WO2023248226A1

WO2023248226A1 - Cannabis compositions for treatment of anxiety

Info

Publication number: WO2023248226A1
Application number: PCT/IL2023/050646
Authority: WO
Inventors: Anat RAPOPORT; Leehee BARAK; Eran Goldberg; Shifra JAMMER; Dadi Segal; Or SEGAL; Lior Zelikovich
Original assignee: Panaxia Pharmaceutical Industries Ltd.
Priority date: 2022-06-23
Filing date: 2023-06-22
Publication date: 2023-12-28

Abstract

Disclosed are cannabis compositions and methods of using same for treating anxiety of a subject in need thereof, the cannabis composition characterized by comprising a predetermined minimal amount/concentration of CBCA.

Description

CANNABIS COMPOSITIONS FOR TREATMENT OF ANXIETY

TECHNICAL FIELD

The present disclosure generally relates to cannabis compositions having a particular content of cannabinoids and use of the cannabis composition for the treatment of anxiety.

BACKGROUND

Anxiety disorders are highly prevalent in the population and are associated with a high disease burden.

Currently, the most common pharmacological treatments for anxiety are antidepressants and benzodiazepines; however, their use is limited due to efficacy and safety concerns.

Scientific evidence shows that the endocannabinoid system (ECS) is involved in modulating anxiety and stress responses. Cannabinoid receptors of the 1 type (CB1) are primarily located in the central nervous system, including such structures as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, and hippocampus.

Cannabis has become more and more widespread in medical treatments and has shown to have various benefits. The main cannabinoids found in cannabis are cannabidiol (CBD) and tetrahydrocannabinol (THC), however about 100 other cannabinoids and 400 non-cannabinoid chemicals (e.g., terpenes and flavonoids) in various amounts and ratios are also found in cannabis plants, including for example, the cannabinoid cannabichromene (CBC) and its acid form CBCA.

Binding to CB 1 receptors, cannabinoids have a modulating effect on GAB Aergic and Glutamatergic transmission, while also influencing the hypothalamic pituitary adrenal (HPA) axis, immune system activation, and neuroplastic mechanisms. Importantly, an anxiolytic effect may be mediated through serotonergic effects of CBD via 5-HT1A receptor activation, and of THC via CB 1 receptor agonism.

Nevertheless, thus far, evidence arising from research on the effect of cannabis on anxiety remains ambiguous. There is a large variability in response to consumption, and while in some cases it may alleviate anxiety, in others it is said to produce feelings of anxiety, panic, paranoia, and even psychosis. It is a well-known fact that the efficacy of prescribed cannabis in providing relief tends to vary from product to product, from strain to strain, and even within the same strain purchased from the same grower. At times even a negative effect is obtained.

The direct causation for this variability in response to consumption of supposedly similar products is unknown, however it is clear that cannabinoids interact differently with receptors and neurotransmitters in the CNS and ECS. Hence, each of them has different effects on anxiety and has an individual therapeutic potential.

Still, this poses a major obstacle to the standardization and authorization of the use of cannabis in medical treatment, and specifically the therapeutic potential of cannabis-based treatment for anxiety remains unclear.

There is, therefore, a need for identifying cannabis compositions having a particular cannabinoid content that makes them suitable for the treatment of anxiety.

SUMMARY

The present disclosure provides cannabis compositions, and methods of evaluating such compositions for having a particular cannabinoid content that makes them suitable for use in the treatment of anxiety, as well as methods for treating anxiety using the composition.

It was advantageously found by the inventors of the herein disclosed invention that cannabis compositions, including a certain amount of the cannabinoid cannabichromene acid (CBCA), correlate with a positive outcome in providing a consistent beneficial effect with regard to treating/reducing anxiety in subjects suffering from various conditions including but not limited to: post-traumatic stress disorder (PTSD), pain, orthopedic pain, neuropathic pain, fibromyalgia, cancer, cancer-associated nausea, cancer-associated pain, epilepsy, Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS), and/or Amyotrophic Lateral Sclerosis (ALS).

It is disclosed that as the CBCA dosage increases above a certain amount the treatment of anxiety is more effective, while the effect is reduced in cannabis containing reduced amounts of CBCA or of its natural form cannabichromene (CBC), the latter generated as a result of the decarboxylation of CBCA, e.g. during smoking. The inventors further found that the positive effect was further enhanced in cannabis compositions including a predetermined minimal amount/concentration of CBCA.

Accordingly, the longtime felt need for efficiently reducing the distress of subjects suffering from anxiety has been provided.

Advantageously, the herein disclosed finding allows avoiding compositions that do not provide a consistent beneficial outcome thereby attenuating/preventing the possible undesired side effect of increased anxiety due to cannabis consumption.

According to some aspects, there is provided a cannabis composition comprising a predetermined minimal amount/concentration of at least 450ug CBC and/or CBCA per daily dose for use in the treatment of anxiety.

In some embodiments, the predetermined minimal amount is at least 550ug, per daily dose.

In some embodiments, the cannabis composition comprises raw cannabis.

In some embodiments, at least a portion of the CBC and/or CBCA in the composition comprises synthetic, extracted, isolated and/or purified CBC and/or CBCA. Each possibility is a separate embodiment.

In some embodiments, at least a portion of the CBC and/or CBCA in the composition comprises isolated CBC and/or CBCA. In some embodiments, at least a portion of the CBC and/or CBCA in the composition comprises extracted CBC and/or CBCA.

In some embodiments, the composition is selected from a plurality of potential cannabis compositions based on an analysis of the content of CBC and/or CBCA in the plurality of potential cannabis compositions.

In some embodiments, the administering comprises administering by route of smoking, inhalation, vaporization, oral administration, buccal administration, nasal administration, topical administration, transdermal administration parenteral administration, or any combination thereof. Each possibility is a separate embodiment.

In some embodiments, the composition comprising a standardized extract of about: 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E. In some embodiments, the composition comprising a standardized extract of about: 5.2% (w/w) THC, 5.2% (w/w) CBD, 0.20% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

In some embodiments, the composition comprises a standardized extract comprising a predetermined minimal amount/concentration of at least 400ug per daily dose CBC and/or CBCA; In some embodiments, the composition comprises a standardized extract comprising a predetermined minimal amount/concentration of at least 450ug per daily dose CBC and/or CBCA; In some embodiments, the composition comprises a standardized extract comprising a predetermined minimal amount/concentration of at least 550ug per daily dose CBC and/or CBCA; In some embodiments, the composition comprises a standardized extract comprising a predetermined minimal amount/concentration of at least 600ug per daily dose CBC and/or CBCA; In some embodiments, the composition comprises a standardized extract comprising a predetermined minimal amount/concentration of at least 2100ug per daily dose CBC and/or CBCA

In some embodiments, the cannabis composition comprises a content of CBC and/or CBCA between the predetermined minimal amount/concentration and a maximum amount/concentration of about 500,000ug, per daily dose.

In some embodiments, the cannabis composition comprises a standardized extract comprising a content of CBC and/or CBCA between the predetermined minimal amount/concentration and a maximum amount/concentration of about 500,000ug, per daily dose.

In some embodiments, the cannabis composition comprises cannabis extracts enriched with CBC and/or CBCA.

