Compositions and methods comprising cannabis extracts for the treatment of animals in need thereof

Abstract

The present disclosure relates to non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for the treatment of a disease, disorder, syndrome, and / or condition in an animal in need thereof.

Description

[Technical field]

[0001] The present disclosure relates to non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for the treatment of a disease, disorder, syndrome, and / or condition in an animal in need thereof. [Background technology]

[0002] Industrial hemp products containing 0.3% or less tetrahydrocannabinol (THC) are legal according to the Industrial Hemp Act. These products, alone or in combination with other cannabinoids (CBD), have been reported to have health benefits including analgesic, anti-anxiety, anti-inflammatory, anti-anxiolytic, and anti-epileptic. Numerous companies selling cannabis products, including CBD oil, claim that they are safe and effective for various medical conditions in humans and animals. When optimal treatment with conventional drugs does not exist for patients in need, other potentially effective agents such as CBD are often sought. However, there is very little published data supporting the safety and efficacy claims regarding the use of these products in human and veterinary patients.

[0003] Thus, there is a need for safer and more targeted cannabis products. Summary of the Invention

[0004] In one aspect, the technology relates to a method for treating recurrent diarrhea in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a primate. In some embodiments, the primate is a non-human primate. In some embodiments, the non-human primate is a macaque. In some embodiments, the recurrent diarrhea is idiopathic diarrhea. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is administered in the form of a chew, marshmallow, gum, or via a syringe. In some embodiments, the cannabis extract is administered at a dosage of about 2 mg / kg, about 4 mg / kg, or about 8 mg / kg. In some embodiments, the cannabis extract is administered until the veterinary subject has a stool score of 2 or less for 3 days or 21 days. In some embodiments, the cannabis extract is administered once a day, twice a day, three times a day, or four times a day.

[0005] In another aspect, the technology relates to a method for treating inflammation in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract modulates neutrophil function, reactive oxygen species production, phagocytosis, eicosanoid concentrations, chemotaxis, cytokine production, and / or fibroblast response. In some embodiments, these modulations are measured using in vitro assays using samples from the veterinary subject. In some embodiments, these modulations occur in vivo, and are optionally measured in vivo.

[0006] In another aspect, the technology relates to a method for treating noise aversion in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a dog. In some embodiments, the noise aversion is a phobia. In some embodiments, the phobia is storm phobia or noise phobia. In some embodiments, the noise aversion is to fireworks or thunderstorms. In some embodiments, the cannabis extract is administered at a dosage of 2mg / kg to 10mg / kg. In some embodiments, the cannabis extract is administered at a dosage of 4mg / kg to 10mg / kg.

[0007] In another aspect, the technology relates to a method for treating hair plucking in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a bird. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract comprises 70 mg / mL total cannabinoids. In some embodiments, the cannabis extract comprises 60 mg / mL CBD and CBDA. In some embodiments, the cannabis extract is administered at a dosage of 15 mg / kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dosage of 30 mg / kg to 120 mg / kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dosage of 40 mg / kg to 80 mg / kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dosage of 30 mg / kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dosage of 60 mg / kg twice daily for three months. In some embodiments, the cannabis extract is administered at a dosage of 120 mg / kg twice daily for three months.

[0008] In another aspect, the technology relates to a method for treating arthritis in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a rabbit. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered at a dosage of 10 mg / kg to 25 mg / kg. In some embodiments, the cannabis extract is administered at a dosage of about 15 mg / kg. In some embodiments, the cannabis extract is administered at a dosage of about 20 mg / kg. In some embodiments, the cannabis extract is administered twice daily.

[0009] In another aspect, the present technology relates to a method for treating lameness in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a horse. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered at a dosage of 1 mg / kg every 12 hours. In some embodiments, the cannabis extract is administered as an acute dose of 2 mg / kg to 8 mg / kg.

[0010] In another aspect, the technology relates to a method for promoting wound healing in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the cannabis extract is administered topically. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBG and CBGA. In some embodiments, 20 mg of CBG and CBGA are applied to the wound. In some embodiments, CBG and CBGA are applied to the wound every 12 hours.

[0011] In another aspect, the technology relates to a method for treating cancer in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD, CBDA, or a combination thereof. In some embodiments, the cannabis extract is administered at a dose of 5mg / kg.

[0012] In another aspect, the technology relates to a method for treating pyoderma in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the cannabis extract is administered topically. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBG. In some embodiments, 30 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, 35 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, 40 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, 45 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, 50 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, 30 mg to 50 mg of CBD and CBG are applied to the site of the pyoderma. In some embodiments, CBD and CBG are applied to the site of the pyoderma every 12 hours.

[0013] In another aspect, the technology relates to a method for treating atopy in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBDA. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is administered via a capsule. In some embodiments, the cannabis extract comprises CBD and CBDA, and the cannabis extract is administered such that a dose of about 2mg / kg of CBD and CBDA is administered. In some embodiments, the cannabis extract is administered once every 12 hours.

[0014] In another aspect, the technology relates to a method for treating pruritus in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the veterinary subject is a dog. In some embodiments, the cannabis extract comprises CBD and CBDA. In some embodiments, the cannabis extract is administered orally. In some embodiments, the cannabis extract is administered via a capsule. In some embodiments, the cannabis extract comprises CBD and CBDA, and the cannabis extract is administered such that a dose of about 2mg / kg of CBD and CBDA is administered. In some embodiments, the cannabis extract is administered once every 12 hours.

[0015] In another aspect, the technology relates to a method for treating a neurological condition in a subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In some embodiments, the subject is a human. In some embodiments, the subject is a veterinary subject. In some embodiments, the neurological condition comprises traumatic neurological injury or a degenerative neurological disease (e.g., ALS, Parkinson's disease, dementia, or proteopathies such as Alzheimer's disease). In some embodiments, the cannabis extract comprises tetrahydrocannabinolic acid (THCA).

[0016] In some embodiments, the cannabis extract comprises cannabidiol and cannabidiolic acid, and the ratio of cannabidiol to cannabidiolic acid is about 0.6:1 to about 1:0.6. In some embodiments, the cannabis extract further comprises cannabigerolic acid, Δ9-tetrahydrocannabinol, and cannabichromene. In some embodiments, the cannabis extract also comprises THCA.

[0017] In some embodiments the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Δ9-tetrahydrocannabinol, and Contains cannabichromene, The ratio of cannabidiol to cannabidiol acid is from about 0.6:1 to about 1:0.6.

[0018] In some embodiments the cannabis extract comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Further contains α-bisabolol.

[0019] In some embodiments, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In some embodiments, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is about 0 mg / mL. In some embodiments, the cannabis extract also contains THCA.

[0020] In some embodiments the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0021] In some embodiments the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0022] In some embodiments the cannabis extract comprises: Approximately 0.09-0.13% α-pinene, Approximately 0.23-0.44% β-myrcene, Approximately 0.04-0.09% β-pinene, Approximately 0.05-0.09% δ-limonene, Approximately 0.03-0.06% linalool, Approximately 0.04-0.07% β-caryophyllene, Approximately 0.02-0.04% α-humulene, Approximately .04 to .07% Nerolidol 2, about 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0023] In some embodiments the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0024] In some embodiments, the cannabis extract also contains THCA.

[0025] In some embodiments the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, about 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0026] In some embodiments, the cannabis extract also contains THCA.

[0027] In some embodiments, the cannabis extract is formulated in a carrier. In some embodiments, the carrier is selected from the group consisting of hemp seed oil, flaxseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil. In some embodiments, the carrier is grapeseed oil. In some embodiments, the carrier is catnip oil. In some embodiments, the carrier is sesame oil. In some embodiments, the cannabis extract comprises lecithin. In some embodiments, the lecithin is sunflower lecithin. In some embodiments, the sunflower lecithin is up to 40%. In some embodiments, the cannabis extract further comprises NF-971P. In some embodiments, the NF-971P is up to 2% weight / volume. In some embodiments, the cannabis extract comprises nepetalactone. In some embodiments, the cannabis extract comprises taurine.

[0028] In some embodiments the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Δ9-tetrahydrocannabinol, and Contains cannabichromene, The carrier is grape seed oil.

[0029] In some embodiments the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Cannabigerol, Δ9-tetrahydrocannabinol, and Contains cannabichromene, The carrier is grape seed oil.

[0030] In some embodiments, the ratio of cannabidiol to cannabidiolic acid is selected from the group consisting of about 1:100, about 1:50, about 1:10, and about 1:1. In some embodiments, the ratio of cannabidiol to cannabidiolic acid is about 1:1. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In some embodiments, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In some embodiments, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3 mg / mL. In some embodiments, the cannabis extract also contains THCA.

[0031] In some embodiments the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0032] In some embodiments the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0033] In some embodiments the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, Cannabigerol, about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0034] In some embodiments the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Cannabigerol, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0035] In some embodiments the cannabis extract comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Contains alpha-bisabolol.

[0036] In some embodiments the cannabis extract comprises: Approximately 0.09-0.13% α-pinene, Approximately 0.23-0.44% β-myrcene, Approximately 0.04-0.09% β-pinene, Approximately 0.05-0.09% δ-limonene, Approximately 0.03-0.06% linalool, Approximately 0.04-0.07% β-caryophyllene, Approximately 0.02-0.04% α-humulene, Approximately 0.04-0.07% nerolidol 2, Approximately 0.02-0.04% guaiol, about 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0037] In some embodiments the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0038] In some embodiments the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, about 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0039] In some embodiments, the cannabis extract is administered in a dosage form that includes one or more pharma- ceutically acceptable additives, flavoring agents, surfactants, and adjuvants. In some embodiments, the flavoring agent is selected from the group consisting of peppermint oil, mango extract, beef, chicken, and seafood. In some embodiments, the flavoring agent is selected from the group consisting of peanut butter, catnip oil, chicken liver powder, chicken extract, maltodextrin, butter, and bacon. In some embodiments, the flavoring agent is chicken liver powder. In some embodiments, the flavoring agent is catnip oil. In some embodiments, the flavoring agent is molasses or dried molasses. In some embodiments, the flavoring agent is peanut butter. In some embodiments, the dosage form includes nepetalactone. In some embodiments, the dosage form includes taurine. In some embodiments, the dosage form is formulated as a sublingual spray. In some embodiments, the dosage form is formulated as a water, polyethylene glycol, glycerol, or alcohol soluble solution or cream for topical or transdermal application. In some embodiments, the dosage form is formulated as a gel for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a paste for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a powder. In some embodiments, the dosage form is formulated as a solution for subcutaneous injection. In some embodiments, the dosage form is formulated as a tablet. In some embodiments, the dosage form is formulated as a capsule. In some embodiments, the dosage form is formulated as a hard chewable. In some embodiments, the dosage form is formulated as a soft chewable. In some embodiments, the dosage form is formulated for administration using a nebulizer. In some embodiments, the dosage form is formulated for inhalation. In some embodiments, the dosage form is formulated for administration using a pet collar. In some embodiments, the composition is formulated as an edible product for oral administration. In some embodiments, the edible product comprises pet food.

[0040] In some embodiments, the dosage form is formulated as a chew for oral administration. In some embodiments, the chew is produced using cold extrusion. In some embodiments, the chew weighs about 0.5-10 g. In some embodiments, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In some embodiments, the chew weighs about 4 g.

[0041] In some embodiments, the chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerolic acid, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0042] In some embodiments, the chew also contains THCA.

[0043] In some embodiments, the dosage form is formulated in a carrier for oral administration. In some embodiments, the carrier is selected from the group consisting of hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil. In some embodiments, the carrier is grapeseed oil. In some embodiments, the carrier is catnip oil. In some embodiments, the carrier is sesame oil.

[0044] In some embodiments, the dosage form comprises: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Contains water.

[0045] In some embodiments, the dosage form comprises: Approximately 12-17% Glucosamine HCl, Approximately 1-4% chondroitin sulfate (76%), Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0046] In some embodiments, the dosage form comprises: Approximately 15.6% Glucosamine HCl, Approximately 2.6% chondroitin sulfate (76%), Approximately 30% beer yeast, Approximately 4.7% gum arabic, Approximately 0.9% guar gum, Approximately 14.2% flavorings; Approximately 0.05% Verdilox, Previon, about 0.9% Approximately 4.7% cannabis extract, Approximately 15.1% glycerin, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0047] In some embodiments, the dosage form comprises: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Contains water.

[0048] In some embodiments, the dosage form comprises: Approximately 12-17% Glucosamine HCl, Approximately 0.01 to 1% hyaluronic acid, Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0049] In some embodiments, the dosage form comprises: Approximately 16% Glucosamine HCl, Approximately 0.1% hyaluronic acid, Approximately 30.6% beer yeast, Approximately 4.8% gum arabic, Approximately 0.97% guar gum, Approximately 14.5% flavorings; Approximately 0.05% Verdilox, Previon at approximately 0.97% Approximately 4.8% cannabis extract, Approximately 15.5% glycerin, Approximately 5.8% sunflower lecithin, and Contains approximately 5.8% water.

[0050] In some embodiments, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, Rice starch, and Contains guar gum.

[0051] In some embodiments, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 10.0-20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, Approximately 1.0-5.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0052] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.25% water, Approximately 13.0% glycerin, Approximately 2.0% potato starch, Approximately 1.0% dehydrated peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0053] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 13.0% rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 6.0%; Approximately 9.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.5% water, Approximately 13.0% glycerin, Approximately 4.0% potato starch, Approximately 1.0% dehydrated peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0054] In some embodiments, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, DigestaWell PET, Rice starch, and Contains guar gum.

[0055] In some embodiments, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 5.0 to 20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, Approximately 0.1-3.0% DigestaWell PET, Approximately 1.0 to 8.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0056] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.0% rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 7.25% water, Approximately 10.0% glycerin, Approximately 5.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 0.5% DigestaWell PET, Approximately 6.0% rice starch, and Contains approximately 2.0% guar gum.

[0057] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 8.0%; dry molasses, about 9.0%; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 6.0% water, Approximately 10.0% glycerin, Approximately 6.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 0.5% DigestaWell PET, Approximately 6.5% rice starch, and Contains approximately 2.0% guar gum.

[0058] In some embodiments, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, Chondroitin, DigestaWell PET, Rice starch, and Contains guar gum.

[0059] In some embodiments, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 5.0 to 20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, Approximately 0.5 to 5.0% chondroitin, Approximately 0.1-3.0% DigestaWell PET, Approximately 1.0 to 8.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0060] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.0% rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 7.25% water, Approximately 10.0% glycerin, Approximately 4.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 2.5% chondroitin, Approximately 0.5% DigestaWell PET, Approximately 4.5% rice starch, and Contains approximately 2.0% guar gum.

[0061] In some embodiments, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 8.0%; dry molasses, about 9.0%; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 6.0% water, Approximately 10.0% glycerin, Approximately 5.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 2.5% chondroitin, Approximately 0.5% DigestaWell PET, about 5.0% rice starch, and Contains approximately 2.0% guar gum.

[0062] In some embodiments, the cannabis extract, dosage form, or pharmaceutical composition is packaged to provide one or more doses of cannabis extract per package. In some embodiments, the package is resealable. In some embodiments, a dose of cannabis extract is a therapeutically effective amount. [Brief description of the drawings]

[0063] Aspects, features, benefits, and advantages of the embodiments described herein will become apparent with regard to the following description, the appended claims, and the accompanying drawings.

