respectively.

[033] Natural cannabinoids, including CBD, CBDV, and A ⁹ -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.

[034] 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, CBDV, or THC may be prepared using any one of the methods disclosed in the art, e.g., by resolution of the racemic form by recrystallization techniques; chiral synthesis; extraction with chiral solvents; or chromatographic separation using a chiral stationary phase. A non-limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including simulated moving bed chromatography, can also be used. A wide variety of chiral stationary phases are commercially available.

[035] In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is from about 10: 1 to about 20:1, from about 15: 1 to about 20: 1, from about 10: 1 to about 15: 1, from about 12: 1 to about 18: 1, or from about 14: 1 to about 16: 16. In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is about 10: 1, about 11: 1, about 12: 1, about 13: 1, about 14:1, about 15: 1, about 16: 1, about 17: 1, about 18:1, about 19: 1, or about 20: 1. In some embodiments, the weight ratio of CBD to CBDV in the cannabinoid combination is about 15: 1, or 15 mg CBD per one mg CBDV.

[036] In some embodiments, and for any weight ratio of CBD:CBDV, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is from about 20:1 to about 30: 1, from about 25: 1 to about 30: 1, from about 20: 1 to about 25: 1, from about 22:1 to about 28:1, or from about 24:1 to about 26:1. In some embodiments, the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is 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. In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC is about 30: 1, or 30 mg of CBD per 1 mg of A ⁹ -THC.

[037] In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD: CBDV: A ⁹ -THC in the cannabinoid combination is about 30:2: 1.

[038] In some embodiments, the cannabinoid combination does not comprise A ⁹ -THC.

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

[040] In some embodiments, the cannabinoid combination consists essentially of CBD, CBDV, and optionally A ⁹ -THC.

[041] The phrase “consisting essentially of’ used herein with respect to the cannabinoid combination of the present invention means that the CBD, CBDV, and optionally A ⁹ -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 epilepsy and disorders associated with epilepsy are not considered as part of the cannabinoid combination, however they may be administered together therewith, as further discussed below.

[042] Each one of the CBD, CBDV, and A ⁹ -THC (if present) of the cannabinoid combination of any of the embodiments described above may be separately formulated as a pharmaceutical composition for administration concurrently with any of the other cannabinoids, or separately, at any order. Alternatively, two of the cannabinoids may be formulated together as a single pharmaceutical composition, while the third is formulated as a separate pharmaceutical composition. The resulting pharmaceutical compositions may be administered concomitantly or sequentially at any order.

[043] 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 all 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; CBDV has a half-life of about 200-220 minutes; and 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.

[044] Accordingly, in some embodiments, the CBD, CBDV, and A ⁹ -THC (when present) according to any of the above embodiments, are administered concomitantly or sequentially at any order.

[045] In some embodiments, the CBD, CBDV, and A ⁹ -THC, when present, 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.

[046] Each one of the pharmaceutical compositions mentioned above, which includes one, two, or all three of the CBD, CBDV, and optionally A ⁹ -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.

[047] 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.

[048] 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).

[049] The pharmaceutical compositions disclosed herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19* 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.

[050] 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.

[051] 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.

[052] 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.

[053] 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.

[054] 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).

[055] 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.

[056] 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, chew able 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.

[057] 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.

[058] 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.

[059] 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.

[060] 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.

[061] CBD, CBDV, and A ⁹ -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.

[062] In some embodiments, the daily dose of CBD for treating epilepsy or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about l50mg to about 600mg, from about 200mg to about 450mg, from about 200mg to about 300mg, or l5mg/kg for up to 30kg and about 450mg for 30 kg and above.

[063] In some embodiments, the daily dose of CBDV for treating epilepsy or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about lOmg to about 40mg, from about l5mg to about 30mg, from about l5mg to about 20mg, or about lmg/kg for up to 30kg and about 30mg for 30kg and above;

[064] In some embodiments, the daily dose of A ⁹ -THC (when present) for treating epilepsy or a disorder associated therewith in a subject by administering the cannabinoid combination of any of the above embodiments is from about 5mg to about 20mg, from about 7.5mg to about l5mg, from about 7.5mg to about lOmg, or about 0.5mg/kg for up to 30kg and about l5mg for 30 kg and above.

[065] In some more specific embodiments, the maximal daily dose of the CBD is about 450 mg; the maximal daily dose of the CBDV is about 30 mg; and/or the maximal daily dose of the D ⁹ - THC (when present), is about 15 mg.

[066] In some other specific embodiments, the maximal daily dose of the CBD is about 600 mg. In some embodiments, the maximal daily dose of the CBDV is about 40 mg. In some embodiments, the maximal daily dose of the A ⁹ -THC (when present), is about 20 mg.

[067] 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. [068] Accordingly, in some embodiments, each of the pharmaceutical compositions defined above, comprising one, two or three of the CBD, CBDV, and optionally A ⁹ -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 daily, or three times daily, more than three times per day, such as 4, 5, 6 or more times per day as needed, provided that all cannabinoids comprised in the cannabinoid combination are present in the circulation of the subject at the same time.

[069] 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.

[070] As explained above, approximately a third of people with epilepsy remain resistant to pharmacotherapy, even after polytherapy. These refractory patients are especially a target of the present invention, as treating with the cannabinoid combination of the invention may accentuate the effect of the anti-epileptic therapy.