In some embodiments, the cannabis extracts enriched with CBC and/or CBCA comprises at least about 2 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount.

In some embodiments, the cannabis extracts enriched with CBC and/or CBCA comprises at least about 200 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount. In some embodiments, the cannabis extract enriched with CBC and/or CBCA comprises extracted, isolated, purified, or synthetic CBC/CBCA.

In some embodiments, at least a portion of the CBC and/or CBCA in the composition comprises isolated or synthetic CBC and/or CBCA. In some embodiments, at least a portion of the CBC and/or CBCA in the composition a standardized extract comprising isolated or synthetic CBC and/or CBCA. Each possibility is a separate embodiment.

According to some aspects, there is provided a method for classifying cannabis compositions as being suitable for the treatment of anxiety, the method comprising: receiving a potential cannabis composition; evaluating the content of CBC and/or CBCA in the potential cannabis composition; classifying the composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above a predetermined minimal amount/concentration.

In some embodiments, the predetermined minimal amount is at least 450ug, per daily dose. In some embodiments, the predetermined minimal amount is at least 550ug, per daily dose.

In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above the predetermined minimal amount/concentration.

In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 450ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount of CBC and/or CBCA is at least 550ug, per daily dose.

In some embodiments, the suitable cannabis composition comprises a content of CBC and/or CBCA between the predetermined minimal amount/concentration and a maximum amount/concentration of about 500,000ug, per daily dose.

According to some aspects, there is provided a standardized cannabis extract comprising extracts from a natural source and a predetermined minimal amount/concentration of isolated or synthetic CBC and/or CBCA. Each possibility is a separate embodiment. In some embodiments, the standardized cannabis extract comprising extracts from a natural source and a predetermined minimal amount/concentration of isolated or synthetic CBC and/or CBCA of at least 450ug, per daily dose; In some embodiments, the standardized cannabis extract comprising extracts from a natural source and a predetermined minimal amount/concentration of isolated or synthetic CBC and/or CBCA of at least 550ug, per daily dose. Each possibility is a separate embodiment.

In some embodiments, the standardized cannabis extract comprises about: 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

In some embodiments, the standardized cannabis extract comprises about: 5.2% (w/w) THC, 5.2% (w/w) CBD, 0.2% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

In some embodiments, the standardized cannabis extract comprises a CBC and/or CBCA amount between the predetermined minimal amount and a maximum amount of about 500,000ug, per daily dose.

In some embodiments, the cannabis extract is enriched with CBC and/or CBCA.

In some embodiments, the cannabis extract enriched with CBC and/or CBCA comprises at least about 2 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount.

In some embodiments, the cannabis extract enriched with CBC and/or CBCA comprises at least about 200 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount.

In some embodiments, the cannabis extract enriched with CBC and/or CBCA comprises extracted, isolated, purified, or synthetic CBC/CBCA.

According to some embodiments, there is provided a method for treating anxiety of a subject in need thereof, the method comprising: administering a therapeutically effective amount of a suitable cannabinoid composition to the subject, the suitable cannabis composition characterized by comprising predetermined minimal amount/concentration of CBC and/or CBCA. According to some embodiments, there is provided a method for treating anxiety of a subject in need thereof, the method comprising: selecting, from a plurality of cannabis compositions, a suitable cannabis composition, the suitable cannabis composition characterized by comprising a predetermined minimal amount/concentration of CBC and/or CBCA, and administering a therapeutically effective amount of the suitable cannabinoid composition to the subject.

According to some embodiments, the predetermined minimal amount is at least about 450 ug, per daily dose. According to some embodiments, the predetermined minimal amount is at least about 550 ug, per daily dose.

According to some embodiments, the suitable cannabis compositions comprise raw cannabis. According to some embodiments, the cannabis plant is a genetically modified cannabis plant. According to some embodiments, the suitable cannabis compositions comprise cannabis extracts. According to some embodiments, the cannabis compositions comprise a standardized cannabis extract. According to some embodiments, the suitable cannabis compositions comprise synthetic cannabis. According to some embodiments, the suitable cannabis compositions comprise isolated cannabis.

According to some embodiments, the CBC and/or CBCA comprises synthetic, extracted, isolated, and/or purified CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, the method further comprises selecting the suitable cannabis composition from a plurality of cannabis compositions, wherein the selecting comprises analyzing a content of CBC and/or CBCA in the plurality of cannabis compositions. Each possibility is a separate embodiment.

According to some embodiments, the method further comprises adding CBC and/or CBCA to the composition if the CBC and/or CBCA content is below the predetermined minimal amount/concentration. Each possibility is a separate embodiment.

According to some embodiments, the administering comprises smoking, inhalation, vaporization, oral administration, buccal administration, nasal administration, topical administration, transdermal administration parenteral administration, or any combination thereof. Each possibility is a separate embodiment. According to some embodiments, there is provided a cannabis composition comprising a predetermined minimal amount/concentration of CBC and/or CBCA.

According to some embodiments, the predetermined minimal amount is at least 450ug, per daily dose. According to some embodiments, the predetermined minimal amount is at least 550 ug, per daily dose.

According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise synthetic, extracted, isolated and/or purified CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise isolated CBC and/or CBCA. According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise synthetic CBC and/or CBCA. According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise isolated or synthetic CBC and/or CBCA.

According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise extracted CBC and/or CBCA. According to some embodiments, at least a portion of the CBC and/or CBCA in the cannabis compositions comprise purified CBC and/or CBCA.

According to some embodiments, the cannabis composition is selected from a plurality of potential cannabis compositions based on an analysis of the content of CBC and/or CBCA in the plurality of potential cannabis compositions.

According to some embodiments, the administering comprises smoking, inhalation, vaporization, oral administration, buccal administration, nasal administration, topical administration, transdermal administration parenteral administration or any combination thereof. Each possibility is a separate embodiment.

According to some embodiments, there is provided a method for classifying cannabis compositions as being suitable for the treatment of anxiety, the method comprising: receiving a potential cannabis composition; evaluating the content of CBC and/or CBCA in the potential cannabis composition; classifying the composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above a predetermined minimal amount/concentration.

According to some embodiments, the method further comprises labeling the potential composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above the predetermined minimal amount/concentration.

According to some embodiments, there is provided a method for treating anxiety of a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising a predetermined minimal amount/concentration of synthetic, extracted, isolated, and/or purified CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, there is provided a cannabis extract comprising a predetermined minimal amount/concentration of isolated CBC and/or CBCA.

Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein.

In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed descriptions.

BRIEF DESCRIPTION OF THE FIGURES

The invention will now be described in relation to certain examples and embodiments with reference to the following illustrative figures.

FIG. 1 shows a typical chromatogram of the specific HPLC method applied in this study, obtained at 235nm wavelength.

FIGs. 2A-2B show line graphs presenting the UV spectra of CBCA across all samples obtained using HPLC (FIG. 2A) and the UV spectra obtained for CBCA standard (FIG. 2B).

FIG. 2C shows line graphs presenting the UV spectra of all 59 clusters (each cluster defining a cannabis molecule).

