Cannabinoid compositions for treatment of aromatase inhibitor-induced arthralgia

Abstract

Cannabinoid compositions formulated for use in the treatment of Aromatase Inhibitor- Induced Arthralgia (AHA) are disclosed. The compositions include cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC) as the major components therein, which may be isolated, purified or extracted from cultivars and blended together. The compositions include CBD, CBG and THC in certain ratios, formulated for the use in the treatment of AHA.

Description

CANNABINOID COMPOSITIONS FOR TREATMENT OF AROMATASE INHIBITOR-INDUCED ARTHRALGIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 641,896, filed May 2, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates generally to treatment of Aromatase Inhibitor- Induced Arthralgia (Al-induced arthralgia or AIIA), and more specifically to the use of certain cannabinoid compositions for treating AIIA.BACKGROUND

[0003] As standard of care, postmenopausal women with hormone responsive breast cancer undergo adjuvant therapy with third generation aromatase inhibitors (AIs). By targeting the aromatase enzyme and preventing the peripheral conversion of androgens to estrogens within tissues, such as fat to estrogen in postmenopausal women, AIs cause estrogen deprivation, which may be systemic and localized (within tissues). The gene name of aromatase is CYP19A1. As anti -estrogen therapy, treatment with AIs reduces risk of recurrence and death from estrogen receptor (ER) and / or progesterone receptor (PR) positive breast cancer. Recent studies also indicate benefits of prolonged therapy with these drugs for 5 to 10 years.

[0004] Despite the efficacy of Al therapy, side effects may prove limiting.Musculoskeletal symptoms of both joint pain and stiffness can affect up to 40% of women taking AIs. Commonly associated with menopause, joint symptoms are associated with loss of ovarian function and resultant decline in estrogen levels; further reduction resulting from Al therapy can either lead to the onset or worsening of joint arthropathy. Detrimental effects of joint symptoms include diminished quality of life, reduced adherence, and even discontinuation of treatment. While NSAIDs may help relieve symptoms of joint arthropathy, such medications are not uniformly well tolerated due to gastrointestinal and renal toxicity. Two recent randomized clinical trials showed reductions in Al-induced joint symptoms with 1) duloxetine (a selective serotonin uptake inhibitor) versus placebo at 12 weeks and acupuncture versus sham / wait list control at 6 weeks; however, side effects,possible drug interactions (duloxetine) and high cost and limited access (acupuncture) may limit the broad uptake of such interventions. There is a critical need for additional novel strategies to alleviate Al-induced arthralgia — especially for interventions that are safe, well- tolerated, and highly effective. Thus, what is needed in the art are alternative treatments for AIIA.BRIEF SUMMARY

[0005] In some aspects, provided is a method of treating pain and health in Aromatase Inhibitor-Induced Arthralgia (Al-induced arthralgia or AIIA) in a human in need thereof. In some embodiments, the method comprises: administering a cannabinoid composition comprising cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC) present as a major component therein.

[0006] In certain embodiments, the CBD, CBG and / or THC may be provided as: (i) one or more botanical drug substances (“BDS”); (ii) one or more extracts from cannabis plants (“extracts”); (iii) one or more extracts from cannabis plants blended with additional sources of CBD, CBG and / or THC (“blended extracts”); (iv) purified CBD, CBG and / or THC, e.g., obtained from purifying the extracts or blended extracts; or (v) isolates of CBD, CBG and / or THC. In some variations, the cannabinoid composition further comprises other cannabinoids and non-cannabinoids (e.g., terpenes) formulated in a vehicle (e.g., a lipid vehicle) to yield the final product composition that may be administered to a human in need thereof. Such other cannabinoids and non-cannabinoids (e.g., terpenes) are present from the source from which the composition is obtained.BRIEF SUMMARY

[0007] In some aspects, provided is a method of treating Aromatase Inhibitor-Induced Arthralgia (AIIA) in a subject in need thereof. In some embodiments, the method comprises: administering a cannabinoid composition comprising cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC) present as a major component therein.

[0008] In certain embodiments, the CBD, CBG and / or THC may be provided as: (i) one or more botanical drug substances (“BDS”); (ii) one or more extracts from cannabis plants (“extracts”); (iii) one or more extracts from cannabis plants blended with additional sources of CBD, CBG and / or THC (“blended extracts”); (iv) purified CBD, CBG and / or THC, e.g.,obtained from purifying the extracts or blended extracts; or (v) isolates of CBD, CBG and / or THC. In some variations, the cannabinoid composition further comprises other cannabinoids and non-cannabinoids (e.g., terpenes) formulated in a vehicle (e.g., a lipid vehicle) to yield the final product composition that may be administered to a subject in need thereof. Such other cannabinoids and non-cannabinoids (e.g., terpenes) are present from the source from which the composition is obtained.DETAILED DESCRIPTION

[0009] The following description sets forth exemplary compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0010] Cannabinoids are compounds structurally or pharmacologically related to the constituents of the cannabis plant or to the endogenous agonists (endocannabinoids) of the cannabinoid receptors CB1 or CB2. Cannabinoids may be naturally derived from cannabis plants or synthetically derived. Cannabis plants comprise a highly complex mixture of compounds, and hundreds of such compounds have been identified.

[0011] Traditionally, crude extracts from cannabis plants containing CBD have been used by patients suffering from various diseases and disorders. However, such crude products are generally unsuitable for use in pharmaceutical formulations. Those seeking to prepare more consistent CBD formulations for use in treating diseases or disorders have made an effort to either prepare CBD synthetically or attempt to remove all compounds other than CBD, particularly psychoactive compounds such as THC, from plant derived cannabinoids.

[0012] The present invention encompasses the surprising discovery that particular compositions comprising CBD in combination with CBG and THC have an improved therapeutic efficacy for treating pain and health in Aromatase Inhibitor-Induced Arthralgia (AHA).Cannabinoid Compositions

[0013] In some aspects, provided are cannabinoid compositions comprising a combination of CBD, CBG and THC, which are collectively present as the major components of the cannabinoids in the compositions. In certain embodiments, the compositions herein,including the compositions administered in the methods herein, are drug formulations that comprise a combination of extracts or isolated compounds from one or more cultivars that are blended to achieve certain ratios of CBD, CBG and THC. For example, in some variations, extracts from genetically identical clones of three different cultivars (e.g., high CBD cultivars, high CBG cultivars, and high THC cultivars) may be used to produce the drug formulations. The components of the cannabinoid compositions provided herein are described in further detail below.

[0014] In some variations, the CBD, CBG and THC are collectively greater than 50%, greater than 60%, greater than 70%, greater 80%, greater than 85%, greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%; or between 50% and 99.9%, between 60% and 99%, between 70% and 99%, between 80% and 99%, between 85% and 99%, between 85% and 95%, or between 90% and 99% by weight of the cannabinoids present in the composition.

[0015] It should be understood that in addition to the cannabinoids, in some embodiments, the cannabinoid compositions may include other cannabinoids as well as noncannabinoids formulated in a vehicle, such as a lipid vehicle, as described in further detail below. Such other cannabinoids as well as non-cannabinoids are present from the cannabis plant from which the compositions are obtained. Thus, in some variations, the composition comprises CBD, CBG and THC in the ratios and amounts as described herein, as well as other components, such as terpenes, and lipid excipients.

[0016] The structures of CBD, CBG and THC are well understood in the art. In some embodiments, the THC present in the compositions herein is primarily in the form of (-)- delta-9-trans-tetrahydrocannabinol (A9-THC).

[0017] In some variations, the CBD, CBG and THC are present in a molar ratio between about 100: 100: 1 and about 1 : 1 : 1; or between about 100:50: 1 and about 20: 1 : 1. In certain variations, the CBD and CBG are present in a molar ratio between about 100: 1 and about 1 : 1. In certain variations, the molar ratio of CBD and THC is between about 50: 1 and about 1 : 1.

[0018] In some variations, the CBD, CBG and THC are present in a weight ratio between about 100: 100: 1 and about 1 : 1 : 1; or between about 100:50: 1 and about 20: 1 : 1. In some variations, the CBD, CBG and THC are present in a weight ratio between about 1 :0.05- 0.42:0.003-0.03. In certain variations, the CBD and CBG are present in a weight ratiobetween about 100: 1 and about 1 : 1. In certain variations, the CBD and CBG are present in a weight ratio between about 1 :0.05-0.42. In certain variations, the weight ratio of CBD and THC is between about 50: 1 and about 1 : 1. In certain variations, the weight ratio of CBD and THC is between about 1 :0.003-0.03.

[0019] In some variations, the CBD is greater than half of the cannabinoids present in the composition by weight. In certain variations, the CBD is greater than 49% by weight, or between 49% and 98% by weight of the cannabinoids present in the composition. In other variations, the combination of CBD and CBG is greater than half of the cannabinoids present in the composition by weight.

[0020] In some variations, the CBD is greater than 5 mg / ml, between about 50 mg / ml and 150 mg / ml, or between about 5mg / ml and 500 mg / ml in the total composition; and the CBG is between about 5 mg / ml and 95 mg / ml, between about 7 mg / ml and 21 mg / ml, between about 5 mg / ml and 50 mg / ml, or between about 5 mg / ml and 20 mg / ml in the total composition. In a variation of the foregoing, the “total composition” includes cannabinoids, non-cannabinoids (e.g., terpenes, if present), and a vehicle (e.g., lipid vehicle).

[0021] It should be understood that any suitable methods and techniques known in the art may be employed to measure the amounts of the components in the compositions. For example, gravimetric or volumetric methods may be employed to quantify the components present in the composition. One of skill in the art would appreciate how to convert the mg / ml units to other suitable units, such as mg / g.

[0022] In other variations, the CBD is greater than 1% by weight, or between 1% and 90% by weight of the total composition; and the CBG is greater than 0.3% by weight, or between 0.3% and 49% by weight of the total composition. In a variation of the foregoing, the “total composition” includes cannabinoids, non-cannabinoids (e.g., terpenes, if present), and a vehicle (e.g., lipid vehicle).

[0023] In some variations, the THC is present in an amount less than the limit set forth by the appropriate regulatory agencies, including for example, the U.S. Food and Drug Administration (FDA) or the U.S. Drug Enforcement Administration (DEA) or the United States Department of Agriculture (USDA) (e.g., with respect to the 2018 Farm Bill for Hemp products). In certain variations, the THC is less than 0.3% by weight, or between 0.05 % and 0.3% by weight of the cannabinoids present in the composition. In certain variations, theTHC is less than 2 mg / ml, or between about 0.5 mg / ml and 1.5 mg / ml in the total composition. In a variation of the foregoing, the “total composition” includes cannabinoids, non-cannabinoids (e.g., terpenes, if present), and a vehicle (e.g., lipid vehicle).

[0024] In some embodiments, the CBD is about 100 mg / ml, the CBG is about 15 mg / ml, and the THC is about 1.5 mg / ml. In some embodiments, the CBD is between about 50 mg / ml and 150 mg / ml, the CBG is between about 7 mg / ml and 21 mg / ml, and the THC is between about 0.5 mg / ml and 1.5 mg / ml. In some variations of the foregoing, the THC is less than 0.3% by weight of the cannabinoids present in the composition. In certain variations, the minor cannabinoids are less than about 5% or less than about 2% by weight of the cannabinoids present in the composition.

[0025] In some embodiments, the cannabinoid compositions provided herein further comprise additional components, including other cannabinoids and / or non-cannabinoids. For example, in some variations, the composition further comprises one or more of the following: cannabidiolic acid (CBDA), tetrahydrocannabinolic acid (THCA), cannabichromene (CBC), and terpenes (such as alpha-bisabolol, guaiol, beta-caryophyllene, caryophyllene oxide, alpha-humulene or alpha-caryophyllene, limonene, linalool, beta-myrcene, trans-nerolidol, (E)-b-ocimene, alpha-pinene, beta-pinene, terpineols, terpnolene, and valencene).

[0026] In other variations, the composition further comprises one or more of the following: cannabinol (CBN), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA), cannabichromene acid (CBCA), cannabichromene acid (CBCA), tetrahydrocannabinolic acid (THCA), and cannabidiolic acid (CBDA), or any derivatives thereof.