[071] Accordingly, in some embodiments, the subject treated by the cannabinoid combination described in any of the above embodiments is suffering from drug-resistant epilepsy (DRE).

[072] The term "drug-resistant epilepsy" or "DRE" is defined in the International League Against Epilepsy (ILAE) criteria (Kwan et al. Epilepsia, 51(6): 1069-1077, 2010). DRE is defined as failure of adequate trials of two tolerated, appropriately chosen and used anti -epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. However, in children, refractory/intractable epilepsy is more broadly defined as failure to achieve complete or at least acceptable control of seizures in response to AEDs or other treatment modalities.

[073] In some embodiments, the subject is a child. In some embodiments, the subject is adolescent. In some embodiments, the subject is an adult. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.

[074] Epileptic seizures are the hallmark of epilepsy. Epileptic seizures are episodes that can vary from brief and nearly undetectable periods to long periods of vigorous shaking. The most common type (60%) of seizures is convulsive seizures. Of these, one-third begin as generalized seizures from the start, affecting both hemispheres of the brain. Two-thirds begin as focal seizures (which affect one hemisphere of the brain) which may then progress to generalized seizures. The remaining 40% of seizures are non-convulsive. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence and atonic seizures, all involving loss of consciousness. Briefly, tonic seizures cause muscle stiffness; clonic seizures are characterized by repeated, jerky muscle movements of the face, neck, and arms; myoclonic seizures cause spontaneous quick twitching of the arms and legs; tonic-clonic seizures (used to be called "grand mal seizures") include stiffening of the body, shaking, loss of bladder and bowel control, biting of the tongue, and loss of consciousness; atonic seizures cause loss of muscle control; and absence seizures (used to be called "petit mal seizure") cause a blank stare. The seizure is followed by the "post-ictal" state, which is the period of recovery from a seizure.

[075] Accordingly, in some embodiments, the method of treating epilepsy according to any of the above embodiments is directed to treating epileptic seizures. The epileptic seizures treated by the cannabinoid combination of the invention may be convulsive seizures or non-convulsive seizures. In some embodiments, the convulsive seizures are focal seizures. In some embodiments, the convulsive seizures are generalized seizures. The generalized seizures may be tonic, clonic, tonic-clonic, or myoclonic seizures.

[076] In some embodiments, the seizures occur while the subject is awake. In some embodiments, the seizures occur during sleep.

[077] In some embodiments, the method of treating epilepsy according to any of the above embodiments is directed to reducing at least one of the seizures-related parameters, such as seizure duration, seizure frequency, seizure severity, and post-ictal recovery time.

[078] Apart from seizures, equally as relevant are the neurobiochemical changes, cognitive decline, and psychosocial dysfunction which are important components in this multifaceted condition. Epilepsy may be progressive, carrying risks of structural damage to the brain and nervous system, comorbidities (osteoporosis, fractures), and increased mortality (from suicide, accidents, sudden unexpected death in epilepsy, pneumonia, vascular disease), as well as psychological (depression, anxiety), educational, social (stigma, driving), and vocational consequences. Adding to this burden is neuropsychiatric impairment caused by underlying epileptogenic processes (“essential comorbidities”), which appears to be independent of the effects of ongoing seizures themselves.

[079] Therefore, in some embodiments, the method of treating epilepsy of the present invention is directed to treating an epileptic subject further having a disorder associated with epilepsy, such as cognitive decline, depression, anxiety, and sleep impairment.

[080] In some embodiments, the method according to any of the embodiments defined above comprises administering the cannabinoid combination further in combination with an anti- epileptic drug (AED), or at least one (i.e., one, two, three, or more) AED. The cannabinoid combination adds value by improving the efficacy of the AED, or by providing relief from symptoms not addressed by the AED. Different AEDs act via different mechanisms of action: barbiturates such as primidone and phenobarbital are allosteric modulators and (at higher doses) agonists of GABA receptors; carbamazepine, lamotrigine, and phenytoin act by blocking sodium channel; ethosuximide affects neuronal excitability including blocking of T-type calcium channels, and may include effects on other classes of ion channel; valproate/valproic acid probably acts by blocking voltage-gated sodium channels and increasing brain levels of gamma- aminobutyric acid (GABA).

[081] Accordingly, the cannabinoid combination of the invention is administered to a patient who is also treated by an AED selected from the group consisting of an AED that interacts with GABA receptors, an AED which blocks sodium channels, and an AED which blocks calcium channels.

[082] In some embodiments, the AED is selected from the group consisting of acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

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

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

[085] 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 epilepsy.

[086] In an additional aspect, the present invention provides a method for treating epileptic seizures selected from non-convulsive seizures, or convulsive seizures such as focal or generalized seizures, the method comprising administering to a subject in need thereof a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof. In some embodiments, the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20:1 to about 30: 1. In some embodiments, the generalized seizures are selected from tonic, clonic, tonic-clonic, and myoclonic seizures. [087] In yet an additional aspect, the present invention provides a method for treating disorders associated with epilepsy, selected from cognitive decline, depression, anxiety, and sleep impairment in a subject suffering from epilepsy, the method comprising administering to the subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally D ⁹ - tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof. In some embodiments, the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20: 1 to about 30: 1.