FIG. 3 shows a scatter plot of ranked treatment efficacy and ranked CBCA concentrations across 11 strains, r=0.88, p-value=0.023 (after FDR multiple testing correction). Number of batches included in the study per strain in parentheses.

FIG. 4 schematically illustrates the basic design principle of the clinical trial being performed to evaluate the effect of standardized cannabis extracts comprising at least the predetermined minimal amount/concentration of CBC and/or CBCA, on subjects suffering from anxiety. Period 1 is for evaluation of the baseline. Periods 2-3 is for evaluation of the CBC treatment against the placebo. DETAILED DESCRIPTION

In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure.

According to an aspect of the disclosure, there is provided a method for treating anxiety in a subject in need thereof, the method comprising: selecting, from a plurality of optional cannabis compositions, a suitable cannabis composition, the suitable cannabis composition characterized by containing a predetermined minimal amount/concentration of CBC and/or CBCA and administering a therapeutically effective amount of the suitable cannabinoid composition to the subject.

As used herein, the singular forms “a”, “an”, and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

As used herein, the term "about" or “approximately” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or in some instances ±10%, or in some instances ±5%, or in some instances ±1%, or in some instances ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the terms "subject", "patient" or "individual" may be used interchangeably and generally refer to a human, although the methods of the invention are not necessarily limited to humans and should be useful in other mammals.

In some embodiments, the subject suffers from anxiety.

As used herein, the term “anxiety” should be interpreted in its broad medical meaning as referring to any type of anxiety that is diagnosed in a formal manner by one of ordinary skill in the art, as accepted in the relevant field (i.e., medicine, psychiatry, neurology, or psychology). For example, in some embodiments, the term “anxiety” may refer to “anxiety disorders” such as, but not limited to, Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder (PD)) and/or a phobia (such but, not limited to, agoraphobia), as defined per DSM 5; or in some other embodiments, the term “anxiety” may refer to a state of high stress (distress) with anxiety levels within normative, non-pathological range.

Additionally, the anxiety may be manifested as a primary disorder thus referring to a distinct diagnostic entity that may arise spontaneously for unknown or obscure reasons (i.e., idiopathic) and is unrelated to a possible another condition the suffering subject may have, or it may be manifested as a secondary disorder, comorbidity, that is associated with at least one other psychiatric/neurologic or any other medical condition the suffering subject may have in addition to being suffering from anxiety.

In some embodiments, comorbid anxiety may be associated with psychiatric, neurologic or other medical condition, including but not-limited to: a subject that suffers from anxiety and was previously diagnosed with any one or more of: Post Traumatic Stress Disorder (PTSD), Obsessive Compulsive Disorder (OCD), depression, pain including but not limited to neuropathic pain and/or orthopedic pain, fibromyalgia, cancer and/or tumor progression including but not limited to cancer related side effects such as nausea and/or pain, Epilepsy, Inflammatory Bowel Disease (IBD), Irritable bowel syndrome (IBS), Multiple Sclerosis (MS), Chronic pain, Heart disease, Diabetes, Amyotrophic Lateral Sclerosis (ALS), Substance Use Disorder (SUD), Austism spectrum disorder (ASD), and Attention Deficet Disorder (ADHD). Each possibility is a separate embodiment.

In some embodiments, the subject suffers from anxiety was previously diagnosed with any one or more of: Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD), Panic Disorder (PD), and/or phobia (e.g., agoraphobia), or any combination thereof. Each possibility is a separate embodiment.

As used herein, the term "treating" refers to an approach for obtaining beneficial or desired results (also when provided as palliative care), including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of disease/disorder or condition, stabilization of the state of disease/disorder or condition, prevention of deterioration of the disease or condition, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total).

The terms “alleviation”, “amelioration”, “reduction”, “attenuation”, “inhibition” may be used interchangeably.

As used herein, the term “selecting” may refer to choosing from a plurality of options or choosing a product/formulations/extracts according to it fulfilling a certain requirement, here a minimal CBC and/or CBCA concentration. According to some embodiments, the selecting comprises selecting according to a product specification that outlines the amount/concentration of the cannabinoids found in the product. According to some embodiments, the selecting comprises measuring the concentration of the cannabinoid, for example using HPLC. According to some embodiments, the selecting comprises selecting a composition having a suboptimal concentration/amount of a desired cannabinoid, here CBC and/or CBCA, and adding to the composition the cannabinoid (CBC and/or CBCA) so as to achieve the desired concentration/amount. In some embodiments, the selecting, from a plurality of cannabis compositions, a suitable cannabis composition, comprises analyzing a content of CBC and/or CBCA in the plurality of cannabis compositions.

As used herein, the term “plurality” may refer to two or more, three or more, four or more. Each possibility is a separate embodiment.

According to some embodiments, the composition is selected based on an analysis of the content of CBC and/or CBCA in the plurality of cannabis compositions. According to some embodiments, based on the analysis of the content of CBC and/or CBCA, one or both is added to the composition to reach the predetermined minimal content or more. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below a predetermined minimal amount/concentration. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.077 % w/w. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.130%. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.140%. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.150%. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.160%. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.180%. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA measured is below 0.200% .According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 450 ug per daily dose. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 500 ug per daily dose. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 550 ug per daily dose. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 600 ug per daily dose. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 700 ug per daily dose. According to some embodiments CBC and/or CBCA is added to the composition if the content of CBC and/or CBCA is below 2100 ug per daily dose.

As used herein, the term “cannabis composition” may broadly refer to any composition, e.g., potential, suitable, or optional, having cannabis as a major constituent. According to some embodiments, the cannabis composition may be a cannabis product applicable for medical use (medical grade). According to some embodiments, the cannabis composition comprises THC and/or CBD as well as one or more additional cannabinoids. According to some embodiments, the cannabis composition may be raw cannabis, such as buds, inflorescence, or resins. According to some embodiments, the cannabis composition may be cannabis extract or a cannabis oil. According to some embodiments, the cannabis composition may be a composition (e.g. a pharmaceutical composition) including one or more isolated cannabinoids (in addition to THC and/or CBD). According to some embodiments, the cannabis composition may be a composition (e.g. a pharmaceutical composition) including one or more synthetic cannabinoids (in addition to THC and/or CBD). According to some embodiments, the composition may be in the form of a liquid, a powder, a tablet, a capsule or any other suitable form.

As used herein the term “optional cannabis composition” may refer to a line of actual cannabis products/formulations/extracts between which one can choose. Alternatively, the optional cannabis compositions may be theoretical compositions (e.g. all cannabis composition known and/or available). The term “optional cannabis composition” may refer to a medical cannabis product, a cannabis formulation, or a standardized cannabis extract. According to some embodiments, an optional cannabis composition comprises a standardized extract.

As used herein the term “suitable cannabis composition” refers to a cannabis composition which can be chosen for use because it fulfils certain requirements that are not fulfilled by all the potential cannabis compositions (whether actual such as the herein disclosed predetermined minimal amount or theoretical).

In some embodiments, choosing a suitable cannabis composition, comprises analyzing a content of CBC and/or CBCA in the plurality of cannabis compositions.