[0064] [Figure 1A] 1 is a graph showing a cannabinoid-treated 48-hour MTT proliferation assay performed with cannabidiol (CBD) in accordance with an embodiment of the present teachings. [Figure 1B] FIG. 1 is a graph showing a cannabinoid-treated 48-hour MTT proliferation assay performed with cannabidiolic acid (CBDA) in accordance with an embodiment of the present teachings. [Figure 1C] FIG. 1 shows a graph showing a cannabinoid treated 48 hour MTT proliferation assay performed with a CBD-rich cannabis whole plant extract according to an embodiment of the present teachings. [Diagram 2] 1 is a bar graph showing the percentage of trypan blue positive for fibroblasts, 17-71, D17, and CMT12, 48 hours after treatment with 15, 7.5, 3.75 ug / mL CBD and methanol vehicle control (VC) in accordance with an embodiment of the present teachings. [Figure 3A] 1 is an image of an immunoblot for cleaved caspase 3 (17 Kda) after 8 and 16 hours of CBD treatment compared to methanol vehicle control, according to an embodiment of the present teachings. [Figure 3B] 1 is a bar graph showing apoptosis of neoplastic cell line 17-71 following treatment with 15 μg / mL CBD, in accordance with an embodiment of the present teachings. [Figure 3C] 1 is a bar graph showing apoptosis of neoplastic cell line D17 following treatment with 15 μg / mL CBD, according to an embodiment of the present teachings. [Figure 3D] 1 is a bar graph showing apoptosis of the neoplastic cell line CMT12 following treatment with 15 μg / mL CBD, according to an embodiment of the present teachings. [Figure 4A] 13 shows time course immunoblot images of phosphorylated MAP kinase relative to baseline protein expression using vehicle control treatment or 10 μg / mL CBD for ERK and phosphorylated ERK expression at times 2, 4, and 8 hours according to an embodiment of the present teachings. [Figure 4B] 13 shows time course immunoblot images of phosphorylated MAP kinase relative to baseline protein expression using vehicle control treatment or 10 μg / mL CBD for JNK and phosphorylated JNK expression at times 2, 4, and 8 hours according to an embodiment of the present teachings. [Figure 5A]13A-13C are images of immunoblots for LC3 I / II in 17-71, CMT12, and D17 cell lines treated with vehicle control or 10 μg / mL CBD for 2, 4, or 8 hours, according to an embodiment of the present teachings. [Figure 5B] 13A-13C are immunofluorescence images for LC3A / B with CMT12 (600x) and D17 (400x) cells shown in columns according to an embodiment of the present teachings. [Figure 6A] FIG. 1 is a box plot showing VAS scores for CBD-treated and control dogs at weeks zero, two, and four. Significant differences are marked with asterisks at weeks zero and four. [Figure 6B] FIG. 1 is a box plot showing CADESI scores for CBD-treated and control dogs at weeks zero, two, and four. Significant differences are marked with asterisks at weeks zero and four. [Figure 7A] 1 is a graph showing alkaline aminotransferase levels in dogs treated with either CBD or placebo. Values ​​are shown for both zero and four weeks. [Figure 7B] 1 is a graph showing alkaline phosphatase levels in dogs treated with either CBD or placebo. Values ​​are shown for both zero and four weeks. [Figure 8] FIG. 1 is a bar graph showing alkaline phosphatase levels in dogs when CBD treatment was combined with various other drugs, or when CBD treatment was administered without other drugs (far right column), as indicated. [Figure 9A] 1 is a plot showing serum levels of monocyte chemoattractant protein-1 (MCP-1) for dogs receiving either CBD treatment or placebo at zero and four weeks. [Figure 9B] 1 is a plot showing serum levels of IL-6 for dogs receiving either CBD treatment or placebo at zero and four weeks. [Figure 10A] 1 is a plot showing serum levels of IL-31 for dogs receiving either CBD treatment or placebo at zero and four weeks. [Figure 10B] 1 is a plot showing serum levels of IL-34 for dogs receiving either CBD treatment or placebo at zero and four weeks. [Figure 11] FIG. 1 shows serum levels of CBDA, CBD, THCA, and THC at the indicated time points in macaques receiving oral cannabis extract doses. [Figure 12A] CYP3A12 activity following treatment with vehicle or various potential inhibitors is shown. For each potential inhibitor, data are shown both with (left bar, no outline) and with 20 min preincubation (right bar, outline). [Figure 12B] CYP2D15 activity after treatment with vehicle or various potential inhibitors is shown. For each potential inhibitor, data are shown both with (left bar, no outline) and with 20 min preincubation (right bar, outline). [Figure 12C] CYP2B11 activity after treatment with vehicle or various potential inhibitors is shown. For each potential inhibitor, data are shown both with (left bar, unoutlined) and with 20 min preincubation (right bar, outlined). [Figure 13A] Figure 1 shows CYP3A12 activity after treatment with vehicle or various potential inhibitors. Data are shown for each potential inhibitor at various concentrations. No preincubation was used. [Figure 13B] Figure 1 shows CYP3A12 activity after treatment with vehicle or various potential inhibitors. Data is shown for each potential inhibitor at various concentrations. A 20 minute preincubation was used. [Figure 14A] Figure 2 shows CYP2B11 activity after treatment with vehicle or various potential inhibitors. Data is shown for each potential inhibitor at various concentrations. No preincubation was used. [Figure 14B]Figure 2 shows CYP2B11 activity after treatment with vehicle or various potential inhibitors. Data is shown for each potential inhibitor at various concentrations. A 20 minute preincubation was used. [Figure 15A] Figure 2 shows CYP2D15 activity after treatment with vehicle or various potential inhibitors. Data is shown for each potential inhibitor at various concentrations. No preincubation was used. [Figure 15B] Figure 2 shows CYP2D15 activity after treatment with vehicle or various potential inhibitors. Data is shown for each potential inhibitor at various concentrations. A 20 minute preincubation was used. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] For clarity, it will be understood that the following disclosure describes various aspects of the embodiments. It should be noted that a particular embodiment is not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. An aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and may be implemented in any other embodiment. References throughout this specification to "one embodiment," "an embodiment," or "an example embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," or "an example embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, although they may. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, although some embodiments described herein include some features but not other features included in other embodiments, combinations of features of different embodiments are intended to be within the scope of the invention. For example, in the following claims, any of the claimed embodiments may be used in any combination.

[0066] definition Listed below are definitions of various terms used in this specification. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0067] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0068] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including" as well as other forms such as "include," "includes," "included," etc. are not limiting.

[0069] As used herein, the term "about" is understood by those of ordinary skill in the art and varies to some extent depending on the context in which it is used. When used herein when referring to a measurable value such as an amount, a duration over time, etc., the term "about" is intended to encompass a ±5% variation from the specified value when such a variation is appropriate for carrying out the disclosed method.

[0070] As used in the specification and claims, the term "comprise" can include "consisting of" and "consisting essentially of" embodiments. As used herein, "comprise(s)", "include(s)", "having", "has", "may", "contain(s)", and variations thereof are intended to be open-ended transitional phrases, terms, or words that require the presence of the specified ingredients / steps and permit the presence of other ingredients / steps. However, such descriptions should also be construed as describing the composition or process as consisting of and "consisting essentially of" and "consisting essentially of" the recited compounds, which allows for the presence of only the specified compounds, along with any pharma- ceutically acceptable carriers, and excludes other compounds.

[0071] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., the range "50 mg to 500 mg" includes the endpoints 50 mg and 500 mg, as well as all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not limited to the exact ranges or values, but are inexact so as to include values ​​that are close to those ranges and / or values.

[0072] As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound provided herein, to a patient or subject (alone or in combination with another pharmaceutical agent), or to a tissue or cell line isolated from a patient (e.g., for diagnostic or ex vivo uses), for the purpose of curing, curing, mitigating, alleviating, altering, relieving, ameliorating, or affecting the symptoms of a disease, disorder, syndrome, or condition. Such treatments may be specifically tailored or modified based on knowledge obtained from the field of pharmacology.

[0073] In certain embodiments, the compositions described herein treat and / or reduce the severity of a disease, disorder, syndrome, or condition in a subject.For example, the compositions described herein treat and / or improve one or more symptoms of inflammation, inappropriate urination (periuria), anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, pain of neurological dysfunction, nociceptive pain, postoperative pain), skin disorder, cancer, psychotic disorder, seizures, epilepsy, osteoarthritis, lymphoma, atopy, allergy, diarrhea (e.g., idiopathic diarrhea), noise aversion, hair pulling, hair pulling, skin wounds, pyoderma, gastrointestinal conditions, behavioral problems, obsessive-compulsive behavior, migraine, headache, insect bites, diabetes, inflammatory bowel disease, skin conditions (e.g., pruritus, pyoderma), urinary conditions, anxiety, or frustration.

[0074] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease in cases where the disorder or disease has not occurred at all, or the absence of further onset of a disorder or disease in cases where the disorder or disease has already occurred. Also contemplated is the ability to prevent some or all of the symptoms associated with a disorder, disease, and / or condition.

[0075] As used herein, the term "use" includes, unless otherwise indicated, any one or more of the following embodiments of the invention, respectively, where appropriate and convenient: use in the treatment of a disease, disorder, syndrome, and / or condition, for the manufacture of a pharmaceutical composition for use in the treatment of said disease, disorder, syndrome, and / or condition, such as use in the manufacture and / or preparation of a medicament; a method of use of a compound of the invention in the treatment of said disease, disorder, syndrome, and / or condition; a pharmaceutical preparation having a compound of the invention for the treatment of said disease, disorder, syndrome, and / or condition; and a compound of the invention for use in the treatment of said disease, disorder, syndrome, and / or condition,

[0076] As used herein, the terms "patient," "individual," or "subject" are intended to include organisms that suffer from or may suffer from a disease, disorder, syndrome, and / or condition. Examples of subjects include animals. Examples of subjects include mammals. Examples of subjects include dogs, cats, horses, cows, pigs, sheep, goats, mice, rabbits, rats, birds, fish, non-human primates, amphibians, reptiles, and transgenic non-human animals.

[0077] When used in relation to the methods of treatment / prevention and the use of the compounds and pharmaceutical compositions described herein, an individual "in need thereof" may be an individual who has been diagnosed with or previously treated for the condition to be treated. With respect to prevention, an individual in need thereof may also be an individual at risk for the condition (e.g., family history of a disease, disorder, syndrome, and / or condition, lifestyle factors indicative of risk for a disease, disorder, syndrome, and / or condition, etc.). Typically, when a step of administering a compound of the present invention is disclosed herein, the present invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

[0078] In some embodiments, the individual is a mammal, including but not limited to a cow, horse, cat, rabbit, dog, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, the individual is a human or other animal, and is a geriatric, adult, young adult, child, adolescent, newborn, pre-weaning, infant, or premature infant. In some embodiments, the individual is a non-mammal. In some embodiments, the primate is a non-human primate, such as a chimpanzee and other ape and monkey species. The term "individual" does not denote a particular age or sex. In some embodiments, the individual is female. In some embodiments, the individual is male.

[0079] As used herein, the term "pharmaceutical acceptable" refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or deleteriously interacting with any of the components of the composition in which it is contained.

[0080] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with an appropriate amount of base or acid (e.g., stoichiometric amounts) in water or an organic solvent, or in a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0081] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of a pharma- ceutically acceptable carrier and at least one compound useful within the present invention. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques of administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0082] As used herein, the term "pharmaceutically acceptable carrier" or "carrier" refers to a pharma- ceutically acceptable material, composition, or carrier, such as a liquid or solid (e.g., solid filler), stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in carrying or transporting a compound useful within the invention in or to a patient or subject, thereby enabling it to perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation containing the compound useful within the invention and not harmful to the patient or subject. Some examples of materials that can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, sucrose, etc.; starches such as corn starch, potato starch, etc.; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, etc.; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter, coconut butter, suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, polyethylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffers such as magnesium hydroxide, aluminum hydroxide; surfactants; alginic acid; water such as tap water, purified water, distilled water, milli-q water, pyrogen-free water, etc.; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, a "pharmaceutically acceptable carrier" also includes any coatings, antibacterial agents, antifungal agents, antioxidants, absorption delaying agents, preservatives, stabilizers, and the like, that are compatible with the activity of the compounds useful within the invention and are physiologically acceptable to the patient or subject. One or more supplementary active and / or inactive compounds can also be incorporated into the composition. A "pharmaceutically acceptable carrier" or "carrier" can further include one or more pharmaceutically acceptable salts of one or more compounds useful within the invention.Other additional ingredients that may be included in pharmaceutical compositions used in the practice of the invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0083] As used herein, the term "stabilizer" refers to a polymer that can chemically inhibit or prevent degradation. Stabilizers are added to formulations of compounds to improve the chemical and physical stability of the compounds.

[0084] As used herein, the term "adjuvants" may include, for example, preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, perfuming agents, emulsifying agents, and dispensing agents. Prevention of microbial action is generally provided by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars and sodium chloride, may also be included. Prolonged absorption of injectable pharmaceutical forms may be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin. Auxiliaries may also include wetting agents, emulsifying agents, pH buffers, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.

[0085] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological result. This result may be a reduction or alleviation of the signs, symptoms, and / or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0086] As used herein, the term "weight percent" refers to the amount by weight of a compound and / or component in a composition as a percentage of the weight of the total composition. Weight percent can also be calculated by multiplying mass fraction by 100. "Mass fraction" is the ratio of mass m1 of one substance to the mass of the total composition mT, such that weight percent=(m1 / mT)*100.

[0087] "Aqueous buffer" refers to an aqueous solution that resists changes in hydronium ion and hydroxide ion concentration (and the resulting pH) upon addition of small amounts of acid or base or upon dilution. Buffers consist of weak acids and their conjugated bases (more common) and / or weak bases and their conjugated acids (less common). Buffers can be prepared by methods well known in the art with appropriate buffering agents to obtain the desired pH value. Examples of suitable buffering agents include hydrochloric acid, lactic acid, acetic acid, citric acid, malic acid, maleic acid, pyruvic acid, succinic acid, tris-hydroxymethylaminomethane, sodium hydroxide, sodium bicarbonate, phosphoric acid, sodium phosphate, and other biologically acceptable buffering agents. Aqueous buffers are readily available commercially and can be used in the preparation of the compositions of the present invention without further processing.

[0088] As used herein, the term "cannabis extract" refers to a composition of cannabinoids and terpenes isolated from a cannabis plant. The terms "cannabis extract", "CBD oil", and "cannabis oil" have the same meaning and are used interchangeably herein. Cannabis extracts can be obtained by any method known in the art. For example, cannabis extracts can be obtained by supercritical (or subcritical) CO2 extraction, which uses carbon dioxide under high pressure and low temperature to isolate, preserve, and maintain the purity of the cannabis extract. In one embodiment, cannabis extracts are obtained from supercritical CO2 extraction. For example, supercritical CO2 extraction is described in U.S. Patent No. 8,895,078, which is incorporated herein by reference in its entirety. Alternatively, solvents such as petroleum ether, ethanol, methanol, butanol, acetone, dry ice, or olive oil can be used at room temperature (ambient temperature) with stirring by passive extraction, as known in the art, and heated to a temperature above room temperature or heated under reflux to obtain cannabis extracts. In another embodiment, cannabis extracts from butanol extraction are used as starting material for the methods disclosed herein.

[0089] As used herein, the term "quality of life" or "QoL" is generally considered a multidimensional concept involving a subjective assessment of factors that contribute to overall health, with more recent publications suggesting fatigue, anxiety, and digestive function. The Likert scaling system appears to be a sound assessment of QoL and is used in some embodiments herein (see Giuffrida et al. (2018) J Arner Vet Med Assoc. 252:1073-1083, which is incorporated herein by reference in its entirety). The pruritus visual analog scale (pVAS) appears to be a sound assessment of QoL and is used in some embodiments herein.

[0090] Cannabinoids are compounds isolated from the cannabis plant. Classes of cannabinoids include, but are not limited to, cannabichromene, cannabicyclol, cannabidiol, cannabielsoin, cannabigerol, cannabinol, cannabinodiol, cannabiditriol, delta-8-tetrahydrocannabinol, and delta-9-tetrahydrocannabinol. Examples of cannabinoid compounds include cannabichromene (CBC), cannabichromene acid (CBCA), cannabichromevarin (CBCV), cannabichromevaric acid (CBCVA), cannabicyclol (CBL), cannabicyclol acid (CBLA), cannabicyclovaline (CBLV), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiolic acid (CBDA), cannabidiol col (CBD-C1), cannabidivarin (CBDV), cannabidivaric acid (CBDVA), cannabielsonic acid B (CBEA-B), cannabielsoin (CBE), cannabielsoinic acid A (CBEA-A), cannabigerol (CBG), ), cannabigerol monomethyl ether (CBGM), cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerovarin (CBGV), cannabigerovaric acid (CBGVA), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabinol (CBN), cannabinol methyl ether (CBNM), cannabinol-C2 (CBN-C2), cannabinol-C4 (CBN-C4), cannabinolic acid (CBNA), cannabiorcool (CBN-C1), cannabivarin (CBV), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-Dihydroxy-delta-6a-tetrahydrocannabinol, cannabidiol (CBT), cannabidiol valine (CBTV), delta-8-tetrahydrocannabinol (Δ8-THC), delta-8-tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinol-C4 (THC-C4), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol cole (THC-C 1), delta-9-tetrahydrocannabiol cholic acid (THCA-C1), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivarinic acid (THCVA), 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), cannabichromanone (CBCF), cannabifuran (CBF), cannabiglendol, cannabilipsol (CBR), cannabicitran (CBT), ehydrocannabifuran (DCBF), delta-9-cis-tetrahydrocannabinol (cis-THC), and trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC).