[088] In a further aspect, the present invention provides a method for improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith and administered with an anti-epileptic drug (AED), or at least one AED (such as one, two, three or more AEDs), the method comprising further administering to said subject a therapeutically effective amount of a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20:1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20: 1 to about 30:1.

[089] The phrase "improving the efficacy" as used herein means that the combined administration of the cannabinoid combination and the anti-epileptic treatment may result in improved response to the combined treatment compared with the response to the anti-epileptic 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 epilepsy or to disorders associated therewith as described herein. Improved efficacy may also mean that the anti-epileptic drug administered as part of the treatment may be administered at a lower dose or at a lower frequency.

[090] In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is from about 10: 1 to about 20: 1, from about 15:1 to about 20: 1, from about 10: 1 to about 15: 1, from about 12: 1 to about 18: 1, or from about 14: 1 to about 16: 16. In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is about 10: 1, about 11: 1, about 12: 1, about 13: 1, about 14:1, about 15: 1, about 16: 1, about 17: 1, about 18: 1, about 19: 1, or about 20: 1. In some embodiments, the weight ratio of CBD to CBDV in the cannabinoid combination is about 15: 1, or 15 mg CBD per one mg CBDV.

[091] In some embodiments, and for any weight ratio of CBD:CBDV, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is from about 20: 1 to about 30: 1, from about 25: 1 to about 30: 1, from about 20:1 to about 25: 1, from about 22: 1 to about 28: 1, or from about 24: 1 to about 26: 1. In some embodiments, the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is 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. In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC is about 30: 1, or 30 mg of CBD per 1 mg of A ⁹ -THC.

[092] In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD: CBDV: A ⁹ -THC in the cannabinoid combination is about 30:2: 1.

[093] In some embodiments, the cannabinoid combination does not comprise A ⁹ -THC.

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

[095] In some embodiments, the cannabinoid combination consists essentially of CBD, CBDV, and optionally A ⁹ -THC.

[096] In some embodiments, the CBD, CBDV, and A ⁹ -THC (when present), are administered concomitantly or sequentially at any order.

[097] In some embodiments, the CBD, CBDV, and A ⁹ -THC, when present, 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.

[098] In some embodiments, each of the CBD, CBDV, and A ⁹ -THC, when present, is independently administered sublingually, orally, or by inhalation.

[099] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about l50mg to about 600mg; the daily dose of the CBDV is from about 10 to about 40; and/or the daily dose of the A ⁹ -THC (when present), is from about 5 to about 20.

[0100] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about 200mg to about 450mg; the daily dose of the CBDV is from about 15 to about 30; and/or the daily dose of the A ⁹ -THC (when present), is from about 7.5 to about 15.

[0101] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about 200mg to about 300mg; the daily dose of the CBDV is from about 15 to about 20; and/or the daily dose of the A ⁹ -THC (when present), is from about 7.5 to about 10. [0102] In some more specific embodiments, the daily dose of the CBD is about 15 mg/kg for up to 30 kg or about 450 mg for 30 kg and above; the daily dose of the CBDV is about 1 mg/kg for up to 30 kg or about 30 mg for 30 kg and above; and/or the daily dose of the A ⁹ -THC (when present) is about 0.5 mg/kg for up to 30 kg or about 15 mg for 30 kg and above. In some specific embodiments, the maximal daily dose of the CBD is about 450 mg; the maximal daily dose of the CBDV is about 30 mg; and/or the maximal daily dose of the A ⁹ -THC (when present), is about 15 mg.

[0103] In some embodiments, each of the CBD, CBDV, and A ⁹ -THC, when present, is independently administered once, twice, or three times a day.

[0104] In some embodiments, the subject is suffering from drug-resistant epilepsy (DRE).

[0105] In some embodiments, the subject is a child. In some embodiments, the subject is adolescent. In some embodiments, the subject is an adult. In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.

[0106] In some embodiments, the anti-epileptic treatment is directed to treating epileptic seizures. The epileptic seizures treated by the cannabinoid combination of the invention may be convulsive seizures or non-convulsive seizures. In some embodiments, the convulsive seizures are focal seizures. In some embodiments, the convulsive seizures are generalized seizures. The generalized seizures may be tonic, clonic, tonic-clonic, or myoclonic seizures. In some embodiments, the seizures occur while the subject is awake. In some embodiments, the seizures occur during sleep.

[0107] In some embodiments, the anti-epileptic treatment is directed to reducing at least one of the seizures-related parameters, such as seizure duration, seizure frequency, seizure severity, and post-ictal recovery time.

[0108] In some embodiments, the disorder associated with epilepsy is cognitive decline, depression, anxiety, or sleep impairment.

[0109] In some embodiments, the AED is selected from an AED that interacts with GABA receptors, an AED which blocks sodium channels, and an AED which blocks calcium channels.

[0110] In some embodiments, the AED is selected from acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

[0111] In some embodiments, administration of the cannabinoid combination of the invention for treating epilepsy facilitates using sub-therapeutic doses of the presently used drugs. [0112] According to an additional aspect, the present invention provides a cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally D ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, for use in treating epilepsy or a disorder associated therewith, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20:1 to about 30: 1.