In some embodiments, the cannabis composition is a suitable cannabis composition; in some embodiments, a suitable cannabis composition comprises a standardized extract; in some embodiments, the suitable cannabis composition comprises a predetermined minimal amount/concentration per day of CBC and/or CBCA; in some embodiments, the suitable cannabis composition comprises a predetermined minimal amount/concentration per day of at least 450ug CBC and/or CBCA; in some embodiments, the suitable cannabis composition comprises a predetermined minimal amount/concentration per day of at least 550ug CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprises a standardized extract. According to some embodiments, a potential/suitable/optional cannabis composition comprises a standardized extract. Each possibility is a separate embodiment.

The terms “medical cannabis product”, “product”, “formulation”, or “standardized cannabis extract” may be used interchangeably, and may all refer to the cannabis composition of the present disclosure.

The term "cannabinoid" refers hereinafter to a class of diverse chemical compounds that act on cannabinoid receptors present in cells that repress neurotransmitter release in the brain. Cannabinoid compounds may include the endocannabinoids (produced naturally in the body by humans and animals), the phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids. According to some embodiments, the at least one cannabinoid of the composition may be in the form of an extract including the cannabinoid, a purified or distilled cannabinoid or combination of cannabinoids derived from an extract, or a cannabinoid or combination of cannabinoids synthetically produced. As used herein, the term “synthetic” refers to a chemically synthesized CBC and/or CBCA molecule.

As used herein, the term “extract” or “extracted” refers to a molecule(s) extracted from a natural source (i.e., plant source) and may be further added to a mixture composition/formulation. As a non-limiting example, an extracted CBC and/or CBCA molecule may also include additional extracted components (e.g. additional cannabinoids), which are also added to the mixture/composition/formulation, but which are not necessarily required as part of the plant/extract used in the composition.

The extracted molecule(s) may be a cannabis plant extract, or it may be extracted from other plant source, including a plant genetically modified to include/express the molecule(s). The extracted molecule(s) may be used as the main extract for the production of cannabis composition/formulation of the present invention, or the extracted molecule(s) may be added to the cannabis composition/formulation/extract of the present invention

As used herein, the term “isolated” refers to CBC and/or CBCA molecules which are extracted from a natural resource, so as to become a major component of the extracted mixture. The extracted mixture may also include smaller amounts of other molecules. As a non-limiting example, isolated CBC and/or CBCA refers to an extracted mixture containing mostly CBC and/or CBCA, e.g. at least about 50%, at least about 60%, at least about 70% at least about 80% or at least about 90% CBC and/or CBCA. Each possibility is a separate embodiment.

As used herein, the term “purified” refers to CBC and/or CBCA molecules which are isolated from a natural source, and purified so as to become the essentially only component, i.e. other components are present in residual amounts only. As a non-limiting example, purified CBC and/or CBCA refers to an extract containing essentially only CBC and/or CBCA, e.g. less than about 10% or less than about 5% less than about 2% of other molecules or less than about 1% of other molecules. Each possibility is a separate embodiment.

As used herein, the term “natural source” refers to a plant source and should be interpreted in its broader sense. For example, a natural source may include a genetically modified, gene edited or transgenic plant. As used herein, the term “genetically modified” refers to a gene edited plant or a transgenic plant, and include both cannabis plants, and other non-cannabis plants, genetically modified to express/include a cannabinoid at significantly higher concentrations.

According to some embodiments, the cannabis plant is a genetically modified cannabis plant. According to some embodiments, the cannabis compositions comprise a standardized cannabis extract. According to some embodiments, the cannabis compositions comprise synthetic cannabinoids.

According to some embodiments, the cannabis composition comprises a cannabinoid extracted, purified or isolated from a genetically modified plant. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprising a cannabinoid extracted, purified or isolated from a genetically modified plant comprises a significantly higher concentrations of said extracted, purified or isolated cannabinoid, relative to a same cannabis composition comprising a cannabinoid extracted, purified or isolated from a plant which is not genetically modified. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprises a CBC and/or CBCA extracted, purified or isolated from a genetically modified cannabis plant. Each possibility is a separate embodiment.

According to some embodiments, there is provided a composition for use in the treatment of anxiety, the composition comprising a predetermined minimal amount/concentration of synthesized, extracted, isolated and/or purified CBGVA and/or CBGV. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprising a CBC and/or CBCA extracted, purified or isolated from a genetically modified cannabis plant comprises a significantly higher concentrations of said extracted, purified or isolated CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprising a synthetic cannabinoid may comprise a significantly higher concentrations of said synthetic cannabinoid; in some embodiments the synthetic cannabinoid is CBC and/or CBCA. According to some embodiments, the cannabis composition comprises extracts from a natural source and a significantly higher concentrations of synthetic CBC and/or CBCA.

According to some embodiments, the cannabis composition comprises extracts from a natural source and a significantly higher concentrations of CBC and/or CBCA purified or isolated from a genetically modified cannabis plant.

As used herein, the term “significantly higher” refers to CBC and/or CBCA extracted, purified or isolated from a genetically modified plant or to synthetic CBC and/or CBCA, and includes concentrations which are at least about 2 times higher, at least about 10 times higher, at least about 50 times higher, at least about 100 times higher than the herein provided predetermined minimal amount/concentration, or at least about 2 times higher, at least about 10 times higher, at least about 50 times higher, at least about 100 times higher than any amount/concentration indicated by any one of the embodiment provided herein by the inventors.

As used herein, the term “administering” includes routes of administration which allow the compositions of the invention to perform their intended function. In some embodiments, a variety of routes of administration are possible including, but not necessarily limited to, smoking, vaporization, inhalation, nasal and/or buccal spraying, drops administered orally or nasally, oral administration (e.g., of tablets or capsules), topical administration, transdermal administration, parenteral administration or the like. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition may include a physiologically acceptable vehicle or carrier and optional excipients, adjuvants and preservatives suitable for the route of administration. For solutions or emulsions or solid oral dosage forms (e.g., of tablets or capsules or caplets), suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media, sterile water, creams, ointments, lotions, oils, pastes and solid carriers.

The term “predetermined minimal amount/concentration” refers to the content of CBC and/or CBCA herein found to positively correlate with reduction in anxiety in subjects consuming about 10g per month or about 0.333g per day of medical cannabis product. In accordance, the cannabis composition of the invention comprising a certain predetermined minimal amount/concentration that may be required to be consumed at cumulative amounts during the day in order for them to reach (i.e., administer the subject with) the predetermined minimal amount/concentration per daily dose of composition/product, thereby facilitating the benefits of the treatment that alleviate/attenuate or reduce the anxiety.

The term “daily dose” simply refers to an amount that is consumed per day. In some of the herein disclosed embodiments, it may be understood with respect to the total (i.e., cumulative) amount of CBC and/or CBCA to be consumed daily in order to obtain an efficient amelioration of anxiety (e.g., at least 450ug/day or at least 550ug/day). In some of the herein disclosed embodiments, it may also be understood with respect to the cannabis composition/product referring to the actual total dosage a subject consumes from the cannabis product per day (or to the total dosage that is recommended to the subject to consume per day) in order to ensure that the dosage includes a minimal amount of at least 450ug or at least 550ug CBC and/or CBCA.

