TECHNICAL FIELD

This disclosure generally relates to the use of one or more minor cannabinoids in the treatment of epilepsy and other seizure disorders.

BACKGROUND

Epileptic and seizure disorders affect millions of sufferers worldwide. Some disorders can be adequately controlled by anti-epileptic drugs (AED); however, there are intractable or treatment resistant epilepsy (TRE) disorders that cannot be treated with conventional AED.

There are a number of known transient receptor potential (TRP) channels that are related to epilepsy, including TRPA1 , TRPM7, and TRPV1 , as well as TRPV4, TRPC7, TRPC5, and TRPC1/4 that are related to neuronal cell death. Cannabis products, including delta-9- tetrahydrocannacinol (A9-THC) and cannabidiol (CBD), have been used to treat epileptic and seizure disorders by targeting TRP channels. For example, A9-THC and CBD are known agonists for some TRP receptors, such as TRPA1 , TRPV2, TRPV3, and TRPV4, and CBD is a known agonist of TRPV1 , which is thought to be the mechanism of action for the anticonvulsive effects of CBD. However, there are a number of drawbacks to using A9-THC and CBD to treat seizure disorders. For example, A9-THC is generally unsuitable for treating seizure disorders, especially in children, as A9-THC can have undesirable psychoactive side effects. CBD is also sedating, and tolerance may develop leading to decreased efficacy of seizure treatment over time (Uliel- Sibony, et al. “Cannabidiol-enriched oil in children and adults with treatment-resistant epilepsydoes tolerance exist?”, Brain and Development, 43:1 , 2021 , 89-96).

Furthermore, as shown in Figure 1 (prior art), neural cells in epileptic brains have a decreased number of CBi receptors in excitatory neurons and an increase number of CBi receptors in astrocytes and CCK(+) inhibitory neurons (Sugaya, Yuki & Kano, Masanobu. “Control of Excessive Neural Circuit Excitability and Prevention of Epileptic Seizures by Endocannabinoid Signaling”, Cellular and Molecular Life Sciences, 75, 2018, 2793 - 2811). Accordingly, agonists of CBi could be used to treat seizure disorders. However, CBD has a high potency as an antagonist of the CBi and CB2 cannabinoid receptors in the endocannabinoid system (ECS).

Accordingly, novel compositions and treatments for treating epilepsy and other seizure disorders are desired. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a prior art schematic representative of the changes in CBi receptor signalling observed in epileptic patients and animal models of epilepsy;

FIG. 2 shows a schematic representation of the decarboxylation process whereby cannabigerol (CBG) is derived from cannabigerolic acid (CBGA); and

FIG. 3 shows a schematic representation of the biosynthetic pathway of CBG and cannabichromene (CBC).

SUMMARY

According to one aspect, there is provided a use of a minor cannabinoid in the management or treatment of a seizure disorder in a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBI_A).

According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the management or treatment of a seizure disorder in a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

In some embodiments, the minor cannabinoid is at least one of: CBC, CBCA, CBG, and CBGA.

In some embodiments, the minor cannabinoid is at least one of: CBC and CBGA.

In some embodiments, the minor cannabinoid is CBC.

In some embodiments, the minor cannabinoid is CBCA.

In some embodiments, the minor cannabinoid is CBG.

In some embodiments, the minor cannabinoid is CBGA.

In some embodiments, the minor cannabinoid is used in combination with cannabidiol (CBD).

In some embodiments, the minor cannabinoid is CBGA, and CBGA and CBD are used in a ratio of 2:1. In some embodiments, the minor cannabinoid is CBC, and CBC and CBD are used in a ratio of 1:1.

In some embodiments, CBGA and CBC are used as minor cannabinoids, and CBGA, CBC and CBD are used in a ratio of 1 : 1 : 1.

In some embodiments, the seizure disorder is an acute seizure disorder.

In some embodiments, the acute seizure disorder is selected from the group consisting of: febrile seizures; neonatal seizures; reflex seizures; status epilepticus; and secondary seizures to an acute condition.

In some embodiments, the acute condition is a brain injury, alcohol withdrawal, drug withdrawal, electrolyte imbalances; and an infection.

In some embodiments, the infection is meningitis or encephalitis.

In some embodiments, the seizure disorder is a chronic seizure disorder.

In some embodiments, the chronic seizure disorder is selected from the group consisting of: generalized seizure disorders; Lennox-Gastaut syndrome; Dravet syndrome; West syndrome; Landau-Kleffner syndrome; juvenile myoclonic epilepsy; Rasmussen's encephalitis; temporal lobe epilepsy; frontal lobe epilepsy; parietal lobe epilepsy; occipital lobe epilepsy; benign rolandic epilepsy; childhood absence epilepsy; Sturge-Weber syndrome; tuberous sclerosis; benign neonatal convulsions; benign myoclonic epilepsy in infancy; progressive myoclonic epilepsies; gelastic and dacrystic seizures; autosomal dominant nocturnal frontal lobe epilepsy; and psychogenic non-epileptic seizures (PNES).

In some embodiments, the patient is a mammal, preferably a human or a domestic animal.

In some embodiments, the seizure disorder is selected from the group consisting of: a focal seizure disorder; a generalized seizure disorder; a febrile infection related epilepsy syndrome (FIRES); and dravet syndrome.

In some embodiments, the seizure disorder is one of a primary epilepsy and a secondary epilepsy.

In some embodiments, the seizure disorder is idiopathic epilepsy.

In some embodiments, the seizure disorder is one of: a primary generalized seizure and a secondary generalized seizure. In some embodiments, the seizure disorder is genetic.

In some embodiments, the focal seizure disorder causes at least one of: focal aware seizures, focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, gelastic seizures, nonepileptic seizures, and dacrystic seizures.

In some embodiments, the generalized seizure disorder causes at least one of: a generalized tonic-clonic seizure (GTC), a tonic seizure, a clonic seizure, an absence seizure, a myoclonic seizure, an atonic seizure, an infantile spasm, an electrographic seizure and an epileptic spasm.

In some embodiments, the FIRES causes a complex febrile seizure.

In some embodiments, the patient is a human.

In some embodiments, the patient is an animal.

In some embodiments, the animal is a domestic animal.

In some embodiments, the minor cannabinoid is extracted from a cannabis plant and optionally isolated from the plant extract.

In some embodiments, the cannabis plant comprises an undetectable concentration of at least one of: delta-9-tetrahydrocannacinol (A9-THC) and cannabidiol (CBD).

In some embodiments, the cannabis plant is at least one of: HURV19PAN, C2B, Valerie 16, Vendetta, Orchards CBC, Orchards CBG, Orchards CBDV, and Orchards CBD.

In some embodiments, the minor cannabinoid is at least one of CBC and CBCA, and the at least one of CBC and CBCA is in a composition at a concentration of at least 1% w/w.

In some embodiments, the concentration of the at least one of CBC and CBCA is about 10% w/w.

In some embodiments, the minor cannabinoid is at least one of CBG and CBGA and the at least one of CBG and CBGA is in a composition at a concentration of at least 1% w/w.

In some embodiments, the concentration of the at least one of CBG and CBGA is about 10% w/w.

In some embodiments, the minor cannabinoid is to be used in combination with at least one antiepileptic drug (AED).

In some embodiments, the at least one AED is at least one of levetiracetam, valproic acid, lamotrigine, phenytoin, clobazam, zonisamide, carbamazepine, oxcarbazepine, and topiramate.

In some embodiments, the minor cannabinoid is configured for oral administration, parenteral administration, topical administration, nasal administration, or inhalation.

In some embodiments, the minor cannabinoid is provided in a composition at a concentration of between about 10 mg/ml and about 300 mg/ml, preferably between about 30 mg/ml and about 300 mg/ml.

In some embodiments, the composition comprises the minor cannabinoid and a pharmaceutically acceptable carrier.

In some embodiments, the minor cannabinoid is configured for administration in a dose of between about 10 mg/kg of body weight and about 300 mg/kg of body weight.