[0113] In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is from about 10: 1 to about 20: 1, from about 15:1 to about 20: 1, from about 10: 1 to about 15: 1, from about 12: 1 to about 18: 1, or from about 14: 1 to about 16: 16. In some embodiments, the weight ratio of CBD:CBDV in the cannabinoid combination is about 10: 1, about 11: 1, about 12: 1, about 13: 1, about 14:1, about 15: 1, about 16: 1, about 17: 1, about 18: 1, about 19: 1, or about 20: 1. In some embodiments, the weight ratio of CBD to CBDV in the cannabinoid combination is about 15: 1, or 15 mg CBD per one mg CBDV.

[0114] In some embodiments, and for any weight ratio of CBD:CBDV, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is from about 20: 1 to about 30: 1, from about 25: 1 to about 30: 1, from about 20:1 to about 25: 1, from about 22: 1 to about 28: 1, or from about 24: 1 to about 26: 1. In some embodiments, the weight ratio of CBD:A ⁹ -THC in the cannabinoid combination is 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. In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD:A ⁹ -THC is about 30: 1, or 30 mg of CBD per 1 mg of A ⁹ -THC.

[0115] In some embodiments, the cannabinoid combination comprises A ⁹ -THC, and the weight ratio of CBD: CBDV: A ⁹ -THC in the cannabinoid combination is about 30:2: 1.

[0116] In some embodiments, the cannabinoid combination does not comprise A ⁹ -THC.

[0117] In some embodiments, the cannabinoid combination does not comprise terpenes.

[0118] In some embodiments, the cannabinoid combination consists essentially of CBD, CBDV, and optionally A ⁹ -THC.

[0119] In some embodiments, the CBD, CBDV, and A ⁹ -THC (when present), are administered concomitantly or sequentially at any order.

[0120] In some embodiments, the CBD, CBDV, and A ⁹ -THC, when present, 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.

[0121] In some embodiments, each of the CBD, CBDV, and A ⁹ -THC, when present, is independently administered sublingually, orally, or by inhalation. [0122] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about l50mg to about 600mg; the daily dose of the CBDV is from about 10 to about 40; and/or the daily dose of the A ⁹ -THC (when present), is from about 5 to about 20.

[0123] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about 200mg to about 450mg; the daily dose of the CBDV is from about 15 to about 30; and/or the daily dose of the A ⁹ -THC (when present), is from about 7.5 to about 15.

[0124] In some embodiments, the daily doses for treating epilepsy or an associated disorder in a subject by administering the cannabinoid combination of any of the above embodiments, are: the daily dose of the CBD is from about 200mg to about 300mg; the daily dose of the CBDV is from about 15 to about 20; and/or the daily dose of the A ⁹ -THC (when present), is from about 7.5 to about 10.

[0125] In some more specific embodiments, the daily dose of the CBD is about 15 mg/kg for up to 30 kg or about 450 mg for 30 kg and above; the daily dose of the CBDV is about 1 mg/kg for up to 30 kg or about 30 mg for 30 kg and above; and/or the daily dose of the A ⁹ -THC (when present) is about 0.5 mg/kg for up to 30 kg or about 15 mg for 30 kg and above.

[0126] In some specific embodiments, the maximal daily dose of the CBD is about 450 mg; the maximal daily dose of the CBDV is about 30 mg; and/or the maximal daily dose of the A ⁹ -THC (when present), is about 15 mg.

[0127] In some embodiments, each of the CBD, CBDV, and A ⁹ -THC, when present, is independently administered once, twice, or three times a day.

[0128] In some embodiments, the epilepsy is drug-resistant epilepsy (DRE).

[0129] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating epilepsy or a related disorder in a male subject. In some embodiments the subject is female. In some embodiments, the subject is a child. In some embodiments, the subject is adolescent. In some embodiments, the subject is an adult.

[0130] In some embodiments, the cannabinoid combination of any of the above embodiments is used for treating epileptic seizures. The epileptic seizures treated by the cannabinoid combination of the invention may be convulsive seizures or non-convulsive seizures. In some embodiments, the convulsive seizures are focal seizures. In some embodiments, the convulsive seizures are generalized seizures. The generalized seizures may be tonic, clonic, tonic -clonic, or myoclonic seizures. In some embodiments, the seizures occur while the subject is awake. In some embodiments, the seizures occur during sleep.

[0131] In some embodiments, the cannabinoid combination of any of the above embodiments are used for reducing at least one of the seizures -related parameters, such as seizure duration, seizure frequency, seizure severity, and post-ictal recovery time.

[0132] In some embodiments, the disorder associated with epilepsy is cognitive decline, depression, anxiety, or sleep impairment.

[0133] In some embodiments, said subject is further treated with at least one anti-epileptic drug.

[0134] In some embodiments, the at least one anti-epileptic drug is selected from the group consisting of acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, prysoline, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

[0135] In some embodiments, the at least anti-epileptic drug is used at a sub-therapeutic dose.

[0136] According to yet a further aspect, the present invention provides a cannabinoid combination for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith and administered with an anti-epileptic drug (AED) or at least one AED (such as one, two, three, or more AEDs), said cannabinoid combination comprising, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and D ⁹ - THC, when present, are at weight ratio of from about 20:1 to about 30: 1.