[0091] Suitable methods for measuring the cannabinoid and terpene content in cannabis extracts are known in the art. In one embodiment, the cannabinoid content is determined using liquid chromatography with mass spectrometry detection (LC-MS). In another embodiment, the terpene content is determined using gas chromatography with flame ionization detection (GC-FID) analysis of the headspace.

[0092] As used herein, the term "flavoring agent" refers to an ingredient added to a composition to impart a particular flavor, odor, or other organoleptic characteristic. Flavoring agents can be natural or artificial.

[0093] As used herein, the term "oil" refers to a non-polar viscous liquid that is both hydrophobic and lipophilic. Oils may be isolated from animals, plants, or petrochemicals.

[0094] As used herein, the term "chew" refers to a product or portion thereof that has rheological and other textural and organoleptic properties that tend to encourage chewing of the article by a target subject. Generally speaking, a chewable matrix exhibits sufficient ductility to be at least slightly malleable when chewed by a target subject, and sufficient palatability that the target subject is not deterred from multiple chews by their taste. In contrast, "chewable" does not simply mean that the article can be chewed by a subject (i.e., does not simply mean that a portion of the article fits in the subject's mouth sufficiently to allow the subject's teeth to engage against that portion).

[0095] As used herein, the "maximum serum concentration level" of a substance refers to the maximum level of the substance found in a plasma sample following a single administration.

[0096] As used herein, the term "cold extrusion" refers to a process for producing edible food products that includes several unit operations, including adding, mixing, kneading, pressing, shearing, shaping, and forming, that are carried out at or near ambient temperature.

[0097] As used herein, the term "psychotropic effect" refers to alterations in brain function that result in changes in perception, mood, consciousness, and / or behavior.

[0098] overview The embodiments disclosed herein provide non-naturally occurring or engineered compositions and methods comprising one or more cannabis extracts for treatment in animals in need of treatment of diseases, disorders, syndromes, and / or conditions, including, but not limited to, inflammation, urinating in inappropriate places, anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, pain of neurological dysfunction, nociceptive pain, post-operative pain), skin disorders, cancer, psychotic disorders, seizures, epilepsy, osteoarthritis, lymphoma, atopy, allergies, diarrhea (e.g., idiopathic diarrhea), noise aversion, hair pulling, hair pulling, skin wounds, pyoderma, gastrointestinal conditions, behavioral problems, obsessive behaviors, migraines, headaches, insect bites, diabetes, inflammatory bowel disease, skin conditions (e.g., pruritus, pyoderma), urinary conditions, anxiety, or frustration. Clinical trials and pharmacokinetic data regarding administration and dosing in treatment are disclosed herein.

[0099] With regard to the treatment of inflammation, the endocannabinoid receptor system is known to play a role in pain regulation and reducing inflammation. Cannabinoid receptors (CB1 and CB2) are widely distributed throughout the central and peripheral nervous systems and are also present in the synovium. However, the psychotropic effects of certain cannabinoids prevent extensive research into their use as single agents for pain relief. Cannabinoids are a group of as many as 60 different compounds that may or may not act at CB receptors. One class of cannabinoid, cannabidiol (CBD), can actually be an antagonist of CB receptors. In lower vertebrates, CBD also has immunomodulatory, antihyperalgesic, antinociceptive, anxiolytic, and anti-inflammatory effects, making it an attractive therapeutic option in animals.

[0100] With regard to the treatment of urinating in an inappropriate place (inappropriate elimination problems), this condition in cats can be divided into those related to latrine behavior and those related to marking. Chronic pain and anxiety / frustration may be present in both of these conditions. Marking is generally seen as a response to a threat to important resources within the cat's core area, while latrine-related problems generally arise from problems related to access to what the cat perceives as an appropriate latrine (Barcelos et al., (2018) Front. Vet. Sci. 5:108). Both of these can be seen as limitations to the cat's independence and are therefore likely to cause frustration. This can be combined with anxiety when the animal either perceives a physical threat from other individuals (in the case of marking) or is potentially distressed by lack of access to the latrine to a desired toilet spot. Furthermore, if the cat has any pain condition of the urinary system, anxiety may arise in anticipation of discomfort during elimination. A recent review showed that cats with inappropriate urination are about four times more likely to have a history of urinary tract disease (Barcelos et al., 2018). It has been recently reported that cats may change posture from crouching to spraying or vice versa if inappropriate elimination becomes uncomfortable (Ramos et al., (2018) J Feline Med Surg. doi:10.1177 / 1098612X18801034). Also, about 40% of seemingly healthy subjects with inappropriate urination may have a medical problem detectable on initial clinical examination, and the figures rise to 66.7% for spraying cats and 56.5% for latrining cats with more thorough medical evaluation (Ramos et al., 2018).

[0101] Regarding the treatment of migraine, this condition is a common neurovascular disorder that manifests itself in headache attacks that can reach severe pain levels in many patients and lead to substantial functional impairment. The recent Global Burden of Disease Study 2010 (GBD2010) conducted by the World Health Organization estimated the global migraine prevalence at 14.7%, ranking migraine third among the most common diseases, seventh among specific causes of disability, and first among neurological disorders as a cause of total years of life with disability. Thus, migraine affects millions of people. To date, the pathophysiology of migraine is not fully understood.

[0102] Regarding the treatment of neurological disorders, the use of cannabinoid derivatives in the treatment of various neurological disorders in humans, especially chronic pain and epilepsy, has been investigated in recent years. Industrial hemp-based dietary supplements (HBN), rich in full-spectrum cannabinoids with less than 0.3% THC, have been shown to have no psychotropic effects and little activity through non-cannabinoid receptor pathways affecting serotonergic, glycinergic, and GABA neurotransmitter pathways, which can reduce pain as well as inflammation. Recent studies using full-spectrum cannabinoid-rich HBN, such as Gamble LJ, Boesch JM, Frye CW, Schwark WS, Mann S, Wolfe L, Brown H, Berthelsen ES and Wakshlag JJ (2018), Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs, Front.Vet.Sci.5:165, DOI 10.3389 / fvets.2018.00165, which is incorporated herein by reference in its entirety, have demonstrated the efficacy of these products in dogs with chronic pain. Furthermore, investigations of epilepsy in humans and the launch of EPIDIOLEX®, available from Greenwich Biosciences, Carlsbad, California, as a viable treatment, have shown benefits for cannabidiol in the treatment of epilepsy.

[0103] Regarding the treatment of cancer, cannabinoids have been studied and used to alleviate cancer symptoms or treat side effects associated with standard cancer therapy (see, for example, Eyal Meiri, Haresh Jhangiani, James J. Vredenburgh, Luigi M. Barbato, Frederick J. Carter, Hwa-Ming Yang, and Vickie Baranowski, Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting, 2007, Current Medical Research and Opinion, 23:3, 533-543, DOI:10.1185 / 030079907X167525; Gonzalez-Rosales F and Walsh D, Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol(dronabinol), J Pain Symptom Manage, 1997 Nov,14(5),pp.311-4,doi:10.1016 / S0885-3924(97)00229-7, and May MB and Glode AE,Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics,Cancer Manag.Res.,2016 May,12(8),pp.49-55,doi:10.2147 / CMAR.S81425, which are incorporated herein by reference in their entirety. However, more recent studies have investigated CBD and its direct antitumor properties alone or in combination with standard cancer therapies such as chemotherapy or ionizing radiation (see, e.g., Sanchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, and Guzman M, Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor, Cancer Res, 2001 Aug 1, 61(15), 5784-9; Scott KA, Dalgleish AG, and Liu WM, The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model, Mol. Cancer Ther, 2014). Dec,13(12),pp.2955-67,doi:10.1158 / 1535-7163,Deng L,Ng L,Ozawa T,and Stella N,Quantitative Analyzes of Synergistic Responses between Cannabidiol and DNA-Damaging Agents on the Proliferation and Viability of Glioblastoma and Neural Progenitor Cells in Culture,J.Pharmacol.Exp.Ther.,2017 Jan,360(1),pp.215-224,doi:10.1124 / jpet.116.236968, and Luciano De Petrocellis,Alessia Ligresti,Aniello Schiano Moriello,Mariagrazia Iappelli,Roberta Verde,Colin G Stott,Luigia Cristino,Pierangelo Orlando,and Vincenzo Di Marzo,Non-THC cannabinoids counteract prostate carcinoma growth in vitro and in vivo:pro-apoptotic effects and underlying mechanisms.Br.J.Pharmacol.2012,168,pp.79-102 (which are incorporated herein by reference in their entirety). Although its role in cancer cell biology has not been fully elucidated (see, for example, Brown AJ and Robin Hiley C, Is GPR55 an anandamide receptor?, Vitamin. Horm., 2009, 81, pp. 111-37, doi:10.1016 / S0083-6729(09)81005-4, and De Petrocellis L and Di Marzo V, Non-CB1, non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels, J. Neuroimmune Pharmacol., 2010 Mar,5(1),pp.103-21,doi:10.1007 / s11481-009-9177-z (which are incorporated herein by reference in their entireties)), appear to regulate ion channels or induce activation of signaling cascades (e.g., Ross RA, The enigmatic pharmacology of GPR55, Trends Pharmacol. Sci., 2009 Mar,30(3),pp.156-63.doi:10.1016 / j.tips.2008.12.004, and Console-Bram L, Braillouiu E, Braillouiu GC, Sharir H, and Abood ME, Activation of GPR18 by cannabinoid compounds: a tale of biased agonism, Br. J. Pharmacol., 2014 Aug, 171(16), pp. 3908-17, doi:10.1111 / bph.12746, which are incorporated herein by reference in their entireties, show that the ability of CBD to activate GPCR18 and GPCR55 is comparable.

[0104] Moreover, with regard to cancer treatment, glioblastoma multiforme has become a major focus of cannabinoid-based research in human tumor models. These studies have demonstrated a decrease in cell viability in glioma cell lines treated with CBD, as well as a synergistic decrease in cell viability in combination with ionizing radiation and / or DNA-damaging agents both in vitro and in xenograft mouse models (see, e.g., Scott KA, Dalgleish AG, and Liu WM, The combination of cannabidiol and Δ9-tetrahydrocannabinol enhances the anticancer effects of radiation in an orthotopic murine glioma model, Mol Cancer Ther., 2014, 13(12), pp. 2955-2967; Deng L, Ng L, Ozawa T, and Stella N, Quantitative analysis of synergistic responses between cannabidiol and DNA-damaging agents on the proliferation and viability of glioblastoma and neural progenitor cells in culture, J Pharmacol Exp Ther, 2017, 360(1), pp. 215-224; and Marcu et al., J Cancer Ther., 2013, 111-115). JP, Christian RT, Lau D, Zielinski AJ, Horowitz MP, Lee J, Pakdel A, Allison J, Limbad C, Moore DH, Yount GL, Desprez PY, and McAllister SD, Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival,Mol Cancer Ther,2010 Jan,9(1),pp.180-9,doi:10.1158 / 1535-7163, which are incorporated herein by reference in their entireties. Induction of apoptosis has been observed in many cell culture models and a number of cell signaling pathways, namely mammalian target of rapamycin (mTOR), phosphatidyl-inositol-3 kinase (PI3K), and mitogen-activated protein (MAP) kinases, appear to be affected, leading to apoptosis and / or autophagy (see e.g. Sultan AS, Marie MA, and Sheweita SA, Novel mechanism of cannabidiol-induced apoptosis in breast cancer cell lines, Breast, 2018, 41, pp. 34-41; Roperh I, Sanchez C, and Cortes M, Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-related kinase activation, Nature Med, 2000, 6, pp. 313-9; Powles T, te Poele R, Shamash J, Chaplin T, Propper D, Joel S, Oliver T, and Liu WM, Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway,Blood,2005 Feb 1,105(3),pp.1214-21,doi:10.1182 / blood-2004-03-1182,Ellert-Maklaszemska A,Kaminsha B,and Konarska L.Cannabinoids downregulate PI3K / Akt and Erk signaling pathways and activate proapoptotic function of bad protein,Cell Signal.,2005,17,pp.25-37, and Sarker KP, Biswas KK, Yamakuchi M, Lee KY, Hahiguchi T, Kracht M, Kitajima I, and Maruyama I, ASK1-p38 MAPK / JNK signaling cascade mediates anandamide-induced PC12 cell death, J Neurochem, 2003 Apr, 85(1), pp. 50-61, doi:10.1046 / j.1471-4159.2003.01663.x, which are incorporated herein by reference in their entireties. To date, there has been little or no testing of the effects of CBD, or of standard CBD-rich cannabis extracts, on canine cell culture models.

[0105] Furthermore, with regard to cancer treatment, the use of cannabis extracts in controlling cell growth is complicated considering that cannabis extracts with relatively similar CBD concentrations seem to have differential effects on cell culture systems, lending itself to the proposal of an “entourage effect” in which terpenes and other cannabinoids may act synergistically with CBD to affect cell proliferation (see, e.g., Russo EB and Taming THC, Potential cannabis synergy and phytocannabinoid-terpenoid entourage effects, Brit J Pharmacol, 2011, 163(7), pp. 1344-1364; Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, Tundidor I, Andradas C, Garcia-Taboada E, Wade J, Smith S, Guzman M, Perez-Gomez E, Gordon M, and Sanchez C, Appraising the”entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer, Biochem Pharmacol, 2018 Nov, 157, pp. 285-293, doi:10.1016 / j.bcp.2018.06.025, and Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, and Mechoulam R, An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity, European journal of pharmacology, 1998 Jul 17, 353(1), pp. 23-31, which are incorporated by reference in their entireties.The cell death response may be combined with chemotherapeutic agents commonly used in veterinary treatments, as many pet owners may wish to utilize CBD-rich cannabis products during chemotherapy for their effect on the cancer itself, or to maintain or improve their pet's quality of life (e.g., Kogan LR, Hellyer PW, and Robinson NG, Consumers' perceptions of hemp products for animals, J Am Holist Vet Med Assoc., 2016, 42, pp. 40-48, which is incorporated herein by reference in its entirety).

[0106] Regarding the treatment of lymphoma, this disease is one of the most commonly diagnosed hematopoietic cancers in dogs. The most common chemotherapy protocol used for this disease is a doxorubicin-based multi-drug protocol (L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisone). Remission rates for such protocols range from 80-90%. Median survival times for dogs diagnosed with lymphoma treated with doxorubicin-based chemotherapy protocols range from 6-12 months. Approximately 20% to up to 50% of dogs receiving CHOP or L-CHOP chemotherapy may experience varying degrees of GI toxicity (Tomiyasu et al. (2010) J Vet Med Sci. 72(11):1391-7; Mason et al. (2014) J Small Anim Pract. 55(8):391-8, which are incorporated herein by reference in their entirety). The availability of intensive treatment modalities and increased willingness of clients to continue treatment has led to improved survival rates for veterinary cancer patients. However, more intensive therapies also increase the risk of associated morbidity, making the balance between quantity and quality of life an important role for veterinary oncologists. Owners of terminally ill pets tend to value quality of life (QoL) over their lifespan and are willing to trade QoL for survival (Iliopoulou et al. (2013) J Am Vet Med Assoc. 242(12):1679-87; Giuffrida et al. (2018) J Amer Vet Med Assoc. 252:1073-1083, which are incorporated herein by reference in their entirety).

[0107] Pharmaceutical Compositions In one aspect, provided herein is a pharmaceutical composition comprising a cannabis extract and a carrier, the cannabis extract comprising: Cannabidiol, and Contains cannabidiol acid.

[0108] In another embodiment, the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Δ9-tetrahydrocannabinol, and Contains cannabichromene.