In some embodiments, the dose is between about 25 mg/kg of body weight and about 200 mg/kg of body weight.

In some embodiments, the dose is between about 75 mg/kg of body weight and about 150 mg/kg of body weight.

According to another aspect, there is provided a composition comprising a minor cannabinoid and a pharmaceutically acceptable carrier for use in the management or treatment of a seizure disorder in a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBI_A).

In some embodiments, the minor cannabinoid is at least one of: CBC, CBCA, CBG, and CBGA.

In some embodiments, the minor cannabinoid is at least one of: CBC and CBGA.

In some embodiments, the seizure disorder is an acute seizure disorder, such as an acute seizure disorder as defined herein.

In some embodiments, the minor cannabinoid is at least one of: CBC, CBCA, CBG, and CBGA.

In some embodiments, the minor cannabinoid is CBC.

In some embodiments, the minor cannabinoid is CBCA.

In some embodiments, the minor cannabinoid is CBG. In some embodiments, the minor cannabinoid is CBGA.

In some embodiments, the composition further comprises cannabidiol (CBD).

In some embodiments, the composition comprises CBGA and CBD in a ratio of 2:1.

In some embodiments, the composition comprises CBC and CBD in a ratio of 1 :1.

In some embodiments, the composition comprises CBGA, CBC, and CBD in a ratio of 1 :1 :1.

In some embodiments, the seizure disorder is selected from the group consisting of: a focal seizure disorder; a generalized seizure disorder; a febrile infection related epilepsy syndrome (FIRES); and dravet syndrome.

In some embodiments, the seizure disorder is one of a primary epilepsy and a secondary epilepsy.

In some embodiments, the seizure disorder is idiopathic epilepsy.

In some embodiments, the seizure disorder is one of: a primary generalized seizure and a secondary generalized seizure.

In some embodiments, the seizure disorder is genetic.

In some embodiments, the focal seizure disorder causes at least one of: focal aware seizures, focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, gelastic seizures, nonepileptic seizures, and dacrystic seizures.

In some embodiments, the generalized seizure disorder causes at least one of: a generalized tonic-clonic seizure (GTC); a tonic seizure, a clonic seizure, an absence seizure, a myoclonic seizure, an atonic seizure, an infantile spasm; electrographic seizure, and an epileptic spasm.

In some embodiments, the FIRES causes a complex febrile seizure.

In some embodiments, the patient is a human.

In some embodiments, the patient is an animal.

In some embodiments, the animal is a domestic animal.

In some embodiments, the minor cannabinoid is extracted from a cannabis plant and optionally isolated from the plant extract. In some embodiments, the cannabis plant comprises an undetectable concentration of at least one of: delta-9-tetrahydrocannacinol (A9-THC) and cannabidiol (CBD).

In some embodiments, the cannabis plant is selected from at least one of: HURV19PAN, C2B, Valerie 16, Vendetta, Orchards CBC, Orchards CBG, Orchards CBDV, and Orchards CBD.

In some embodiments, the minor cannabinoid is at least one of CBC and CBCA and the composition comprises the at least one of CBC and CBCA in a concentration of at least 1% w/w.

In some embodiments, the concentration of the at least one of CBC and CBCA is about 10% w/w.

In some embodiments, the minor cannabinoid is at least one of CBG and CBGA and the composition comprises the at least one of CBG and CBGA in a concentration of at least 1% w/w.

In some embodiments, the concentration of the at least one of CBG and CBGA is about 10% w/w.

In some embodiments, the pharmaceutically acceptable carrier is selected from an oil, a nonionic surfactant comprising a fatty acid ester copolymerized with ethylene oxide, and any combination thereof.

In some embodiments, wherein the composition further comprises at least one anti-epileptic drug (AED).

In some embodiments, the at least one AED is at least one of levetiracetam, valproic acid, lamotrigine, phenytoin, clobazam, zonisamide, carbamazepine, oxcarbazepine, and topiramate.

In some embodiments, the composition is configured for oral administration, parenteral administration, topical administration, or nasal administration.

In some embodiments, the composition comprises the minor cannabinoid in a concentration of between about 0.1 mg/ml and about 300 mg/ml.

In some embodiments, the composition is configured for administration in a dose of between about 10 mg/kg of body weight and about 300 mg/kg of body weight.

In some embodiments, the dose is between about 25 mg/kg of body weight and about 200 mg/kg of body weight.

In some embodiments, the dose is between about 75 mg/kg of body weight and about 150 mg/kg of body weight. According to another aspect, there is provided a method of treating or managing a seizure disorder comprising administering a minor cannabinoid to a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

In some embodiments, the seizure disorder is an acute seizure disorder, such as an acute seizure disorder as defined herein.

In some embodiments, the minor cannabinoid is at least one of: CBC, CBCA, CBG, and CBGA.

In some embodiments, the minor cannabinoid is at least one of: CBC and CBGA.

In some embodiments, the minor cannabinoid is administered in combination with cannabidiol (CBD).

In some embodiments, the minor cannabinoid is CBGA, and CBGA and CBD are administered in a ratio of 2:1.

In some embodiments, the minor cannabinoid is CBC, and CBC and CBD are administered in a ratio of 1 : 1.

In some embodiments, CBGA and CBC are administered as minor cannabinoids, and CBGA, CBC and CBD are used in a ratio of 1 :1 :1.

In some embodiments, the seizure disorder is selected from the group consisting of: a focal seizure disorder; a generalized seizure disorder; a febrile infection related epilepsy syndrome (FIRES); and dravet syndrome.

In some embodiments, the seizure disorder is one of a primary epilepsy and a secondary epilepsy.

In some embodiments, the seizure disorder is idiopathic epilepsy.

In some embodiments, the seizure disorder is one of: a primary generalized seizure and a secondary generalized seizure.

In some embodiments, the seizure disorder is genetic.

In some embodiments, the focal seizure disorder causes at least one of: focal aware seizures, focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, gelastic seizures, nonepileptic seizures, and dacrystic seizures. In some embodiments, the generalized seizure disorder causes at least one of: a generalized tonic-clonic seizure (GTC), a tonic seizure, a clonic seizure, an absence seizure, a myoclonic seizure, an atonic seizure, an infantile spasm, electrographic seizure, and an epileptic spasm.

In some embodiments, the FIRES causes a complex febrile seizure.

In some embodiments, the patient is a human.

In some embodiments, the patient is an animal.

In some embodiments, the animal is a domestic animal.

In some embodiments, the minor cannabinoid is extracted from a cannabis plant and optionally isolated from the plant extract.

In some embodiments, the cannabis plant comprises an undetectable concentration of at least one of: delta-9-tetrahydrocannacinol (A9-THC) and cannabidiol (CBD).

In some embodiments, the cannabis plant is at least one of: HURV19PAN, C2B, Valerie 16, Vendetta, Orchards CBC, Orchards CBG, Orchards CBDV, and Orchards CBD.

In some embodiments, the minor cannabinoid is at least one of CBC and CBCA and the at least one of CBC and CBCA is in a composition comprising the at least one of CBC and CBCA in a concentration of at least 1 % w/w.

In some embodiments, the concentration of the at least one of CBC and CBCA is about 10% w/w.

In some embodiments, the minor cannabinoid is at least one of CBG and CBGA and the at least one of CBC and CBCA is in a composition comprising the at least one of CBG and CBGA in a concentration of at least 1 % w/w.

In some embodiments, the concentration of the at least one of CBG and CBGA is about 10% w/w.

In some embodiments, the minor cannabinoid is administered in a composition comprising a pharmaceutically acceptable carrier being selected from an oil, a nonionic surfactant comprising a fatty acid ester copolymerized with ethylene oxide, and any combination thereof.

In some embodiments, the method further comprises administering the composition in combination with at least one anti-epileptic drug (AED). In some embodiments, the method further comprises administering the minor cannabinoid in combination with at least one anti-epileptic drug (AED).