[0137] In some embodiments, the cannabinoid combination for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith comprises, as the only cannabinoids, cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and D ⁹ - THC, when present, are at weight ratio of from about 20:1 to about 30: 1, formulated as a sole pharmaceutical or nutraceutical composition.

[0138] 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. [0139] In a further aspect, the present invention is directed to the use of cannabidiol (CBD), cannabidivarin (CBDV), and optionally D ⁹ - tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, as the only cannabinoids, in the preparation of a pharmaceutical composition for treating epilepsy or associated disorders, wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20:1 to about 30: 1.

[0140] In yet a further aspect , the present invention is directed to the use of cannabidiol (CBD), cannabidivarin (CBDV), and optionally A ⁹ -tetrahydrocannabinol (A ⁹ -THC), or an enantiomer, diastereomer, or racemate thereof, for the preparation of a pharmaceutical composition for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith administered with an AED or at least one AED (such as one, two, three, or more AEDs), wherein the CBD and CBDV are at a weight ratio of from about 10: 1 to about 20: 1, and the CBD and A ⁹ -THC, when present, are at weight ratio of from about 20: 1 to about 30:1.

[0141] It is conceivable that the cannabinoid combination of the invention, including CBD, CBDV, and A ⁹ -THC (when present) will be provided as a kit. Such a kit may include the two or three cannabinoids in two or three separate composition. For example, if all three cannabinoids are present, the kit may include three compositions, including one cannabinoid each, or two compositions - one including two cannabinoids and the third including the third cannabinoid.

[0142] In yet an additional aspect, the present invention further provides a kit for use in treating epilepsy or a disorder associated therewith, the kit comprising two or three composition, each composition comprising one or two of CBD, CBDV, and A ⁹ - THC, or an enantiomer, diastereomer, or racemate thereof, wherein the kit includes, as the only cannabinoids, CBD and CBDV, or CBD, CBDV, and A ⁹ -THC, and the CBD and CBDV in the kit are at a weight ratio of from about 10:1 to about 20: 1, and the CBD and A ⁹ -THC, when present, in the kit are at weight ratio of from about 20: 1 to about 30: 1.

[0143] In still a further aspect, the present invention provides a kit for use in improving the efficacy of an anti-epileptic treatment in a subject suffering from epilepsy or a disorder associated therewith being treated by at least one AED, comprising two or three composition, each composition comprising one or two of CBD, CBDV, and A ⁹ -THC, or an enantiomer, diastereomer, or racemate thereof, wherein the kit includes, as the only cannabinoids, CBD and CBDV, or CBD, CBDV, and A ⁹ -THC, and the CBD and CBDV in the kit are at a weight ratio of from about 20:1 to about 10: 1, and the CBD and A ⁹ -THC, when present, in the kit are at weight ratio of from about 30: 1 to about

20: 1. [0144] Unless otherwise indicated, all numbers expressing, e.g., weight ratios of the 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.

[0145] The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Example 1: Anticonvulsant properties of cannabis strain extracts containing high CBD content.

[0146] Air dried cannabis strains Topaz and Turkiz were obtained from BOL Pharma, Revadim Industrial Zone Israel. Cannabinoids were extracted from each plant using ethanol extraction, a method which can extract many compounds without inducing any reactions (that occur due to heat). To obtain a decarboxylated extract, raw plant material was wrapped in aluminum foil and incubated in an oven at l20°c for 1 hr. The extract was dissolved in ethanol into a vehicle solution consisting of 1: 1: 18 ethanol: cremophor (Sigma- Aldrich): saline to a final concentration of 20 mg/ml of total extract. The cannabis extract or control (vehicle solution) was injected intraperitoneally (150 mg/kg) 30 minutes before Pentylenetetrazole (PTZ) injections.

[0147] Two cannabis strains were used for the experiments, Topaz, with a ratio of cannabinoids of CBD:CBDV:A ⁹ -THC = 30:2: 1, respectively, and a weight % of the acid form of 75, 5, and 2.5 % respectively, and Turkiz with a ratio of cannabinoids of CBD:CBDV:A ⁹ -THC = 20:0.5:0.5 , respectively (or 40: 1: 1, , respectively), and a weight % of the acid form of 75, 1.8, and 1.8 %, respectively.

[0148] 30 minutes after cannabis or control injections mice were injected subcutaneously with Pentylenetetrazole (PTZ; 80 mg/kg) and they were monitored for 30 min. The epileptic seizures were captured using a video recording epileptic behavioral analysis system (SeizureScan, Clever Sys., Inc., Virgina, USA). During this time, the progress of seizure activity from normal behavior (P0) to Behavior Arrest (Pl), to Twitches (P2), to Forelimb Clonus (P3), to Generalized Clonic Seizures (P4), to Jumpy/Bouncy Seizures (P5), to Tonic Extension (P6) were analyzed.