For example, a cannabis composition/product prepared, for example, according to the standardized extracts of formulas 1-4 (in Example 3), contain 0.1% or 0.2% CBC, that correspond to Img CBC and 2mg CBC per 1g of product. In some embodiments, a subject that is recommended to consume 0.5g per day of these cannabis products, is administered with a daily amount of 500ug or lOOOug of CBC and/or CBCA, respectively. Accordingly, in some embodiments, the subject should consume at least 0.450g per day of the 0.1% CBC containing cannabis product or at least 0.225g of the 0.2% CBC containing cannabis product, respectively, to be administered with a predetermined minimal amount/concentration of at least 450ug CBC and/or CBCA, per daily dose.

The terms “daily dose”, “per day”, “per daily dose unit” may be interchangeably used.

According to some embodiments, the predetermined minimal concentration comprises at least about 0.08% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.1% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.130% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.140% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.150% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.180% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.200% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.230% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.250% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.300% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.400% w/w of CBC and/or CBCA. According to some embodiments, the predetermined minimal concentration comprises at least about 0.500% w/w of CBC and/or CBCA.

According to some embodiments, the predetermined minimal concentration comprises between about 0.050% w/w and about 0.5% w/w of CBC and/or CBCA In some embodiments, the predetermined minimal concentration comprises between about 0.08% w/w and about 0.400% w/w of CBC and/or CBCA, or in some embodiments, the predetermined minimal concentration comprises between about 0.08% w/w and about 0.300% w/w of CBC and/or CBCA, or in some embodiments, the predetermined minimal concentration comprises between about 0.100% w/w and about 0.400% w/w of CBC and/or CBCA, or in some embodiments, the predetermined minimal concentration comprises between about 0.150% w/w and about 0.350% w/w of CBC and/or CBCA, or in some embodiments, the predetermined minimal concentration comprises between about 0.200% w/w and about 0.300% w/w of CBC and/or CBCA. Each possibility is a separate embodiment.

According to some embodiments, the predetermined minimal amount comprises at least about 300ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 400ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 450ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 500ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 550ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 600ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 700ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the predetermined minimal amount comprises at least about 2100ug of CBC and/or CBCA per daily dose.

According to some embodiments, the predetermined minimal amount comprises between about 300ug and about 3000ug of CBC and/or CBCA per daily dose unit According to some embodiments, the predetermined minimal amount comprises between about 300ug and about 2100ug of CBC and/or CBCA per daily dose unit, sometimes the predetermined minimal amount comprises between about 300ug and about 700ug of CBC and/or CBCA per daily dose unit, sometimes the predetermined minimal amount comprises between about 350ug and about 650ug of CBC and/or CBCA per daily dose unit, or sometimes the predetermined minimal amount comprises between about 400ug and about 600ug of CBC and/or CBCA per daily dose unit, or sometimes the predetermined minimal amount comprises between about 450ug and about 550ug of CBC and/or CBCA per daily dose unit. Each possibility is a separate embodiment.

According to some embodiments, the cannabis composition comprises CBC and/or CBCA amount/concentration above the predetermined minimal amount/concentration of per daily dose, and up to a maximal amount/concentration.

According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of CBC and/or CBCA per daily dose.

According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 300,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 400,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 450,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 500,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 550,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises less than a maximum amount/concentration of about 600,000ug of CBC and/or CBCA per daily dose unit. According to some embodiments, the cannabis composition comprises CBC and/or CBCA between the predetermined minimal amount of CBC and/or CBC A and the maximum amount/concentration of CBC and/or CBCA.

According to some embodiments, the cannabis composition comprises CBC and/or CBCA between the predetermined minimal amount and the maximum amount/concentration of about 600,000ug per daily dose, about 500,000ug per daily dose, about 400,000ug per daily dose, about 350,000ug per daily dose, or about 300,000ug per daily dose. Each possibility is a separate embodiment.

Accordingly, in some embodiments, the cannabis composition comprises between about 350ug of CBC and/or CBCA per daily dose unit and about 600,000ug of CBC and/or CBCA per daily dose unit. In some embodiments, the cannabis composition comprises between about 450ug of CBC and/or CBCA per daily dose unit and about 550,000ug of CBC and/or CBCA per daily dose unit. In some embodiments, the cannabis composition comprises between about 450ug of CBC and/or CBCA per daily dose unit and about 500,000ug of CBC and/or CBCA per daily dose unit. In some embodiments, the cannabis composition comprises between about 550ug of CBC and/or CBCA per daily dose unit and about 550,000ug of CBC and/or CBCA per daily dose unit. In some embodiments, the cannabis composition comprises between about 550ug of CBC and/or CBCA per daily dose unit and about 500,000ug of CBC and/or CBCA per daily dose unit.

An effective amount of the cannabis composition and the daily dose, necessary to achieve a therapeutic effect, may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response.

According to some embodiments, the composition contains THC, CBD, and CBC and/or CBCA as the only cannabinoids. According to some embodiments, the composition comprises THC, CBD, and CBC and/or CBCA. According to some embodiments, the composition further comprises at least one additional cannabinoid, different from THC, CBD, CBC, and/or CBCA.

According to an aspect of the disclosure, there is provided a method for classifying cannabis compositions as being suitable for the treatment of anxiety, the method comprising: receiving a potential cannabis composition; evaluating the level of CBC and/or CBCA in the potential cannabis composition; classifying the composition as being suitable for the treatment of anxiety when the amount/concentration of CBC and/or CBCA is equal to or above a predetermined amount.

According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.08% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.130% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.140% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.150% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.160% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.180% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.200% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.230% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.250% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.300% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.400% w/w. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 0.500% w/w.

According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 300ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 400ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 450ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 500ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 550ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 600ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 700ug per daily dose. According to some embodiments, the potential composition is classified as being suitable for the treatment of anxiety if the concentration of CBC and/or CBCA is at least about 2100ug per daily dose.

According to some embodiments, the method further comprises labeling the potential composition as being suitable for the treatment of anxiety when the concentration of CBC and/or CBCA is equal to or above the predetermined amount.

In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 350ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 400ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 450ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 500ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 550ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 600ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 700ug, per daily dose. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 2100ug, per daily dose.

In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.08% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.130% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.140% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.150% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.160% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.200% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.230% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.250% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least 0.300% w/w. In some embodiments, the method further comprising labeling the potential composition as being suitable for the treatment of anxiety when the predetermined minimal amount is at least about 0.400% w/w.

According to some embodiments, the selecting comprises choosing according to a product specification which outlines the concentration of the cannabinoids found in the product. According to some embodiments, the selecting comprises measuring the amount/concentration of the cannabinoid, for example by HPLC.

As used herein, the term “cannabis extract” refers to a herbal preparation prepared by extraction of cannabis plant material. According to some embodiments, extraction of a cannabis extract may be achieved by various techniques, including but not limited to using solvents, like alcohols or other organic solvents, gasses like CO2 and butane, and/or to physical methods like presses and extruders. Each possibility is a different embodiment.

According to some embodiments, the cannabis extract comprises THC rich content. According to some embodiments, the cannabis extract comprises CBD rich content. According to some embodiments, the cannabis extract has THC dominance. According to some embodiments, the cannabis extract has CBD dominance. According to some embodiments, the cannabis extract has a balanced THC and CBD content. According to some embodiments, the cannabis extract comprises CBC and/or CBCA.According to some embodiments, the cannabis extract comprises CBG rich content.