In some embodiments, the at least one AED is at least one of levetiracetam, valproic acid, lamotrigine, phenytoin, clobazam, zonisamide, carbamazepine, oxcarbazepine, and topiramate.

According to another aspect, there is provided a use of a minor cannabinoid as an agonist of at least one endocannabinoid system (ECS) receptor and at least one transient receptor potential (TRP) receptor, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

In some embodiments, the at least one ECS receptor is at least one of a cannabinoid type-1 receptor (CBi) and a cannabinoid type-2 receptor (CB2).

In some embodiments, the at least one TRP receptor is at least one of: transient receptor potential cation channel subfamily A member 1 (TRPA1), transient receptor potential cation channel subfamily V member 1 (TRPV1), transient receptor potential cation channel subfamily V member 2 (TRPV2), transient receptor potential cation channel subfamily V member 3 (TRPV3), and transient receptor potential vanilloid-type 4 (TRPV4).

In some embodiments, the minor cannabinoid is at least one of: CBC, CBCA, CBG, and CBGA.

In some embodiments, the minor cannabinoid is at least one of: CBC and CBGA.

In some embodiments, the minor cannabinoid is used in combination with cannabidiol (CBD).

In some embodiments, the minor cannabinoid is CBGA, and CBGA and CBD are used in a ratio of 2:1.

In some embodiments, the minor cannabinoid is CBC, and CBC and CBD are used in a ratio of 1:1.

In some embodiments, CBGA and CBC are used as minor cannabinoids, and CBGA, CBC and CBD are used in a ratio of 1 :1 :1.

In some embodiments, the use is for the management or treatment of a seizure disorder in a patient.

In some embodiments, the seizure disorder is selected from the group consisting of: a focal seizure disorder; a generalized seizure disorder; a febrile infection related epilepsy syndrome (FIRES); and dravet syndrome. In some embodiments, the seizure disorder is one of a primary epilepsy and a secondary epilepsy.

In some embodiments, the seizure disorder is idiopathic epilepsy.

In some embodiments, the seizure disorder is one of: a primary generalized seizure and a secondary generalized seizure.

In some embodiments, the seizure disorder is genetic.

In some embodiments, the focal seizure disorder causes at least one of: focal aware seizures, focal impaired awareness seizures, focal to bilateral tonic-clonic seizures, gelastic seizures, nonepileptic seizure, and dacrystic seizures.

In some embodiments, the generalized seizure disorder causes at least one of: a generalized tonic-clonic seizure (GTC), a tonic seizure, a clonic seizure, an absence seizure, a myoclonic seizure, an atonic seizure, an infantile spasm, an electrographic seizure, and an epileptic spasm.

In some embodiments, the FIRES causes a complex febrile seizure.

In some embodiments, the patient is a human.

In some embodiments, the patient is an animal.

In some embodiments, the animal is a domestic animal.

In some embodiments, the minor cannabinoid is extracted from a cannabis plant and optionally isolated from the plant extract.

In some embodiments, the cannabis plant comprises an undetectable concentration of at least one of: delta-9-tetrahydrocannacinol (A9-THC) and cannabidiol (CBD).

In some embodiments, the cannabis plant is at least one of: HURV19PAN, C2B, Valerie 16, Vendetta, Orchards CBC, Orchards CBG, Orchards CBDV, and Orchards CBD.

In some embodiments, the minor cannabinoid is at least one of CBC and CBCA, and the at least one of CBC and CBCA is in a composition at a concentration of at least 1% w/w.

In some embodiments, the concentration of the at least one of CBG and CBGA is about 10% w/w.

In some embodiments, the minor cannabinoid is at least one of CBG and CBGA and the at least one of CBG and CBGA is in a composition at a concentration of at least 1% w/w. In some embodiments, the concentration of the at least one of CBC and CBCA is about 10% w/w.

In some embodiments, the minor cannabinoid is to be used in combination with at least one antiepileptic drug (AED).

In some embodiments, the at least one AED is at least one of levetiracetam, valproic acid, lamotrigine, phenytoin, clobazam, zonisamide, carbamazepine, oxcarbazepine, and topiramate.

According to another aspect, there is provided a use of a minor cannabinoid in the management or treatment of an acute condition that causes seizures secondary to the acute condition in a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBI_A).

According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the management or treatment of an acute condition that causes seizures secondary to the acute condition in a patient, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

In some embodiments, the acute condition is a brain injury.

In some embodiments, the acute condition is alcohol withdrawal.

In some embodiments, the acute condition is drug withdrawal.

In some embodiments, the acute condition is an electrolyte imbalance.

In some embodiments, the acute condition is an infection.

In some embodiments, the infection is meningitis.

In some embodiments, the infection is encephalitis.

According to another aspect, there is provided a use of a minor cannabinoid in the treatment of a brain injury in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA). According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the treatment of a brain injury in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclol ic acid (CBLA).

According to another aspect, there is provided a use of a minor cannabinoid in the treatment of alcohol withdrawal in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the treatment of alcohol withdrawal in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

According to another aspect, there is provided a use of a minor cannabinoid in the treatment of drug withdrawal in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the treatment of drug withdrawal in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

According to another aspect, there is provided a use of a minor cannabinoid in the treatment of an infection in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA). According to another aspect, there is provided a use of a minor cannabinoid in the manufacture of a medicament for the treatment of an infection in a patient to manage seizure symptoms, wherein the minor cannabinoid comprises at least one of: cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBLA).

In some embodiments, the infection is meningitis.

In some embodiments, the infection is encephalitis.

DETAILED DESCRIPTION

General definitions

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a minor cannabinoid" also contemplates a mixture of two or more minor cannabinoids. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.

The terms "about" or “approximately” as used herein mean within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, /.e., the limitations of the measurement system. For example, "about" or “approximately” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" or “approximately” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the terms can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" or “approximately” meaning within an acceptable error range for the particular value should be assumed. Minor cannabinoids

The present disclosure is related to the use of minor cannabinoids, such as minor cannabinoids isolated from a cannabis plant, such as hemp, to manage or treat seizure or epileptic disorders. In the present disclosure, “minor cannabinoids” refer to the less abundant cannabinoids as opposed to the major cannabinoids present in cultivars or strains, such as THC and CBD. In some embodiments, the minor cannabinoids can include cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV) and/or cannabicyclolic acid (CBI_A). The definition of minor cannabinoids can also include derivatives of these minor cannabinoids that retain the desired activity. Derivatives that retain substantially the same activity as the starting material, or exhibit improved activity, may be produced using standard medical chemistry techniques that are well known in the art. Such derivatives may exhibit a lesser degree of activity than the starting material but are within the definition of minor cannabinoids if they retain sufficient activity to be therapeutically effective. Derivatives may exhibit improvements in other properties that are desirable in pharmaceutically active agents, such as enhanced uptake, improved solubility, and/or reduced toxicity.

In some embodiments, the minor cannabinoids to be used to manage or treat seizure or epileptic disorders, can be extracted from various Cannabis plant varieties, a non-exhaustive list includes: HURV19PAN, C2B, Valerie 16, Vendetta, Orchards CBC, Orchards CBG, Orchards CBDV, Orchards CBD and others. In some embodiments, the minor cannabinoids can be extracted from varieties having an undetectable concentration of CBD and A9-THC using conventional detection methods (e.g., high performance liquid chromatography - HPLC). In other embodiments, the minor cannabinoids can be extracted from any part of the cannabis plant, preferably the flowers. Various methods can be used to extract the minor cannabinoids from the plant parts and are known in the field. Once the extract comprising the minor cannabinoid(s) is obtained, one can further proceed to purification, if required, to isolate one or more minor cannabinoids of interest. Purification methods are also known in the art and can include, for instance, flash chromatography, or amine-cannabinoid salt precipitation.