[0149] As can be seen from Fig. 1, the Topaz extract reduced Pentylenetetrazole (PTZ)-induced mortality, and significantly increased latency to first tonic-clonic seizures. Additionally, treatment with extract from both strains lowered the % of mice developing tonic-clonic seizures, however the Topaz extract was more effective. Treatment of drug resistant epilepsy (ORE) by different combinations of pure cannabinoids

[0150] The primary objective of the trial is to study the effect of different combinations of CBD, CBDV and A ⁹ -THC as add-on to conventional treatments on seizure frequency in subjects with drug-resistant epilepsy or in pediatric subjects with intractable epilepsy (not completely responsive to at least 4 conventional drugs).

Methods

Preparation of purified cannabinoids

[0151] Cannabis sativa flowers were dried and ground. The ground plant material contained CBD, CBDV, and A ⁹ -THC in their acidic forms - CBDa, CBDVa, and A ⁹ -THCa. Decarboxylation process performed at l40°C turned the CBDa, CBDVa, and A ⁹ -THCa to CBD, CBDV, and D ⁹ - THC, while releasing C0 ₂ gas. CBD, CBDV, and A ⁹ -THC were extracted from the decarboxylated material via supercritical C0 ₂ 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.

[0152] For CBD (cannabidiol, CAS Number: 13956-29-1) and CBDV (cannabidivarin, CAS Number: 24274-48-4) 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. For CBD preparation: after crystallization, the CBD was dried and milled, and stored in air tight containers, protected from air and light at room temperature. For CBDV preparation: crystalline CBD was filtered out, and the remaining mother liquor was rich with CBDV. The pentane was then evaporated under vacuum (-15% assay). The residual oil was purified under short path distillation (-40% assay). The distillate was dissolved in MeOH:H ₂ 0 80:20 and subjected to reverse phase chromatography. Clean CBDV fractions were concentrated via rotary evaporation. The Solution was cooled and CBDV crystalized, filtered and dried.

[0153] For A ⁹ -THC (A ⁹ -THC, A ⁹ - 1 c t a h y d o c a n n a b i n o 1 , 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 A ⁹ -THC. A ⁹ -THC was stored at 4°C under nitrogen in glass containers, protected from light.

[0154] The cannabinoids were about >99% pure.

Cannabinoids in oil

[0155] Cannabinoids were added to olive oil in a beaker to a concentration of 295 mg/ml CBD, 19.6 mg/ml CBDV and 9.8 mg/ml A ⁹ -THC to achieve a concentration of 10 mg CBD, 0.67 mg CBDV and 0.33 mg THC per drop. 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. The appropriate number of drops was used to deliver the chosen dose. Assessment methods

Seizure Diary both pediatric and adult patients

[0156] Subjects (or the parent/guardian) are requested to complete seizure diaries throughout the study from the Screening Period, throughout the entire period of the study. The seizure diary is a form devised by the Israeli league for the prevention of epilepsy and modified for the purpose of this study. It is comprised of a table with rows for each day of the month, and columns for waking periods, sleeping periods and comments/medication changes. The instructions advise the patient (or the parent/guardian) to record the seizure according to the time at which it occurred (awake/asleep) and its duration. In this study, the patients choose one of 7 possible types of seizures for each seizure they record, and grade the severity of each seizure on a 3 point Likert scale (1 - mild; 2- moderate; 3- severe).

The Beck Depression Inventory II (BDI-II) - adults

[0157] BDI-II is used to measure depression. This questionnaire includes 21 self-report questions designed to assess the severity of depressive symptoms in the 2 weeks before the questionnaire is completed. Four coding options (0 to 3) exist for each item. The total score on the questionnaire is the sum of these items and ranges from 0 to 63, with higher scores reflecting greater severity of symptoms. It has been shown to the ability to identify major depression in epilepsy patients (Jones et al., Epilepsia. 2005;46(5):731—735).

Quality of Life in Epilepsy Inventory (QOLIE31 ) - adults

[0158] The QOLIE-31 is a self-assessment tool. It includes 31 items clustered in seven multi-item scales centered on the following domains: 1) Seizure Worry (SW); 2) Overall Quality of Life (OQ); 3) Emotional Well-Being (EWB); 4) Energy/Fatigue (EF); 5) Cognitive Function (CF); 6) Medication Effects (ME); and 7) Social Function (SF). The overall score is obtained by using a weighted average of the multi-item scaled scores, a higher score reflecting a higher level of QOL. The validated Hebrew version is used. Patients are instructed to fill the questionnaire and answers will be reviewed at each visit (Cramer JA. QOLIE-31 (Hebrew translation). New Haven, CT: RAND, Yale University. 1993).

The Pittsburgh Sleep Quality Index - adults

[0159] The Pittsburgh Sleep Quality Index (PSQI) is a standardized self-administered questionnaire for the assessment of subjective sleep quality. It has been translated into several languages and is widely used in clinical research studies. The PSQI is composed of seven clinically derived components of sleep difficulty, including subjective sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, daytime dysfunction and sedative medication use, all of which are summed to a single global score. The validated Hebrew version is used (Buysse et ah, Psychiatry research. l989;28(2): 193—213).

Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) - pediatric

[0160] One of the most widely used epilepsy-specific instruments is the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). The QOLCE-55 is a modified version of the original 76- item QOLCE, which assesses parent-reported HRQL of children with epilepsy aged 4-18 years of age. It is self-administered. The four main domains of the QOLCE-55 include cognitive functioning (22 items), emotional functioning (17 items), social functioning (7 items), and physical functioning (9 items). Items are rated on a five-point Likert scale, 0 = very often; 1 = fairly often; 2 = sometimes; 3 = almost never; and 4 = never. The composite HRQL score is the unweighted average of the four subscales, ranging from 0 to 100. Higher scores indicate better HRQL. The QOLCE-55 has been validated in children with drug-resistant epilepsy (Conway et al., Epilepsia. 2017; 58(4):646-656).