The herein disclosed cannabis composition may comprise such a standardized extract in some embodiments thereof, and in some embodiments the herein disclosed cannabis composition may refer to such a standardized extract.

The term “enriched” refers to a cannabis extract, or to a cannabis composition comprising cannabis extracts, having more than about 2 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract, or to a cannabis composition comprising cannabis extracts (respectively), that has amount/concentration of CBC and/or CBCA below the predetermined minimal/concentration amount. In some embodiments, the enriched cannabis extract, or the cannabis composition comprising enriched cannabis extracts, comprises extracted, isolated, purified, or synthetic CBC/CBCA. Each possibility is a separate embodiment.

As used herein, the term “non-enriched extract” refers to cannabis extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount.

According to some embodiments, the cannabis extract is enriched with CBC and/or CBCA. In some embodiments, the cannabis extract enriched with CBC and/or CBCA comprises at least about 2 times, sometimes at least about 4, or at least about 10 times, or sometimes at least about 30 times, or at least about 100 times, or sometimes at least about 200 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal/concentration amount. Each possibility is a separate embodiment. According to some embodiments, the cannabis composition comprises cannabis extracts with enriched levels of CBC/CBCA extracted from natural source. According to some embodiments, the cannabis composition comprises cannabis extracts with enriched levels of CBC/CBCA isolated from natural source. According to some embodiments, the cannabis composition comprises cannabis extracts with enriched levels of CBC/CBCA purified from natural source. According to some embodiments, the cannabis composition comprises cannabis extracts with enriched levels of synthetic CBC/CBCA.

As used herein, in some embodiments, a cannabis extract having a THC rich content may refer to cannabis extracts having a THC content greater by at least about 2 times, at least about 20 times, at least about 50 times, at least about 100 times, or at least about 200 times, than its CBD content. Each possibility is a different embodiment.

As used herein, in some embodiments, a cannabis extract having a CBD rich content may refer to cannabis extracts having a CBD content greater by at least about 2 times, at least about 20 times, at least about 50 times, at least about 100 times, at least about 200 times, than its THC content. Each possibility is a different embodiment.

As used herein, in some embodiments, a cannabis extract with THC dominance may have a THC content greater than its CBD content by between about 1 to about 20 times.

As used herein, in some embodiments, a cannabis extract with CBD dominance may have a CBD content greater than its THC content by between about 1 to about 20 times.

As used herein, in some embodiments, a cannabis extract with balanced THC and CBD content may comprise contents of THC and CBD within the range of a ratio of THC:CBD 1:2 to a ratio of THC:CBD 2: 1.

As used herein, the term “standardized extract”, “cannabis extract”, and “standardized cannabis extract” may be interchangeably used and refer to a formulation, standardized to include a certain content of one or more active ingredient, such as but not limited to: cannabinoids like THC, CBD, CBC and/or CBCA. ,

The herein disclosed cannabis composition may comprise such a standardized extract in some embodiments thereof, and in some embodiments the herein disclosed cannabis composition may refer to such a standardized extract. According to some embodiments, standardization can be achieved by mixing extracts from different sources and active ingredients ratios, with or without dilution with excipients.

According to some embodiments, standardization can be achieved by adding to the formulation extracted, isolated, purified, and/or synthetic active ingredient.

According to some embodiments, the suitable/optional cannabis composition comprises a standardized extract obtained/prepared according to any one of formulation 1-4. Each possibility is a separate embodiment.

Reference is now made to Example 3 that details non-limiting examples of the formulation and ways of obtaining them.

The following examples are presented in order to more fully illustrate some embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

EXAMPLES

Example 1 - Efficacy evaluation of potential cannabis compositions in treating Anxiety, and identification of cannabinoids that correlates with a positive outcome.

This study was approved by the Ethics Committee of Shaare-Zedek Medical Center, Jerusalem, Israel.

Efficacy evaluation of potential cannabis compositions in treating Anxiety

1417 subjects/patients aged above 18 years old with a standing medical cannabis licenses prescribed for different medical conditions agreed to complete a questionnaire which was reviewed by a medical doctor. Patients were asked to self-evaluate the level of severity of their anxiety on a scale of 1-5, where 1 represents low severity/slightly disturbing and 5 represents very severe/not functioning. Of all the patients (n=1417), 76 patients indicated that they had severe anxiety (ranked 5 out of 5) (n=76, 5.4%). Patients were asked about side effects and comorbid indications. While Israeli legislation allows for licensing due to only one main indication, often several indications were self-reported by the patients as main indications.

Most anxiety subjects indicated that they received their license due to PTSD as main/primary indication, and/or that they suffer from other conditions and symptoms. The most common comorbid conditions and symptoms are reported in Table 1.

Table 1: Medical background of Anxiety Patients

From the 76 subjects/patients that evaluated themselves as suffering from severe anxiety at level 5 (ranked 5 out of 5), for 73 patients (n=73, 96%), chemical data matching the cannabis strains they consumed was located and analyzed, and consequently were included in this study. Their questionnaires included demographic data: age, gender, employment status, and years of cannabis as indicated in Table 2.

Table 2 - Descriptive Demographic Characteristics of self-reported level 5 Anxiety Patients

The patients also reported the name of the cannabis strain they consumed, dosage and consumption method (inflorescence smoking or orally consumed oil; only inflorescence products were included in the study as there were not enough patient rankings data for oils, and as the merging of chemical and clinical data from oil and inflorescence batches may lead to methodological errors). The patients reported they administer the cannabis by vaping or smoking any of 11 strains of cannabis, namely Black label, Havarra wedding, Zarrdde gold, Jerusalem espress, De Dutch, Kush Ben Yamin, Super silver bullet, Red Rhino, Kahavvai mode, Tachlta Till, Argvana heart.

In addition, the patients answered a questionnaire regarding the perceived efficacy of the cannabis treatment in reducing the level of anxiety on a scale of 1-10, where 1 represents lack of any cannabis effect (i.e., inefficient/ineffective treatment) and 10 represents high efficacy of treatment (i.e., extremely effective).

The most common self-reported effects of medical cannabis consumption reported by Anxiety patients (n=73) are presented in Table 3, with calmness being the most frequent effect, reported by 71.2% of the patients (n=52).

Table 3. Reported Effects of cannabis consumption,

The efficacies reported by each subject were assigned to the composition administered.

Each strain was assigned a mean effectiveness score which was calculated by averaging the efficacy rankings of all patients who were administered this strain and ranked its treatment efficacy for severe anxiety.

The above comprise the clinical data. Identifying cannabinoids correlated with a positive outcome.

A total of 109 inflorescence batches of the 11 cannabis strains reported to be administered were then evaluated, chemically analyzed by HPLC to identify and quantify its molecular profile (cannabinoids and other cannabis molecules). The evaluation/analysis is based on the fact that different cannabinoids interact differently with the adsorbent resin included in the HPLC’s column, causing different flow rates and leading to the separation in time of the cannabinoids, as they flow out of the column.