The minor cannabinoids discussed herein can thus be found in different quantities in varieties of cannabis plants. For example, CBGA is a known precursor for CBG, which is a common precursor found in cannabis plants for CBC, tetrahydrocannabinol (THC), including A9-THC, and cannabidiol (CBD). As shown in Figure 2, CBG is derived from CBGA after undergoing decarboxylation. CBGA or 3-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]-2,4-dihydroxy-6-pent yl-benzoic acid (C22H32O4) is represented by the following chemical structure:

After undergoing decarboxylation, CBG is represented by the following chemical structure:

Referring now to Figure 3, a biosynthetic pathway of CBGA and CBCA, which is derived from CBGA, is shown. Geranyl diphosphate (GPP) is condensed with olivetolic acid (OA) using a geranyldiphosphate:olivetolate geranyltransferase (GOT) to produce CBGA. CBCA is derived from CBGA with a CBCA synthase, to produce CBCA or 5-hydroxy-2-methyl-2-(4-methyl-3- penten-1-yl)-7-pentyl-2H-chromene-6-carboxylic acid (C22H30O4), which is represented by the following chemical structure:

CBCA

CBC or 2-Methyl-2-(4-methyl-3-penten-1-yl)-7-pentyl-2H-chromen-5-ol (C21H30O2) can be derived from CBCA through decarboxylation. CBC is represented by the following chemical structure:

CBC

Minor cannabinoids can also include CBDV, CBL, and CBLA, which are represented by chemical structures (i), (ii), and (ii), respectively:

In conventional cannabis flowers, CBG generally accounts for less than 1% w/w of the flower. However, some varieties have an increased concentration of CBGA and an undetectable concentration of CBD and A9-THC. Varieties with undetectable concentrations of A9-THC are desirable, as A9-THC is responsible for the psychoactive effects of cannabis strains and can be prohibited or heavily regulated for medical use in some jurisdictions. For example, as shown in Table 1 , the HURV19PAN variety of cannabis contains 21.87% (218.65 mg/g) of CBGA, and undetectable amounts (0.0 mg/g) of CBD and THC.

Table 1

Other varieties of cannabis can comprise detectable levels of CBDA and CBCA, such that extracts from these cannabis plants can be used to formulate a medicament that comprises CBDA, CBCA or both CBDA and CBCA. For example, the Valerie 29 variety comprises approximately 13% CBDA and 4% CBCA. Uses and methods

The minor cannabinoids disclosed herein may be used in the management or treatment of seizure disorders.

In this context, “seizure disorders” can include central nervous system (neurological) disorders in which brain activity because abnormal, causing seizures or periods of abnormal behavior, sensations, and/or loss of awareness. “Seizure disorders” can include acute seizures or chronic seizures. “Acute seizures”, which can also be referred to as acute symptomatic seizures, include seizures that are provoked by an external stimuli that interrupts the normal connections between nerve cells in the brain, such as an electrolyte disorder, toxins, a head injury, an infection, a vascular anomaly, tumor or other mass lesion, high fever, high or low blood sugar, alcohol or drug withdrawal, etc. In other words, acute seizures are those that occur as a one-time event or are provoked by some immediate stimulus or injury. Acute seizures are not expected to recur once the inciting cause has resolved or been treated. Acute seizure disorders can include febrile seizures, neonatal seizures, reflex seizures, status epilepticus, and seizures secondary to acute conditions such as a traumatic brain injury, alcohol or drug withdrawal, electrolyte imbalances, and certain infections, such as meningitis or encephalitis. It is noted that febrile seizures include seizures that occur as a response to high fever (e.g., in children). Neonatal seizures can be caused by various acute conditions in newborns, such as brain injuries or metabolic imbalances. Reflex seizures include seizures triggered by specific stimuli, like flashing lights. Although status epilepticus can occur in the context of chronic epilepsy, it is considered an acute life-threatening emergency.

In contrast, “chronic seizures” includes seizures that are recurrent and unprovoked, which are often caused by a neurological disorder. In other words, chronic seizures typically occur as part of an underlying condition, often referred to generally as epilepsy, and are not directly provoked by immediate events, although certain triggers may exacerbate them. Chronic seizures can include generalized seizure disorders, including absence seizures, tonic-clonic seizures, atonic seizures, clonic seizures, and myoclonic seizures; Lennox-Gastaut syndrome; Dravet syndrome (severe myoclonic epilepsy of infancy); West syndrome (infantile spasms); Landau-Kleffner syndrome; juvenile myoclonic epilepsy; Rasmussen's encephalitis; temporal lobe epilepsy; frontal lobe epilepsy; parietal lobe epilepsy; occipital lobe epilepsy; benign rolandic epilepsy (also referred to as benign childhood epilepsy with centrotemporal spikes); childhood absence epilepsy; Sturge-Weber syndrome; tuberous sclerosis; benign neonatal convulsions; benign myoclonic epilepsy in infancy; progressive myoclonic epilepsies, which can include conditions such as lafora disease, myoclonus epilepsy with ragged red fibers (MERRF), and Unverricht-Lundborg disease; gelastic and dacrystic seizures; autosomal dominant nocturnal frontal lobe epilepsy; and psychogenic non-epileptic seizures (PNES).

Both acute and chronic seizures can be caused by a variety of seizure disorders, including focal (or partial) seizure disorders, such as focal onset aware seizures (also referred to as simple partial seizures), focal onset impaired awareness seizures (also referred to as complex partial seizures), focal to bilateral tonic-clonic seizures, gelastic seizures, non-epileptic seizure, and/or dacrystic seizures; generalized seizure disorders, such as a generalized tonic-clonic (GTC) seizure (also referred to as grand mal seizures), a tonic seizure, a clonic seizure, an absence seizure (also referred to as petit mal seizures), a myoclonic seizure, an atonic seizure, an infantile spasm, an electrographic seizure, and/or an epileptic spasm; febrile infection related epilepsy syndrome (FIRES), such as a complex febrile seizure; status epilepticus; psychogenic non-epileptic seizures (PNES), reflex seizures, gelastic seizures, dacrystic seizures, hypsarrhythmia, and/or autosomal dominant nocturnal frontal lobe epilepsy. Seizure disorders can also include genetic or other conditions that cause seizures, primary epilepsy, secondary epilepsy, a primary generalized seizure, and/or a secondary generalized seizure. Seizures may also be secondary to an underlying structural disorder, which may include a brain tumour, stroke, intracranial hemorrhage, traumatic brain injury, infection, inflammatory disorders, auto-immune conditions and others. In the context of the present disclosure, “manage” or “management” of seizure disorders means to reduce the number seizures experienced by the patient and/or reducing the severity of the seizure or abnormal behaviour, sensations, and/or loss of awareness that is experienced during a seizure or episode of a seizure disorder.

The classification of a seizure being “chronic” or “acute” is based on a clinical understanding that while acute seizures may be caused by an immediate event, chronic seizures are recurrent without a direct provocation. As would be understood by the skilled artisan, a patient, such as a human or domestic animal, that experiences acute seizures does not necessarily have a chronic seizure disorder; however, a patient with a chronic seizure disorder can experience both chronic and acute seizures.

In some embodiments, the minor cannabinoids disclosed herein, including CBG and CBC, as well as their carboxylic acid metabolites (CBGA and CBCA, respectively), may be used to target both transient receptor potential (TRP) receptors and endocannabinoid system (ECS) receptors. As noted above, TRP receptors are known drug targets for anticonvulsant or seizure disorder therapies. Furthermore, the ECS is comprised, inter alia, of cannabinoid type-1 receptor (CBi) and cannabinoid type-2 receptor (CB2), which are Class A G protein-coupled receptors (GPCRs). Reduced CB2 receptor activity has been shown to be associated with increased seizure susceptibility and thus CB2 receptors are a potential therapeutic target for the treatment of seizure disorders (Shapiro, L., et. al. “Reduced Cannabinoid 2 Receptor Activity Increases Susceptibility to Induced Seizures in Mice.” Epilepsia, 60, 12, 22 November 2019, 2359-2369). Furthermore, mixed CB1/CB2 agonists and CB1 specific agonists have been shown to display anticonvulsant effects against clonic seizures in Sprague- Dawley rat models treated with the chemoconvulsant methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM); in contrast, CBi and CB2 antagonists increased seizure severity (Huizenga, M. et. al. “Anticonvulsant Effect of Cannabinoid Receptor Agonists in Models of Seizures in Developing Rats”, Epilepsia, 58, 9, 10 July 2017, 1593-1602). Accordingly, therapeutic treatments that target both the endocannabinoid receptor pathways and the TRP receptor pathways can be used to treat and/or manage seizure disorders. Table 2 below shows the measurements of affinity of A9-THC, CBD, cannabidivarinic acid (CBDVA), CBG, CBGA, and CBC on cannabinoid receptors, namely the ECS receptors.