[0027] In other embodiments, the composition may further comprise one or more of the following compounds:• Cannabigerol-type compounds: cannabigerol ((E)-CBG C-5), cannabigerol monomethyl ether ((E)-CBGM C-5A), Cannabinerolsaure A ((Z)-CBGA C-5A), Cannabigerovarin (((e)-BGV C-3), Cannabigerol saure A(e)-CBGA C-5A), A Cannabigerol saure monomethyl ether ((e)-CBGAM C-5A), Cannabigerovarinsaure A ((e)-CBGVA-C3A);Cannabichromene-type compounds: cannabichromene (CBC-C5),Cannabichromensaure A (CBCA C-5A), Cannabichromevarin (CBCVC-3), Cannabichromevarinsaure A (CBCVA-C3A);• Cannabidiol-type compounds: cannabidiol (CBD-C5), cannabidiol monomethyl (CBDM-C5), cannabidiol-C4 (CBD-C4), Cannabidivarin (CBDV-C3), Cannabidiorcol (CBD-C1), cannabidiolic (CBDA C-5), Cannabidivarinsaure (CBDVA C-3);• Cannabinodiol-type compounds: Cannabinodiol (CBND C-5), Cannabinodivarin (CBND C-3);• Tetrahydrocannabinol-type compounds: A9-tetrahydrocannabinol (A9-THC-C5), A9- tetrahydrocannabinol-C4 (A9-THC-C4), A9-tetrahydrocannabivarin (A9-THCV-C3), A9-Tetrahydrocannabiorcol (A9-THCO C-l), A9-Tetrahydrocannabinolsaure (A9THCA-C-5A), A9-Tetrahydrocannabinolsaure B (A9THCA-C-5B), A9- Tetrahydrocannabinolsaure-C4 (A9THCA-C-4A and / or B), A9- Tetrahydrocannabivarinsaure A (A9-THCVA-C3 A), A9-Tetrahydrocannabiorcolsaure (A9-THCOA-C1 A and / or B), (-)-A8-trans-(6aR, 10aR)-8-tetrahydrocannabinol (A8- THC-C5), (-)-A8-trans-(6aR, 10aR)-Tetrahydrocannabinolsaure A (A8-THCA-C 5 A); (-)-(6a S, 10a R)-A9-tetrahydrocannabinol ((-)-cis-A9-THC-C5);• Cannabinol-type compounds: Cannabinol CBN-C5, cannabinol C4 (CBN-C4), Cannabivarin (CBN-C3), cannabinol C2 (CBN-C2), Cannabiorcol (CBN-C1), Cannabinol saure A (C5 CBNA-A), Cannabinolmethylether (CBNM C-5);• Cannabitriol-type compounds: (-)-(9R,10R)-trans-Cannabitriol ((-)-trans-CBT-C5), (+)-(9S,10S)-Cannabitriol ((+)-trans-CBT C-5), (±)-(9R, 10S / 9S, 10R)-Cannabitriol ((±)-cis-CBT-C5), (-)-(9R,10R)-trans [10-0-thyl-cannabitriol] ((-)-trans-CBT-OEt- C5), (±)-(9R, 10R / 9S, 10S)-Cannabitriol-C3 ((±)-trans-CBT-C3), 8,9-dihydroxy-A6a (10a) tetrahydrocannabinol (8,9-di-OH-CBT-C5), cannabidiolic A (CBDA C-59-OH- CBT-C5 ester), (-)-(6aR, 9S, 10S, 10aR)-9,10-dihydroxy-hexahydrocannabinol, Cannabiripsol Cannabiripsol-C5, (-)-6a, 7, lOa-trihydroxy- A9-tetrahydrocannabinol ((- )-Cannabitetrol), 10-oxo-A6a (10a) tetrahydrocannabinol (OTHC);• Cannabielsoin-type compounds: (5aS, 6S, 9R, 9aR)-C5-Cannabielsoin (CBEC-5), (5aS, 6S, 9R, 9aR)-C3-Cannabielsoin (CBE C-3), ( 5aS, 6S, 9R, 9aR)- Cannabielsoinsaure A (CBEA-C5 A), (5aS, 6S, 9R, 9aR)-Cannabielsoinsaure B (CBEA-C5 B), (5aS, 6S, 9R, 9aR)-C3 Cannabielsoinsaure B (CBEA-C3 B), Cannabiglendol-C3 (OH-iso-HHCV C-3), Dehydrocannabifuran (DCBF C-5), Cannabifuran (CBF-C5);• Isocannabinoide-type compounds: (-)-A7-trans-(lR, 3R, 6R)Isotetrahydrocannabinol, (±) -A7-l,2-cis- (1R, 3R, 6S / 1S, 3S, 6R)-Isotetrahydrocannabivarin, (-)-A7-trans-(lR, 3R, 6R)-Isotetrahydrocannabivarin;• Cannabicyclol-type compounds: (±)-(laS, 3aR, 8bR, 8Cr-cannabicyclol (CBL-C), (±)-(laS, 3aR, 8bR, 8Cr-Cannabicyclolsaure A (CBLA-C5A) (±)-(laS, 3aR, 8bR, 8Cr-Cannabicyclovarin (CBLV C-3);• Cannabicitran-type compounds: Cannabicitran (CBT-C5); and• Cannabichromanon-type compounds: Cannabichromanon (CBCN C-5), Cannabichromanon-C3 (CBCN C-3), Cannabicoumaronon (CBCON C-5).

[0028] In addition to the above cannabinoids, the carboxylic acids which are biosynthetic precursors of each are contemplated as cannabinoids that may be present in the compositions described herein. In such instances, such cannabinoids are present as a minor component in the composition. In some variations, the cannabinoid precursors are not present in a detectable amount in the composition.

[0029] In some variations, minor cannabinoids present are collectively less than about 5%, less than about 2.5% or less than about 2% by weight of the total composition. In a variation of the foregoing, the “total composition” includes cannabinoids, non-cannabinoids (e.g., terpenes, if present), and a vehicle (e.g., lipid vehicle).

[0030] In other variations, the compositions further comprise terpenes. Examples of terpenes that may be detected in the compositions include, for example, alpha-bisabolol, guaiol, beta-caryophyllene, caryophyllene oxide, alpha-humulene or alpha-caryophyllene, limonene, linalool, beta-myrcene, trans-nerolidol, (E)-b-ocimene, alpha-pinene, beta-pinene, terpineols, terpnolene, and valencene, alpha-bisabolol, beta-caryophyllene oxide, and guaiol.In one variation, depending on the source of the cannabinoids as described in further detail below, no detectable amounts of terpenes may be found.

[0031] In yet other variations, the composition further comprises flavonoids. In one variation, depending on the source of the cannabinoids as described in further detail below, no detectable amounts of flavonoids may be found.

[0032] It should be understood that the minor cannabinoids, terpenes and flavonoids, if present in the composition, may be from the BDS and / or extracts used to provide the CBD, CBG and THC, and such sources are described in further detail below.Sources of CBD, CBG and THC

[0033] In some embodiments of the cannabinoid compositions provided herein, the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.

[0034] In some variations when the compositions comprise a combination of BDS, extracts or blended extracts (as described in further detail below), such compositions are polymodal compositions that include multiple active components that affect multiple targets and implicate multiple mechanisms of action simultaneously. The polymodality of such compositions may positively affect efficacy and safety profile. Such polymodal compositions may be viewed as distinct from fixed dose combinations (“FDCs”) that typically will use highly purified or isolated cannabinoid components.BDS

[0035] In some embodiments, one or more of CBD, CBG and THC are provided in the form a botanical drug substance (BDS). In some variations, the CBD, CBG and THC are each in the form of BDS. In some variations, a ‘‘botanical drug substance” or “BDS” is defined in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Pood and Drug .Administration Centre for Drug Evaluation and Research as: “A drug derived from one or more plants, algae, or microscopic fungi. It is prepared from botanical raw materials by one or more of the following processes: pulverisation, decoction, expression, aqueous extraction, ethanolic extraction or other similar processes.” A botanical drug substance does not include a highly purified or chemicallymodified substance derived from natural sources. Thus, in the case of cannabis, BDS derived from cannabis plants do not include highly purified pharmaceutical grade cannabinoids.Extracts

[0036] In other embodiments, one or more of CBD, CBG and THC are provided as extracts from the cannabis plant. Such extracts may be obtained using any suitable methods and techniques known in the art. For example, dried cannabis flowers are soaked in water or alcohol to obtain the trichomes from the plant. The trichomes undergo solvent extraction and optionally additional purification steps to obtain a cannabinoid-rich oil, also referred to as an “extract”.

[0037] In some variations, the CBD, CBG and THC are provided as a combination of cannabis extracts or isolated from 2-4 cannabis cultivars. In certain variations, the CBD, CBG and THC are provided as a combination of cannabis extracts from genetically identical clones of 3 different cannabis cultivars. In one variation for the foregoing, the 3 different cultivars are a high CBD cultivar, a high CBG cultivar and a high THC cultivar. In some variations, the cannabis cultivars are Cannabis sativa cultivars.

[0038] In some variations, when the CBD, CBG and THC are provided as extracts, the compositions provided herein further include terpenes. In certain variations, when the CBD, CBG and THC are provided as extracts, the compositions provided herein further include terpenes and flavonoids.Blended Extracts

[0039] In other embodiments, one or more of the CBD, CBG and THC are provided as a blend of the extracts described above in combination with additional CBD, CBG and / or THC obtained from other sources to achieve the particular ratios and amounts of CBD, CBG and THC as described herein. For example, in some variations, the composition comprises CBD, CBG and THC provided as extracts from the cannabis plants, blended with additional CBD provided in a purified form or as an isolate to achieve the ratios and amounts of CBD, CBG and THC as described herein.Purified Forms

[0040] In yet other embodiments, one or more of the CBD, CBG and THC are provided in a purified form. Such purified forms of the cannabinoids may be obtained using any suitable methods and techniques known in the art. For example, the extract or blended extracts described above may undergo distillation (e.g., molecular distillation) to remove certain constituents, such as terpenes and lipids, that are non-cannabinoids, and also separate out specific cannabinoids. In some variations, the purified extracts are oils.

[0041] In certain variations, the CBD, CBG and THC are a combination of highly purified CBD, highly purified CBG and highly purified THC, wherein each of which are extracted from a cannabis plant and purified to the extent that other cannabinoids and a majority of non-cannabinoid components that are co-extracted with the cannabinoids have been removed. In one variation, the highly purified CBD is greater than or equal to 90% (w / w) pure; the highly purified CBG is greater than or equal to 90% (w / w) pure; and the highly purified THC is greater than or equal to 90% (w / w) pure.Isolates

[0042] In some variations, one or more CBD, CBG and THC are provided as isolates. Such isolates may be obtained using any suitable methods and techniques known in the art. For example, the isolates may be obtained by crystallization or precipitation of a purified extract as described above to isolate a specific cannabinoid, followed by filtration to yield a powder that is essentially a pure cannabinoid with excess solvent removed. In some variations the isolates are powders. In one variation, the CBD isolate is greater than or equal to 99% (w / w) pure; the CBG isolate is greater than or equal to 99% (w / w) pure; and the THC isolate is greater than or equal to 99% (w / w) pure.

[0043] In certain variations, CBD, CBG and THC are provided a combination of isolates, which may be with or without BDS, extracts or blended extracts. In one variation, the CBD, CBG and THC are provided as a combination of isolates and BDS.Natural vs. Synthetic Sources

[0044] In some variations, the CBD, CBG and THC are all naturally derived. In other variations, at least a portion of the CBD, CBG and / or THC is naturally derived, and the otherportion is synthetic and / or biosynthetic. Synthetic cannabinoids may include compounds that have a cannabinoid-like structure and are manufactured using chemical processes rather than by the plant. Biosynthetic cannabinoids may include compounds that have a cannabinoid- like structure and are produced using biological processes rather than by the plant. In certain embodiments, at least a portion of CBD present in the composition is prepared synthetically or biosynthetically. In certain embodiments, at least a portion of CBG present in the composition is prepared synthetically or biosynthetically. In certain embodiments, at least a portion of THC present in the composition is prepared synthetically or biosynthetically.

[0045] It should be understood that the compositions provided herein may include CBD, CBG and THC provided in a combination of different forms described above. For example, in certain variations, the CBD, CBG and THC are provided in the form of BDS in combination with additional refined or synthetic or biosynthetic CBD, CBG and THC to achieve the ratios and amounts described herein.Lipid Vehicles

[0046] In some embodiments, the combination of cannabinoids described herein are formulated in lipid vehicles to yield the compositions, e.g., the drug formulation. In some variations, the compositions herein may further comprise at least one lipid excipient. In certain variations, suitable excipients may include glyceryl monolinoleate.

[0047] In some variations, the lipid vehicle comprises a winterized oil composed of long- chain mono-, di-, and triglycerides. In certain variations, the lipid vehicle comprises mono-, di- and triglycerides of mainly linoleic (Ci8:2) and oleic (Ci8:i) acids. In one variation of the foregoing, the diester fraction is predominant.

[0048] In other embodiments, the lipid vehicle comprises self-emulsifying drug delivery systems.Other Components

[0049] In other embodiments, the compositions provided herein may further include or more additional components. For example, in some variations, the compositions further comprise at least one fatty acid. In certain variations, the compositions further compriselong-chain omega-3 polyunsaturated fatty acids (O-3 s). In one variation, the compositions further comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EP A).

[0050] In some embodiments, the drug substance compositions comprise (i) CBD, CBG and THC, collectively a major component of the cannabinoids present in the composition, in the ratios and amounts as described herein; (ii) fats and fatty acids; and (iii) terpenes. In certain embodiments, the drug substance compositions consists essentially of (i) CBD, CBG and THC, collectively a major component of the cannabinoids present in the composition, in the ratios and amounts as described herein; (ii) fats and fatty acids; and (iii) terpenes.

[0051] In some variations, the drug substance compositions comprise between 70% and 90% cannabinoids, including CBD, CBG and THC, collectively a major component of the cannabinoids present in the composition, in the ratios and amounts as described herein; between 10% and 15% fats and fatty acids; and between 1% and 5% terpenes. For example, in one variation, the composition comprises about 80% cannabinoids in the ratios and amounts as described herein, about 15% fats and fatty acids, and about 5% terpenes. In certain variations, the drug substance compositions consist essentially of (i) between 70% and 90% cannabinoids in the ratios and amounts as described herein (ii) between 10% and 15% fats and fatty acids, and (iii) between 1% and 5% terpenes.

[0052] In some embodiments, the drug product compositions comprise CBD, CBG and THC, collectively a major component of the cannabinoids present in the composition, in the ratios and amounts as described herein; fats and fatty acids; terpenes; and at least one lipid, such as a winterized oil composed of long-chain mono-, di-, and triglycerides. In certain embodiments, the drug product compositions consist essentially of (i) CBD, CBG and THC, collectively a major component of the cannabinoids present in the composition, in the ratios and amounts as described herein, (ii) fats and fatty acids, (iii) terpenes, (iv) and at least one lipid, such as a winterized oil composed of long-chain mono-, di-, and triglycerides.Preparation Methods

[0053] The cannabinoid compositions provided herein may be obtained from combining plant-derived, synthetic and / or biosynthetic CBD, CBG and THC, in order to achieve the appropriate amounts and ratios of these components.

[0054] As discussed above, when CBD, CBG and THC are plant-derived, they may be obtained from a cannabis plant. Various methods, techniques and conditions to cultivate, harvest and process cannabis plants are generally known in the art. Further, the resulting cannabis extract may be characterized using methods known in the art. Any suitable processes known in the art may be employed to obtain the CBD, CBG and THC used herein.