Samples were prepared by extraction of 7.5 g of cannabis inflorescences with 130 g of methanol using a Distek Prep Engine2 system for 2 min at 5000 rpm. A portion of the prepared solution was collected and filtered through a 0.22 pm PTFE syringe filter. This solution, and a second solution further diluted 1:5, were injected to the HPLC and analyzed for characterization and quantification.

It is important to note that the chemical analysis by HPLC was performed on inflorescence strains, which typically contain cannabinoids in their acidic form. However, in common consumption methods of inflorescence, patients consume the cannabinoids in their neutral form as they are ingested after being heated above their decarboxylation temperatures, so when inhaled the molecules are already in their neutral form. Thus, for both inflorescence and decarboxylated products (e.g. orally-consumed oils) the neutral forms are considered to have the healing effect in vivo. While this research identifies molecules in their acidic form in the inflorescence, it is important to note that the clinical applications are relevant to the neutral forms in decarboxylated products.

The HPLC results (relative (to THC) retention time (RRT)) for all observed molecules (peaks in the HPLC chromatograms) in all samples were subsequently analyzed by a K-means classification algorithm. For an initial clustering, a two-part K-means algorithm was applied for clustering molecules, characterized by their RRT, from all the HPLC runs of all the batches. This is an unsupervised machine learning algorithm, used for grouping data into clusters with similar characteristics. Each peak in each HPLC run represents a different, unique molecule, and therefore a constrained version of the K-means algorithm was applied. The constraints were set such that 19 known cannabis molecules will host unique clusters. The number of clusters was automatically determined by Elbow and Silhouette techniques, and each cluster represented a different molecule. This two-part algorithm was first run on the spectra data, grouping all peaks with similar spectra . Then a clustering based on RRT was applied, thus dividing all molecules into clusters using-a two-dimensional method, based on both spectra and RRT.

Finally, the resulting clusters were further explored by plotting for each cluster an overlay of the spectra of all its peaks (from the different HPLC runs), allowing easy identification of outlier spectra which most probably belong to another cluster with a nearby RRT. The clusters were refined manually by analytical chemists to ensure that each cluster indeed contained all the peaks, from all HPLC runs, and only these peaks, related to this clu ster/molecule .

This approach classified 59 cannabis molecules.

The concentration of each molecule was evaluated according to the area under the curve value in each chromatogram standardized to the area of an ibuprofen standard injected in each HPLC run. The concentration of each cluster (representing a cannabis molecule) for each of the 11 strains was calculated as the median of the strain’s batches. For clusters representing known cannabinoids, absolute amounts were also calculated using their analytical standards.

One of the molecular clusters was advantageously identified as CBCA based on the following:

1. The peaks comprising this cluster have a RRT range of 1.26-1.28 whereas the RRT of the CBCA standard (provided by Cerilliant, item no. C-150, batch no. FE05091703) is 1.28 (CBCA RT is 17.329, THC RT is 13.532) in the specific HPLC method applied in this study (FIG. 1).

2. The UV spectra of these peaks match the spectrum of the CBCA standard (compare FIG. 2A with FIG. 2B).

The UV spectra of all 59 clusters (each cluster defining a cannabis molecule) can be seen in FIG. 2C.

The above comprise the chemical data. Correlation between CBCA concentration and clinical efficacy across strains

To evaluate the potential efficacy of the different cannabis molecules in the treatment of anxiety, the clinical data and chemical data were statistically analyzed together.

An algorithm was developed which allows identifying peaks recurring in different batches, based on their RRT’s and UV spectra, thereby identifying cannabinoids characteristic to certain cannabis strains and for which a correlation was found with efficient or inefficient treatment response as answered by the subjects’ in the questionnaire.

In short, each cannabis strain was assigned a representative efficacy score, based on the mean efficacy assigned to the strain in the questionnaire. As the efficacy score was provided to a strain, regardless of batch, the chemical data for each strain was taken as the median for each peak (representing a cannabis molecule) across all batches of the strain.

A potential efficacious cannabis molecule’s amount concentration (as measured chemically) should be positively correlated with treatment efficacy (as reported by the patients), across all strains, in a statistically significant manner.

Advantageously, using this approach a molecule showing a statistically significant high correlation indicates that as its dosage increases the treatment of anxiety is more effective.

A Spearman correlation was then used to quantify the correlation between the questionnaire’s efficacy of each strain (the label) and the concentration of a specific cannabis molecule in each strain. Since 59 clusters were tested, the p-values were adjusted using the False Discovery Rate (FDR) method, taking into account multiple tests.

The Spearman correlation coefficient (r) was 0.88 with a p-value of 0.0003 and p-value of 0.023 after multiple testing corrections using the FDR method, indicating a statistically significant positive correlation between CBCA concentration and treatment efficacy of severe anxiety (FIG. 3). Further multiple testing corrections using the more stringent Bonferroni correction method maintained significance (a=0.0008), highlighting the strength and non- arbitrary nature of this correlation. Advantageously, it was found that the ranked median concentrations (as represented by the area under the curve value in each chromatogram) of the cluster representing CBCA across the 11 strains (ranging from 0.077%w/w to 0.309%w/w) were positively correlated in a statistically significant manner with the strains’ efficacy rankings provided by patients with severe anxiety.

As each strain was assigned with its median CBCA amount (%w/w concentration of a molecule in the dry cannabis plant sample), the 50% (median) and 75% percentiles were calculated based on all the strains medians.

In accordance, a minimal amount/concentration of 456 ug/day (rounded to 450ug/day) was determined based on the 50% percentile, which was 0.137%, and considering minimal consumption of at least about O.333grams/per day by a subject (i.e., 10g per month); and a minimal amount/concentration of 539ug/day (rounded to 550ug/day) was determined based on the 75% percentile which was 0.162% and considering minimal consumption of at least about O.333grams/per day by a subject (i.e., 10g per month).

In conclusion, it was found that the concentrations of the cluster representing CBCA across the strains were positively correlated with the efficacies of these strains in treating/attenuating/reducing/preventing anxiety as was self-reported by the subjects suffering from severe anxiety.

Example 2 - Clinical trial for evaluation of novel standardized cannabis extract formulations for the treatment of Anxiety

The following study is conducted according to the laws and regulations governing medical product clinical trials in Malta /EU and GCP standards.

Protocol synopsis:

Example 3 - Medical Cannabis Products

The following are non-limiting examples of formulation and ways of obtaining them, they should in no way be construed as limiting the broad scope of the invention.

Example of formulation 1: Standardized extract of 26mg/g (25mg/mL) THC, 26mg/g (25mg/mL) CBD, 1 mg/g CBC.

To obtain 10,000g of the standardized extract, two extracts are used: a THC rich extract as a source of both THC and CBC (extract A: 70%w/w THC, 0.5%w/w CBD, 1.33%w/w CBC) and a CBD rich extract as a source of both CBD and CBC (extract B: 2%w/w THC, 65%w/w CBD, 1.30%w/w CBC).

360g of extract A is mixed with 398g of extract B, 9192g of MCT oil and 50g of Vitamin E.

The resulting 10,000g standardized extract contains 26mg/g of THC, 26mg/g of CBD and l.Omg/g of CBC.