[0109] In another embodiment, the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Cannabigerol, Δ9-tetrahydrocannabinol, and Contains cannabichromene.

[0110] In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50 to about 1:20. In one embodiment, the ratio of cannabidiol to cannabidiolic acid is about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiolic acid is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 1:1.

[0111] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0112] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8 mg / mL. In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4 mg / mL. In one embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.2 mg / mL. In yet another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.05 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is about 0 mg / mL.

[0113] In one embodiment the cannabis extract comprises: Approximately 0.1-20 mg / mL of cannabidiol, Approximately 0.1-20 mg / mL of cannabidiolic acid, Approximately 0.01-0.5 mg / mL of cannabigerolic acid, About 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0114] In another embodiment, the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, About 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0115] In yet another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.27 mg / mL of cannabichromene.

[0116] In one embodiment the cannabis extract comprises: Approximately 0.1-20 mg / mL of cannabidiol, Approximately 0.1-20 mg / mL of cannabidiolic acid, Approximately 0.01-0.5 mg / mL of cannabigerolic acid, Cannabigerol, About 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0117] In another embodiment, the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, Cannabigerol, About 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0118] In yet another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, Cannabigerol, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.27 mg / mL of cannabichromene.

[0119] In some embodiments, the cannabis extract contains tetrahydrocannabinolic acid (THCA).

[0120] In one embodiment, the cannabis extract comprises about 0.01 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 0.05 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 0.1 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 0.5 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 1 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 2 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 3 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 4 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 5 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 10 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 20 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 30 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 40 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 50 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 60 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 70 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 80 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 90 mg / mL cannabinoids. In one embodiment, the cannabis extract comprises about 100 mg / mL cannabinoids. In one embodiment, the cannabinoids are cannabidiol and cannabidiolic acid. According to some embodiments, about 0.05 to 0.5 mL of the extract is administered topically.

[0121] In one embodiment, provided herein is a pharmaceutical composition comprising a cannabis extract and a carrier, the cannabis extract comprising: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, caryophyllene oxide, and / or Contains alpha-bisabolol.

[0122] In another embodiment, the cannabis extract comprises: Approximately 0.09-0.13% α-pinene, Approximately 0.23-0.44% β-myrcene, Approximately 0.04-0.09% β-pinene, Approximately 0.05-0.09% δ-limonene, Approximately 0.03-0.06% linalool, Approximately 0.04-0.07% β-caryophyllene, Approximately 0.02-0.04% α-humulene, Approximately 0.04-0.07% nerolidol 2, Approximately 0.02-0.04% guaiol, about 0.04-0.08% caryophyllene oxide, and / or Contains approximately 0.01-0.04% α-bisabolol.

[0123] In another embodiment, the cannabis extract comprises: Approximately 0.07-0.30% α-pinene, Approximately 0.10 to 0.60% β-myrcene, Approximately 0.02-0.20% β-pinene, Approximately 0.03 to 0.20% δ-limonene, Approximately 0.01 to 0.08% linalool, Approximately 0.03-0.09% β-caryophyllene, Approximately 0.01 to 0.06% α-humulene, about 0.02-0.09% nerolidol 2, and / or It contains approximately 0.01-0.06% guaiol.

[0124] In another embodiment, the cannabis extract comprises: Approximately 0.01 to 0.50% α-pinene, Approximately 0.01 to 0.90% β-myrcene, Approximately 0.01 to 0.50% β-pinene, Approximately 0.01 to 0.50% δ-limonene, Approximately 0.01 to 0.50% linalool, Approximately 0.01 to 0.50% β-caryophyllene, Approximately 0.01 to 0.50% α-humulene, Approximately 0.01 to 0.50% Nerolidol 2, Approximately 0.01-0.50% guaiol, About 0.01 to 0.50% caryophyllene oxide, and / or Contains approximately 0.01-0.50% α-bisabolol.

[0125] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0126] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, about 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0127] In another embodiment, the cannabis extract comprises: Approximately 0.01-0.04% camphene, Approximately 0.01-0.05% β-ocimene, Approximately 0.01 to 0.07% eucalyptol, About 0.01 to 0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0128] In another embodiment, the cannabis extract comprises: Approximately 0.01 to 0.50% camphene, Approximately 0.01-0.50% β-ocimene, Approximately 0.01 to 0.50% eucalyptol, About 0.01 to 0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0129] In one embodiment the cannabis extract is terpene-free.

[0130] In one embodiment, the cannabis extract comprises one or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0131] In one embodiment, the cannabis extract comprises two or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0132] In one embodiment, the cannabis extract comprises three or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0133] In one embodiment, the cannabis extract comprises four or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0134] In one embodiment, the cannabis extract comprises five or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0135] In one embodiment, the cannabis extract comprises six or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0136] In one embodiment, the cannabis extract comprises seven or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0137] In one embodiment, the cannabis extract comprises eight or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0138] In one embodiment, the cannabis extract comprises nine or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0139] In one embodiment, the cannabis extract comprises ten or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0140] In one embodiment, the cannabis extract comprises 11 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0141] In one embodiment, the cannabis extract comprises 12 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0142] In one embodiment, the cannabis extract comprises 13 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0143] In one embodiment, the cannabis extract comprises 14 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0144] In one embodiment, the cannabis extract comprises 15 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0145] In one embodiment, the cannabis extract comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0146] In one embodiment, the composition is formulated as oil.In another embodiment, the carrier is selected from the group consisting of hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil.In yet another embodiment, the carrier is grapeseed oil.In one embodiment, the carrier is sesame oil.

[0147] In one embodiment, the dosage form comprises nepetalactone.

[0148] In one embodiment, the dosage form comprises taurine.

[0149] In one embodiment, the pharmaceutical composition comprises lecithin. In another embodiment, the lecithin is sunflower lecithin. In another embodiment, the sunflower is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.

[0150] In one embodiment, the pharmaceutical composition comprises NF-971P, hi one embodiment, the NF-971P is in a weight / volume ratio of about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, or about 3.0%.

[0151] In one embodiment, the pharmaceutical composition is formulated as a sublingual spray. In yet another embodiment, the pharmaceutical composition is formulated as a water or alcohol soluble solution, gel, or cream for topical or transdermal application. In one embodiment, the pharmaceutical composition is applied to the back of the neck. In one embodiment, the pharmaceutical composition is applied via transdermal ear application. In another embodiment, the pharmaceutical composition is administered at a dose of 4 mg / kg. In another embodiment, the pharmaceutical composition is administered twice daily for four weeks. In one embodiment, the pharmaceutical composition is formulated as a gel for buccal or mucosal administration. In one embodiment, the pharmaceutical composition is formulated as a paste for buccal or mucosal administration. In one embodiment, the pharmaceutical composition is formulated as a powder. In another embodiment, the pharmaceutical composition is formulated as a solution for subcutaneous injection. In yet another embodiment, the pharmaceutical composition is formulated as a tablet. In yet another embodiment, the pharmaceutical composition is formulated as a capsule. In one embodiment, the pharmaceutical composition is formulated as a hard chewable. In one embodiment, the pharmaceutical composition is formulated as a soft chewable.

[0152] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs about 0.5-10 g. In yet another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In yet another embodiment, the chew weighs about 0.5 g. In one embodiment, the chew weighs about 1 g. In another embodiment, the chew weighs about 1.5 g. In yet another embodiment, the chew weighs about 2 g. In yet another embodiment, the chew weighs about 3 g. In one embodiment, the chew weighs about 4 g. In another embodiment, the chew weighs about 5 g. In yet another embodiment, the chew weighs about 6 g. In yet another embodiment, the chew weighs about 7 g. In one embodiment, the chew weighs about 8 g. In another embodiment, the chew weighs about 9 g. In yet another embodiment, the chew weighs about 10 g.

[0153] In one embodiment, a 4g chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerolic acid, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0154] The pharmaceutical compositions of the present disclosure may be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, comminuting, pulverizing, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.

[0155] Thus, the compositions for use according to the present disclosure can be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and auxiliaries, that facilitate the processing of the active compounds into pharma- ceutically usable preparations.The appropriate formulation depends on the selected route of administration.

[0156] Dosage form In one aspect, Cannabidiol, Cannabidiolic acid, and / or Dosage forms comprising one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants are provided herein.

[0157] In another embodiment, the dosage form comprises: Cannabidiol, Cannabidiolic acid, Cannabidiolic acid, Δ9-tetrahydrocannabinol, cannabichromene, and / or It may include one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0158] In another embodiment, the dosage form comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Cannabigerol, Δ9-tetrahydrocannabinol, cannabichromene, and / or It may include one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0159] In some embodiments, the source of the cannabinoid in the dosage form is a cannabis extract or pharmaceutical composition disclosed herein.

[0160] In one embodiment, the ratio of cannabidiol to cannabidiol acid is selected from the group consisting of about 1:100, about 1:50, about 1:10, and about 1:1. In one embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 1:1.

[0161] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0162] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8 mg / mL. In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4 mg / mL. In one embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.2 mg / mL. In yet another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.05 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is about 0 mg / mL.

[0163] In one embodiment, the dosage form comprises: Approximately 0.1-20 mg / mL of cannabidiol, Approximately 0.1-20 mg / mL of cannabidiolic acid, Approximately 0.01-0.5 mg / mL of cannabigerolic acid, About 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0164] In another embodiment, the dosage form comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, About 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0165] In yet another embodiment, the dosage form comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.27 mg / mL of cannabichromene.

[0166] In some embodiments, the cannabis extract comprises THCA.

[0167] In some embodiments, the dosage form comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, caryophyllene oxide, and / or Contains alpha-bisabolol.

[0168] In another embodiment, the dosage form comprises: Approximately 0.09-0.13% α-pinene, Approximately 0.23-0.44% β-myrcene, Approximately 0.04-0.09% β-pinene, Approximately 0.05-0.09% δ-limonene, Approximately 0.03-0.06% linalool, Approximately 0.04-0.07% β-caryophyllene, Approximately 0.02-0.04% α-humulene, Approximately 0.04-0.07% nerolidol 2, Approximately 0.02-0.04% guaiol, about 0.04-0.08% caryophyllene oxide, and / or Contains approximately 0.01-0.04% α-bisabolol.

[0169] In another embodiment, the dosage form comprises: Approximately 0.07-0.30% α-pinene, Approximately 0.10 to 0.60% β-myrcene, Approximately 0.02-0.20% β-pinene, Approximately 0.03 to 0.20% δ-limonene, Approximately 0.01 to 0.08% linalool, Approximately 0.03-0.09% β-caryophyllene, Approximately 0.01 to 0.06% α-humulene, about 0.02-0.09% nerolidol 2, and / or It contains approximately 0.01-0.06% guaiol.

[0170] In another embodiment, the dosage form comprises: Approximately 0.01 to 0.50% α-pinene, Approximately 0.01 to 0.90% β-myrcene, Approximately 0.01 to 0.50% β-pinene, Approximately 0.01 to 0.50% δ-limonene, Approximately 0.01 to 0.50% linalool, Approximately 0.01 to 0.50% β-caryophyllene, Approximately 0.01 to 0.50% α-humulene, Approximately 0.01 to 0.50% Nerolidol 2, Approximately 0.01-0.50% guaiol, About 0.01 to 0.50% caryophyllene oxide, and / or Contains approximately 0.01-0.50% α-bisabolol.

[0171] In another embodiment, the dosage form comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0172] In another embodiment, the dosage form comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, about 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0173] In another embodiment, the dosage form comprises: Approximately 0.01-0.04% camphene, Approximately 0.01-0.05% β-ocimene, Approximately 0.01 to 0.07% eucalyptol, About 0.01 to 0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0174] In another embodiment, the dosage form comprises: Approximately 0.01 to 0.50% camphene, Approximately 0.01-0.50% β-ocimene, Approximately 0.01 to 0.50% eucalyptol, About 0.01 to 0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0175] In one embodiment the cannabis extract is terpene-free.

[0176] In one embodiment, the cannabis extract comprises one or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0177] In one embodiment, the cannabis extract comprises two or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0178] In one embodiment, the cannabis extract comprises three or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0179] In one embodiment, the cannabis extract comprises four or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0180] In one embodiment, the dosage form comprises five or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0181] In one embodiment, the dosage form comprises six or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0182] In one embodiment, the dosage form comprises seven or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0183] In one embodiment, the dosage form comprises eight or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0184] In one embodiment, the dosage form comprises nine or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0185] In one embodiment, the dosage form comprises 10 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0186] In one embodiment, the dosage form comprises 11 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0187] In one embodiment, the dosage form comprises 12 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0188] In one embodiment, the dosage form comprises 13 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0189] In one embodiment, the dosage form comprises 14 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0190] In one embodiment, the dosage form comprises 15 or more of the following: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0191] In one embodiment, the dosage form comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

[0192] In one embodiment, the flavoring agent is selected from the group consisting of peanut butter, catnip oil, peppermint oil, mango extract, beef, chicken, and seafood, hi another embodiment, the flavoring agent is peanut butter.

[0193] In one embodiment, the dosage form is formulated as a sublingual spray. In yet another embodiment, the dosage form is formulated as a water or alcohol soluble solution, gel, or cream for topical or transdermal application. In one embodiment, the dosage form is applied to the back of the neck. In one embodiment, the dosage form is applied via transdermal ear application. In another embodiment, the dosage form is administered at a dose of 4 mg / kg. In another embodiment, the dosage form is administered twice daily for four weeks. In one embodiment, the dosage form is formulated as a gel for buccal or mucosal administration. In some embodiments, the dosage form is formulated as a paste for buccal or mucosal administration. In one embodiment, the dosage form is formulated as a powder. In another embodiment, the dosage form is formulated as a solution for subcutaneous injection. In yet another embodiment, the dosage form is formulated as a tablet. In yet another embodiment, the dosage form is formulated as a capsule. In one embodiment, the dosage form is formulated as a soft chewable.

[0194] In some embodiments, the invention includes infusing an edible product with cannabis extract. In another embodiment, the edible product is an extruded food, baked food, nut butter, spread, pelleted feed, or processed food. In another embodiment, the edible product is a pet food. In another embodiment, the edible product is in a dry shelf-stable form, such as dried fish, dried dairy, fish meal, fish meal, grains, flour, carbohydrates, dried fruit, etc. In another embodiment, the edible product is moist or semi-moist. In another embodiment, the edible product contains additives or supplements, such as, for example, chemicals, enzymes, etc., capable of removing plaque or tartar from the teeth of an animal, vitamins, minerals, medicines, etc. In one embodiment, the cannabis extract is administered with catnip oil. In another embodiment, any of the dosage forms described may also include catnip.

[0195] In another embodiment, the cannabis extract is administered using a nebulizer. In another embodiment, the nebulizer delivery device and system can effectively and efficiently administer one or more atomized drugs to animals. In another embodiment, the nebulizer system can be easily used on animals without removing the animals from their natural environment. In another embodiment, the nebulizer delivery device and system allows animals to be easily treated daily or multiple times a day without undue stress or extensive resources. In another embodiment, the nebulizer delivery device and system can be used on animals with various levels of training.

[0196] In one embodiment, the cannabis extract is administered using a diffuser. A diffuser can be any device that disperses the cannabis extract into the air. The cannabis extract can be dispersed by any method, including natural convection, forced convection, for example, heating a wick or pad that holds the cannabis extract, using a pump, or using a fan.

[0197] In one embodiment, the cannabis extract is administered by an animal collar. The animal collar may include a belt with a buckle on one side, a free end on the other side, and an attachment means such as a longitudinally disposed opening in the central portion of the belt for fastening the collar in a closed loop configuration, or an easy-to-remove fastening mechanism. The animal collar may be made from a variety of materials, including nylon, polyester leather, or other suitable materials. The belt material may be treated with a water-resistant compound. The nylon or polyester belt may be interwoven with reflective fibers to increase the visibility of the animal collar at night. In one embodiment, the collar is infused with cannabis extract.

[0198] Kiss In one embodiment, the dosage form is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs about 0.5-10 g. In yet another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In yet another embodiment, the chew weighs about 0.5 g. In one embodiment, the chew weighs about 1 g. In another embodiment, the chew weighs about 1.5 g. In yet another embodiment, the chew weighs about 2 g. In yet another embodiment, the chew weighs about 3 g. In one embodiment, the chew weighs about 4 g. In another embodiment, the chew weighs about 5 g. In yet another embodiment, the chew weighs about 6 g. In yet another embodiment, the chew weighs about 7 g. In one embodiment, the chew weighs about 8 g. In another embodiment, the chew weighs about 9 g. In yet another embodiment, the chew weighs about 10 g.