Table 2

*Gurm et al., “Cannabinoid Signalling in Immune-Reproductive Crosstalk during Human Pregnancy”, Biomedicines 2021 , 9(3), 267.

**Filipiuc, et al., “Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors?”, Pharmaceutics 2021 , 13(11), 1823.

Table 3 shows the measurements of affinity and function of A9-THC, CBD, CBG, and CBC on non-cannabinoid receptors, namely the TRP receptors, as well as alpha-2 adrenergic receptor (a-2), serotonin 1A receptor (5-HT1A), and peroxisome proliferator-activated receptor gamma (PPARy).

Table 3

As shown in Table 2, in contrast to CBD, which is an CBi and CB2 receptor antagonist and thus theorized to increased seizure severity, A9-THC, CBC, and CBG are agonists of the CB2 receptor. Furthermore, CBG is a CB1 receptor agonist. As shown in Table 3, A9-THC, CBD, CBG, and CBC are agonists of the TRPA1, TRPV3, and TRPV4 receptors. A9-THC, CBD, and CBG are agonists of the TRPV2 and PPARy receptors and antagonists of the TRPM8 receptor. Furthermore, CBD and CBG are agonists of the TRPV1 receptor. CBD is an indirect agonist of the 5-HT1A receptor, whereas CBG is an antagonist of the 5-HT1A receptor. Lastly, CBG is an agonist of the a-2 receptor. Therefore, CBC and/or CBG may be used in the treatment and/or management of seizure disorders by targeting the endocannabinoid receptor pathways and the TRP receptor pathways, without having the undesirable psychoactive side effects that occur with A9-THC. In particular, TRPV1 has been shown to be a potential mechanism for the anticonvulsive effect of CBD, and reduced CB1 and CB2 activity can increase seizure susceptibility. Accordingly, CBC and CBG have the unique property over A9-THC and CBD of being agonists of TRPV1 , CB1, and CB2, without psychoactive side effects.

The minor cannabinoids disclosed herein can be used in the management and/or treatment of seizure disorders in a patient, who can be a human or an animal. For example, one or more minor cannabinoids, including compilations thereof, can be administered to adults or children with a seizure disorder or exhibiting symptoms of a seizure disorder, without the psychoactive effects of THC. Furthermore, one or more minor cannabinoids can be administered to animals with a seizure disorder or exhibiting symptoms of a seizure disorder, such as domestic animals, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. In some embodiments, the patient being administered the therapeutic dose of the minor cannabinoids is a human.

In some embodiments, the minor cannabinoids disclosed herein can be used in the management and/or treatment of an acute condition that causes seizures as a symptom. For example, acute conditions such as brain injuries, alcohol withdrawal, drug withdrawal, electrolyte imbalances, and infections (including meningitis or encephalitis) can be treated with minor cannabinoids to manage seizure symptoms. In certain embodiments, one or more of the minor cannabinoids described herein can be used to treat patients with a brain injury, alcohol withdrawal, drug withdrawal, and/or an infection such as meningitis and encephalitis, to manage and/or preemptively prevent the onset of seizure symptoms.

In certain embodiments, the present description provides a method of treating a disorder as described herein in a patient (e.g., human or other mammal animal) comprising administering to the patient identified as in need thereof, at least one minor cannabinoid or a composition comprising the same of the present description. The identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients that are at risk of developing the above disorders that can be treated by the present method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical/family history.

In some embodiments, the minor cannabinoids can be administered in combination with at least one anti-epileptic drug (AED), /.e., an anti-epileptic drug which is different than a minor cannabinoid as described herein. For example, a combination of an AED and a minor cannabinoid can be useful in treating intractable or treatment resistant epilepsy. As used herein, the term "combination” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present description. In some embodiments, the AED can be selected from levetiracetam, valproic acid, lamotrigine, phenytoin, clobazam, zonisamide, carbamazepine, oxcarbazepine, and topiramate.

Compositions and administration route

In some embodiments, the minor cannabinoids described herein can be administered to a patient alone or admixed with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The expression "pharmaceutically acceptable carrier”, and equivalent expressions, refer to a nontoxic carrier, adjuvant, diluent, excipient, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, diluents, excipients, or vehicles that may be used in the compositions of this disclosure include, but are not limited to, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, oils, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and nonionic surfactant.

In some embodiments, the minor cannabinoids according to the present disclosure can be administered in a composition comprising a carrier selected from an oil, a nonionic surfactant, and a combination thereof. Example of oils can include medium-chain triglyceride (MCT) oil, hempseed, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils. The minor cannabinoid can also be available in a purified form and administered as a capsule or pill. In some embodiments, the nonionic surfactant can comprise a polyethylene glycol (PEG) ether or a PEG fatty acid ester. The nonionic surfactant can thus comprise a fatty acid ester copolymerized with ethylene oxide. In some embodiments, the nonionic surfactant can be polyethylene glycol sorbitan monooleate (Polysorbate 80), also known as Tween-80.

In some embodiments, the minor cannabinoid can include cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG) and/or cannabigerolic acid (CBGA). In some embodiments, the minor cannabinoid can include cannabichromevarin (CBCV), and/or cannabicyclolic acid (CBU\). In some embodiments, the minor cannabinoid can include cannabichromenic acid (CBCA), cannabigerolic acid (CBGA), cannabichromevarin (CBCV), and/or cannabicyclolic acid (CBI_A). In some embodiments, the CBC, CBCA, CBG, CBGA, CBCV, and/or CBU\ can be administered in a composition comprising a nonionic surfactant comprising a polyethylene glycol (PEG) ether or a PEG fatty acid ester, preferably a fatty acid ester copolymerized with ethylene oxide, more preferably polyethylene glycol sorbitan monooleate (Tween-80).

Compositions described herein can be administered orally, parenterally, topically, or nasally, or by inhalation. The term "parenteral" as used herein includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

Liquid dosage forms for oral administration can include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other diluents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, MCT, hempseed, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, ll.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound(s) is(are) mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Dosage forms for topical or transdermal administration can include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component can be admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing an alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

In some embodiments, the minor cannabinoid(s) can be provided in a composition, such as a pharmaceutical formulation, comprising at least one carrier or vehicle, at a concentration of between about 0.1 mg/ml and about 300 mg/ml, preferably between about 30 mg/ml and about 300 mg/ml.

The amount of minor cannabinoid(s) that can be administered, alone or combined with at least one carrier material, can vary depending upon the patient to be treated and the particular mode of administration. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 0.01 - 300 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 0.01 - 250 mg/kg body weight, or between 0.01 - 200 mg/kg body weight, or between 0.01 - 150 mg/kg body weight, or between 0.01 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 10 - 300 mg/kg body weight, or between 10 - 250 mg/kg body weight, or between 10 - 200 mg/kg body weight, or between 10 - 150 mg/kg body weight, or between 10 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 20 - 300 mg/kg body weight, or between 20 - 250 mg/kg body weight, or between 20 - 200 mg/kg body weight, or between 20 - 150 mg/kg body weight, or between 20 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 25 - 300 mg/kg body weight, or between 25 - 250 mg/kg body weight, or between 25 - 200 mg/kg body weight, or between 25 - 150 mg/kg body weight, or between 25 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 30 - 300 mg/kg body weight, or between 30 - 250 mg/kg body weight, or between 30 - 200 mg/kg body weight, or between 30 - 150 mg/kg body weight, or between 30 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 40 - 300 mg/kg body weight, or between 40 - 250 mg/kg body weight, or between 40 - 200 mg/kg body weight, or between 40 - 150 mg/kg body weight, or between 40 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 50 - 300 mg/kg body weight, or between 50 - 250 mg/kg body weight, or between 50 - 200 mg/kg body weight, or between 50 - 150 mg/kg body weight, or between 50 - 100 mg/kg body weight. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 75 - 300 mg/kg body weight, or between 75 - 250 mg/kg body weight, or between 75 - 200 mg/kg body weight, or between 75 - 150 mg/kg body weight, or between 75 - 100 mg/kg body weight.