[0055] For example, bulk plant material is isolated from dried cannabis flower. The bulk plant material is separated from the botanical starting material. The botanical starting materials are weighed and stored in an amber jar. The botanical starting material are added to an extraction vessel with solvent. The solvent is removed via vacuum distillation until only refined cannabis oil is present, with a low solvent concentration. The crude cannabis oil is then heated to for a suitable time to convert the THCA to THC to yield a refined cannabis oil. The main cannabinoids, THCA, CBDA and CBGA are converted to the base molecule THC, CBD and CBG, respectively.

[0056] The cannabinoid extracts described above may undergo further purification using methods and techniques known in the art to obtain purified extracts or isolates. The purified extracts are typically in oil form, whereas the isolates are typically in powder form. In some variations, cannabis extracts may undergo distillation to remove certain constituents, such as terpenes and lipids, that are non-cannabinoids, and also separate out specific cannabinoids to yield a purified extract. In other variations, such purified extract may undergo crystallization or precipitation to isolate a specific cannabinoid, followed by filtration to yield a powder that is essentially a pure cannabinoid with excess solvent removed.

[0057] The cannabinoid compositions provided herein are pharmaceutical cannabinoid compositions, formulated based on the mode of intended administration. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In one variation, the cannabinoid composition is formulated for oral administration. In some embodiments, the cannabinoid composition is formulated as a solution for oral administration. In some embodiments, the composition may further comprise one or more flavoring or masking agents, including agents that may mask bitterness of the composition (e.g., any bitterness from the BDS).

[0058] In some embodiments, the cannabinoid compositions may be formulated with one or more excipients to increase stability, increase shelf-life, or increase efficacy. Cannabinoidcompositions disclosed herein may be formulated for administration according to methods known in the art.Treatment Methods

[0059] In some aspects, provided is a method for treating Aromatase Inhibitor-Induced Arthralgia (Al-induced arthralgia or AIIA) in a subject in need thereof.

[0060] In some aspects, provided is a method for treating inflammation induced by an aromatase inhibitor (Al) therapy in a subject in need thereof.

[0061] In some aspects, provided is a method for reducing inflammation induced by an aromatase inhibitor (Al) therapy in a subject in need thereof.

[0062] In some aspects, provided is a method for treating arthralgia induced by a hormonal imbalance in a subject in need thereof.

[0063] In some aspects, provided is a method for reducing arthralgia induced by a hormonal imbalance in a subject in need thereof.

[0064] In some aspects, provided is a method for treating inflammation induced by a hormonal imbalance in a subject in need thereof.

[0065] In some aspects, provided is a method for reducing inflammation induced by a hormonal imbalance in a subject in need thereof.

[0066] In some aspects, provided is a method for treating symptoms of a hormonal imbalance in a subject in need thereof.

[0067] In some aspects, provided is a method for reducing symptoms of a hormonal imbalance in a subject in need thereof.

[0068] In some aspects, provided is a method for treating arthralgia induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof.

[0069] In some aspects, provided is a method for reducing arthralgia induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof.

[0070] In some aspects, provided is a method for treating inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof.

[0071] In some aspects, provided is a method for reducing inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof.

[0072] In some aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof.

[0073] In some aspects, provided is a method for reducing arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof.

[0074] In some aspects, provided is a method for treating inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof.

[0075] In some aspects, provided is a method for reducing inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof.

[0076] In some aspects, provided is a method for treating symptoms of an estrogen deficiency, symptoms of a reduction in estrogen levels, or symptoms of a drop in circulating estrogen in a subject in need thereof.

[0077] In some aspects, provided is a method for reducing symptoms of an estrogen deficiency, symptoms of a reduction in estrogen levels, or symptoms of a drop in circulating estrogen in a subject in need thereof.

[0078] In some aspects, provided is a method for treating inflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof.

[0079] In some aspects, provided is a method for reducing inflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof.

[0080] In some aspects, provided is a method for treating symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof.

[0081] In some aspects, provided is a method for reducing symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof.Subjects

[0082] In some variations of the foregoing aspects, the subject (e.g., human) is taking or has taken a medication or therapy that reduces estrogen levels. In some variations, the subject has taken a medication or therapy that causes aromatase inhibition.

[0083] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from an estrogen-sensitive or estrogen-dependent cancer (e.g., is dependent on estrogen for growth and / or survival). In some variations, the estrogen-sensitive or estrogendependent cancer is breast cancer, endometrial cancer, ovarian cancer, or any combination thereof.

[0084] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from breast cancer. In certain variations, the human suffers or suffered from hormone receptor positive breast cancer. In some variations, the human is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer. In certain variations, the human is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer stages 0-III. In some variations, the subject is a perimenopausal woman who suffers or has suffered from hormone receptor positive breast cancer. In certain variations, the subject is a perimenopausal woman who suffers or has suffered from hormone receptor positive breast cancer stages 0-III. In some variations, the human is taking or has taken adjuvant aromatase inhibitor (Al) therapy. In some variations, the human suffers from Al-induced join pain. In some variations, the human suffers from Al-induced inflammation. In some variations, the human suffers from Al-induced decreased bone mineral density.

[0085] In some variations of the foregoing aspects, the subject (e.g., human) is a postmenopausal woman that previously received breast cancer treatment. In some variations, the post-menopausal woman that previously received breast cancer treatment has a reduction in estrogen production. In some variations, the post-menopausal woman that previously received breast cancer treatment is estrogen deficient. In some variations, the postmenopausal woman that previously received breast cancer treatment is experiencing estrogen deficiency. In some variations, the post-menopausal woman that previously received breast cancer treatment has a reduced ability to produce estrogen. In some variations, the postmenopausal woman that previously received breast cancer treatment is experiencing estrogen deprivation. In some variations, the post-menopausal woman that previously received breast cancer treatment is experiencing a reduction in estrogen levels. In some variations, the postmenopausal woman that previously received breast cancer treatment has a reduced ability to convert androgens into estrogens.

[0086] In some variations of the foregoing aspects, the subject (e.g., human) has a histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast. In certain variations, the subject has a stage 0 histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast. In certain variations, the subject has a stage I histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast. In certain variations, the subject has a stage II histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast. In certain variations, the subject has a stage IIIA histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast. In certain variations, the subject has no metastatic disease. In some variations, the subject has undergone breast cancer surgery and recovered. In some variations, the subject has undergone definitive breast cancer surgery and recovered. In some variations, the subject has estrogen-receptor positive (ER+), progesterone-receptor positive (PR+) cancer, or a combination thereof. In certain variations, the subject has estrogen- receptor positive (ER+) cancer. In certain variations, the subject has progesterone-receptor positive (PR+) cancer.

[0087] In some variations of the foregoing aspects, the subject (e.g., human) is taking or has taken a medication or therapy that increases androgen levels. In some variations, the subject has taken a medication or therapy that causes aromatase inhibition.

[0088] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from precocious puberty. In certain variations, the subject suffers or suffered from McCune- Albright syndrome. In certain variations, the subject suffers or suffered from or familial male-limited precocious puberty. In some variations, the subject is taking or has taken an aromatase (Al) therapy. In some variations, the subject is taking or has taken an Al therapy to help slow estrogen-mediated bone maturation. In some variations, the subject suffers from Al-induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the subject suffers from Al-induced arthralgia. In certain variations, the subject is an adolescent male.

[0089] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from a growth disorder. In some variations, the subject is taking or has taken an aromatase (Al) therapy. In some variations, the subject is taking or has taken an Al therapy to delay bone maturation and / or prolong the bone growth period. In some variations, the subject suffers from Al-induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the subject suffers from Al-induced arthralgia. In some variations, the subject is an adolescent male with a growth disorder. In some variations, the adolescent male suffers from short stature.

[0090] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from pubertal gynecomastia. In some variations, the subject is taking or has taken an Al therapy to reduce estrogen-driven growth of breast tissue. In some variations, the subject suffers from Al-induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the subject suffers from Al-induced arthralgia. In certain variations, the subject is an adolescent male.

[0091] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from prostate cancer. In some variations, the subject is resistant to anti-androgen therapies. In some variations, the resistance to anti-androgen therapies is caused by mutations in the androgen receptor. In some variations, the subject suffers from Al-induced arthralgia,inflammation, or a combination thereof. In certain variations, the subject suffers from AI- induced arthralgia. In certain variations, the subject is an adult male.

[0092] In some variations of the foregoing aspects, the subject (e.g., human) underwent or is undergoing fertility treatment. In some variations, the subject is a woman undergoing fertility treatment. In certain variations, the woman suffers or suffered from polycystic ovary syndrome (PCOS). In certain variations, the woman suffers or suffered from anovulatory infertility. In some variations, the woman is taking or has taken an Al therapy to induce ovulation. In other variations, the subject is a male undergoing fertility treatment. In certain variations, the male suffers or suffered from low testosterone, elevated estradiol, hypogonadism, or any combination thereof. In some variations, the subject suffers from AI- induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the subject suffers from Al-induced arthralgia.

[0093] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from hypogonadism. In certain variations, the subject is a male that suffered or is suffering from hypogonadism. In certain variations, the male has low testosterone, elevated estradiol, or a combination thereof. In some variations, the elevated estradiol is due to obesity. In some variations, the male suffers from Al-induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the male suffers from Al-induced arthralgia.

[0094] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from endometriosis. In some variations, the subject is a woman that suffered or is suffering from endometriosis. In some variations, the woman is taking or has taken an aromatase (Al) therapy to reduce estrogen-dependent endometrial tissue growth. In some variations, the woman suffers from Al-induced arthralgia, inflammation, decreased bone mineral density, or any combination thereof. In certain variations, the woman suffers from Al-induced arthralgia.

[0095] In some variations of the foregoing aspects, the subject (e.g., human) suffers or suffered from desmoid tumors.

[0096] In some variations of the foregoing aspects, the subject is a human whose ability to produce estrogen is reduced. In certain variations, the subject is a woman whose ability toproduce estrogen is reduced. In certain variations, the woman whose ability to produce estrogen is reduced is due to the removal of one or both ovaries.

[0097] In some variations of the foregoing aspects, the subject (e.g., human) is unable to produce estrogen. In certain variations, the subject is a woman who is unable to produce estrogen.

[0098] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing an estrogen deficiency. In some variations, the subject is an estrogen deficient woman.

[0099] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing estrogen deprivation.

[0100] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing a reduction in estrogen levels.

[0101] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing a drop in circulating estrogen.

[0102] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing an androgen surplus.

[0103] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing an increase in androgen levels.

[0104] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing a rise in circulating androgen.

[0105] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing a hormonal imbalance. In certain variations, the hormonal imbalance is induced by a medication that blocks estrogen receptors, a medication modulates estrogen receptors, or a medication that degrades estrogen receptors, as described herein.

[0106] In some variations of the foregoing aspects, the subject (e.g., human) is experiencing an androgen surplus, an increase in androgen levels, or a rise in circulating androgen. In certain variations, the androgen surplus, the increase the androgen levels, or therise in circulating androgen in a subject in need thereof is induced by an aromatase inhibitor (Al) therapy.

[0107] In any of the foregoing variations, the estrogen deficiency, reduced ability to produced estrogen, inability to produce estrogen, reduction in estrogen levels, estrogen deprivation, or drop in circulating estrogen is induced by an aromatase inhibitor (Al) therapy, removal of one or both ovaries, aging, menopause, perimenopause, premature menopause, premature ovarian failure, an eating disorder, hypothalamic amenorrhea (e.g., excessive exercise), pituitary gland dysfunction, a thyroid disorder, a previous treatment that damaged one or both ovaries, or any combination thereof. In certain variations, the aromatase inhibitor is a third-generation aromatase inhibitor as described herein. In certain variations, the previous treatment that damaged ovaries is chemotherapy, radiation therapy, or a combination thereof.

[0108] In any of the foregoing variations, the subject has previously taken a medication that decreases estrogen production. In certain variations, the subject has previously taken an aromatase inhibitor that decreases estrogen production. In certain variations, the subject has previously taken a third-generation aromatase inhibitor that decreases estrogen production. In some variations, the medication that decreases estrogen production induces an estrogen deficiency, a reduction in estrogen levels, a drop in circulating estrogen, or any combination thereof.

[0109] In any of the foregoing variations, the subject is taking a medication that decreases estrogen production. In certain variations, the subject is currently taking an aromatase inhibitor that decreases estrogen production. In certain variations, the subject is currently taking a third-generation aromatase inhibitor that decreases estrogen production. In some variations, the medication that decreases estrogen production induces an estrogen deficiency, a reduction in estrogen levels, a drop in circulating estrogen, or any combination thereof.

[0110] In any of the foregoing variations, the subject is taking a medication that decreases estrogen production and one or more narcotic medications. In some variations, the subject is taking an aromatase inhibitor (Al) therapy and one or more narcotic medications. In some variations, the subject is taking an (i) Al therapy and (ii) an opioid, a nonsteroidal antiinflammatory drug (NSAID), or any combination thereof. In certain variations, the subject istaking an Al therapy and an opioid. In certain variations, the subject is taking an Al therapy and a NSAID.[OHl] In any of the foregoing variations, the subject is taking or has previously taken a medication that blocks estrogen receptors, a medication modulates estrogen receptors, or a medication that degrades estrogen receptors, or any combination thereof. In some variations, the medication that blocks estrogen receptors is an estrogen receptor antagonist. In one variation, suitable estrogen receptor antagonists may include fulvestrant (e.g., FASLODEX®), lasofoxifene, giredestrant, elacestrant (e.g., ORSERDU®), or any combination thereof. In other variations, the medication that modulates estrogen receptors is a selective estrogen receptor modulator (SERM). In one variation, suitable SERMs may include tamoxifen, raloxifene, bazedoxifene, toremifene, and lasofoxifene, or any combinations thereof. In other variations, the medication the degrades estrogen receptors is a selective estrogen receptor degrader (SERD). In one variation, suitable SERDs may include fulvestrant (e.g., FASLODEX®), elacestrant (e.g., ORSERDU®), camizestrant, giredestrant, amcenestrant, rintodestrant, vepdegestrant, or any combination thereof. In some variations, the medication modulates estrogen receptors and degrades estrogen receptors. In certain variations, the medication modulates estrogen receptors and degrades estrogen receptors is a dual SERM and SERD medication. In one variation, suitable dual SERM and SERD medications may include elacestrant.