[0199] In one embodiment, the dosage form comprises: Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and / or Contains water.

[0200] In another embodiment, the dosage form comprises: Approximately 25-35% brewer's yeast, Approximately 1-10% gum arabic, Approximately 0.1-4% guar gum, Approximately 10-20% flavoring agent, Approximately 0.01-1% Verdilox, Previon of about 0.1 to 2% Approximately 1-10% cannabis extract, Approximately 10-20% glycerin, Approximately 1-10% sunflower lecithin, and / or Contains approximately 1-10% water.

[0201] In another embodiment, the dosage form comprises: Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and / or Contains approximately 3-7% water.

[0202] In yet another embodiment, the dosage form comprises: Approximately 30% beer yeast, Approximately 4.7% gum arabic, Approximately 0.9% guar gum, Approximately 14.2% flavorings; Approximately 0.05% Verdilox, Previon, about 0.9% Approximately 4.7% cannabis extract, Approximately 15.1% glycerin, about 5.7% sunflower lecithin, and / or Contains approximately 5.7% water.

[0203] In one embodiment, the dosage form comprises: Glucosamine HCl, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and / or Contains water.

[0204] In another embodiment, the dosage form comprises: Approximately 10-20% Glucosamine HCl, Approximately 25-35% brewer's yeast, Approximately 1-10% gum arabic, Approximately 0.1-4% guar gum, Approximately 10-20% flavoring agent, Approximately 0.01-1% Verdilox, Previon of about 0.1 to 2% Approximately 1-10% cannabis extract, Approximately 10-20% glycerin, Approximately 1-10% sunflower lecithin, and / or Contains approximately 1-10% water.

[0205] In another embodiment, the dosage form comprises: Approximately 12-17% Glucosamine HCl, Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and / or Contains approximately 3-7% water.

[0206] In yet another embodiment, the dosage form comprises: Approximately 15.6% Glucosamine HCl, Approximately 30% beer yeast, Approximately 4.7% gum arabic, Approximately 0.9% guar gum, Approximately 14.2% flavorings; Approximately 0.05% Verdilox, Previon, about 0.9% Approximately 4.7% cannabis extract, Approximately 15.1% glycerin, about 5.7% sunflower lecithin, and / or Contains approximately 5.7% water.

[0207] In one embodiment, the dosage form comprises: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and / or Contains water.

[0208] In another embodiment, the dosage form comprises: Approximately 10-20% Glucosamine HCl, Approximately 0.1-7% chondroitin sulfate (76%), Approximately 25-35% brewer's yeast, Approximately 1-10% gum arabic, Approximately 0.1-4% guar gum, Approximately 10-20% flavoring agent, Approximately 0.01-1% Verdilox, Previon of about 0.1 to 2% Approximately 1-10% cannabis extract, Approximately 10-20% glycerin, Approximately 1-10% sunflower lecithin, and / or Contains approximately 1-10% water.

[0209] In another embodiment, the dosage form comprises: Approximately 12-17% Glucosamine HCl, Approximately 1-4% chondroitin sulfate (76%), Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and / or Contains approximately 3-7% water.

[0210] In yet another embodiment, the dosage form comprises: Approximately 15.6% Glucosamine HCl, Approximately 2.6% chondroitin sulfate (76%), Approximately 30% beer yeast, Approximately 4.7% gum arabic, Approximately 0.9% guar gum, Approximately 14.2% flavorings; Approximately 0.05% Verdilox, Previon, about 0.9% Approximately 4.7% cannabis extract, Approximately 15.1% glycerin, about 5.7% sunflower lecithin, and / or Contains approximately 5.7% water.

[0211] In another embodiment, the dosage form comprises: Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and / or Contains water.

[0212] In another embodiment, the dosage form comprises: Approximately 0.01 to 3% hyaluronic acid, Approximately 25-35% brewer's yeast, Approximately 1-10% gum arabic, Approximately 0.1-5% guar gum, Approximately 10-20% flavoring agent, Approximately 0.01-1% Verdilox, Previon of about 0.1 to 3% Approximately 1-10% cannabis extract, Approximately 10-20% glycerin, Approximately 1-10% sunflower lecithin, and / or Contains approximately 1-10% water.

[0213] In another embodiment, the dosage form comprises: Approximately 0.01 to 1% hyaluronic acid, Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and / or Contains approximately 3-7% water.

[0214] In yet another embodiment, the dosage form comprises: Approximately 0.1% hyaluronic acid, Approximately 30.6% beer yeast, Approximately 4.8% gum arabic, Approximately 0.97% guar gum, Approximately 14.5% flavorings; Approximately 0.05% Verdilox, Previon at approximately 0.97% Approximately 4.8% cannabis extract, Approximately 15.5% glycerin, about 5.8% sunflower lecithin, and / or Contains approximately 5.8% water.

[0215] In another embodiment, the dosage form comprises: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and / or Contains water.

[0216] In another embodiment, the dosage form comprises: Approximately 10-20% Glucosamine HCl, Approximately 0.01 to 3% hyaluronic acid, Approximately 25-35% brewer's yeast, Approximately 1-10% gum arabic, Approximately 0.1-5% guar gum, Approximately 10-20% flavoring agent, Approximately 0.01-1% Verdilox, Previon of about 0.1 to 3% Approximately 1-10% cannabis extract, Approximately 10-20% glycerin, Approximately 1-10% sunflower lecithin, and / or Contains approximately 1-10% water.

[0217] In another embodiment, the dosage form comprises: Approximately 12-17% Glucosamine HCl, Approximately 0.01 to 1% hyaluronic acid, Approximately 29-33% brewer's yeast, Approximately 3-6% gum arabic, Approximately 0.5-2% guar gum, Approximately 12-16% flavorings, Approximately 0.01-0.1% Verdilox, Previon of about 0.5 to 1.5% Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and / or Contains approximately 3-7% water.

[0218] In yet another embodiment, the dosage form comprises: Approximately 16% Glucosamine HCl, Approximately 0.1% hyaluronic acid, Approximately 30.6% beer yeast, Approximately 4.8% gum arabic, Approximately 0.97% guar gum, Approximately 14.5% flavorings; Approximately 0.05% Verdilox, Previon at approximately 0.97% Approximately 4.8% cannabis extract, Approximately 15.5% glycerin, about 5.8% sunflower lecithin, and / or Contains approximately 5.8% water.

[0219] In yet another embodiment, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, Rice starch, and / or Contains guar gum.

[0220] In another embodiment, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 10.0-20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, About 1.0-5.0% rice starch, and / or Contains approximately 1.0-5.0% guar gum.

[0221] In another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 12.5% ​​rice bran, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.25% water, Approximately 13.0% glycerin, Approximately 2.0% potato starch, Approximately 1.0% dehydrated peanut butter, about 2.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0222] In yet another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 13.0% rice bran, Sweet potatoes account for approximately 6.0%; Approximately 9.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.5% water, Approximately 13.0% glycerin, Approximately 4.0% potato starch, Approximately 1.0% dehydrated peanut butter, about 2.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0223] In one embodiment, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, Rice starch, and / or Contains guar gum.

[0224] In another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.25% water, Approximately 13.0% glycerin, Approximately 2.0% potato starch, Approximately 1.0% dehydrated peanut butter, about 2.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0225] In yet another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 15.0% peanut butter, Approximately 13.0% rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 6.0%; Approximately 9.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 9.5% water, Approximately 13.0% glycerin, Approximately 4.0% potato starch, Approximately 1.0% dehydrated peanut butter, about 2.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0226] In yet another embodiment, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 10.0-20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, About 1.0-5.0% rice starch, and / or Contains approximately 1.0-5.0% guar gum.

[0227] In another embodiment, the dosage form further comprises chondroitin sulfate.

[0228] In one embodiment, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, DigestaWell PET, Rice starch, and / or Contains guar gum.

[0229] In another embodiment, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 5.0 to 20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, Approximately 0.1-3.0% DigestaWell PET, About 1.0-8.0% rice starch, and / or Contains approximately 1.0-5.0% guar gum.

[0230] In another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.0% rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 7.25% water, Approximately 10.0% glycerin, Approximately 5.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 0.5% DigestaWell PET, about 6.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0231] In yet another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 8.0%; Approximately 9.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 6.0% water, Approximately 10.0% glycerin, Approximately 6.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 0.5% DigestaWell PET, Approximately 6.5% rice starch, and / or Contains approximately 2.0% guar gum.

[0232] In one embodiment, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid, Brewer's yeast, sugar, water, Glycerin, Potato starch, dehydrated peanut butter, Chondroitin, DigestaWell PET, Rice starch, and / or Contains guar gum.

[0233] In another embodiment, the dosage form comprises: Approximately 3.0-10.0% cannabis extract, Approximately 5.0 to 20.0% peanut butter, Approximately 10.0-15.0% rice bran, Approximately 5.0-15.0% Glucosamine HCl, Approximately 4.0 to 10.0% of sweet potatoes, Approximately 6.0-13.0% dry molasses; Approximately 0.5 to 5.0% sorbic acid, Approximately 2.0 to 8.0% brewer's yeast, Approximately 3.0-8.0% sugar, Approximately 5.0 to 15.0% water, Approximately 8.0 to 18.0% glycerin, Approximately 1.0-8.0% potato starch, Approximately 0.5 to 5.0% dehydrated peanut butter, Approximately 0.5 to 5.0% chondroitin, Approximately 0.1-3.0% DigestaWell PET, About 1.0-8.0% rice starch, and / or Contains approximately 1.0-5.0% guar gum.

[0234] In another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.0% rice bran, Approximately 12.75% Glucosamine HCl, About 5.5% of sweet potatoes, Approximately 8.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 7.25% water, Approximately 10.0% glycerin, Approximately 4.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 2.5% chondroitin, Approximately 0.5% DigestaWell PET, Approximately 4.5% rice starch, and / or Contains approximately 2.0% guar gum.

[0235] In yet another embodiment, the dosage form comprises: Approximately 5.0% cannabis extract, Approximately 10.0% peanut butter, Approximately 12.5% ​​rice bran, Approximately 8.5% Glucosamine HCl, Sweet potatoes account for approximately 8.0%; Approximately 9.0% dry molasses; Approximately 1% sorbic acid, Approximately 5.0% beer yeast, Approximately 6.0% sugar, Approximately 6.0% water, Approximately 10.0% glycerin, Approximately 5.0% potato starch, Approximately 4.0% dehydrated peanut butter, Approximately 2.5% chondroitin, Approximately 0.5% DigestaWell PET, about 5.0% rice starch, and / or Contains approximately 2.0% guar gum.

[0236] In one embodiment, the dosage form further comprises dried yeast, fructo-oligosaccharides, fumaric acid, lactic acid, citric acid, malic acid, thyme oil, anethole, cinnamaldehyde, vegetable oil, dehydrated alfalfa meal, mineral oil, and / or sodium aluminosilicate.

[0237] In another embodiment, the dosage form comprises 2.0% cannabis extract. In another embodiment, the dosage form comprises 3.0% cannabis extract. In another embodiment, the dosage form comprises 4.0% cannabis extract. In another embodiment, the dosage form comprises 5.0% cannabis extract. In another embodiment, the dosage form comprises 6.0% cannabis extract. In another embodiment, the dosage form comprises 7.0% cannabis extract. In another embodiment, the dosage form comprises 8.0% cannabis extract. In another embodiment, the dosage form comprises 9.0% cannabis extract. In another embodiment, the dosage form comprises 10.0% cannabis extract.

[0238] In one embodiment the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerolic acid, Δ9-tetrahydrocannabinol, and / or Contains cannabichromene.

[0239] In one embodiment, the ratio of cannabidiol to cannabidiol acid is selected from the group consisting of about 1:100, about 1:50, about 1:10, and about 1:1. In one embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.1:1 to about 1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6. In yet another embodiment, the ratio of cannabidiol to cannabidiol acid is about 1:1.

[0240] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50 to about 1:20. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:50. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:45. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:40. In another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:35. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:30. In yet another embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0241] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.9 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.8 mg / mL. In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.7 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.6 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In yet another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.4 mg / mL. In one embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.2 mg / mL. In yet another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of A9-tetrahydrocannabinol is less than about 0.05 mg / mL. In yet another embodiment, the concentration of A9-tetrahydrocannabinol is about 0 mg / mL.

[0242] In one embodiment the cannabis extract comprises: Approximately 0.1-20 mg / mL of cannabidiol, Approximately 0.1-20 mg / mL of cannabidiolic acid, Approximately 0.01-0.5 mg / mL of cannabigerolic acid, About 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0243] In another embodiment, the cannabis extract comprises: Approximately 1-10 mg / mL cannabidiol, Approximately 1-10 mg / mL cannabidiolic acid, Approximately 0.05-0.2 mg / mL cannabigerolic acid, About 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0244] In yet another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerolic acid, about 0.25 mg / mL Δ9-tetrahydrocannabinol, and / or Contains approximately 0.27 mg / mL of cannabichromene.

[0245] In some embodiments, the cannabis extract contains THCA.

[0246] In one embodiment the cannabis extract comprises: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, caryophyllene oxide, and / or Contains alpha-bisabolol.

[0247] In another embodiment, the cannabis extract comprises: Approximately 0.09-0.13% α-pinene, Approximately 0.23-0.44% β-myrcene, Approximately 0.04-0.09% β-pinene, Approximately 0.05-0.09% δ-limonene, Approximately 0.03-0.06% linalool, Approximately 0.04-0.07% β-caryophyllene, Approximately 0.02-0.04% α-humulene, Approximately 0.04-0.07% nerolidol 2, Approximately 0.02-0.04% guaiol, about 0.04-0.08% caryophyllene oxide, and / or Contains approximately 0.01-0.04% α-bisabolol.

[0248] In another embodiment, the cannabis extract comprises: Approximately 0.07-0.30% α-pinene, Approximately 0.10 to 0.60% β-myrcene, Approximately 0.02-0.20% β-pinene, Approximately 0.03 to 0.20% δ-limonene, Approximately 0.01 to 0.08% linalool, Approximately 0.03-0.09% β-caryophyllene, Approximately 0.01 to 0.06% α-humulene, about 0.02-0.09% nerolidol 2, and / or It contains approximately 0.01-0.06% guaiol.

[0249] In another embodiment, the cannabis extract comprises: Approximately 0.01 to 0.50% α-pinene, Approximately 0.01 to 0.90% β-myrcene, Approximately 0.01 to 0.50% β-pinene, Approximately 0.01 to 0.50% δ-limonene, Approximately 0.01 to 0.50% linalool, Approximately 0.01 to 0.50% β-caryophyllene, Approximately 0.01 to 0.50% α-humulene, Approximately 0.01 to 0.50% Nerolidol 2, Approximately 0.01-0.50% guaiol, About 0.01 to 0.50% caryophyllene oxide, and / or Contains approximately 0.01-0.50% α-bisabolol.

[0250] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0251] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, about 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0252] In another embodiment, the cannabis extract comprises: Approximately 0.01-0.04% camphene, Approximately 0.01-0.05% β-ocimene, Approximately 0.01 to 0.07% eucalyptol, About 0.01 to 0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0253] In another embodiment, the cannabis extract comprises: Approximately 0.01 to 0.50% camphene, Approximately 0.01-0.50% β-ocimene, Approximately 0.01 to 0.50% eucalyptol, About 0.01 to 0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0254] In one embodiment, the composition is formulated as oil.In another embodiment, the carrier is selected from the group consisting of hemp seed oil, linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil.In yet another embodiment, the carrier is grapeseed oil.In one embodiment, the carrier is sesame oil.

[0255] In one embodiment, the flavoring agent is selected from the group consisting of peanut butter, catnip oil, chicken liver powder, chicken extract, maltodextrin, butter, and bacon. In another embodiment, the flavoring agent is chicken liver powder. In another embodiment, the flavoring agent is peanut butter.