The amount of minor cannabinoid(s) that can be administered daily, alone or combined with at least one carrier material, can vary depending upon the patient to be treated and the particular mode of administration. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 0.01 - 300 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 0.01 - 250 mg/kg body weight/day, or between 0.01 - 200 mg/kg body weight/day, or between 0.01 - 150 mg/kg body weight/day, or between 0.01 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 10 - 300 mg/kg body weight/day, or between 10 - 250 mg/kg body weight/day, or between 10 - 200 mg/kg body weight/day, or between 10 - 150 mg/kg body weight/day, or between 10 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 20 - 300 mg/kg body weight/day, or between 20 - 250 mg/kg body weight/day, or between 20 - 200 mg/kg body weight/day, or between 20- 150 mg/kg body weight/day, or between 20- 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 25 - 300 mg/kg body weight/day, or between 25 - 250 mg/kg body weight/day, or between 25 - 200 mg/kg body weight/day, or between 25 - 150 mg/kg body weight/day, or between 25 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 30 - 300 mg/kg body weight/day, or between 30 - 250 mg/kg body weight/day, or between 30 - 200 mg/kg body weight/day, or between 30 - 150 mg/kg body weight/day, or between 30 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 40 - 300 mg/kg body weight/day, or between 40 - 250 mg/kg body weight/day, or between 40 - 200 mg/kg body weight/day, or between 40- 150 mg/kg body weight/day, or between 40 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 50 - 300 mg/kg body weight/day, or between 50 - 250 mg/kg body weight/day, or between 50 - 200 mg/kg body weight/day, or between 50 - 150 mg/kg body weight/day, or between 50 - 100 mg/kg body weight/day. In some embodiments, the minor cannabinoids(s) can be administered at a dosage of between 75 - 300 mg/kg body weight/day, or between 75 - 250 mg/kg body weight/day, or between 75 - 200 mg/kg body weight/day, or between 75 - 150 mg/kg body weight/day, or between 75 - 100 mg/kg body weight/day.

In some embodiments, treatment regimens according to the present description can comprise administration to a patient in need of such treatment from about 10 mg to about 20000 mg of the minor cannabinoid(s) per day in single or multiple doses. In some embodiments, the treatment can comprise administration of from about 10 mg to about 20000 mg, or from about 10 mg to about 15000 mg, or from about 10 mg to about 10000 mg, or from about 10 mg to about 5000 mg of the minor cannabinoid(s) per day in single or multiple doses.

In some embodiments, treatment regiments can comprise administering the composition in increasing increments, such as with a starting dose of 2.5 mg/kg twice daily that is increased at weekly increments by 2.5 mg/kg twice daily to a maximum dose of about 300 mg/kg twice daily.

In some embodiments, the composition can include two or more minor cannabinoids in a ratio that provides a compounded effect. In other embodiments, other cannabinoids, such as CBD, can be included in the composition. For example, the composition can include a ratio of CBGA to CBC to CBD of 1 :1 :1. In other embodiments, the composition can include a ratio of CBGA to CBD of 2: 1. In some embodiments, a treatment regiment comprising 5 mg/kg CBGA and 2.5 mg/kg CBD can be orally administered twice a day. In some embodiments, this treatment regiment can be increased incrementally by 5 mg/kg CBGA and 2.5 mg/kg CBD per week to a maximum dose of 300 mg/kg CBGA and 100 mg/kg CBD.

In another embodiment, the composition can include a ratio of CBC to CBD of 1 :1. In some embodiments, a treatment regiment comprising 2.5 mg/kg CBC and 2.5 mg/kg CBD can be orally administered twice a day. In some embodiments, this treatment regiment can be increased incrementally by 2.5 mg/kg CBC and 2.5 mg/kg CBD per week to a maximum dose of 300 mg/kg CBC and 100 mg/kg CBD.

In another embodiment, the composition can include at least one of CBC and CBCA at a concentration of at least 1 % w/w in the composition. In other embodiments, the concentration of the at least one of CBC and CBCA in the composition can be about 10% w/w.

In another embodiment, the composition can include at least one of CBG and CBGA at a concentration of at least 1 % w/w in the composition. In other embodiments, the concentration of the at least one of CBG and CBGA in the composition can be about 10% w/w.

It should also be understood that a specific dosage and treatment regimen for any particular patient can depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated.

In some embodiments, the minor cannabinoid(s) described herein can be in a composition in combination with an additional AED. Alternatively, the additional AED can be administered separately from the minor cannabinoid(s) such as in a separate composition. Hence, additional AED can be administered separately from a composition containing the minor cannabinoid(s), as part of a multiple dosage regimen. Alternatively, those additional AED can be part of a single dosage form, mixed together with the minor cannabinoid(s) in a single composition. If administered as part of a multiple dosage regimen, the two active agents can be submitted simultaneously, sequentially or within a period of time from one another.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of the present description can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The patient may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

In some particular embodiments, one or more of the minor cannabinoids described herein can be extracted from a strain of cannabis that contain a small or undetectable amount of at least one of A9-THC and CBD, and optionally isolated from the resulting extract using precipitation such as amine-cannabinoid salt precipitation, or flash chromatography, although other isolation methods conventionally used in the field can be used. In some embodiments, a composition comprising the isolated minor cannabinoid(s) can be prepared in a carrier oil used for oral administration and dosed with a syringe. In other embodiments, the minor cannabinoid may be available in pill or capsule form in its crystallized form. In other embodiments, the minor cannabinoid composition can comprise at least one carrier such as a nonionic surfactant comprising a polyethylene glycol (PEG) ether or a PEG fatty acid ester, preferably a fatty acid ester copolymerized with ethylene oxide, more preferably Polysorbate 80 (Tween-80). In some embodiments, the composition can further comprise a diluent such as an alcohol, e.g., ethanol and a saline solution (/.e., sodium chloride in water). In a specific example, the composition can include at least one minor cannabinoid diluted in a 1 :1 :18 (v/v/v) ratio of ethanol:Tween-80:saline. In some embodiments, such specific composition can be administered at a dosage of 100 mg/kg. Of course, various compositions can be prepared to administer the minor cannabinoids to a patient in need thereof, to treat the disorders mentioned herein, and these compositions are not limited to the specific ones mentioned above and/or in the following examples.

All publications, articles and/or documents mentioned in the present disclosure are herein incorporated by reference.

EXPERIMENTATION

CBG, CBGA, CBC and CBCA were evaluated as test compounds in seizure models using a screening protocol aimed at identifying pharmacotherapies to address the unmet need in treating acute seizure disorders. The efficacy of CBG, CBGA, CBC, and CBCA in the treatment of acute seizure disorders were investigated in acute seizure models (mouse 6 Hz 44 mA and mouse maximal electroshock (MES) tests).

Compositions

CBCA Test Compound

CBCA was isolated from a cannabis plant to produce an isolated CBCA extract. The CBCA extract can be isolated from a cannabis plant via flash chromatography or amine-salt precipitation and crystallization. Alternatively, CBCA can be transformed via enzymatic conversion from CBGA. For the present experiments, the CBCA was isolated via amine-salt precipitation and crystallization. The isolated CBCA extract was diluted with a mixture comprising a ratio of ethanol:Tween 80:saline of about 1 :1 : 18 to dilute to a desired concentration of CBCA. The CBCA extract can be diluted to a concentration of about 30 mg/ml to about 300 mg/ml prior to administration.