[0112] In some variations, the medication that blocks estrogen receptors, the medication modulates estrogen receptors, and the medication that degrades estrogen receptors, as described herein, induces a hormonal imbalance.

[0113] In some variations, the medication that blocks estrogen receptors, the medication modulates estrogen receptors, and the medication that degrades estrogen receptors, as described herein, induces an estrogen deficiency.

[0114] In any of the foregoing variations, the subject is taking or has previously taken a medication that blocks estrogen receptors, a medication modulates estrogen receptors, or a medication degrades estrogen receptors and one or more narcotic medications. In some variations, the narcotic medication comprises an opioid, a nonsteroidal anti-inflammatory drug (NS AID), or any combination thereof.

[0115] In some variations, the medication that blocks estrogen receptors, as described herein, is an estrogen receptor antagonist that blocks estrogen’s ability to bind and activate estrogen receptors. In some variations, the medication that modulates estrogen receptors, as described herein, is a selective estrogen receptor modulator (SERM) that mimics estrogens effects and / or blocks estrogen’s ability to bind and activate estrogen receptors. In certain variations, the SERM is tissue selective. For example, in some variations, the SERM is an estrogen receptor antagonist in breast tissue but an estrogen receptor agonist in bone and uterus tissue. In other variations, the SERM is an estrogen receptor agonist in bone and an estrogen receptor antagonist in breast and uterus tissue. In some variations, the medication that degrades estrogen receptors, as described herein, binds to and degrades estrogen receptors, thereby preventing estrogen from binding to the estrogen receptor. In some variations, the medications that block estrogen receptors, modulate estrogen receptors, or degrade estrogen receptors induce arthralgia. In some variations, the medications that block estrogen receptors, modulate estrogen receptors, or degrade estrogen receptors induce symptoms of estrogen deficiency, symptoms of reduced estrogen levels, symptoms of a drop in circulating estrogen, or any combination thereof.

[0116] In any variations of the foregoing aspects, the subject is a human. In one variation, the subject is an adult human. In certain variations, the human is a woman. In certain variations, the human is a male. In some variations, the human is an adolescent human. In certain variations, the human is an adolescent male. In one variation, the human is a perimenopausal woman. In one variation, the human is a menopausal woman. In one variation, the human is a postmenopausal woman.Uses

[0117] In some aspects, provided is a method for treating Aromatase Inhibitor-Induced Arthralgia (Al-induced arthralgia or AIIA) in a subject in need thereof. In some variations, the method for treating AIIA in a subject in need thereof comprises administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0118] In some aspects, provided is a method for treating arthralgia induced by a medication that blocks estrogen receptors, modulates estrogen receptors, or degrades estrogen receptors, or any combination thereof, in a subject in need thereof, comprising administeringto the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0119] In some aspects, provided is a method for reducing arthralgia induced by a medication that blocks estrogen receptors, modulates estrogen receptors, or degrades estrogen receptors, or any combination thereof, in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0120] In some aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in the subject in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0121] In some aspects, provided is a method for reducing arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0122] In some aspects, provided is a method for treating inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0123] In some aspects, provided is a method for reducing inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0124] In some aspects, provided is a method for treating inflammation induced by an aromatase inhibitor (Al) therapy in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein. In another aspect, provided is a method for treating inflammation in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as themajor components therein, wherein the inflammation is induced by a third-generation aromatase inhibitor. In some embodiments, the third-generation aromatase inhibitor is anastrozole (e.g., ARIMIDEX®), letrozole (e.g., FEMARA®), and exemestane (e.g., AROMASIN®), or any combination thereof.

[0125] In some aspects, provided is a method for reducing inflammation induced by an aromatase inhibitor (Al) therapy in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein. In another aspect, provided is a method for reducing inflammation in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, wherein the inflammation is induced by a third-generation aromatase inhibitor. In some embodiments, the third-generation aromatase inhibitor is anastrozole (e.g., ARIMIDEX®), letrozole (e.g., FEMARA®), and exemestane (e.g., AROMASIN®), or any combination thereof.

[0126] In some aspects, provided is a method for treating inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0127] In some aspects, provided is a method for reducing inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0128] In some aspects, provided is a method for treating symptoms of an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0129] In some aspects, provided is a method for reducing symptoms of an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a subject inneed thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0130] In some aspects, provided is a method for treating arthralgia induced by a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0131] In some aspects, provided is a method for reducing arthralgia induced by a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0132] In some aspects, provided is a method for treating inflammation induced by a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0133] In some aspects, provided is a method for reducing inflammation induced by a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0134] In some aspects, provided is a method for treating symptoms of a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0135] In some aspects, provided is a method for reducing symptoms of a hormonal imbalance in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0136] In some aspects, provided is a method for treating inflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subjectin need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0137] In some aspects, provided is a method for reducing inflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0138] In some aspects, provided is a method for treating symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0139] In some aspects, provided is a method for reducing symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, comprising administering to the subject a cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein.

[0140] In any variations of the foregoing aspects, the estrogen deficiency, reduction in estrogen levels, or a drop in circulating estrogen is induced by an aromatase inhibitor (Al) therapy, removal of one or both ovaries, aging, menopause, perimenopause, premature menopause, premature ovarian failure, an eating disorder, hypothalamic amenorrhea (e.g., excessive exercise), pituitary gland dysfunction, a thyroid disorder, a previous treatment that damaged one or both ovaries, removal of one or both ovaries, or any combination thereof. In certain variations, the Al therapy is a third-generation aromatase inhibitor as described herein. In one variation, suitable third-generation aromatase inhibitors may include anastrozole (e.g., ARIMIDEX®), letrozole (e.g., FEMARA®), and exemestane (e.g., AROMASIN®), or any combination thereof. In certain variations, the previous treatment that damaged one or both ovaries is chemotherapy, radiation therapy, or a combination thereof.

[0141] In any variations of the foregoing aspects, the symptoms of an estrogen deficiency, the symptoms of a reduction in estrogen levels, or the symptoms of a drop in circulating estrogen are one or more of arthralgia, joint pain, joint stiffness, reduced grip strength, decreased musculoskeletal abilities, decreased bone density, decreased bone related biomarkers, increased anxiety, decreased sleep quality, increased inflammation, or anycombination of the foregoing symptoms. In some variations, the increased inflammation is increased musculoskeletal inflammation.

[0142] In any variations of the foregoing aspects, the hormonal imbalance is induced by a medication that blocks estrogen receptors, a medication modulates estrogen receptors, or a medication that degrades estrogen receptors. In some variations, the medication that blocks estrogen receptors is an estrogen receptor antagonist. In one variation, suitable estrogen receptor antagonists may include fulvestrant (e.g., FASLODEX®), lasofoxifene, giredestrant, elacestrant (e.g., ORSERDU®), or any combination thereof. In other variations, the medication that modulates estrogen receptors is a selective estrogen receptor modulator (SERM). In one variation, suitable SERMs may include tamoxifen, raloxifene, bazedoxifene, toremifene, and lasofoxifene, or any combinations thereof. In other variations, the medication the degrades estrogen receptors is a selective estrogen receptor degrader (SERD). In one variation, suitable SERDs may include fulvestrant (e.g., FASLODEX®), elacestrant (e.g., ORSERDU®), camizestrant, giredestrant, amcenestrant, rintodestrant, vepdegestrant, or any combination thereof. In some variations, the medication modulates estrogen receptors and degrades estrogen receptors. In certain variations, the medication modulates estrogen receptors and degrades estrogen receptors is a dual SERM and SERD medication. In one variation, suitable dual SERM and SERD medications may include elacestrant (e.g., ORSERDU®).

[0143] In any variations of the foregoing aspects, the symptoms of a hormonal imbalance are one or more of arthralgia (e.g., joint pain, joint stiffness), reduced grip strength, decreased musculoskeletal abilities, decreased bone density, decreased bone related biomarkers, increased anxiety, decreased sleep quality, increased inflammation, hot flashes, increased anxiety, depression, nausea, decreased appetite, or any combination thereof. In some variations, the inflammation is musculoskeletal inflammation.

[0144] In any variations of the foregoing aspects, the symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen are one or more of decreased bone density, decreased bone related biomarkers, increased inflammation, and decreased bone turnover.

[0145] In any variations of the foregoing aspects, the medication that blocks estrogen receptors is an estrogen receptor antagonist, as described herein.

[0146] In any variations of the foregoing aspects, the medication that modulates estrogen receptors is a selective estrogen receptor modulator (SERM), as described herein.

[0147] In any variations of the foregoing aspects, the medication that degrades estrogen receptors is a selective estrogen receptor degrader (SERD), as described herein.

[0148] In some variations, provided herein are methods of treating Aromatase-Inhibitor- Associated Arthralgia (AIAA). In some variations, provided herein are methods of treating Aromatase Inhibitor-Induced Musculoskeletal Symptoms (AIMSS). In some variations, provided herein are methods of treating Aromatase-Inhibitor-Associated Arthropathy.

[0149] In any variations of the foregoing aspects provided herein, the method comprises administering to the human the compositions described herein, e.g., comprising CBD, CBG and THC as the major components therein. In some variations of the foregoing aspects, the terms “treating” or “treatment”, as used herein, refer to a method or procedure for obtaining beneficial or desired results — for example, clinical results. Beneficial or desired results may include: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, increasing the quality of life, and / or prolonging survival rates).

[0150] In some variations, treating AIIA comprises treating intractable and debilitating pain symptoms induced by Al therapy. In certain variations, the treatment decreases pain severity experienced by the human. In certain variations, the treatment decreases joint symptoms of pain and stiffness. Such symptoms may be assessed by BPI-SF total pain severity and interference scores and Visual Analog Scale-Pain. In certain variations, the treatment improves the human’s musculoskeletal abilities. In certain variations, the treatment improves the human’s bone density or bone related biomarkers. In one variation, the treatment improves the human’s grip strength. In some variations, the treatment reduces anxiety in the human. In some variations, the treatment improves sleep quality in the human. In some variations, the treatment reduces the amount and / or frequency of one or morenarcotic medication concomitantly administered to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine. In some variations, the treatment increases bone turnover.

[0151] In some variations, treating arthralgia comprises treating intractable and debilitating pain symptoms induced by a medication that blocks estrogen receptors, modulates estrogen receptors, or degrades estrogen receptors, or any combination thereof. In certain variations, the treatment decreases pain severity experienced by the human. In certain variations, the treatment decreases joint symptoms of pain and stiffness. Such symptoms may be assessed by BPI-SF total pain severity and interference scores and Visual Analog Scale- Pain. In certain variations, the treatment improves the human’s musculoskeletal abilities. In certain variations, the treatment improves the human’s bone density or bone related biomarkers. In one variation, the treatment improves the human’s grip strength. In some variations, the treatment reduces anxiety in the human. In some variations, the treatment improves sleep quality in the human. In some variations, the treatment reduces the amount and / or frequency of one or more narcotic medication concomitantly administered to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine. In some variations, the treatment improves inflammation. In some variations, the treatment improves hot flashes. In some variations, the treatment reduces nausea. In some variations, the treatment improves depression. In some variations, the treatment increases bone turnover.

[0152] In some variations, treating symptoms of an estrogen deficiency, treating symptoms of a reduction in estrogen levels, and treating symptoms of a drop in circulating estrogen is treating intractable and debilitating pain symptoms induced by the estrogen deficiency, the reduction in estrogen levels, or the drop in circulating estrogen. In certain variations, the treatment decreases pain severity experienced by the human. In certain variations, the treatment decreases joint symptoms of pain and stiffness. Such symptoms may be assessed by BPI-SF total pain severity and interference scores and Visual Analog Scale- Pain. In certain variations, the treatment improves the human’s musculoskeletal abilities. In certain variations, the treatment improves the human’s bone density or bone related biomarkers. In one variation, the treatment improves the human’s grip strength. In some variations, the treatment reduces anxiety in the human. In some variations, the treatment improves sleep quality in the human. In some embodiments, the treatment reduces theamount and / or frequency of one or more narcotic medication concomitantly administered to the human. In certain variations, the treatment reduces hot flashes. In some variations, the treatment reduces inflammation. In certain variations, the inflammation is musculoskeletal inflammation. In certain variations, the treatment improves bone metabolism. In some variations, the treatment reduces the amount and / or frequency of one or more narcotic medication concomitantly administered to the human. In certain variations, the one or more narcotic medication comprises an opioid, a nonsteroidal anti-inflammatory drug (NSAID). In one variation, suitable opioids may include morphine. In some variations, the treatment improves inflammation. In some variations, the treatment improves hot flashes. In some variations, the treatment reduces nausea. In some variations, the treatment improves depression. In some variations, the treatment increases bone turnover.

[0153] In some variations, treating a hormonal imbalance comprises treating intractable and debilitating pain symptoms induced by a medication that blocks estrogen receptors, modulates estrogen receptors, or degrades estrogen receptors, or any combination thereof. In certain variations, the treatment decreases pain severity experienced by the human. In certain variations, the treatment decreases joint symptoms of pain and stiffness. Such symptoms may be assessed by BPI-SF total pain severity and interference scores and Visual Analog Scale- Pain. In certain variations, the treatment improves the human’s musculoskeletal abilities. In certain variations, the treatment improves the human’s bone density or bone related biomarkers. In one variation, the treatment improves the human’s grip strength. In some variations, the treatment reduces anxiety in the human. In some variations, the treatment improves sleep quality in the human. In some variations, the treatment reduces the amount and / or frequency of one or more narcotic medication concomitantly administered to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine. In some variations, the treatment improves inflammation. In some variations, the treatment improves hot flashes. In some variations, the treatment reduces nausea. In some variations, the treatment improves depression. In some variations, the treatment increases bone turnover.