[0256] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew is produced using cold extrusion. In another embodiment, the chew weighs about 0.5-10 g. In yet another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In yet another embodiment, the chew weighs about 0.5 g. In one embodiment, the chew weighs about 1 g. In another embodiment, the chew weighs about 1.5 g. In yet another embodiment, the chew weighs about 2 g. In yet another embodiment, the chew weighs about 3 g. In one embodiment, the chew weighs about 4 g. In another embodiment, the chew weighs about 5 g. In yet another embodiment, the chew weighs about 6 g. In yet another embodiment, the chew weighs about 7 g. In one embodiment, the chew weighs about 8 g. In another embodiment, the chew weighs about 9 g. In yet another embodiment, the chew weighs about 10 g.

[0257] In one embodiment, a 4g chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerolic acid, about 0.32 mg of Δ9-tetrahydrocannabinol, and / or Contains approximately 0.36 mg of cannabichromene.

[0258] Treatment method In one aspect, provided herein is a method for treating a disease, disorder, syndrome, and / or condition in a veterinary subject in need thereof, comprising administering to the veterinary subject a therapeutically effective amount of any of the compositions or dosage forms described above. In one embodiment, the veterinary subject suffers from inflammation, periuria, anxiety, depression, insomnia, pain (e.g., chronic pain, non-chronic pain, neuropathic pain, pain of neurological dysfunction, nociceptive pain, post-operative pain), skin disorders, cancer, psychotic disorders, seizures, epilepsy, osteoarthritis, lymphoma, atopy, allergies, diarrhea (e.g., idiopathic diarrhea), noise aversion, hair pulling, hair pulling, skin wounds, pyoderma, gastrointestinal conditions, behavioral problems, obsessive-compulsive behaviors, migraines, headaches, insect bites, diabetes, inflammatory bowel disease, skin conditions (e.g., pruritus, pyoderma), urinary conditions, anxiety, or frustration.

[0259] In one embodiment, the veterinary subject is a cat. In one embodiment, the cat is greater than 6 months and less than 12 years old. In one embodiment, the cat is less than 6 months old. In one embodiment, the cat is about 6-12 months old. In one embodiment, the cat is about 1-3 years old. In one embodiment, the cat is about 3-6 years old. In one embodiment, the cat is about 6-9 years old. In one embodiment, the cat is about 9-12 years old. In one embodiment, the cat is about 12-15 years old. In one embodiment, the cat is greater than about 15 years old.

[0260] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.1-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 1-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 10-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 10-25 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 15-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 15-25 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 20-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 25-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 30-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 20-35 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 25-35 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 35-50.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.1-15.0 mg / kg. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.1-10.0 mg / kg. In one embodiment, the dosage is administered orally. In one embodiment, the dosage is administered topically.

[0261] In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.1 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.2 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.3 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.4 mg / kg. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.5 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.6 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.7 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.8 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 0.9 mg / kg. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 1 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 1.5 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 2 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 3 mg / kg. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 4 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 5 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 6 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 7 mg / kg. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 8 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 9 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 10 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 11 mg / kg.In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 12 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 13 mg / kg. In yet another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 14 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 15 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 20 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 25 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 30 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 35 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 40 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 45 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 50 mg / kg. In one embodiment, the dosage is administered orally. In one embodiment, the dosage is administered topically.

[0262] In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at twice the therapeutically effective dose for one week, then at the therapeutically effective dose thereafter. In yet another embodiment, the therapeutically effective dose is about 0.1-0.5 mg / kg. In yet another embodiment, the therapeutically effective dose is about 2 mg / kg. In one embodiment, the therapeutically effective dose is about 8 mg / kg.

[0263] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 1 mg / kg for one week, then at a dosage of about 0.1-0.5 mg / kg thereafter. In another embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 4 mg / kg for one week, then at a dosage of about 2 mg / kg thereafter.

[0264] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 1.0 mg / kg.

[0265] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 2.0 mg / kg.

[0266] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 3.0 mg / kg.

[0267] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 5.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 5.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 5.0 mg / kg. In one embodiment the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 5.0 mg / kg four times daily.

[0268] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 6.0 mg / kg.

[0269] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 7.0 mg / kg.

[0270] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 8.0 mg / kg.

[0271] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 9.0 mg / kg.

[0272] In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered once a day at a dosage of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered twice a day at a dosage of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered three times a day at a dosage of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition, dosage form, or cannabis extract is administered four times a day at a dosage of about 10.0 mg / kg.

[0273] In one embodiment the pharmaceutical composition, dosage form, or cannabis extract is administered at a dosage of about 2mg / kg twice daily.

[0274] In one embodiment, a dropperful of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 0.5 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 1 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 2 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 3 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 4 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 5 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 6 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 7 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 8 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 9 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject. In another embodiment, 10 mL of the pharmaceutical composition, dosage form, or cannabis extract is administered to the subject.

[0275] In one embodiment, the method results in a therapeutically effective median maximum serum concentration of cannabidiol (CBD). In another embodiment, the median maximum serum concentration of CBD is about 30-90 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 30 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 50 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 70 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 90 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 90-310 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD is about 90 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD is about 100 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD is about 102 ng / mL. In one embodiment, the median maximum serum concentration of CBD is about 200 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 300 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD is about 400 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD is about 500 ng / mL. In one embodiment, the median maximum serum concentration of CBD is about 590 ng / mL. In another embodiment, the median maximum serum concentration of CBD is about 600 ng / mL.

[0276] In one embodiment, the method results in a therapeutically effective median maximum serum concentration of cannabidiolic acid (CBDA). In another embodiment, the median maximum serum concentration of CBDA is about 30-90 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 30 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 50 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 70 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 90 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 90-310 ng / mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 90 ng / mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 100 ng / mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 102 ng / mL. In one embodiment, the median maximum serum concentration of CBDA is about 200 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 300 ng / mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 400 ng / mL. In yet another embodiment, the median maximum serum concentration of CBDA is about 500 ng / mL. In one embodiment, the median maximum serum concentration of CBDA is about 590 ng / mL. In another embodiment, the median maximum serum concentration of CBDA is about 600 ng / mL.

[0277] In one embodiment, the method results in a therapeutically effective median maximum serum concentration of CBD and CBDA. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 30-90 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 30 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 50 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 70 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 90 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 90-310 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 90 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 100 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 102 ng / mL. In one embodiment, the median maximum serum concentration of CBD and CBDA is about 200 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 300 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 400 ng / mL. In yet another embodiment, the median maximum serum concentration of CBD and CBDA is about 500 ng / mL. In one embodiment, the median maximum serum concentration of CBD and CBDA is about 590 ng / mL. In another embodiment, the median maximum serum concentration of CBD and CBDA is about 600 ng / mL.

[0278] In one embodiment, the veterinary subject is a dog, a cat, a cow, a pig, or a horse. In another embodiment, the veterinary subject is a dog. In yet another embodiment, the veterinary subject is a cat. In yet another embodiment, the veterinary subject is a horse.

[0279] In one embodiment, the cannabis extract is administered at a dosage of about 0.1-15.0 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 0.1-10.0 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.1 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.2 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.3 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 0.4 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 0.5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.6 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.7 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 0.8 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 0.9 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 1 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 1.5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 2 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 3 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 4 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 6 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 7 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 8 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 9 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 10 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 11 mg / kg. In another embodiment, the cannabis extract is administered at a dosage of about 12 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 13 mg / kg. In yet another embodiment, the cannabis extract is administered at a dosage of about 14 mg / kg. In one embodiment, the cannabis extract is administered at a dosage of about 15 mg / kg.

[0280] In another embodiment, the cannabis extract is administered at twice the therapeutically effective dose for one week, then at the therapeutically effective dose thereafter. In yet another embodiment, the therapeutically effective dose is about 0.1-0.5 mg / kg. In yet another embodiment, the therapeutically effective dose is about 2 mg / kg. In one embodiment, the therapeutically effective dose is about 8 mg / kg.

[0281] In one embodiment, the cannabis extract is administered at a dosage of about 1 mg / kg for one week, then at a dosage of about 0.1-0.5 mg / kg thereafter. In another embodiment, the cannabis extract is administered at a dosage of about 4 mg / kg for one week, then at a dosage of about 2 mg / kg thereafter.

[0282] In one embodiment, the method results in a therapeutically effective median maximum serum concentration of cannabidiol. In another embodiment, the median maximum serum concentration of cannabidiol is about 90-310 ng / mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 90 ng / mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 100 ng / mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 102 ng / mL. In one embodiment, the median maximum serum concentration of cannabidiol is about 200 ng / mL. In another embodiment, the median maximum serum concentration of cannabidiol is about 300 ng / mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 400 ng / mL. In yet another embodiment, the median maximum serum concentration of cannabidiol is about 500 ng / mL. In one embodiment, the median maximum serum concentration of cannabidiol is about 590 ng / mL. In another embodiment, the median maximum serum concentration of cannabidiol is about 600 ng / mL.

[0283] The pharmaceutical compositions and dosage forms of the present disclosure may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous layers (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with any other therapeutic agent. Administration may be systemic or local. In one embodiment, administration is local. In another embodiment, local administration is used to treat localized pain. In another embodiment, the localized pain is joint pain. In one embodiment, the veterinary subject is an animal over 100 kg (e.g., a horse, cow, or pig).

[0284] The therapeutic compositions of the present invention are administered with suitable carriers, excipients, and other agents incorporated into the formulation to provide improved transport, delivery, tolerance, and the like. A large number of suitable formulations can be found in the list of medicines known to all pharmacologists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)-containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci Technol 52:238-311.

[0285] The composition and dosage may vary depending on the age, weight, and sex of the subject to be administered, the target disease, disorder, syndrome, condition, route of administration, etc. A variety of delivery systems, such as liposomes, microparticles, encapsulation in microcapsules, and receptor-mediated endocytosis, are known and may be used to administer the pharmaceutical composition of the present invention (see, for example, Wu et al. (1987) J.Biol.Chem.262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, topical, transdermal, buccal, sublingual, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, such as by infusion or bolus injection, by absorption through epithelial or mucocutaneous layers (such as oral mucosa, rectal and intestinal mucosa, etc.), and may be administered together with other bioactive agents. Administration may be systemic or local.

[0286] Pharmacological preparations for oral use can be made by using solid excipients, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliary agents if necessary, to obtain tablets or dragee cores.Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, gums, methylcellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose, and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added.

[0287] Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0288] Injectable preparations may include dosage forms such as intravenous, subcutaneous, intradermal, and intramuscular injections, local injections, infusions, etc. These injectable preparations may be prepared by publicly known methods. For example, injectable preparations may be prepared by dissolving, suspending, or emulsifying, for example, a pharmaceutical composition, dosage form, or cannabis extract in a sterile aqueous or oily medium that is conventionally used for injections. Aqueous media for injection include, for example, saline, isotonic solutions containing glucose, and other adjuvants, which may be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), non-ionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mole) adduct of hydrogenated castor oil)]. As oily media, for example, sesame oil, soybean oil, etc. may be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injection solution thus prepared may be filled into a suitable ampoule.

[0289] Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active ingredients can be dissolved or suspended in suitable liquids such as fatty acids, liquid paraffin, or liquid polyethylene glycols.

[0290] Alternatively, the composition may be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. The exact formulation, route of administration, and dosage can be chosen by a physician familiar with the patient's condition. (See, for example, Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Chapter I, p.1). Depending on the severity and responsiveness of the condition to be treated, dosing may also be a single dose of a sustained release composition, with the course of treatment lasting from several days to several weeks, or until a cure is effected or a diminution of the disease state is achieved.

[0291] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms in unit doses to suit the dosage of active ingredient.Such dosage forms in unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, chews, etc. In certain embodiments, for the dosages provided above, they are administered in edible products, for example, the delivery of a single serving of 1 mg / kg cannabis extract provided in individual products.

[0292] The cannabis extract, dosage forms, and pharmaceutical compositions described herein may be packaged to provide one or more doses of cannabis extract per package. Any suitable type of packaging may be used, including wrappers, pouches, boxes, tubs, cans, blister packs, and bags. Such packaging is convenient and accessible to the consumer, increases consumer ease of use, reduces the presence of pathogens, extends shelf life, and reduces spoilage. In one embodiment, the cannabis extract, dosage form, or pharmaceutical composition is packaged to provide one or more doses of cannabis extract per package. In one embodiment, the package is resealable. In some embodiments, the dosage form is edible. In some embodiments, the edible dosage form is formed into a flat shape that can be more easily divided. In some embodiments, the flat shape is a disk or cookie shape. In some embodiments, the edible dosage form includes indentations to indicate where the edible dosage form should be divided to provide a particular dosage. In some embodiments, the edible dosage form is provided in multiple pieces. In some embodiments, each of the multiple pieces provides a certain dosage. In some embodiments, the package contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50 or more pieces. In some embodiments, the package is resealable. In one embodiment, the dose of cannabis extract is a therapeutically effective amount. According to the methods disclosed herein, the pharmaceutical formulation may be administered to the patient or subject using any acceptable device or mechanism. For example, administration may be accomplished using a syringe and needle, or with a reusable pen and / or autoinjector delivery device. The methods of the present invention include the use of multiple reusable pen and / or autoinjector delivery devices to administer the pharmaceutical formulation.

[0293] In one embodiment for non-human animal administration, the term "pharmaceutical" as used herein may be replaced by "veterinary."

[0294] In some embodiments, the patient is a subject before, during, and / or after treatment with CHOP chemotherapy, which includes, but is not limited to, cyclophosphamide, doxorubicin, vincristine, and steroids (e.g., prednisolone). EXAMPLES

[0295] Although some examples are contemplated, these examples are intended to be non-limiting.

[0296] Example 1 Single-dose pharmacokinetics in healthy dogs and cats The single-dose oral pharmacokinetics of CBD during 12 weeks of treatment with a cannabis-based product in healthy dogs and cats were determined in this study, as well as an evaluation of safety and adverse effects. Eight of each species were orally administered a concentration of 2 mg / kg total CBD / CBDA (1 mg / kg CBD and 1 mg / kg CBDA) twice daily for 12 weeks, and single-dose pharmacokinetics were screened in six of each species. Pharmacokinetics revealed mean maximum CBD concentrations (Cmax) of 301 ng / mL and 43 ng / mL, areas under the curve (AUC) of 1297 ng-h / mL and 164 ng-h / mL, and times to maximum concentration (Tmax) of 1.4 hours and 2 hours for dogs and cats, respectively. Serum chemistry and CBC results showed no clinically significant changes, although one cat showed persistent elevations in alanine aminotransferase (ALT) above the reference range throughout the study period. In healthy dogs and cats, oral CBD-rich cannabis supplements administered every 12 hours were not harmful based on CBC or biochemistry values. Cats appear to absorb or excrete CBD differently than dogs, showing lower serum concentrations and adverse effects of excessive licking and head shaking during oil administration. Details regarding this study can be found in "Deabold, KA; Schwark, WS; Wolf, L.; Wakshlag, JJ, Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats, Animals 2019, 9, 832, DOI 10.3390 / ani9100832," which is incorporated herein by reference in its entirety.

[0297] Example 2 Pharmacokinetics of oral and transdermal cannabis oil in dogs. The pharmacokinetics of cannabidiol (CBD), cannabidiol acid (CBDA), Δ9-tetrahydrocannabinol (THC), and tetrahydrocannabinolic acid (THCA) in three oral forms of CBD-rich cannabis extract containing approximately equal amounts of CBD and CBDA, and trace amounts (<0.3% by weight) of THC and THCA, were studied in dogs. To better understand the pharmacokinetic differences between the three formulations with respect to THC and CBD, and their metabolism, the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and the CBD metabolites, 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD), were also evaluated. Six purpose-bred female beagles were utilized for research purposes, each with an initial 7-point, 24-hour pharmacokinetic study conducted using a dose of 2 mg / kg body weight CBD / CBDA (approximately 1 mg / kg CBD and approximately 1 mg / kg CBDA). The dogs were then dosed every 12 hours for two weeks, with additional serum analysis performed 6 hours after the morning dose on weeks 1 and 2 to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectrometry (LC-MS / MS). Regardless of the form provided (1, 2, or 3), the 24-hour pharmacokinetics for CBD, CBDA, and THCA were similar, with only form 2 generating data above the lower limit of quantification sufficient to assess the pharmacokinetics of THC. CBDA and THCA concentrations were 2-3 times higher than CBD and THC concentrations, respectively. Steady-state concentrations at 1 and 2 weeks were not significantly different between the two oil or soft chew forms. CBDA concentrations were statistically higher in Form 2 than the other forms, indicating superior absorption / retention of CBDA. Additionally, Form 1 showed less THCA retention than either soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the limit of quantitation of the assay for nearly all samples.Overall, these findings suggest that CBDA and THCA are absorbed or excreted differently than CBD or THC, respectively, and that the partial lecithin base results in superior absorption and / or retention of CBDA and THCA. Details of this study can be found in "Wakshlag JJ, Schwark WS, Deabold KA, Talsma BN, Cital S, Lyubimov A, Iqbal A and Zakharov A, Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract, 2020, Front.Vet.Sci.7:505.DOI 10.3389 / fvets.2020.00505", which is incorporated herein by reference in its entirety. The pharmacokinetics of transdermal administration of CBD-containing base in beagles was also studied, and a transdermal preparation was made using a commercially available carrier (Pencream). The base was 70 mg (CBD / CBDA) and was applied topically to the inner ear twice daily.