Caregiver Evaluations - pediatric

[0161] Parents/caregivers will be requested to provide their global impression of change from Baseline and their global impression of change in seizure duration, using Likert-like scales, and their impressions of sleep disruption, based on the previously-reported methods (Devinsky et al., New England Journal of Medicine. 2017;376(21):2011-2020).

The Global Assessment of Severity of Epilepsy (GASE) - pediatric

[0162] The Global Assessment of Severity of Epilepsy (GASE) Scale is a single item, 7-point global rating scale designed for neurologist-report of overall severity of epilepsy in children. The GASE Scale asked physicians to rate the overall severity of each child’s epilepsy at the time of clinical assessment. It was shown to be valid in both clinical and research settings (Chan et al., Epilepsia. 20l5;56( 12): 1950- 1956).

Physiological parameters both pediatric and adult patients

Patients are assessed periodically for vital signs including temperature, peripheral arterial blood pressure, heart rate, and respiratory rate; and for anti-epileptic drugs levels (Phenobarbital, Primidone, Phenytoin, Valproic Acid, Carbamazepine, Lamotrigine, Levetiracetam). Prior to beginning of treatment, adult patients also are tested for blood chemistry including sodium (Na), potassium (K), chloride (Cl), creatinine, glucose, urea, albumin, calcium total, alkaline phosphatase (ALP), ALT, AST, total bilirubin, direct bilirubin, LDH, total protein, uric acid and CRP; hematology including CBC and ESR; and urinalysis, and children/adolescent are tested prior to beginning of the treatment as well as periodically throughout the treatment period.

Statistical analysis

[0163] The data collected in this study is listed and summarized as appropriate for each analysis population. Continuous data is summarized by the mean, standard deviation (SD), median, first and third quartiles, minimum and maximum. Categorical data is presented by absolute and relative frequencies (n and %) or contingency tables. All statistical tables and listings and analyses are produced using SAS release 8.1 or later (SAS Institute, Inc, Cary, NC, USA) or other validated statistical software. The information in this section is intended to reflect the information in the Statistical Analysis Plan (SAP) document that accompanies this protocol. The SAP is the governing document and will supersede this section of the protocol. The study includes at least 120 evaluable adults or 90 pediatric patients (children and adolescents). This sample size is considered adequate to assess safety and efficacy.

Example 2: Treatment of drug resistant epilepsy (DRE) in adults by different combinations of pure cannabinoids

Patient inclusion criteria

[0164] Subjects are in the age range of 18-80, are suffering from drug-resistant epilepsy based on International League Against Epilepsy (ILAE) criteria (Kwan et al. Epilepsia, 51(6): 1069-1077, 2010), have >3 documented seizures per month, and are not using any medication containing cannabis. Subjects with a history of severe psychiatric disorders in the past or first degree relative with psychotic characteristics younger than 30 years old, treated with anti-psychotic drugs, with psychogenic non-epileptic event, with anxiety disorder, with alcohol or drug abuse within 12 months prior to study entry, or suffering from heart failure, are excluded from the study.

[0165] Patients are treated with at least one of the following medications during the study: acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, prysoline, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

[0166] Patients undergo a complete assessment of their eligibility criteria as having DRE. Patients that have met eligibility criteria are recruited. All patients are provided with diaries in which to document their seizures for 2 months, during which time they are contacted by phone on a monthly basis. At the end of the 2nd month, eligibility criteria are re-evaluated, and diaries surveyed. Patients who continue to meet eligibility criteria and who have documented at least three seizures per month during the 2-month Baseline period are allowed to continue in the study.

Treatment, dosage regimen and dosage form

[0167] At the end of the 2nd month, after complete re-evaluation of DRE, patients are randomized to one of 4 study arms:

[0168] Arm 1 (CBD): 450 mg/day CBD; Arm 2 (CBD:CBDV = 30:2): 450 mg/day CBD, 30 mg/day CBDV; Arm 3 (CBD:CBDV:A ⁹ -THC = 30:2: 1): 450 mg/day CBD, 30 mg/day CBDV, 15 mg/day A ⁹ -THC; Arm 4: placebo.

[0169] Patients are given the study treatment, according to the study arm to which they were assigned, at half the dose planned for the study arm. After 2 weeks on half-dose, the patient arrives for an in-clinic visit. During the visit, a safety evaluation is conducted by the Primary Investigator, and based on his evaluation, a decision is made whether to withdraw the patient from the study, or to increase the dose to the full dose planned for the patient’s assigned study arm. Patients receive the full dose for a total of 10 weeks, during which time they arrive for two additional in-clinic visits. After 10 weeks, dosing is stopped, and the patients are followed-up for another 30 days until the End-Of-Study/Follow-Up visit. Assessment by the appropriate methods (see above - assessment methods for adults) is carried out throughout the study .