[0154] In certain aspects, provided is a method for treating All A in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) treating intractable and debilitating pain symptoms induced by Al therapy. In certain aspects, provided is a method for treating AIIA in a human in need thereof,comprising: a) administering to the human a cannabinoid composition as described herein; and b) decreasing pain severity experienced by the human. In certain aspects, provided is a method for treating All A in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) decreasing joint symptoms of pain and stiffness. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s musculoskeletal abilities. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s bone density or bone related biomarkers. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s grip strength. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing anxiety in the human. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving sleep quality in the human. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing the amount and / or frequency of one or more narcotic medications concomitantly administered to the human. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing inflammation in the human. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing musculoskeletal inflammation in the human. In certain aspects, provided is a method for treating AIIA in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) increasing musculoskeletal bone turnover in the human.

[0155] In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) treating intractable and debilitating pain symptomsinduced by the estrogen deficiency, the reduction in estrogen levels, or the drop in circulating estrogen. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) decreasing pain severity experienced by the human. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s musculoskeletal abilities. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s bone density or bone related biomarkers. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving the human’s grip strength. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) improving sleep quality in the human. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing the amount and / or frequency of one or more narcotic medications concomitantly administered to the human. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing inflammation in the human. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a) administering to the human a cannabinoid composition as described herein; and b) reducing musculoskeletal inflammation in the human. In certain aspects, provided is a method for treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof, comprising: a)administering to the human a cannabinoid composition as described herein; and b) increasing musculoskeletal bone turnover in the human.

[0156] In some variations of any of the foregoing aspects, the methods provided comprise administering to the human the compositions described herein, e.g., comprising CBD, CBG and THC as the major components therein. In some variations of the foregoing aspects, the terms “treating” or “treatment”, as used herein, refer to a method or procedure for obtaining beneficial or desired results — for example, clinical results. Beneficial or desired results may include: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, increasing the quality of life, and / or prolonging survival rates).

[0157] In any variations of the foregoing methods, administering to the human the compositions described herein, e.g., comprising CBD, CBG and THC as the major components therein, reduces the amount and / or frequency of one or more narcotic medication concomitantly administered to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine.

[0158] In some variations of any of the foregoing aspects, the cannabinoid composition is administered at an initial dose between about 50 mg and about 300 mg, wherein the dose is measured against the amount of CBD in the composition. In one variation, the initial dose administered is about 50 mg of the cannabinoid composition. In one variation, the initial dose administered is about 75 mg of the cannabinoid composition. In one variation, the initial dose administered is about 100 mg of the cannabinoid composition. In one variation, the initial dose administered is about 125 mg of the cannabinoid composition. In one variation, the initial dose administered is about 150 mg of the cannabinoid composition. In certain variations, the aforementioned initial doses may be administered once a day or twice a day. In other variations, the aforementioned initial doses may be administered three times a day, four times a day, or five times a day.

[0159] In some variations of any of the foregoing aspects, the human is concomitantly taking an aromatase inhibitor and / or narcotic medication. In some variations of the methods described herein, the method further comprising concomitantly administering an aromatase inhibitor to the human. In certain variations, the aromatase inhibitor comprises a third- generation aromatase inhibitor as described herein. In some variations of the methods described herein, the method further comprises concomitantly administering one or more narcotic medications to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine. In other variations of the methods described herein, the method further comprising concomitantly administering an aromatase inhibitor drug and / or narcotic medication to the human. In some variations, aromatase inhibitor drugs are third-generation aromatase inhibitors as described herein. In one variation, suitable third-generation aromatase inhibitors may include anastrozole (e.g., ARIMIDEX®), letrozole (e.g., FEMARA®), and exemestane (e.g., AROMASIN®), or any combination thereof. In certain variations, the narcotic medication comprises an opioid. In some variations, the administration of the cannabinoid composition as described herein reduces the amount and / or frequency of the narcotic medication taken by the human.

[0160] In other variations of any of the foregoing aspects, the human has previously taken an aromatase inhibitor and / or narcotic medication. In some variations of the methods described herein, the human has previously taken an aromatase inhibitor. In certain variations, the aromatase inhibitor comprises a third-generation aromatase inhibitor as described herein. In one variation, suitable third-generation aromatase inhibitors may include anastrozole (e.g., ARIMIDEX®), letrozole (e.g., FEMARA®), and exemestane (e.g., AROMASIN®), or any combination thereof. In certain variations of the methods described herein, the human has previously taken a narcotic medication.

[0161] In some variations of any of the foregoing aspects, the human is concomitantly taking a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, a medication that degrades estrogen receptors, a narcotic medication, or any combination thereof. In some variations of the methods described herein, the method further comprising concomitantly administering a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors to the human. In some variations of the methods described herein, the methodfurther comprises concomitantly administering one or more narcotic medications to the human. In certain variations, the one or more narcotic medication comprises an opioid, a NSAID. In one variation, suitable opioids may include morphine. In some variations, the administration of the cannabinoid composition as described herein reduces the amount and / or frequency of the narcotic medication taken by the human.

[0162] In other variations of any of the foregoing aspects, the human has previously taken a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, a medication that degrades estrogen receptors, a narcotic medication, or any combination thereof. In some variations of the methods described herein, the human has previously taken a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors. In certain variations of the methods described herein, the human has previously taken a narcotic medication.

[0163] In any variations of any of the foregoing aspects, treatment with the compositions described herein, e.g., comprising CBD, CBG and THC as the major components therein, pain severity is improved, joint symptoms of pain and stiffness are improved, musculoskeletal abilities are improved, bone density or bone related biomarkers is improved, grip strength is improved, anxiety is improved, sleep is improved, inflammation is improved, bone turnover is improved, or any combination of the foregoing outcomes.

[0164] In any variations of any of the foregoing aspects, the cannabinoid composition is administered daily. In other variations, the cannabinoid composition is administered twice daily. In other variations, the cannabinoid composition is administered three times a day. In other variations, the cannabinoid composition is administered four times a day. In some variations, the cannabinoid composition is administered with food. In some variations, the cannabinoid composition is administered without food.

[0165] In some variations of the foregoing aspects, a therapeutically effective amount of the cannabinoid composition is administered. In certain variations, the term “therapeutically effective amount” applied to dose or amount refers to that quantity of a composition or formulation, such as those described herein, that is sufficient to result in a desired clinical benefit after administration to a human in need thereof. It is to be understood that the amount may be in one or more doses, e.g., a single dose or multiple doses may be needed to achieve the desired treatment endpoint. In some variations, the cannabinoid composition isadministered at a dose between 200 mg and 1500 mg. In certain variations, the cannabinoid composition is administered twice daily for a total dose of 100 mg daily, 200 mg daily, 300 mg daily, 400 mg daily, 500 mg daily, 600 mg daily, 700 mg daily, 800 mg daily, 900 mg daily, 1000 mg daily, 1100 mg daily, 1200 mg daily, 1300 mg daily, 1400 mg daily, or 1500 mg daily. It should be understood here that the dose is measured against the amount of CBD.

[0166] In some variations of the foregoing aspects, the cannabinoid composition is administered at a therapeutically effective dose or amount. In some variations, the term “therapeutically effective” applied to dose or amount refers to that quantity of the cannabinoid composition, such as those described elsewhere herein, that is sufficient to result in a desired clinical benefit after administration to a subject in need thereof. It is to be understood that an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be needed to achieve the desired treatment endpoint.

[0167] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating AIIA.

[0168] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating AIIA, wherein pain severity is improved, joint symptoms of pain and stiffness are improved, musculoskeletal abilities are improved, bone density or bone related biomarkers is improved, grip strength is improved, anxiety is improved, sleep is improved, inflammation is improved, bone turnover is improved, or any combination of the foregoing outcomes. In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating AIIA in any of the doses described herein, including in a dose between 100 mg and 1500 mg, a 200 mg daily dose, a 100 mg twice daily dose, a 800 mg daily dose, a 400 mg twice daily dose, 1500 mg daily dose, or a 750 mg twice daily dose. It should be understood that dose here is measured against the amount of CBD.

[0169] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating AIIA, wherein the method comprises administering the composition concomitantly with an aromatase inhibitor and / or narcotic medication. In certain variations, the amount and / or frequency of narcotic medication concomitantly administered is reduced.

[0170] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating arthralgia induced by a medication that blocks estrogen receptors. In some variations, the medication that blocks estrogen receptors is an estrogen receptor antagonist.

[0171] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating arthralgia induced by a medication that modulates estrogen receptors. In some variations, the medication that modulates estrogen receptors is a selective estrogen receptor modulator (SERM).

[0172] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating arthralgia induced by a medication that degrades estrogen receptors. In some variations, the medication that degrades estrogen receptors is a selective estrogen receptor degrader (SERD).

[0173] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen.

[0174] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen.

[0175] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen.

[0176] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing inflammation induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen.

[0177] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating inflammation induced by an aromatase inhibitor (Al) therapy.

[0178] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing inflammation induced by an aromatase inhibitor (Al) therapy.

[0179] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors.

[0180] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing inflammation induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors.

[0181] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating symptoms of an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen, as described herein.

[0182] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing symptoms of an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen, as described herein.

[0183] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating symptoms of an estrogen deficiency or hormonal imbalance induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors, or any combination thereof.

[0184] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treatinginflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, or any combination thereof.

[0185] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing inflammation induced by an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, or any combination thereof

[0186] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of treating symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, or any combination thereof.

[0187] In some variations, provided is a composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, for use in a method of reducing symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a subject in need thereof, or any combination thereof.

[0188] In any of the foregoing variations, the composition for use is cannabinoid composition as described herein, e.g., comprising CBD, CBG and THC as the major components therein, in any of the doses described herein, including in a dose between 100 mg and 1500 mg, a 200 mg daily dose, a 100 mg twice daily dose, 300 mg daily dose, a 150 mg twice daily dose, 400 mg daily dose, a 200 mg twice daily dose, 500 mg daily dose, a 250 mg twice daily dose, 600 mg daily dose, a 300 mg twice daily dose, 700 mg daily dose, a 350 mg twice daily dose, a 800 mg daily dose, a 400 mg twice daily dose, 1000 mg daily dose, a 500 mg twice daily dose, 1200 mg daily dose, a 600 mg twice daily dose, 1400 mg daily dose, a 700 mg twice daily dose, 1500 mg daily dose, or a 750 mg twice daily dose. It should be understood that dose here is measured against the amount of CBD.

[0189] In any variations of the foregoing methods, the cannabinoid composition is administered at an initial dose between about 50 mg and 400 mg. In some variations, the cannabinoid composition is administered at an initial dose between about 50 mg and 300 mg. In some variations, the subject is monitored for clinical response and tolerability of the cannabinoid composition administered. In some variations, the dose of the cannabinoid composition administered to the subject is increased up to a maximum total daily dose of 1500 mg. In some embodiments, the dose of the cannabinoid composition administered to thesubject is increased over 2 weeks. In some variations, the dose is increased in the evenings. In one variation, the initial dose administered is about 100 mg of the cannabinoid composition. In certain variations, the aforementioned initial doses may be administered once a day or twice a day.

[0190] In some variations, the cannabinoid composition is administered twice daily for the at doses starting at 1 mL twice daily up to the highest tolerable dose up to 4 mL twice daily for the first 2 weeks of administration.

[0191] In any variations of the foregoing methods, the initial dose of the cannabinoid composition is between 100 mg and 300 mg total daily dose. In some variations, the initial dose is between 150 mg and 250 mg total daily dose. In some variations, the initial dose of cannabinoid is at least 100 mg total daily dose. In some variations, the initial dose of cannabinoid is at least 200 mg total daily dose. In some variations, the initial dose of cannabinoid is at least 300 mg total daily dose. In certain variations, the initial dose of the cannabinoid composition is 200 mg total daily dose. In some variations, the subject is monitored for clinical response and tolerability of the cannabinoid composition administered. In some variations, the dose of the cannabinoid composition administered to the subject is increased up to a maximum total daily dose of about 1000 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. The dose may be titrated up based on safety and desired effect experienced by the subject. In some variations of the foregoing, the total daily dose noted above may be administered once a day, or twice a day.

[0192] In one aspect, provided is a method of treating AIIA in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on AIIA, or the symptoms of AIIA, experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses).

[0193] In one aspect, provided is a method of treating arthralgia in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on arthralgia experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses). In some variations, the arthralgia is induced by an Al therapy, a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, a medication that degrades estrogen receptors, as described herein, or any combination thereof. In some variations, the arthralgia is induced by estrogen deprivation, a reduction in estrogen levels, or a drop in circulating estrogen, or any combination thereof.

[0194] In one aspect, provided is a method of treating arthralgia induced by an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on arthralgia experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses).

[0195] In one aspect, provided is a method of treating arthralgia induced by a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, or a medication that degrades estrogen receptors in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition asdescribed herein at an initial dose of about 100 mg; monitoring safety and effect on arthralgia experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses).

[0196] In one aspect, provided is a method of treating inflammation in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on inflammation experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses). In some variations, the inflammation is induced by an Al therapy, a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, a medication that degrades estrogen receptors, as described herein, or any combination thereof. In some variations, the inflammation is induced by estrogen deprivation, a reduction in estrogen levels, or a drop in circulating estrogen, or any combination thereof. In some variations, the inflammation is musculoskeletal inflammation.

[0197] In one aspect, provided is a method of treating symptoms of an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on symptoms of estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg,about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses). In some variations, the symptoms of estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen is induced by an Al therapy, a medication that blocks estrogen receptors, a medication that modulates estrogen receptors, a medication that degrades estrogen receptors, removal of one or both ovaries, aging, menopause, perimenopause, premature menopause, premature ovarian failure, an eating disorder, hypothalamic amenorrhea (e.g., excessive exercise), pituitary gland dysfunction, a thyroid disorder, a previous treatment that damaged ovaries, or any combination thereof.