The cannabinoid properties of the CBCA extract isolated via amine-salt precipitation and crystallization was measured using ultra high-pressure liquid chromatography coupled to a LIV detector (UPLC-UV). The isolated CBCA test compound comprised 984.67 mg/g (98.467% w/w) CBCA.

CBC Test Compound

The CBC test composition can be transformed from CBCA via a decarboxylation method applied by exposing the CBCA compound to high temperature. The resulting CBC extract can be diluted with a mixture comprising a ratio of ethanol:Tween 80:saline of about 1 :1 :18 to dilute to a desired concentration of CBC. The CBC extract can be diluted to a concentration of about 30 mg/ml to about 300 mg/mL prior to administration.

The cannabinoid properties of CBC obtained from decarboxylation of CBCA that was obtained via transformation of CBGA isolated from an industrial hemp plant are shown in Table 4. As shown below in Table 4, A9-THC, A9-THC acid, CBG, CBGA, CBCA, CBDV, CBD, CBL, A9- Tetrahydrocannabivarin (A9-THCV), A9-THCV acid, cannabinol (CBN), and CBN acid (CBNA) were not detected (none detected (ND)) in the isolated CBC sample. The isolated CBC test compound comprised 968 mg/g of CBC (96.8% w/w) with small amounts of other minor cannabinoids, such as 30.0 mg/g cannabicitran (CBT) (3.00% w/w).

Table 4

ND = Not Detected, NT = Not Tested, LOD - Limit of Detection, LOQ = Limit of Quantification CBGA Test Compound

The CBGA test composition can include CBGA extract isolated from HURV19PAN via amine- salt precipitation and crystallization. The isolated CBGA extract can be diluted with a mixture comprising a ratio of ethanol:Tween 80:saline of about 1 :1 : 18 to dilute to a desired concentration of CBGA. The CBGA extract can be diluted to a concentration of about 30 mg/ml to about 300 mg/ml prior to administration.

The cannabinoid properties of CBGA isolated via amine-salt precipitation and crystallization was measured using ultra high-pressure liquid chromatography coupled to a UV detector (UPLC-UV). As shown below in Table 5, the isolated CBGA test compound comprised 989 mg/g of CBGA (98.9% w/w) with small amounts of other minor cannabinoids, such as 0.810 mg/g CBG (0.081 % w/w), 2.78 mg/g CBDV (0.278% w/w), and 0.482 mg/g CBDVA (0.048% w/w). The isolated CBGA also contained a small amount of CBDA, namely, 2.35 mg/g CBDA (0.235 % w/w). The total CBD** content of 2.06 mg/g (0.206% w/w) mentioned in Table 5 takes into account that CBDA 5 has a conversion rate to CBD of about 87.7% upon decarboxylation (e.g., by heating the extract).

However, the isolated CBGA test compound did not include any detected amounts of CBD, nor of A9-THC, A9-THC acid, CBC, CBA, CBL, A9-Tetrahydrocannabivarin (A9-THCV), A9-THCV acid, cannabinol (CBN), or CBN acid (CBNA) (none detected (ND)).

Table 5

CBG Test Compound

The CBG test composition can be transformed from CBGA via decarboxylation method applied by exposing the CBGA compound to high temperatures. The resulting CBG extract can be diluted with a mixture comprising a ratio of ethanokTween 80:saline of about 1 :1 :18 to dilute to 5 a desired concentration of CBG. The CBG extract can be diluted to a concentration of about 30 mg/ml to about 300 mg/ml prior to administration.

The cannabinoid properties of CBG isolated via amine-salt precipitation and crystallization was measured using ultra high-pressure liquid chromatography coupled to a LIV detector (UPLC-UV). As can be seen in Table 6, A9-THC, A9-THC acid, CBC, CBCA, CBD, CBDA, and CBN were not detected (none detected (ND)) in the isolated CBG sample. The isolated CBG test compound comprised 996 mg/g of CBG (99.6% w/w) with a small amount of other minor cannabinoids, such as 0.870 mg/g CBGA (0.087% w/w).

Table 6

Test methods

Animals and Test Substances

Male albino CF-1 I Charles River mice (18 - 30 g; Charles River, Kingston, NY) were used as experimental animals. All animals were allowed free access to food (ENVIGO 2920X for all Charles River-derived animals) and water except when they were removed from their cages for the experimental procedure. All animals were housed, fed, and handled in a manner consistent with the recommendations in "Guide for the Care and Use of Laboratory Animals" from the National Research Council (U.S.), Committee for the Update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.). Washington, D.C.: National Academies Press; 2011. No insecticides capable of altering hepatic drug metabolism enzymes were used in the animal facilities. Animals were used once. All animals were euthanized in accordance with the Institute of Laboratory Resources policies on the humane care of laboratory animals. All protocols involving the use of animals have been approved by the Institutional Animal Care and Use Committee at the University of Utah. Compound Preparations For Administration

CBG, CBGA, CBC, and CBCA were individually prepared for intraperitoneal administration using a carrier. In the present examples, the carrier was an ethanol/Tween 80/saline mixture in a 1 :1 :18 ratio, respectively. CBG, CBGA, and CBCA were a solid crystalline material that was weighed and placed in a test tube and ground with glass stir bar. Pure CBC was obtained in an oil format. The carrier was added in 0.5 ml and 1 ml increments, with mixing/vortexing in between, until 10 ml of carrier was added. The admixture was placed in the shaking bath for 20 minutes without heat. Stock admixtures of 300 mg/ml CBGA, 300 mg/ml CBG, and 200 mg/ml of CBCA were prepared using this method. The stock admixtures of CBGA, CBG, and CBCA were opaque, milky, white suspensions. Other concentrations were prepared by diluting the stock admixture with the carrier (ethanol/Tween 80/saline mixture in a 1 :1 :18 ratio).

The CBC oil was kept refrigerated until the compound preparations began. The CBC oil was allowed to remain at room temperature for about 20 minutes and was then weighed. 200.8 mg of CBC oil was weighed and placed into a 15 ml falcon tube. The carrier (ethanol/Tween 80/saline mixture in a 1 :1 :18 ratio) was added in 0.5 mL increments up to a total volume of 3 ml, then the carrier was added in 1 mL increments until a total volume of 10 ml was reached. The falcon tube was tilted and vortexed between each addition of carrier to ensure the oil was well emulsified with the carrier. The CBC stock admixture was a white cloudy suspension with small, evenly distributed oil particles. To ensure the administered dose was a homogenous mixture of the oil and carrier (/.e., to prevent the oil from settling), the CBC stock admixture was bench agitated between each administration as necessary. Further concentrations were prepared by diluting the CBC stock admixture with the carrier.

Identification Prescreen Testing Paradigm

Each acute seizure model usually includes four animals per dose/time point (n = 4 animals/dose/time period). These animals are cumulatively evaluated for rotarod impairment, giving a total group size for the rotarod component of eight (n = 8/dose/time point). Animals were tested for each acute seizure test at two time points (0.5 hours and 2 hours) and three or four doses (0.001 mg/kg (control), 30 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, and/or 300 mg/kg) were administered by Intraperitoneal (IP) administration in a volume of 0.01 ml/g body weight in mice. The data for each condition is presented as N/F, where N is equal to the number of animals protected against acute seizures and F is equal to the total number of animals tested. For tests of impairment (Rotarod), N is equal to the number of animals displaying adverse effects and F is equal to the total number of animals tested. 6 Hz Electrical Stimulation Test

Without treatment by antiseizure compounds, a convulsion current (CC) intensity of 22 mA is sufficient to evoke a seizure in 97% (CC ₉₇ ) of the population of mice that were tested (Woodbury and Davenport, Design and use of a new electroshock seizure apparatus, and analysis of factors altering seizure threshold and pattern; Arch Int Pharmacodyn Ther 1952:92:97-104). The 6Hz electrical stimulation test is a model of focal seizures that show resistance to some current antiseizure drugs. The seizures are induced in mice by a low frequency, long-duration current; specifically, the mice are patient to a 6 Hz, 0.2 msec rectangular pulse for 3 seconds. 44 mA currents are delivered to the mice through corneal electrodes applied to the corneas of the mice after they have been treated with a local anesthetic agent (0.5% tetracaine hydrochloride in 0.9% saline) to anesthetize the corneas and improve electrical conductivity. The treatment of 44 mA stimulation intensity use in the experiments is twice as much as the CC97. A seizure in mice administered with this test is characterized by an initial momentary stun, followed by jaw clonus, forelimb clonus, twitching of the vibrissae, and Straub tail lasting at least one second (1 s). Mice that do not display this behavior within one minute indicates that the mouse is “protected” from 6 Hz electrically stimulated seizures by the test compound.