Formulation 1 in %(w/w): Standardized extract of 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

Example of formulation 2: Standardized extract of 26mg/g (25mg/mL) THC, 26mg/g (25mg/mL) CBD, 1 mg/g CBC.

To obtain 33,OOOg of the standardized extract, the same two extracts from example 1 are used.

1188g of extract A is mixed with 1313.4g of extract B, 30333.6g of MCT oil and 165g of Vitamin E.

The resulting 33,OOOg standardized extract contains 26mg/g of THC, 26mg/g of CBD and l.Omg/g of CBC.

Formulation 2 in %(w/w): Standardized extract of 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E. Example of formulation 3: Standardized extract of 52mg/g (50mg/mL) THC, 52mg/g (50mg/mL) CBD, 2 mg/g CBC.

To obtain 10,000g of the standardized extract, the same two extracts from example 1 are used.

720g of extract A is mixed with 796g of extract B, 8434g of MCT oil and 50g of Vitamin E.

The resulting 10,000g standardized extract contains 52mg/g of THC, 52mg/g of CBD and 2.0mg/g of CBC.

Formulation 3 in %(w/w): Standardized extract of 5.2% (w/w) THC, 5.2% (w/w) CBD, 0.2% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

Example of formulation 4: Standardized extract of 52mg/g (50mg/mL) THC, 52mg/g (50mg/mL) CBD, 2 mg/g CBC.

To obtain 25,000g of the standardized extract, the same two extracts from example 1 are used.

1800g of extract A is mixed with 1990g of extract B, 21085g of MCT oil and 125g of Vitamin E.

The resulting 25,000g standardized extract contains 52mg/g of THC, 52mg/g of CBD and 2.0mg/g of CBC.

Formulation 4 in %(w/w): Standardized extract of 5.2% (w/w) THC, 5.2% (w/w) CBD,

0.2% (w/w) CBC and optionally 0.5% (w/w) Vitamin E. Advantageously, the cannabis composition and/or the suitable cannabis composition may be obtained/prepared according to any one of the non-limiting examples of standardized extracts of any one of formulas 1-4, or the like.

The above non-limiting examples of formulations contain 0.1% or 0.2% CBC, that correspond to Img CBC and 2mg CBC per 1g of product. In some embodiments, a subject that consumes a minimal amount of 0.5g per day of these products, is administered with a CBC amount of 500ug or lOOOug, respectively, in daily dose.

While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

Claims

1. A cannabis composition comprising a predetermined minimal amount/concentration of at least 450ug CBC and/or CBCA per daily dose for use in the treatment of anxiety.

2. The composition of claim 1, wherein the predetermined minimal amount is at least 550ug, per daily dose.

3. The composition of any one of claims 1-2, wherein the cannabis composition comprises raw cannabis.

4. The cannabis composition of any one of claims 1-3, wherein at least a portion of the CBC and/or CBCA in the composition comprises synthetic, extracted, isolated and/or purified CBC and/or CBCA.

5. The cannabis composition of any one of claims 1-4, wherein at least a portion of the CBC and/or CBCA in the composition comprises isolated CBC and/or CBCA.

6. The cannabis composition of any one of claims 1-5, wherein the composition is selected from a plurality of potential cannabis compositions based on an analysis of the content of CBC and/or CBCA in the plurality of potential cannabis compositions.

7. The cannabis composition of any one of claims 1-6, wherein the administering comprises administering by route of smoking, inhalation, vaporization, oral administration, buccal administration, nasal administration, topical administration, transdermal administration parenteral administration or any combination thereof.

8. The cannabis composition of any one of claims 1-7, comprising a standardized extract of about: 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

9. The cannabis composition of any one of claims 1-8, comprising a standardized extract of about: 5.2% (w/w) THC, 5.2% (w/w) CBD, 0.20% (w/w) CBC and optionally 0.5% (w/w) Vitamin E.

10. The cannabis composition of any one of claims 1-9, wherein the cannabis composition comprises a content of CBC and/or CBCA between the predetermined minimal amount/concentration and a maximum amount/concentration of about 500,000ug, per daily dose. The cannabis composition of any one of claims 1-10, wherein the cannabis composition comprises cannabis extracts enriched with CBC and/or CBCA. The cannabis composition of claim 11, wherein the cannabis extracts enriched with CBC and/or CBCA comprises at least about 2 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount. The cannabis composition of claim 12, wherein the cannabis extract enriched with CBC and/or CBCA comprises at least about 200 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount. The cannabis composition of any one of claims 11-13, wherein the cannabis extract enriched with CBC and/or CBCA comprises extracted, isolated, purified, or synthetic CBC/CBCA. The cannabis composition of any one of claims 8-14, wherein at least a portion of the CBC and/or CBCA in the composition comprises isolated or synthetic CBC and/or CBCA. A method for classifying cannabis compositions as being suitable for the treatment of anxiety, the method comprising: receiving a potential cannabis composition; evaluating the content of CBC and/or CBCA in the potential cannabis composition; classifying the composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above a predetermined minimal amount/concentration. The method of claim 16, wherein the predetermined minimal amount is at least 450ug, per daily dose. The method of claim 17, wherein the predetermined minimal amount is at least 550ug, per daily dose. The method of any one of claims 16-18, further comprising labeling the potential composition as being suitable for the treatment of anxiety when the CBC and/or CBCA content is at or above the predetermined minimal amount/concentration. The method of any one of claims 16-19, wherein the suitable cannabis composition comprises a content of CBC and/or CBCA between the predetermined minimal amount/concentration and a maximum amount/concentration of about 500,000ug, per daily dose. A standardized cannabis extract comprising extracts from a natural source and a predetermined minimal amount/concentration of isolated or synthetic CBC and/or CBCA. The standardized cannabis extract of claim 21, wherein the predetermined minimal amount is at least 450ug, per daily dose. The standardized cannabis extract of claim 22, wherein the predetermined minimal amount is at least 550ug, per daily dose. The standardized cannabis extract of any one of claims 21-23, wherein the standardized extract comprises about: 2.6% (w/w) THC, 2.6% (w/w) CBD, 0.1% (w/w) CBC and optionally 0.5% (w/w) Vitamin E. The standardized cannabis extract of any one of claims 21-24, wherein the standardized extract comprises about: 5.2% (w/w) THC, 5.2% (w/w) CBD, 0.2% (w/w) CBC and optionally 0.5% (w/w) Vitamin E. The standardized cannabis extract of any one of claims 21-25, comprising an CBC and/or CBCA amount between the predetermined minimal amount and a maximum amount of about 500,000ug, per daily dose. The cannabis extract of any one of claims 21-26, wherein the cannabis extract is enriched with CBC and/or CBCA. The cannabis extract of claim 27, wherein the cannabis extract enriched with CBC and/or CBCA comprises at least about 2 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount. The cannabis extract of claim 28, wherein the cannabis extract enriched with CBC and/or CBCA comprises at least about 200 times the amount/concentration of CBC and/or CBCA with respect to a non-enriched extract that has amount/concentration of CBC and/or CBCA below the predetermined minimal amount. The cannabis extract of any one of claims 27-29, wherein the cannabis extract enriched with CBC and/or CBCA comprises extracted, isolated, purified, or synthetic CBC/CBCA.