[0198] In one aspect, provided is a method of treating symptoms of an androgen surplus, an increase in androgen levels, or a rise in circulating androgen in a human in need thereof that comprises administering a cannabinoid composition as described herein at a therapeutically effect amount. In one variation, the method comprises administering a cannabinoid composition as described herein at an initial dose of about 100 mg; monitoring safety and effect on symptoms of estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen experienced by the subject; and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, about 900 mg, about 800 mg, about 700 mg, about 600 mg, about 500 mg, about 400 mg, or about 300 mg. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses). In some variations, the symptoms of the androgen surplus, the increase in androgen levels, or the rise in circulating androgen is induced by an Al therapy.

[0199] In some variations of the methods described herein, the cannabinoid composition is administered for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least a 6 days, at 7 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years, or any duration in between. In some variations of the methods described herein, thecannabinoid composition is administered concomitantly with an Al therapy for the duration of the Al therapy.Kits and Articles of Manufacture

[0200] In other aspects, the present disclosure further provides kits for carrying out the methods of the invention. The kits may comprise the cannabinoid compositions described herein and suitable packaging. In some embodiments, provided is a kit, comprising: (i) any of the cannabinoid compositions described herein; and (ii) a label and / or instructions for use in treating AIIA. In some variations of the foregoing, the kit may further comprise a bottle adaptor and / or oral dosing syringe. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses).

[0201] In yet other aspects, the present disclosure further provides an article of manufacture, comprising any of the cannabinoid compositions described herein in a suitable container.

[0202] In some variations of the foregoing, the article of manufacture may further comprise a bottle adaptor and / or oral dosing syringe. In one variation of the foregoing, the total daily dose is administered in one daily dose. In another variation of the foregoing, the total daily dose is administered twice a day (e.g., in two doses).ENUMERATED EMBODIMENTS1 A. A method of treating arthralgia, inflammation, symptoms of estrogen deficiency, symptoms of a reduction in estrogen levels, or symptoms of a drop in circulating estrogen in a human in need thereof, comprising: administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.2A. The method of embodiment of 1 A, wherein arthralgia is Aromatase Inhibitor-Induced Arthralgia (AIIA), arthralgia induced by a medication that blocks estrogen receptors, arthralgia induced by a medication that modulates estrogen receptors, arthralgia induced by a medication that degrades estrogen receptors, or any combination thereof.3 A. The method of embodiment 2A, wherein treating Aromatase Inhibitor-InducedArthralgia (AIIA) in a human in need thereof, comprises: administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.4A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG and / or THC are provided as botanical drug substances (BDS).5 A. The method of embodiment 4A, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the BDS.6A. The method of embodiment 4A, wherein the cannabinoid composition further comprises terpenes that are present from the BDS.7A. The method of any one of embodiments 4A to 6A, wherein the cannabinoid composition further comprises flavonoids that are present from the BDS.8A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG and THC are provided as a combination of cannabis extracts.9A. The method of embodiment 3 A, wherein the CBD, CBG and THC are provided as a combination of extracts from 2-4 cannabis cultivars.10A. The method of embodiment 3 A, wherein the CBD, CBG and THC are provided as a combination of extracts from genetically identical clones of 3 different cannabis cultivars.11 A. The method of embodiment 10A, wherein the 3 different cannabis cultivars are a high CBD cultivar, a high CBG cultivar and a high THC cultivar.12A. The method of any one of embodiments 9A to 11 A, wherein cannabis cultivars are Cannabis sativa cultivars.13A. The method of any one of embodiments 8A to 12A, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the extracts.14 A. The method of any one of embodiments 8 A to 12 A, wherein the cannabinoid composition further comprises terpenes that are present from the extracts.15 A. The method of any one of embodiments 8 A to 13 A, wherein the cannabinoid composition further comprises flavonoids that are present from the extracts.16 A. The method of any one of embodiments 4 A to 15 A, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC provided in purified form.17 A. The method of any one of embodiments 4 A to 15 A, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC isolates.18A. The method of any one of embodiments 1A to 3 A, wherein the CBD, CBG andTHC are provided as a combination of purified CBD, CBG and THC cannabis extracts.19A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are provided as a combination of CBD, CBG and THC isolates.20A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are provided as a combination of BDS and CBD, CBG and / or THC isolates.21 A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are provided as a combination of BDS, and purified CBD, CBG and / or THC cannabis extracts.22A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are provided as a combination of BDS, and CBD, CBG and / or THC isolates.23 A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are provided as BDS in combination with refined or synthetic CBD, CBG and / or THC.24A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG and THC are a combination of highly purified CBD, highly purified CBG and highly purified THC, wherein each of which are extracted from a cannabis plant and purified to the extent that other cannabinoids and a majority of non-cannabinoid components that are co-extracted with the cannabinoids have been removed.25A. The method of embodiment 24A, wherein the highly purified CBD is greater than or equal to 90% (w / w) pure; the highly purified CBG is greater than or equal to 90% (w / w) pure; and the highly purified THC is greater than or equal to 90% (w / w) pure.26A. The method of any one of embodiments 1 A to 3A, wherein the CBD, CBG andTHC are all naturally derived.27A. The method of any one of embodiments 1 A to 3A wherein at least a portion of theCBD, CBG and / or THC is naturally derived, and the other portion is synthetic and / or biosynthetic.28A. The method of any one of the preceding embodiments, wherein the THC is present primarily in the form of (-)-delta-9-trans-tetrahydrocannabinol (A9-THC).29A. The method of any one of the preceding embodiments, wherein the CBD, CBG and THC are collectively greater than 50% by weight of the cannabinoids present in the composition.30A. The method of embodiment 29A, wherein the CBD, CBG and THC are collectively greater than 60% by weight of the cannabinoids present in the composition.31 A. The method of any one of the preceding embodiments, wherein the CBD, CBG and THC are present in a molar ratio between about 100: 100: 1 and about 1 : 1 : 1.32A. The method of embodiment 31 A, wherein the CBD, CBG and THC are present in a molar ratio is between about 100:50: 1 and about 20: 1 : 1.33A. The method of any one of the preceding embodiments, wherein the CBD and CBG are present in a molar ratio between about 100: 1 and about 1 : 1.34A. The method of any one of the preceding embodiments, wherein the molar ratio of CBD and THC is between about 50: 1 and about 1 : 1.35 A. The method of any one of the preceding embodiments, wherein the cannabinoid composition further comprises at least one lipid excipient.36A. The method of embodiment 35A, wherein at least one lipid excipient is a winterized oil comprising long-chain mono-, di-, and triglycerides.37 A. The method of any one of the preceding embodiments, wherein the cannabinoid composition further comprises docosahexaenoic acid (DHA), or eicosapentaenoic acid (EP A), or a combination thereof.38 A. The method of any one of the preceding embodiments, wherein the composition is formulated for oral delivery.39A. The method of any one of the preceding embodiments, wherein the human is a woman.40A. The method of any one of the preceding embodiments, wherein the human is a postmenopausal woman.41 A. The method of any one of the preceding embodiments, wherein the human suffers or suffered from breast cancer.42A. The method of any one of the preceding embodiments, wherein the human suffers or suffered from hormone receptor positive breast cancer.43 A. The method of any one of the preceding embodiments, wherein the human is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer.44A. The method of any one of the preceding embodiments, wherein the human is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer stages 0-III.45A. The method of any one of the preceding embodiments, wherein the human is taking or has taken adjuvant aromatase inhibitor (Al) therapy.46A. The method of any one of the preceding embodiments, wherein treating AIIA comprises treating intractable and debilitating pain symptoms induced by Al therapy.47A. The method of any one of the preceding embodiments, wherein the human suffers from Al-inducted join pain.48A. The method of any one of the preceding embodiments, wherein the treatment decreases pain severity experienced by the human.49A. The method of any one of the preceding embodiments, wherein the treatment decreases joint symptoms of pain and stiffness.50A. The method of any one of the preceding embodiments, wherein the treatment improves the human’s musculoskeletal abilities, bone density or bone related biomarkers.51 A. The method of any one of the preceding embodiments, wherein the treatment improves the human’s grip strength.52A. The method of any one of embodiments 1A to 51 A, wherein the cannabinoid composition is administered daily.53 A. The method of any one of embodiments 1A to 51 A, wherein the cannabinoid composition is administered twice daily.54A. The method of any one of the preceding embodiments, wherein the cannabinoid composition is administered at a dose between 200 mg and 1500 mg.55A. A cannabinoid composition, comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD is between about 90 mg / ml and 110 mg / ml, and the CBG is between about 13.5 mg / ml and 16.5 mg / ml, and wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.56A. The composition of embodiment 55A, wherein the CBD, CBG and / or THC are provided as botanical drug substances (BDS).57A. The composition of embodiment 56A, further comprising other cannabinoid and / or non-cannabinoid components that are present from the BDS.58A. The composition of embodiment 56A, further comprising terpenes that are present from the BDS.59A. The composition of any one of embodiments 55A to 58A, further comprising flavonoids that are present from the BDS.60 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of cannabis extracts.61 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of extracts from 2-4 cannabis cultivars.62 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of extracts from genetically identical clones of 3 different cannabis cultivars.63 A. The composition of embodiment 62A, wherein the 3 different cannabis cultivars are a high CBD cultivar, a high CBG cultivar and a high THC cultivar.64A. The composition of any one of embodiments 61 A to 63 A, wherein cannabis cultivars are Cannabis sativa cultivars.65A. The composition of any one of embodiments 60A to 64A further comprising other cannabinoid and / or non-cannabinoid components that are present from the extracts.66A. The composition of any one of embodiments 60A to 65A, further comprising terpenes that are present from the extracts.67A. The composition of any one of embodiments 60A to 66A, further comprising flavonoids that are present from the extracts.68A. The composition of any one of embodiments 60A to 67A, further comprising additional CBD, CBG and / or THC provided in purified form.69A. The composition of any one of embodiments 60A to 67A, further comprising additional CBD, CBG and / or THC isolates.70A. The composition of embodiment 69A, wherein the CBD, CBG and THC are provided as a combination of purified CBD, CBG and THC cannabis extracts.71 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of CBD, CBG and THC isolates.72 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of BDS and CBD, CBG and / or THC isolates.73 A. The composition of embodiment 55A, wherein the CBD, CBG and THC are provided as a combination of BDS, and purified CBD, CBG and / or THC cannabis extracts.74 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as a combination of BDS, and CBD, CBG and / or THC isolates.75 A. The composition of embodiment 55 A, wherein the CBD, CBG and THC are provided as BDS in combination with refined or synthetic CBD, CBG and / or THC.76A. The composition of embodiment 55A, wherein the CBD, CBG and THC are a combination of highly purified CBD, highly purified CBG and highly purified THC, wherein each of which are extracted from a cannabis plant and purified to the extent that other cannabinoids and a majority of non-cannabinoid components that are co-extracted with the cannabinoids have been removed.77A. The composition of embodiment 76A, wherein the highly purified CBD is greater than or equal to 90% (w / w) pure; the highly purified CBG is greater than or equal to 90% (w / w) pure; and the highly purified THC is greater than or equal to 90% (w / w) pure.78A. The composition of embodiment 55A, wherein the CBD, CBG and THC are all naturally derived.79A. The composition of embodiment 55A, wherein at least a portion of the CBD, CBG and / or THC is naturally derived, and the other portion is synthetic and / or biosynthetic.80A. The composition of any one of the preceding embodiments, wherein the THC is present primarily in the form of (-)-delta-9-trans-tetrahydrocannabinol (A9-THC).81 A. The composition of any one of the preceding embodiments, further comprising at least one lipid excipient.82A. The composition of embodiment 81 A, wherein at least one lipid excipient is a winterized oil comprising long-chain mono-, di-, and triglycerides.83 A. The composition of any one of the preceding embodiments, further comprising docosahexaenoic acid (DHA), or eicosapentaenoic acid (EP A), or a combination thereof.84A. The composition of any one of the preceding embodiments, wherein the THC is present in less than 0.3% by weight of the total composition.85A. The composition of any one of the preceding embodiments, wherein the CBD is about 100 mg / ml, the CBG is about 15 mg / ml, and the THC is about 1 mg / ml.86A. The composition of any one of the preceding embodiments, wherein the composition is formulated for oral delivery.IB. A method of treating arthralgia in a human in need thereof, comprising: administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.2B. A method of treating inflammation in a human in need thereof, comprising: administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.3B. A method of treating symptoms of an estrogen deficiency, symptoms of a reduction in estrogen levels, or symptoms of a drop in circulating estrogen in a human in need thereof, in a subject in need thereof, comprising:administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.4B. The method of any one of the preceding embodiments, wherein the human is taking or has taken a medication or therapy that induces arthralgia.5B. The method of any one of the preceding embodiments, wherein the human is taking or has taken a medication or therapy that induces inflammation.6B. The method of any one of the preceding embodiments, wherein the human is taking or has taken a medication or therapy that induces an estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen.7B. The method of any one of embodiments 4B to 6B, wherein the medication or therapy is an aromatase inhibitor.8B. The method of any of the preceding embodiments, wherein the human suffers or suffered from a growth disorder9B. The method of any of the preceding embodiments, wherein the human suffers or suffered from precocious puberty.10B. The method of any of the preceding embodiments, wherein the huma suffers or suffered from hypogonadism.1 IB. The method of any of the preceding embodiments, wherein the human suffers or suffered from desmoid tumors.12B. The method of any of the preceding embodiments, wherein the human suffers or suffered from cancer.13B. The method of any of the preceding embodiments, wherein the human suffers or suffered from endometriosis.14B. The method of any one of the preceding embodiments, wherein the human is a woman.15B. The method of embodiment 14B, wherein the woman is experiencing an estrogen deficiency, a reduction in estrogen levels, a drop in circulating estrogen, or a hormonal imbalance.16B. The method of embodiment 14B or 15B, wherein the woman is a menopausal woman, perimenopausal woman, or postmenopausal woman.17B. The method of any one of embodiments 14B to 16B, wherein the woman suffers or suffered from an estrogen-sensitive or estrogen-dependent cancer.18B. The method of embodiment 17B, wherein the woman suffers or suffered from breast cancer.19B. The method of embodiment 17B or 18B, wherein the woman suffers or suffered from hormone receptor positive breast cancer.20B. The method of any one of embodiments 17B to 19B, wherein the woman is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer.21B. The method of any one of embodiments 17B to 19B, wherein the woman is a postmenopausal women who suffers or has suffered from hormone receptor positive breast cancer stages O-III.22B. The method of any one of embodiments 16B to 21B, wherein the woman is a post-menopausal woman that previously received breast cancer treatment.23B. The method of any one of embodiments 16B to 22B, wherein the woman is a post-menopausal woman that previously received breast cancer treatment has a reduced ability to produce estrogen.24B. The method of any one of embodiments IB to 13B, wherein the human is a male.25B. The method of embodiment 24B, wherein the male suffers or suffered from prostate cancer.26B. The method of embodiment 24B, wherein the male suffers or suffered from pubertal gynecomastia.27B. The method of embodiment 24B, wherein the male suffers or suffered from hypogonadism.28B. The method of any one of the preceding embodiments, wherein the human’s ability to produce estrogen is reduced.29B. The method of any one of the preceding embodiments, wherein the human is unable to produce estrogen.30B. The method of embodiment 28B or 29B, wherein the human is a woman whose ability to produce estrogen is reduced due to the removal of one or both ovaries.3 IB. The method of any one of embodiments 28B to 30B, wherein the human is a woman whose ability to produce estrogen is reduced due to damage to one or both ovaries.32B. The method of embodiment 3 IB, wherein one or both ovaries was damaged from chemotherapy, radiotherapy therapy, or a combination thereof.33B. The method of any one of the preceding embodiments, wherein the method further comprises administering the cannabinoid composition concomitantly with an aromatase inhibitor and, narcotic medication, or combination thereof.34B. The method of embodiment 7B or 33B, wherein the aromatase inhibitor comprises a third-generation aromatase inhibitor.35B. The method of embodiment 34B, wherein the third-generation aromatase inhibitor comprises anastrozole, letrozole, exemestane, or a combination thereof.36B. The method of any one of embodiments 33B to 35B, wherein the administration of the cannabinoid composition reduces the amount and / or frequency of the narcotic medication taken by the human.37B. The method of any one of embodiments 33B to 36B, wherein the narcotic is an opioid.38B. The method of any one of the preceding embodiments, wherein the cannabinoid composition is administered at a dose between 50 mg and 1500 mg.39B. The method of any one of the preceding embodiments, wherein the cannabinoid composition is administered at a dose of between about 100 mg and 750 mg.40B. The method of any one of the preceding embodiments, wherein the dose is administered once a day.41B. The method of any one of the preceding embodiments, wherein the dose is administered twice a day.42B. The method of any one of the preceding embodiments, wherein the cannabinoid composition is administered at a total daily dose of between about 200 mg and 1,000 mg.43B. The method of embodiment 42B, wherein the cannabinoid composition is administered at a total daily dose of between about 200 mg and 800 mg.44B. The method of claim any one of the preceding embodiments, wherein the cannabinoid composition is administered at an initial dose of at least 100 mg total daily dose, wherein the method further comprises: monitoring safety and effect on arthralgia, inflammation, or the symptoms of an estrogen deficiency, the symptoms of a reduction in estrogen levels, or the symptoms of a drop in circulating estrogen in a human in need thereof, experienced by the human, and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of between about 200 mg and about 800 mg.45B. The method of embodiment 44B, wherein the dose of the cannabinoid composition administered to the human is increased over about 2 to 14 days.46B. The method of embodiment 44B, wherein the dose of the cannabinoid composition administered to the human is increased over 14 days.47B. The method of any one of the preceding embodiments, wherein CBD is between about 90 mg / ml and 110 mg / ml.48B. The method of any one of the preceding embodiments, wherein CBG is between about 13.5 mg / ml and 16.5 mg / ml.49B. The method of any one of the preceding embodiments, wherein THC is between about 0.5 mg / ml and 1.5 mg / ml.50B. The method of any one of the preceding embodiments, wherein CBD is about 100 mg / ml, CBG is about 15 mg / ml, and THC is about 1 mg / ml.5 IB. The method of any one of the preceding embodiments, wherein the treatment:(i) decreases pain severity experienced by the human;(ii) decreases joint symptoms of pain and stiffness;(iii) improves the human’s musculoskeletal abilities, bone density or bone related biomarkers;(iv) improves the human’s grip strength;(v) improves the human’s anxiety;(vi) improves the human’s sleep, or any combination of the foregoing.52B. The method of any one of embodiments IB to 5 IB, wherein the CBD, CBG and / or THC are provided as botanical drug substances (BDS).53B. The method of embodiment 52B, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the BDS.54B. The method of embodiment 52B, wherein the cannabinoid composition further comprises terpenes that are present from the BDS.55B. The method of any one of embodiments 52B to 54B, wherein the cannabinoid composition further comprises flavonoids that are present from the BDS.56B. The method of any one of embodiments IB to 55B, wherein the CBD, CBG and THC are provided as a combination of cannabis extracts.57B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of extracts from 2-4 cannabis cultivars.58B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of extracts from genetically identical clones of 3 different cannabis cultivars.59B. The method of embodiment 58B, wherein the 3 different cannabis cultivars are a high CBD cultivar, a high CBG cultivar and a high THC cultivar.60B. The method of any one of embodiments 57B to 59B, wherein cannabis cultivars are Cannabis sativa cultivars.61B. The method of any one of embodiments 56B to 60B, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the extracts.62B. The method of any one of embodiments 56B to 61B, wherein the cannabinoid composition further comprises terpenes that are present from the extracts.63B. The method of any one of embodiments 56B to 61B, wherein the cannabinoid composition further comprises flavonoids that are present from the extracts.64B. The method of any one of embodiments 52B to 63B, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC provided in purified form.65B. The method of any one of embodiments 52B to 63B, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC isolates.66B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of purified CBD, CBG and THC cannabis extracts.67B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of CBD, CBG and THC isolates.68B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of BDS and CBD, CBG and / or THC isolates.69B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of BDS, and purified CBD, CBG and / or THC cannabis extracts.70B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as a combination of BDS, and CBD, CBG and / or THC isolates.71B. The method of embodiment 52B, wherein the CBD, CBG and THC are provided as BDS in combination with refined or synthetic CBD, CBG and / or THC.72B. The method of embodiment 52B, wherein the CBD, CBG and THC are a combination of highly purified CBD, highly purified CBG and highly purified THC, wherein each of which are extracted from a cannabis plant and purified to the extent that other cannabinoids and a majority of non-cannabinoid components that are co-extracted with the cannabinoids have been removed.73B. The method of embodiment 72B, wherein the highly purified CBD is greater than or equal to 90% (w / w) pure; the highly purified CBG is greater than or equal to 90% (w / w) pure; and the highly purified THC is greater than or equal to 90% (w / w) pure.74B. The method of embodiment 52B, wherein the CBD, CBG and THC are all naturally derived.75B. The method of embodiment 52B, wherein at least a portion of the CBD, CBG and / or THC is naturally derived, and the other portion is synthetic and / or biosynthetic.76B. The method of any one of the preceding embodiments, wherein the THC is present primarily in the form of (-)-delta-9-trans-tetrahydrocannabinol (A9-THC).77B. The method of any one of the preceding embodiments, wherein the CBD, CBG and THC are collectively greater than 50% by weight of the cannabinoids present in the composition.78B. The method of embodiment 77B, wherein the CBD, CBG and THC are collectively greater than 60% by weight of the cannabinoids present in the composition.79B. The method of any one of the preceding embodiments, wherein the CBD, CBG and THC are present in a molar ratio between about 100: 100: 1 and about 1 : 1 : 1.80B. The method of embodiment 79B, wherein the CBD, CBG and THC are present in a molar ratio is between about 100:50: 1 and about 20: 1 : 1.8 IB. The method of any one of the preceding embodiments, wherein the CBD and CBG are present in a molar ratio between about 100: 1 and about 1 : 1.82B. The method of any one of the preceding embodiments, wherein the molar ratio of CBD and THC is between about 50: 1 and about 1 : 1.83B. The method of any one of the preceding embodiments, wherein the cannabinoid composition further comprises at least one lipid excipient.84B. The method of embodiment 83B wherein at least one lipid excipient is a winterized oil comprising long-chain mono-, di-, and triglycerides.85B. The method of any one of the preceding embodiments, wherein the cannabinoid composition further comprises docosahexaenoic acid (DHA), or eicosapentaenoic acid (EP A), or a combination thereof.86B. The method of any one of the preceding embodiments, wherein the composition is formulated for oral delivery.87B. The method of any one of the preceding embodiments, wherein the method comprises: administering an initial dose of a cannabinoid composition comprising: cannabidiol(CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars, wherein the initial dose is between about 150 mg and 250 mg total daily dose, monitoring safety and effect, or the symptoms, experienced by the human in need thereof, and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1000 mg.EXAMPLES