[0298] Example 3 Research in cynomolgus monkeys This study evaluates the pharmacokinetics and utility of a proprietary cannabis oil containing a mix of cannabinoids, with approximately 90% of the mix being CBD and CBDA, in the management of idiopathic diarrhea in cynomolgus monkeys.

[0299] In one experiment, a group of four macaques was evaluated for pharmacokinetic properties. Each macaque was administered a single oral dose of 2 mg / kg cannabis oil via gummy treat. Figure 11 shows serum levels of CBDA (top / blue dashed line), CBD (top / blue solid line), THCA (bottom / green dashed line), and THC (bottom / green solid line) at the indicated time points. Note that the acidic form of the cannabinoids appears to be better absorbed. Furthermore, CBDA and CBD were present in approximately equal proportions in the cannabis oil.

[0300] In another experiment, nine macaques diagnosed with idiopathic diarrhea were given a unique dose of cannabis oil concealed in marshmallows at a dose of 2 mg / kg once every 12 hours. This treatment was given in addition to the typical treatment to macaques in the colony diagnosed with idiopathic diarrhea. Macaques that received both the cannabis oil treatment and the typical treatment showed a 33% reduction in length of hospital stay compared to historical data for macaques that only received the typical treatment (p=0.1).

[0301] In another experiment, 15 macaques (7 females, 8 males) were administered a single dose of 2, 4, or 8 mg of cannabis extract. The macaques were bled at zero, 0.5, 1, 2, 4, 8, 12, 24, 168 (7 days), and 336 hours (14 days) after dosing. Data on various cannabinoids and cannabinoid metabolites in macaque serum was collected and analyzed via targeted mass spectrometry, and the results are shown in Table 1 below. Animals 1, 2, 5, 7, 8, 9, 12, and 14 were administered cannabis extract in oil form. Animals 3, 4, 6, 10, 11, 13, and 15 were administered cannabis extract in gummy form. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 2]

[0302] Example 4 Noise aversion treatment in dogs This study evaluates the effectiveness of a proprietary cannabis oil in treating noise aversion in dogs.

[0303] method The study evaluates a cohort of 15 dogs. Patients receive a cannabis oil-based chew formulation at a dose of 4mg / kg once 2 hours before the event over a one-day period. The proprietary cannabis oil contains a mix of cannabinoids, with approximately 90% of the mix being CBD and CBDA. The study has a crossover design, includes a three-day washout period, and is double-blind.

[0304] Inclusion criteria included dogs that were manageable and cooperative with study procedures. Dogs must also react with at least three signs of fear to recordings of fireworks, storms, or thunder (day 1) and score at least 30 on the Lincoln Sound Sensitivity Scale. Owners must be able to connect via video conference. A diagnosis of noise aversion must be established (storm phobia, noise phobia). Acceptable medications include heartworm prevention (topical and oral), antiparasitic treatments, vaccinations, eye medications (including corticosteroids), antibiotics or antimicrobials, and nonsteroidal anti-inflammatory agents. Owners must be able to collect saliva and dogs must not have a history of aggression towards their owners.

[0305] Exclusion criteria include underlying diagnoses contributing to clinical signs of noise aversion, such as, but not limited to: a. current or past urinary tract disease in the past 30 days, b. current or past history of urolithiasis in the past 30 days, or c. diagnosed or suspected renal failure, diabetes, hypothyroidism, and neurological disease. Excluded medications include general anesthesia or sedatives within days 0 to 5, or use of CBD products, corticosteroids, diuretics, pheromones, tramadol, trazodone, benzodiazepines, gabapentin, opioids, hormones, or antihistamines within 7 days of the Day 0 study visit or at any time during the study. Excluded medications include buspirone, monoamine oxidase inhibitors, serotonin reuptake inhibitors, serotonergic drugs (not otherwise listed here), tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, and serotonin reuptake inhibitors / antagonists within 30 days of day 0. Excluded supplements and diets include those containing psychoactive ingredients, such as, but not limited to, l-theanine, magnolia, phellodendron, alpha-casosepin, and Shen Calmer within 7 days of day 0.

[0306] The daily protocol is as follows: Day 1: A 3-minute habituation period in which the dog is with a pet owner in a clinical setting with a study coordinator. The only handling allowed is typical stroking. For cortisol measurements, saliva is collected within 3 hours of waking in the absence of stressful events. Day 4: The unique cannabis oil or placebo is administered orally. After 2 hours, the dog is with a pet owner in a clinical setting with a study coordinator. The only handling allowed is typical stroking. The dog is exposed to the sounds of a thunderstorm for 3 minutes. Saliva is collected for cortisol measurements. Day 7: The unique cannabis oil or placebo is administered orally. After 2 hours, the dog is with a pet owner in a clinical setting with a study coordinator. The only handling allowed is typical stroking. The dog is exposed to the sounds of a thunderstorm for 3 minutes. Saliva is collected for cortisol measurements. Saliva will be collected for cortisol measurement.

[0307] Example 5 Safety and efficacy of cannabis oil administration in pet birds This study evaluates the safety and efficacy in managing intractable feather-picking in pet psittacine birds.

[0308] method The study evaluated a group of 24 birds. Patients were administered the proprietary cannabis oil at a dose of 15mg / kg every 12 hours for three months. The proprietary cannabis oil contains a mix of cannabinoids, with approximately 90% of the mix being CBD and CBDA.

[0309] The study included birds with feather-plucking behaviour where no underlying medical reason was identified that had been excluded by radiographs, direct fecal examination and blood tests, birds with identified and medically managed disease that had not improved clinically, and birds from which regular monthly blood samples could be taken to assess blood serum chemistry.

[0310] Excluded from the study were birds under 175 grams, birds exhibiting any identified medical conditions associated with untreated feather plucking or where clients were not following veterinary recommendations, and birds exposed to the stressful and unhealthy environmental conditions typically associated with feather plucking.

[0311] Eligible birds will be bled for hematology and chemistry and an aliquot (200 μL) will be taken for HPLC-MS method development.

[0312] Example 6 Treatment of aggressive lymphoma in dogs with CBD / CBDA This study evaluates quality of life in dogs with intermediate- to high-grade lymphoma treated with a standardized CBD+CBDA protocol.

[0313] method The study evaluates a population of 30 dogs. The study is blinded and patients with a cytological diagnosis of multicentric large cell lymphoma are randomized to one of two treatment groups, (A) prednisone alone, and (B) prednisone + CBD oil (5 mg / kg mix of CBD / CBDA as softgels). Dosages are as follows: (A) prednisone alone (2 mg / kg, PO, q24h for 1 week, then 1 mg / kg, PO, q48h), and (B) prednisone (2 mg / kg, PO, q24h for 1 week, then 1 mg / kg, PO, q48h) + CBD oil (5 mg / kg). Patients are evaluated by clinicians on days 0, 21, and 42. During each visit, a physical examination is performed and the following measurements are performed: lymph nodes, CBC, chemistry profile, and UA. 0.5 mL of serum will be reserved after each visit and stored at approximately -20°C for future CBD / CBA analysis. Patients will be evaluated by their owners on days 0, 21, and 42 to assess quality of life using a quality of life (QOL) questionnaire.

[0314] The following diagnostic procedures were performed on admission: physical examination, complete blood count, chemistry profile, urinalysis, lymph node measurements, and immunophenotyping.

[0315] The following inclusion and exclusion criteria apply: 1. Dogs with a cytologically or histopathologically diagnosed intermediate to high grade (medium to large cell) peripheral lymphoma are included, 2. Dogs with an estimated life expectancy without any interventional therapy of ≥ 3 days are included, 3. Dogs with known or suspected gastrointestinal involvement are excluded, 4. Dogs with known or suspected skin involvement are excluded, 5. Dogs with known or suspected internal disease only (liver / spleen) (without peripheral lymph node involvement) are excluded, 6. Dogs with clinically significant comorbidities and small cell lymphoma are excluded, and 7. Dogs receiving chemotherapy, L-asparaginase, and / or corticosteroids prior to enrollment are excluded. Corticosteroid therapy (oral and / or topical) within 2 months prior to enrollment is not permitted.

[0316] Four responses are evaluated in patients: (1) complete remission (CR), defined as the complete disappearance of all signs of disease; (2) partial remission (PR), defined as at least a 30% decrease in the mean sum LD (unidimensional) of target lesions; (3) progressive disease (PD), defined as at least a 20% increase in the mean sum LD of target lesions; and (4) stable disease (SD), defined as neither a sufficient decrease to qualify as a PR nor an increase to qualify as a PD. Patients who experience CR, PR, or SD continue to receive treatment until they develop PD. If CR is achieved, disease-free intervals (DFI), and / or median survival times (MST) are compared using Kaplan-Meier survival curves. In this study, two termination criteria are applied: (1) PD for more than 10 days, and (2) the development of cancer-related clinical signs or unacceptable toxicity, as determined by the owner / guardian or veterinarian.

[0317] All cases are reviewed by the same clinical pathologist. For patients with cytology, histopathology, and / or immunophenotyping, 3-6 lymph node aspirates are collected per case on positively charged slides. It is preferable to obtain slides from a single lymph node. Slides from enrolled cases are labeled with the patient name, lymph node site, and collection date. Slides are then placed in a slide container and set aside for sending to the laboratory (EVP) once every 2 months.

[0318] A quality of life (QOL) questionnaire will be used by the owner to assess the patient's status. Dog owners will be provided with the "Canine Cancer Treatment Survey" document (pdf). A baseline form (day 0) will be completed by the dog owner at the time of enrollment and submitted to the State of Iowa. Subsequent QOL questionnaires will be completed by Iowa State staff via telephone with the dog owner on days 7, 14, and then monthly thereafter. A terminal QOL questionnaire will be completed by Iowa State staff after the dog dies or is euthanized. Dog owners can expect Iowa State staff to call for updates and completion of the QOL survey based on the outlined timeline.

[0319] Example 7 Treatment of skin wounds in dogs with CBG / CBGA This study evaluates the effects of topical CBG / CBGA on wound healing and topical CBD / CBG pyoderma models in dogs.

[0320] method The study will evaluate a cohort of six dogs. Patients will receive 20mg of CBG / CBGA or vehicle control every 12 hours to the area (unilateral treatment, unilateral vehicle control) and the lesions will be photographed every 2 days until resolution or until required closure at 2 weeks. The study will be blinded and will include a 2 week washout period. The second phase will be the application of 30mg of CBD / CBG to the induced pyoderma area. Dogs will be screened for any skin abnormalities and a physical examination will be performed.

[0321] During Phase 1, lesions are photographed every 2 days until resolution or until necessary closure at 2 weeks. Visual assessment of lesions is performed daily by a clinician blinded to treatment. Images are evaluated for granulation and re-epithelialization. At the end of the study, skin biopsies are taken for histopathology and aerobic and anaerobic cultures, and a complete blood count (CBC), blood chemistry panel, and urinalysis are performed to evaluate any systemic effects of treatment. Blood cannabinoid levels are also evaluated.

[0322] During the second phase, dogs are shaved bilaterally in the area just above the shoulders. A Staphylococcus aureus inoculum is applied for 3 days to mechanically disrupt the epidermal layer in this area and induce superficial pyoderma. Once pyoderma is induced (confirmed by visual inspection and impression cytology, and superficial aerobic bacterial cultures are also taken), the area is then treated with either vehicle control or 40 mg CBD / CBG. Pyoderma is assessed by a blinded clinician via daily clinical lesion scoring and skin impression cytology every 2 days until resolution. Photographs of lesions are also taken. Skin biopsies for histopathology and superficial swabs for aerobic skin cultures are taken at the end of the study, at resolution, or at termination 2 weeks later. Dogs undergo CBC, blood chemistry panel, and urinalysis to evaluate the systemic effects of treatment. Blood cannabinoid levels are also evaluated.

[0323] Example 8 Pharmacokinetics of cannabis oil treatment in horses This study evaluates the pharmacokinetics of proprietary cannabis oil in horses. The proprietary cannabis oil contains a mix of cannabinoids, with approximately 90% of the mix being CBD or CBDA. The study evaluates a cohort of eight horses at a dose of 2mg / kg. Patients receive proprietary cannabis oil (70mg / mL) at a dose of 12mg / kg once every 12 hours for a period of time. The study includes a 2-week washout period between randomized CBD or CBDA treatments. Collection times for serum samples are as follows: Day 1: 0, 1, 2, 4, 12, and 24 hours, Day 7: 0, 1, and 2 hours, and Day 14: 0, 1, and 2 hours.

[0324] Example 9 Pharmacokinetic and safety studies of cannabidiol-based oil treatment in horses This study evaluates the pharmacokinetics and safety of proprietary cannabis oil in horses.

[0325] method The study will evaluate a group of seven horses. The patients will receive CBD or CBDA isolate oil at a dose of 1 mg / kg CBD or CBDA once every 12 hours for six weeks. The study will have a crossover design and will include a two-week washout period. Selection of the horses will be based on previously diagnosed chronic musculoskeletal pathology.

[0326] Specific clinical and laboratory evaluations will be performed on each horse to meet the following three objectives: (1) Pharmacokinetics: Blood samples will be obtained from each horse at time points (0, 15 min, 30 min, 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, 24 hr, and 1, 2, 4, 6 weeks of each oil dosing period). Serum will be stored at -80°C for subsequent cannabinoid concentration evaluation. (2) Safety: The safety of the cannabinoid oil will be evaluated based on the following: 2a. Clinical Tests: Performed daily during the 12 week dosing period to rule out psychotropic effects and evaluate the occurrence of signs suggestive of complications. 2b. Diagnostic Tests to evaluate body system function and changes in inflammatory and metabolic status: Blood tests will include a complete blood count (CBC), serum chemistry panel, metabolic panel (baseline cortisol, ACTH, insulin, leptin), and cytokine panel. Blood will be collected and analyzed at the following time points (0, 2 weeks, 6 weeks, 10 weeks, and 14 weeks after enrollment). 2c. Liver Ultrasound and Histopathological Evaluation: Transcutaneous ultrasound evaluation will be performed at the beginning and end of the study to evaluate the final changes in liver structure and echogenicity and to identify the location of liver biopsy. Liver biopsies will be obtained percutaneously using a tru-cut device under ultrasound guidance. Liver biopsy samples will be performed at the beginning (week 0) and end (week 14) of the study period. (3) Efficacy: The clinical response to the administration of CBD, particularly its effect on chronic pain, will be evaluated using a standardized objective pain scoring system and lameness assessment utilizing a commercially available inertial sensor system (Equinosis Q™ with lameness locator® biomechanical platform [Columbia, Missouri, USA]) that provides an objective measurement of sound. After recording baseline data at time 0 before CBD administration, a pain scoring system will be applied daily for 14 weeks, while claudication will be graded and recorded weekly via a claudication locator system.

[0327] Example 10 Pharmacokinetics of cannabis oil treatment in horses This study evaluated the intestinal pharmacokinetics and gastrointestinal motility of a cannabidiol-based oil treatment in horses.