[0170] The dosage form used in the study is medicated drops in oil preparation for sublingual administration, and is taken orally, three times daily. Following titration, patients receive a total daily dose as indicated above. The placebo formulation is very similar to the investigational formulation, but without CBD, A ⁹ -THC, or CBDV.

[0171] Patients that are treated with the following anti-epileptic drugs (AEDs): Phenobarbital, Primidone, Phenytoin, Carbamazepine, Valproic Acid, Lamotrigine, Levetiracetam are tested for trough levels.

[0172] The primary outcomes of the study are: 1. Change in seizure frequency, more specifically - change in median monthly seizure frequency over study period (based on seizure diaries) compared to a 2-month Baseline period; and 2. Treat-emergent Adverse events (TEAEs) and serious adverse events during treatment.

[0173] Secondary outcomes of the study are: changes in seizure severity; change in post-ictal recovery; changes in seizure characteristics (focal/generalized); change in mood; changes in quality of life based on the QOLIE31; changes in sleep quality.

[0174] It is expected that patients receiving a combination of cannabinoids will have an improvement in any of the above parameters compared to patients treated with CBD alone, and that patients treated with CBD alone will show improved parameters compared to patients treated with placebo.

Example 3: Treatment of drug resistant epilepsy in children and adolescent by different combinations of pure cannabinoids

Patient inclusion criteria

[0175] Subjects are in the age range of 2-18, are suffering from intractable epilepsy (not fully responding to conventional drugs), and are not using any medication containing cannabis. Subjects with severe psychiatric disorders with psychotic characteristics are excluded from the study.

[0176] Pediatric subjects with intractable epilepsy (not fully responding to 4 conventional drugs) undergo a complete assessment of their eligibility criteria. Patients that have met eligibility criteria are recruited. Patients' parents or guardians are provided with diaries in which to document their seizures for 2 months, during which time they are contacted by phone on a monthly basis. At the end of the 2nd month, eligibility criteria are re-evaluated, and diaries surveyed. Patients who continue to meet eligibility criteria and who have documented at least three focal or generalized convulsive seizures per month during the 2-month Baseline period are allowed to continue in the study.

[0177] Patients are treated with at least one of the following medications during the study: acetazolamide, brivaracetam, carbamazepine, clobazam, clonazepam, ethosuximide, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, prysoline, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, valproate, vigabatrin, and zonisamide.

Treatment, dosage regimen and dosage form

[0178] At the end of the 2nd month, after complete re-evaluation of DRE, patients are randomized to one of 4 study arms:

[0179] Arm 1 (CBD): <30kg: 15 mg/kg/day CBD, >30kg: 450 mg/day CBD; Arm 2 (CBD:CBDV = 30:2): <30kg: 15 mg/kg/day CBD, 1 mg/kg/day CBDV, >30kg: 450 mg/day CBD, 30 mg/day CBDV; Arm 3 (CBD:CBDV:A ⁹ -THC = 30:2: 1): <30kg: 15 mg/kg/day CBD, 1 mg/kg/day CBDV, 0.5 mg/kg/day A ⁹ -THC, >30kg: 450 mg/day CBD, 30 mg/day CBDV, 15 mg/day A ⁹ -THC; Arm 4: placebo

[0180] Patients are given the study treatment, according to the study arm to which they were assigned, at half the dose planned for the study arm. After 2 weeks on half-dose, the patient arrives for an in-clinic visit. During the visit, a safety evaluation is conducted by the Primary Investigator, and based on his evaluation, a decision is made whether to withdraw the patient from the study, or to increase the dose to the full dose planned for the patient’s assigned study arm. Patients receive the full dose for a total of 3 months, during which time they arrive for three additional in-clinic visits. After 3.5 months, patients arrive at the clinic for a visit in which their dose is reduced to half-dose for a period of 2 additional weeks, during which time they are instructed to taper the dose down gradually. Treatment ends after a total of 4 months, at which point patients arrive at the clinic for the end-of-treatment visit. Assessment by the appropriate methods (see above) is carried out throughout the study.

[0181] The dosage form used in the study is medicated drops in oil preparation for sublingual administration, and is taken orally, twice daily. Following titration, patients receive a total daily dose as indicated above. The placebo formulation is very similar to the investigational formulation, without CBD, A ⁹ -THC, or CBDV.

[0182] Patients that are treated with the following AEDs: Phenobarbital, Primidone, Phenytoin, Carbamazepine, Valproic Acid, Lamotrigine, Levetiracetam, Prysoline, Clobazam are tested for trough levels.

[0183] The primary outcomes of the study are: 1. Change in seizure frequency, more specifically - change in median monthly seizure frequency over study period (based on seizure diaries) compared to a 2-month Baseline period; and 2. Treat-emergent Adverse events (TEAEs) and serious adverse events during treatment.

[0184] Secondary outcomes of the study are: changes in seizure severity; change in post-ictal recovery; changes in seizure characteristics (focal/generalized); change in mood; changes in quality of life based on the Quality of Life in Childhood Epilepsy Questionnaire; changes in sleep quality.

[0185] It is expected that patients receiving a combination of cannabinoids will have an improvement in any of the above parameters compared to patients treated with CBD alone, and that patients treated with CBD alone will show improved parameters compared to patients treated with placebo.

Example 4

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