[0204] The presently disclosed human matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.Example 1AEXTRACTION AND ISOLATION OF CANNABINOIDS FROM THE PLANT

[0205] Bulk plant material was isolated from dried cannabis flower. The bulk plant material was separated from the botanical starting material. The botanical starting materials were weighed and stored in an amber jar. The botanical starting material were added to an extraction vessel with solvent. The solvent was removed via vacuum distillation until only refined cannabis oil was present, with a low solvent concentration. The crude cannabis oil was then heated to for a suitable time to convert the THCA to THC to yield a refined cannabis oil. The main cannabinoids, THCA, CBDA and CBGA were converted to the base molecule THC, CBD and CBG, respectively.Example IBCHARACTERIZATION OF AN EXEMPLARY CANNABINOID COMPOSITION

[0206] Exemplary cannabinoid compositions were produced according to Example 1 A above, blended with botanical isolates to arrive at the amounts and ratios of CBD, CBG and THC as set forth in Table 1 below, and combined with an oil containing long chain mono, di, and triglycerides as the lipid vehicle. The following Table 1 provides the profile of exemplary drug product compositions, characterized based on cannabinoid content. The compositions were characterized using methods and techniques known in the art, including ultra-performance liquid chromatography (UPLC).Table 1.Example 2STUDY OF EFFICACY, TOLERABILITY AND SAFETY OF CANNABINOID COMPOSITION IN THE TREATMENT OF AROMATASE INHIBITOR-INDUCED ARTHRALGIA IN POSTMENOPAUSAL WOMEN WITH HORMONE RECEPTOR POSITIVE BREAST CANCER

[0207] This study is a single site pilot randomized placebo controlled double blind trial of Cannabinoid Composition A for postmenopausal women taking adjuvant Al therapy for estrogen receptor positive breast cancer stages O-III and experiencing Al-induced joint pain. After completion of a baseline assessment, patients meeting eligibility criteria will be enrolled and randomized to cannabis extract or placebo for 3 months. After completion of study treatment, patients are followed up at 30 days.

[0208] BPI-SF, Visual Analog Scale-Pain, anxiety, and sleep assessments will be obtained monthly from 0 to 3 months; FACT-ES will be obtained at 0 and 3 months. Blood samples will be obtained at 0 and 3 months for clinical safety labs (ALT), estradiol. Cannabinoid metabolites, and biomarker analyses. Daily logs of study agent doses and side effects / symptoms will be monitored monthly. Daily logs will be used to determine adherence. Diet questionnaires will be completed at 0 and 3 months. Adverse events (AE) and AE attributions as possibly, probably, or definitely related to study agent will be determined.

[0209] The primary objective of this study is to assess the preliminary efficacy of Cannabinoid Composition A versus placebo by change in BPI-SF worst pain severity scores from 0 to 3 months.

[0210] The secondary objectives of this study are to:• To evaluate indicators of preliminary efficacy of Cannabinoid Composition A on joint symptoms of pain and stiffness assessed by BPI-SF total pain severity and interference scores and Visual Analog Scale-Pain• To evaluate tolerability by adverse events, anxiety by PROMIS Emotional Distress- Anxiety SF 6a, sleep by PROMIS Sleep Disturbance SF 4a, quality of life by FACT- ES• To evaluate safety by clinical laboratory tests (ALT)• To evaluate changes in physical function by dynamometer measurements of grip strength

[0211] The exploratory objectives of this study are to:• To evaluate blood-based biomarkers related to AIIA and Cannabinoid Composition A vs placebo• To determine the pharmacokinetics of Cannabinoid Composition APrimary Endpoint(s):

[0212] BPI-SF worst pain severity score change 0 to 3 months of Cannabinoid Composition A versus placebo.Secondary Endpoint(s) :

[0213] Change scores for BPI-SF total pain severity and interference, Visual AnalogScale for Pain, FACT-ES from 0 to 3 months

[0214] Adverse events and attributions for Cannabinoid Composition A and placebo study participants

[0215] Change scores for patient reported outcomes measured by PROMIS Emotional Distress-Anxiety SF 6a, PROMIS Sleep Disturbance SF 4a, and FACT-ES from 0 to 3 months

[0216] Changes in liver function test ALT at 0, 1, and 3 months

[0217] Changes and change scores in grip strength from 0 to 3 monthsExploratory Endpoint(s) :

[0218] Cannabinoid metabolite analyses at 0 to 3 months of study agent

[0219] Changes in exploratory biomarkers of exposure and effect from 0 and 3 months of study agentIntervention Description

[0220] Following randomization, study participants will be started on a flexible dosing regimen, initiating therapy at 50-300 mg daily and up-titrated based on clinical response and tolerability over 2 weeks to a maximum of 1500 mg daily or starting at a fixed dose of up to 1500 mg daily. Dose increases taking place in the evening.