The qualitative screen for anticonvulsant activity was performed with N = 4 male CF-1 mice with doses ranging from 10 mg/kg to 300 mg/kg at 30-minute (0.5 h) and 120-minute (2 h) timepoints. Quantification of the effective dose that confers protection in 50% of mice treated with the compound (ED50) was conducted at the time of peak effect (TPE).

Maximal Electroshock Seizure (MES) Test (mouse, rat)

MES was used as a model for generalized tonic-clonic seizures and provides an indication of a test compound’s ability to prevent seizure spread when all neuronal circuits in the brain are maximally active. MES induced seizures are electrophysiologically consistent with human seizures. For the MES tests, 50 mA, 60 Hz of alternating current are delivered for 0.2 seconds by corneal electrodes. Prior to stimulation, the corneas are treated with a local anesthetic agent (0.5% tetracaine hydrochloride in 0.9% saline) to anesthetize the corneas and improve electrical conductivity. The behavioral seizures are characterized by hindlimb tonic extension that is followed by clonic activity of the limbs. Absence of this tonic/clonic activity indicates that the mouse is “protected” from MES-induced seizures.

The qualitative screen for anticonvulsant activity in the MES test are performed with n = 4 male CF-1 or C57BL/6 mice or Sprague-Dawley CD albino rats with doses of 10 mg/kg, 30 mg/kg, and 100 mg/kg at 30 minute and 120-minute timepoints. Quantification of the effective dose that confers protection in 50% of animals treated with the test compound (ED50) is conducted at the time of peak effect (TPE).

Behavioral Assessment (Rotarod Assay)

The rotarod assay test was used to assess the test compounds possible adverse effect on motor function (motor impairment) (Dunham and Miya TA, A note on a simple apparatus for detecting neurological deficit in rats and mice, J. Amer. Pharm. Ass. Sci. Ed., 1957:46:208-9). A mouse is placed on a 1-inch knurled rod that rotates at a speed of 6 rpm. Mice that do not show motor impairment can maintain equilibrium on the knurled rod for long periods of time. The mouse being tested was considered to show adverse effects on their motor function (/.e., motor impairment) if the mouse fell off the rotating knurled rod at least three times during a 1 -minute period.

Corneal Kindling Seizure Test (mouse)

The corneal kindling seizure test can be used as a model for human focal seizures and identify the anticonvulsant properties of a test compound. Five- to six-month old male C57BL/6 or CF-1 mice is kindled electrically via corneal electrodes to a criterion of 5 consecutive Stage 5 seizures (facial clonus and head nodding progressing to forelimb clonus and rearing and falling accompanied by a generalized clonic seizure). C57BL/6 mice is kindled by a 1.5 mA, 60 Hz, 3 second stimulation and CF-1 mice is kindled by a 3 mA, 60 Hz, 3 second stimulation. Prior to stimulation, the corneas are treated with a local anesthetic agent (0.5% tetracaine hydrochloride in 0.9% saline) to anesthetize the corneas and improve electrical conductivity. The mice are receiving twice daily corneal stimulations and are predicted to reach the first Stage 5 seizure between approximately 10 to 15 days. The twice daily stimulations are continued until the mouse has achieved the criterion of 5 consecutive stage 5 seizures, in which case the mouse is categorized as “fully kindled”. Fully kindled mice are then be stimulated once every 2 days until all other mice have reached this criterion. Non-fully kindled mice are not included in the evaluation of the test compounds.

The evaluation of the test compounds begins at least seven days after the last stimulation. The mice are stimulated again on the day before the compounds are to be analyzed to ensure that all the mice present with a Stage 5 seizure. To test the test compounds, the mice are randomly assigned to groups and mice displaying a seizure score of less than 3 are considered “protected”. The test compounds are administered to a group of 4 fully kindled mice at the TPE and ED50 determined in the initial screening in acute models (MES and 6 Hz models). Results

As described above, the 6 Hz 44 mA model assesses the ability of a test compound to prevent seizures induced by 6 Hz corneal stimulation at the 44 mA current intensity. Seizure protection in the maximal electroshock (MES) seizure model suggests the ability to prevent the spread of seizure activity in a model of generalized tonic-clonic seizures. The rotarod test was used to assess whether the mice experience motor impairment after administration of the test compounds.

Performance of the test compounds against seizures in the test subjects that are induced by the 44 mA stimulation current (6 Hz), against MES-induced tonic extension seizures are shown in Table 7. Also shown in Table 7 is whether the test compounds show adverse effect on motor function in the rotarod assay. Comparative results for levetiracetam (Keppra®) and phenytoin, which are known antiseizure pharmaceutical compounds, are shown in Table 8. The levetiracetam (Keppra®) and phenytoin compounds were testing using 6 Hz 44 mA seizure models, MES models, and rotarod assays models under similar conditions as the test compounds.

Table 7 Table 8

The data for each test is presented as N/F, where N is equal to the number of animals protected and F is equal to the number of animals tested. For the rotarod tests shown in Table 7, N is equal to the number of animals displaying adverse motor effects and F is equal to the number of animals tested.

In addition to the above experiments, the dose of the CBGA test compound that produces the desired antiseizure effect in 50% of tested animals (ED50) was calculated and compared to known compounds of levetiracetam and phenytoin in the 6Hz mouse model. The ED50 for CBGA was 137 mg/kg (+/- 10.1 standard of error) compared to >500 mg/kg for levetiracetam and >500mg/kg for phenytoin.

The observed efficacy of CBG, CBGA, CBC and CBCA in seizure models suggests that these minor cannabinoid compounds can have therapeutic potential for the treatment of acute seizures in other mammals, including humans. It is theorized that the physiological role of the endocannabinoid system in the central nervous system can be targeted with the minor cannabinoids to prevent or reduce the severity of acute seizure disorders. The endocannabinoid system includes widespread receptors that play a pivotal role in modulating neuronal excitability, synaptic plasticity, and overall neuroprotection. Through the interaction of the minor cannabinoids with the endocannabinoid system, either directly or indirectly, it is theorized that the minor cannabinoids influence the minimum seizure threshold and propagation in the recipient. In some instances, the pharmacokinetic profiles and molecular targets of the minor cannabinoids are often analogous, bolstering the rationale for anticipating similar therapeutic benefits for other minor cannabinoids in treating acute seizures, such as cannabidivarin (CBDV), cannabicyclol (CBL), cannabichromevarin (CBCV), and cannabicyclolic acid (CBI_A).

As shown in Table 8, levetiracetam and phenytoin demonstrated limited efficacy in the acute seizure test models. However, as is well understood by the skilled artisan, both of these antiseizure pharmaceutical compounds have well established therapeutic benefits in human acute seizure disorders. Referring back to Table 7, the tested minor cannabinoids, namely CBG, CBGA, CBC, and CBCA, demonstrated greater efficacy than levetiracetam and phenytoin in the same experimental seizure models. As is understood by the skilled artisan, the tested minor cannabinoid compounds are thus theorized to have efficacy against acute seizure models when administered in other mammals, such as human.