[0221] Patients will remain on the dose identified during the titration period until the final study visit or discontinuation. Additional dose adjustments following the titration period should be avoided but will be permitted at PI discretion.

[0222] The target dose will be taken for 2.5 months. BPI-SF, Visual Analog Scale-Pain, anxiety, and sleep assessments will be obtained monthly from 0 to 3 months; FACT-ES will be obtained at 0 and 3 months. Blood samples will be obtained at 0 and 3 months for clinical safety labs (LFTs) and cannabinoid and metabolite, estradiol / estrogen bioactivity, and biomarker analyses. Daily logs of study agent doses and side effects / symptoms will be monitored monthly. Dosing logs will be used to determine adherence. Diet questionnaires will be completed at 0 and 3 months. Adverse events and AE attributions as possibly, probably, or definitely related to study agent will be determined.Main Inclusion Criteria

[0223] Disease characteristics:

[0224] Histologically confirmed primary invasive adenocarcinoma of the breast or ductal carcinoma in situ of the breast:Stage 0, 1, II, or III A diseaseNo metastatic disease

[0225] Must have undergone definitive breast cancer surgery and recovered

[0226] Estrogen-receptor positive (ER+) and / or progesterone-receptor positive (PR+)

[0227] Currently taking a third-generation aromatase inhibitor (Al) [e.g., anastrozole (Arimidex®), letrozole (Femara®), or exemestane (Aromasin®)] for > 90 days prior to registration with plans to continue for > 180 days after registration

[0228] Must a worst pain / stiffness of > 4 on the BPI (item #2) that has started or increased with Al therapy

[0229] Patient characteristics:

[0230] Postmenopausal by last menses > 12 months or medically induced for Al therapy

[0231] At least 5 years since other malignancy except adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or adequately treated stage I or II cancer from which the patient is currently in complete remission.

[0232] Following randomization, study participants will be started on a flexible dosing regimen of Cannabinoid Composition A, initiating therapy at 200 mg daily and up-titrated based on tolerability over 2 weeks to a maximum of 1500 mg daily or matching placebo. Dose increases are recommended to take place in the evening, beginning the evening dose of Day 2.

[0233] Following the Titration Period from 0-2 weeks, patients will remain on the dose identified during the titration period until the final study visit or discontinuation. If the tolerable dose is identified prior to Day 14, this dose level will be maintained for the remainder of the Titration Period and continued for duration of the study at 3 months. Additional dose adjustments following the titration period should be avoided but will be permitted at PI discretion.Table 2. Regimen Description for Titration Period

[0234] Study Drug: Cannabinoid Composition

[0235] The study drug is referred to herein as “Cannabinoid Composition A”, which is produced in accordance with the procedures set forth above in Tables 1 A and IB. For example, the study drug may include 100 mg / ml CBD, 15 mg / ml CBG, and 1 mg / ml A9- THC. The study drug is a botanically derived extract that contains less than 0.3% THC and other minor plant components in the lipid vehicle composed of mono-, di-, and triglycerides. The THC content is below the 0.3% THC allowable limit established by the United States Department of Agriculture (USDA) 2018 Farm Bill for Hemp products. The study drug is formulated for oral use in a lipid vehicle.

[0236] Administration Instructions

[0237] Cannabinoid Composition A and placebo will be self-administered with twice daily doses according to the Up Titration schedule for the first two weeks to the highest tolerable dose up to 4 mL twice daily. The study agents are dispensed in amber glass bottles with plastic child-proof twist caps. Doses will be measured and taken via pre-marked syringes or droppers.

[0238] Placebo provides excipient without active CBD or related substances.

[0239] Clinical assessments

[0240] Participants will be evaluated in clinic prior to initiation of the study intervention at 0 months and then at 3 months of treatment for history and physical examination that will include vital signs, height, and weight.

[0241] Musculoskeletal evaluations: Grip strength will be quantitated by hand dynamometer (Jarman) at 0 and 3 months. This test involves squeezing a dynamometer for 2 to 3 seconds and then releasing. Three trials will be taken with each hand and a period of one- minute rest will occur between trials. Grip strength will be measured at 0 and 3 months. The dominant hand will be recorded for each participant at baseline.

[0242] Assessment of Dietary Intake: As a measure of usual dietary patterns, food frequency questionnaires (FFQ) will be obtained at the baseline and 3-month study visits. Instruction in completion of the FFQ will be provided.

[0243] Results

[0244] Twelve participants have been enrolled in this study; eight participants have completed both the 3-month study period and the 30-day follow up period. No serious adverse events have been reported to date from any of the participants. Participants of the study reported the following:• One participant who completed the study reported significant relief from joint pain and a striking improvement in mobility, and that the participant could “get up and go” without hesitation, whereas previously the participant needed to rise cautiously and wait to feel steady before walking.• Another participant who completed the study reported that after just three and a half weeks, the participant’s heel pain, previously a 7 or 8, had dropped to a 1 or 2, and the participant’s ankle pain had completely resolved.Other participants have reported symptom recurrence in the 30-day follow-up period (after the 3-month study period and having stopped receiving the study drug).

Claims

CLAIMSWhat is claimed is:

1. A method of treating Aromatase Inhibitor-Induced Arthralgia (AIIA) in a human in need thereof, comprising: administering a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars.

2. The method of claim 1, wherein the human is a woman.

3. The method of claim 1 or 2, wherein the human is a postmenopausal woman.

4. The method of claim 1 or 2, wherein the human is a perimenopausal woman.

5. The method of any one of the preceding claims, wherein the human is a woman experiencing estrogen deficiency, a reduction in estrogen levels, or a drop in circulating estrogen, or any combination thereof.

6. The method of any one of claims 2 to 5, wherein the woman’s ability to produce estrogen is reduced.

7. The method of any one of claims 2 to 5, wherein the woman is unable to produce estrogen.

8. The method of any one of claims 2 to 7, wherein at least one of the woman’s ovaries are removed.

9. The method of any one of claims 2 to 8, wherein at least one of the woman’s ovaries are damaged.

10. The method of claim 9, wherein a previous treatment damaged at least one of the woman’s ovaries.

11. The method of claim 10, wherein the previous treatment comprises chemotherapy treatment, radiation therapy, or a combination thereof.

12. The method of any one of the preceding claims, wherein the human suffers or suffered from breast cancer.

13. The method of any one of the preceding claims, wherein the human suffers or suffered from hormone receptor positive breast cancer.

14. The method of any one of the preceding claims, wherein the human is a postmenopausal woman or perimenopausal woman who suffers or has suffered from hormone receptor positive breast cancer stages O-III.

15. The method of any one of claims 12 to 14, wherein the human has undergone breast cancer surgery and recovered.

16. The method of claim 5, wherein the cannabinoid composition is administered at a dose between 50 mg and 1500 mg.

17. The method of any one of the preceding claims, wherein the cannabinoid composition is administered at a dose of between about 100 mg and 750 mg.

18. The method of any of the preceding claims, wherein the dose is administered once a day.

19. The method of any of the preceding claims, wherein the dose is administered twice a day.

20. The method of any one of the preceding claims, wherein the cannabinoid composition is administered at a total daily dose of between about 200 mg and 1,000 mg.

21. The method of claim 20, wherein the cannabinoid composition is administered at a total daily dose of between about 200 mg and 800 mg.

22. The method of claim any one of the preceding claims, wherein the cannabinoid composition is administered at an initial dose of at least 100 mg total daily dose, wherein the method further comprises:monitoring safety and effect on AIIA, or the symptoms induced by AIIA, experienced by the human, and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of between about 200 mg and about 800 mg.

23. The method of claim 22, wherein the dose of the cannabinoid composition administered to the human is increased over about 2 to 14 days.

24. The method of claim 22, wherein the dose of the cannabinoid composition administered to the human is increased over 14 days.

25. The method of any one of the preceding claims, wherein CBD is between about 90 mg / ml and 110 mg / ml.

26. The method of any one of the preceding claims, wherein CBG is between about 13.5 mg / ml and 16.5 mg / ml.

27. The method of any one of the preceding claims, wherein THC is between about 0.5 mg / ml and 1.5 mg / ml.

28. The method of any one of the preceding claims, wherein CBD is about 100 mg / ml, CBG is about 15 mg / ml, and THC is about 1 mg / ml.

29. The method of any one of the preceding claims, wherein the subject is concomitantly taking a narcotic.

30. The method of claim 29, wherein the narcotic comprises an opioid.

31. The method of claim 29 or 30, wherein administering the cannabinoid composition reduces the amount and / or frequency of the narcotic concomitantly taken by the human.

32. The method of any one of the preceding claims, wherein the human is taking or has taken an aromatase inhibitor therapy.

33. The method of any one of the preceding claims, wherein the method further comprises concomitantly administering an aromatase inhibitor to the human.

34. The method of any one of the preceding claims, wherein treating AIIA comprises treating intractable and debilitating pain symptoms induced by Al therapy.

35. The method of any one of the preceding claims, wherein the treatment:(i) decreases pain severity experienced by the human;(ii) decreases joint symptoms of pain and stiffness;(iii) improves the human’s musculoskeletal abilities, bone density or bone related biomarkers;(iv) improves the human’s grip strength;(v) improves the human’s anxiety;(vi) improves the human’s sleep,(vii) reduces inflammation experienced by the human; or any combination of the foregoing.

36. The method of claim any of the preceding claims, wherein the CBD, CBG and / or THC are provided as botanical drug substances (BDS).

37. The method of claim 36, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the BDS.

38. The method of claim 36, wherein the cannabinoid composition further comprises terpenes that are present from the BDS.

39. The method of any one of claims 36 to 38, wherein the cannabinoid composition further comprises flavonoids that are present from the BDS.

40. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of cannabis extracts.

41. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of extracts from 2-4 cannabis cultivars.

42. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of extracts from genetically identical clones of 3 different cannabis cultivars.

43. The method of claim 42, wherein the 3 different cannabis cultivars are a high CBD cultivar, a high CBG cultivar and a high THC cultivar.

44. The method of any one of claims 41 to 43, wherein cannabis cultivars are Cannabis sativa cultivars.

45. The method of any one of claims 40 to 44, wherein the cannabinoid composition further comprises other cannabinoid and / or non-cannabinoid components that are present from the extracts.

46. The method of any one of claims 40 to 44, wherein the cannabinoid composition further comprises terpenes that are present from the extracts.

47. The method of any one of claims 40 to 45, wherein the cannabinoid composition further comprises flavonoids that are present from the extracts.

48. The method of any one of claims 37 to 47, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC provided in purified form.

49. The method of any one of claims 37 to 47, wherein the cannabinoid composition further comprises additional CBD, CBG and / or THC isolates.

50. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of purified CBD, CBG and THC cannabis extracts.

51. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of CBD, CBG and THC isolates.

52. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of BDS and CBD, CBG and / or THC isolates.

53. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of BDS, and purified CBD, CBG and / or THC cannabis extracts.

54. The method of claim 36, wherein the CBD, CBG and THC are provided as a combination of BDS, and CBD, CBG and / or THC isolates.

55. The method of claim 36, wherein the CBD, CBG and THC are provided as BDS in combination with refined or synthetic CBD, CBG and / or THC.

56. The method of claim 36, wherein the CBD, CBG and THC are a combination of highly purified CBD, highly purified CBG and highly purified THC, wherein each of whichare extracted from a cannabis plant and purified to the extent that other cannabinoids and a majority of non-cannabinoid components that are co-extracted with the cannabinoids have been removed.

57. The method of claim 56, wherein the highly purified CBD is greater than or equal to90% (w / w) pure; the highly purified CBG is greater than or equal to 90% (w / w) pure; and the highly purified THC is greater than or equal to 90% (w / w) pure.

58. The method of claim 36, wherein the CBD, CBG and THC are all naturally derived.

59. The method of claim 36, wherein at least a portion of the CBD, CBG and / or THC is naturally derived, and the other portion is synthetic and / or biosynthetic.

60. The method of any one of the preceding claims, wherein the THC is present primarily in the form of (-)-delta-9-trans-tetrahydrocannabinol (A9-THC).

61. The method of any one of the preceding claims, wherein the CBD, CBG and THC are collectively greater than 50% by weight of the cannabinoids present in the composition.

62. The method of claim 61, wherein the CBD, CBG and THC are collectively greater than 60% by weight of the cannabinoids present in the composition.

63. The method of any one of the preceding claims, wherein the CBD, CBG and THC are present in a molar ratio between about 100: 100: 1 and about 1: 1 : 1.

64. The method of claim 63, wherein the CBD, CBG and THC are present in a molar ratio is between about 100:50: 1 and about 20: 1 : 1.

65. The method of any one of the preceding claims, wherein the CBD and CBG are present in a molar ratio between about 100: 1 and about 1 : 1.

66. The method of any one of the preceding claims, wherein the molar ratio of CBD and THC is between about 50: 1 and about 1 : 1.

67. The method of any one of the preceding claims, wherein the cannabinoid composition further comprises at least one lipid excipient.

68. The method of claim 67, wherein at least one lipid excipient is a winterized oil comprising long-chain mono-, di-, and triglycerides.

69. The method of any one of the preceding claims, wherein the cannabinoid composition further comprises docosahexaenoic acid (DHA), or eicosapentaenoic acid (EP A), or a combination thereof.

70. The method of any one of the preceding claims, wherein the composition is formulated for oral delivery.

71. A method of treating Aromatase Inhibitor-Induced Arthralgia (AIIA) in a human in need thereof, comprising: administering an initial dose of a cannabinoid composition comprising: cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabinol (THC), collectively a major component of the cannabinoids present in the composition, wherein the CBD, CBG and THC are provided as a combination of extracts or isolated from at least two cannabis cultivars, wherein the initial dose is between about 150 mg and 250 mg total daily dose, monitoring safety and effect on AIIA, or the symptoms of AIIA, experienced by the human in need thereof, and administering an increased dose of the cannabinoid composition, wherein the increased dose is up to a maximum total daily dose of about 1000 mg.

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