[0328] method The study evaluated a cohort of eight horses. The horses were administered a single dose of proprietary cannabis oil (70mg / mL) at either a dose of 2mg / kg or 8mg / kg. The proprietary cannabis oil contains a mix of cannabinoids, with approximately 90% of the mix being CBD and CBDA. The study included healthy adult horses with a two-week washout period and a body condition score of 3-7 out of 9. Prior to the washout period, one dose (either 2mg / kg or 8mg / kg) was administered. Following the washout period, the horses were administered a second dose containing the dose that had not yet been administered. The following parameters were calculated: plasma concentrations of cannabidiol (and other cannabinoids) at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, and 48 hours after oral administration of cannabis oil at 2 mg / kg CBD and CBDA; plasma concentrations of cannabidiol at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, and 48 hours after oral administration of CBD and CBDA at 8 mg / kg; physical examination findings including any clinical abnormalities identified; neurological examination findings and recordings; weight of stool produced every 6 hours; and number of barium balls excreted in the stool every 6 hours. From the collected data, the following parameters are calculated: Tmax: time to reach maximum measured plasma concentration; Cmax: maximum measured plasma concentration; t0.5: measured plasma concentration half-life; AUC: area under the plasma concentration curve; K: first order elimination rate constant; kilograms of feces produced per hour; and number of barium balls per kilogram of feces produced.

[0329] Tables 2 and 3 below show pharmacokinetic data for eight different horses administered doses of 2mg / kg and 8mg / kg cannabis oil. Blood samples were taken from each horse at the indicated time points and subjected to targeted mass spectrometry to determine serum concentrations of the indicated cannabinoid compounds and metabolites. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0330] Example 11 Pharmacokinetic study of cannabis extract paste in cats This study evaluates the pharmacokinetics of cannabis oil paste in cats.

[0331] method The study will evaluate a cohort of 10 cats. Patients will be administered a paste at a dose of 2mg / kg of the proprietary cannabis oil once every 12 hours for approximately 15 days. The proprietary cannabis oil contains a mix of cannabinoids, with approximately 90% of the mix being CBD and CBDA. Patients will be healthy short-haired house cats between 1 and 8 years old and weighing between 4 and 5.5kg.

[0332] The study will utilize 10 cats for 15 days. On day 0, the test article will be administered in the morning and food will be provided immediately after. Serial blood draws for pharmacokinetic analysis will be obtained from each cat over a 24 hour period. Following the 24 hour blood draw, starting on day 1, the test article will be administered BID for 14 days. On days 7 and 14, 6 hour blood draws will be performed for pharmacokinetic analysis after morning dosing. All cats will be fed only the control diet during the study. Daily observations, food consumption, and weekly body weights will be assessed throughout the study. Physical examinations will be performed prior to the start of the study and at the completion of the study. Blood analyses (CBC and chemistry screen) will be performed prior to the start of the study and at the conclusion of the study.

[0333] Example 12 Anti-inflammatory effects of CBD / CBDA in dogs This study evaluates the pharmacokinetics of cannabis oil chews in dogs.

[0334] method In this study, a cohort of eight dogs will be evaluated. Blood will be collected from the dogs and undergo lymphocyte and neutrophil isolation. PMA-induced neutrophil chemotaxis, reactive oxygen species production, and phagocytic function will be evaluated after 24-48 hours using in vitro assays. Incubations with 50 and 500 ng of CBD, CBDA, and whole plant extract will be performed. Additionally, ConA and PHA stimulated T cell functional assays will be performed with similar incubations examining T cell production of pro-inflammatory cytokines (IL-17, IL2, IL-4, and IFN gamma) and the anti-inflammatory cytokine IL-10 using ELISPOT assays over a 72 hour period. Additional prostaglandin ELISAs will be performed on neutrophil supernatants and A-72 fibroblast assays will be performed after 48 hours of CBD, CBDA, and whole plant extract stimulation followed by 24 hours of LPS. Additionally, cytokine arrays of treated A-72 fibroblast supernatants will be performed by Eve Technologies. Based on the results, to further understand the effect of cannabis oil on immune cell function, a second set of studies will be evaluated examining the in vivo effects on cells before and after treatment in dogs with chronic inflammatory conditions.

[0335] Example 13 Pharmacokinetic study of CBG / CBGA cannabis oil in dogs This study evaluates the pharmacokinetics of cannabis oil containing cannabigerol (CBG) and cannabigerolic acid in dogs.

[0336] method The study evaluates a cohort of six dogs. Patients will be administered a proprietary cannabis oil containing cannabigerol / cannabigerolic acid at an oral dose of 2 mg / kg (approximately 1 mg CBG and 1 mg CBGA) in a sesame oil base, with 24-hour pharmacokinetics assessed, then every 12 hours on days 2-14, and serum assessed 6 hours after the morning dose on days 7 and 14 of dosing in weeks 1 and 2. Dogs will fast during this phase and be given food 2 hours after dosing during this study phase. Dogs will then have a 2-week washout period, after which they will undergo the same protocol of being fed 1 / 4 can of wet food while on CBG / CBGA oil for the next 2-week period. Dogs will be assessed for physical examination and heart rate multiple times on the first day of dosing, then every 3-4 days during the study week.

[0337] The daily protocol is as follows: Day 1: blood draws, physical examination, and heart rate measurements are performed at 0.5, 1, 2, 4, 8, 12, and 24 hours. Day 2: blood draws, physical examination, and heart rate measurements are performed. Day 3: blood, heart rate measurements, and physical examination are performed. Day 7: physical examination, heart rate measurements, and blood draws are performed. Day 10: physical examination and heart rate measurements are performed. Day 14: physical examination, heart rate measurements, and blood draws are performed. Day 27: blood draws, physical examination, and heart rate measurements are performed. Day 28: blood draws, physical examination, and heart rate measurements are performed at 1, 2, 4, 8, and 12 hours. Day 29: blood draws, physical examination, and heart rate measurements are performed. Day 30: physical examination and heart rate measurements are performed. Day 35: physical examination, heart rate measurements, and blood draws are performed. Day 38: physical examination and heart rate measurements are performed. Day 42: A physical examination, heart rate measurement, and blood draw will be performed.

[0338] Example 14 P450 and P-gp characterization of CBD, CBDA, and cannabis extracts in dogs These two studies aimed to identify the key canine P450 and P-gp proteins involved in the metabolism of CBD and CBDA in the liver and to determine the potential of CBD, CBDA, and cannabis extracts rich in CBD and CBDA to inhibit canine P450 drug metabolism.

[0339] Methods (P450 characterization) In this first study, an in vitro substrate depletion assay is performed to measure the metabolic rate of CBD and CBDA in dog liver. Incubations are performed using pooled dog liver microsomal fractions and P450 cofactors. Substrate remaining during incubation is measured by HPLC-MS and compared to a negative control reaction using inactivated microsomes. Complementary studies to evaluate direct conjugation by UDP-glucosyltransferases (UGTs) as an alternative (non-P450) metabolic pathway are also performed using the same approach (UGT cofactors instead of P450 cofactors).

[0340] Determine the metabolic rates of CBD and CBDA by all available canine recombinant P450 enzymes (8 commercially available and 3 produced in PI's laboratory). The assay is the same as above, except that recombinant P450 enzymes are used instead of liver microsomes. Because the amount of each P450 enzyme varies widely in the liver, the results for canine liver are extrapolated using the tissue-specific P450 concentrations previously determined for each isoform.

[0341] Inhibitory potency (i.e., IC50) is determined by measuring the metabolic reduction of P450-specific marker activity in pooled dog liver microsomes with increasing concentrations of CBD, CBDA, and cannabis extract. P450-specific markers include bupropion 6-hydroxylation (CYP2B11), dextromethorphan O-demethylation (CYP2D15), and omeprazole sulfoxidation (CYP3A12). IC50 values ​​are determined both with and without preincubation of liver microsomes with potential inhibitors to assess whether there is mechanism-based, time-dependent inhibition.

[0342] The following parameters will be evaluated: (1) the rates of CBD and CBDA metabolism by dog ​​liver microsomes and 11 recombinant dog P450 enzymes, (2) the predicted contribution of each P450 to total CBD and CBDA metabolism in dog liver, and (3) IC50 values ​​for inhibition of CYP2B11, CYP2D15, and CYP3A12 metabolism in dog liver both with and without inhibitor preincubation.

[0343] partial results

[0344] The initial results are shown in Figures 12-15.

[0345] CBD and CBDA extracts produced results that were identical to the respective pure compounds. See Figures 12A-12C, compare "10 μM CBD" with "10 μM CBDA-extract" and "10 μM CBDA" with "10 μM CBD-extract."

[0346] CBD and CBD-extract showed a time-dependent inhibition (TDI) of all P450 activities, whereas CBDA and CBDA-extract showed no TDI (compare "No preincubation" bar (left bar, unoutlined) with "20 min preincubation" (right bar, outlined)).

[0347] Figures 13-15 show activity assays for CYP3A12 (Figures 13A and 13B), CYP2B11 (Figures 14A and 14B), and CYP2D15 (Figures 15A and 15B). Assays were performed using either no preincubation (Figures 13A, 14A, and 15A) or 20 min preincubation (Figures 13B, 14B, and 15B). Only CBD and CBD extracts showed strong inhibition (e.g., IC50 less than 1 μM). This occurred when either CBD or CBD-extracts were preincubated with microsomes and NADPH, and neither CYP2B11 activity (tramadol N-demethylation, Figure 14B) nor CYP3A12 activity (midazolam hydroxylation, Figure 13B) was measured.

[0348] CYP2D15 activity (tramadol O-demethylation, Figures 15A and 15B) was much less potently inhibited by all compounds (IC50 >3 uM), regardless of preincubation.

[0349] 5. Overall, these results suggest that CBD and CBD-extracts may have clinically relevant interactions with CYP2B11 and CYP3A12 substrates in vivo. However, these results are preliminary.

[0350] Methods (P-gp characterization) In this second study, a competitive P-gp substrate assay incorporating a canine P-gp expressing cell line is used to evaluate the ability of each test compound to compete with the P-gp substrate rhodamine 123. Each concentration is tested on three different days in duplicate. Positive and negative controls are included in each run.

[0351] The results for each concentration of test compound evaluated are reported as a non-P-gp substrate, a weak P-gp substrate, a moderate P-gp substrate, or a strong P-gp substrate. The concentrations for CBD and CBDA are as follows: 10 ng / mL, 100 ng / mL, and 1,000 ng / mL.

[0352] result

[0353] A competitive P-gp substrate assay using a canine P-gp expressing cell line was used to evaluate CBDA and / or CBD as substrates for canine P-glycoprotein.

[0354] Suggested concentrations for CBD and CBDA are: 10 ng / mL, 100 ng / mL, and 1,000 ng / mL.

[0355] Data for CBD at 1,000 ng / mL are shown in Table 4. The highest concentration of CBD tested did not compete with rhodamine for PGP efflux, with an MFI ratio essentially identical to the negative control, implying that CBD is not a substrate for canine PGP in this assay. Results for lower concentrations of CBD appear similar, but final data have not been collected. [Table 5]

[0356] Example 15 Effects of cannabidiol on canine neoplastic cell proliferation and mitogen-activated protein kinase activation during autophagy and apoptosis This study evaluates both the antiproliferative and cell death responses associated with in vitro treatment of canine cancer cell lines with CBD alone and in combination with common chemotherapeutic agents, as well as proliferation pathways (e.g., p38, JNK, AKT, and mTOR) potentially involved in the response to treatment with CBD.

[0357] Materials and Methods

[0358] 1. Cannabinoids and chemotherapeutic agents CBD and its acid derivative, CBDA, are purchased as 10 mg / mL and 1 mg / mL formulations in methanol, respectively (Cayman Chemical Corporation, Ann Arbor, Michigan). Cannabis-based whole extracts are received directly from the manufacturer, and third-party analysis (Proverde Laboratory, Milford, Massachusetts) revealed a product containing approximately 30 mg / mL CBD, 31 mg / mL CBDA, 1.4 mg / mL THC, and 1.3 mg / mL tetrahydrocannabinolic acid (THCA) in an ethanol base, along with less than 1 mg / mL cannabigerolic acid, cannabichromene, and cannabinol, and 5.2 mg terpenes (ElleVet Sciences, Portland, Maine). Extracts are diluted to 20 mg / mL in a 50% / 50% mix of ethanol and DMSO. The final stock extract contains 20 mg / mL cannabidiol as an equal mix of CBD (10 mg) and CBDA (10 mg), as well as 0.4 mg / mL THC, 0.4 mg THCA, up to 0.1 mg cannabichromene (CBC) and cannabigerol (CBG) along with 1.8 mg of conjugated terpenes. The chemotherapeutic agent doxorubicin hydrochloride (Sigma Aldrich, St. Louis, Missouri) is freshly diluted in water to a 2 mM stock solution, while vincristine sulfate (Sigma Aldrich, St. Louis, Missouri) is prepared as a 10 μM stock solution in sterile water prior to utilization in cell culture experiments.

[0359] 2. Cell lines and culture conditions

[0360] Five established canine neoplastic cell lines, a mammary epithelial carcinoma cell line-CMT12, a B-cell lymphoma line-17-71, and three mesenchymal osteosarcoma lines, HMPOS, D17 (#CCL-183; ATCC, Manassas, Virginia) and Abrams, are obtained and used in all experiments. The Abrams cell line is validated from its original source, while the D17 cell line is a validated cell line from the American Type Culture Collection. The CMT12, 17-71, and HMPOS cell lines have not been genetically validated, but display cell markers and characteristics of epithelial, round, and osteosarcoma cell lines, respectively. All cell lines are deemed mycoplasma-free by polymerase chain reaction from the Animal Health and Diagnostic Laboratory at Cornell University.

[0361] All cells are maintained on tissue culture treated plates (Laboratory Product Sales [LPS], Rochester, New York) using Roswell Park Memorial Institute (RPMI) medium 1640 (Invitrogen, Carlsbad, California) containing 10% fetal bovine serum (FBS; Invitrogen, Carlsbad, California) and 1% antibiotic and antimycotic solution (Invitrogen, Carlsbad, California).

[0362] Unless otherwise indicated, cell lines are grown at 37°C and 5% CO2 for all experiments and cell passage. Primary canine dermal fibroblasts (Applied Biological Materials [ABM], Richmond, BC, Canada) are grown and maintained on PriCoat T25 flasks (ABM) in Prigrow II medium (ABM) containing 10 HI-FBS and 1% penicillin / streptomycin (Invitrogen, Carlsbad, California). Dermal fibroblasts are used to determine the effect of the extract on normal cells.

[0363] 3. 48-hour MTT proliferation of cannabidiol- and CBD-rich cannabis 3-(4,5-Dimethyltyzol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays are performed on all previously described cell lines: CMT12, HMPOS, D17, Abrams, and 17-71. Cells are seeded at a density of 2500 cells per well in 96-well tissue culture treated plates (Laboratory Product Sales, Rochester, New York). Cells are treated for 48 hours with vehicle (methanol or ethanol / DMSO mix) or various concentrations of CBD, CBDA, or CBD-rich cannabis extract ranging from 0.42 to 20 μg / mL in serial dilutions. After 48 hours of treatment, MTT assays are performed by adding 20 μL of MTT dye (5 mg / mL filtered at 0.7 μM in phosphate buffered saline [PBS]) to each well and incubating for 2 hours at 37°C in 5% CO2. The medium is then aspirated, washed once with 200 μL PBS, and then solubilized in 200 μL ethanol. Immediate analysis of the optical density of each well is performed using a spectrophotometric plate reader (Epoch; Biotek, Winooski, Vermont) at a wavelength of 570 nm, as previously described (see, for example, Vega-Avila E and Pugsley MK, An overview of colorimetric assay methods used to assess survival or proliferation of mammalian cells, Proc West Pharmacol Soc., 2011, 54, pp. 10-14, which is incorporated herein by reference in its entirety). The percentage of proliferating cells of the control for each concentration is averaged and reported as the mean + / - SD from triplicate wells across three experiments.

[0364] 4. Doxorubicin Cytotoxicity / Proliferation Assay CMT12, 17-71, and D17 cells are seeded at a density of 2500 cells per well in 96-well tissue culture treated plates (Laboratory Product Sales, Rochester, New York). All cell lines are treated with identical concentrations of pure CBD (0.34, 0.67, 1.25, 2.5, 5, 10, 20 g / mL) and various concentrations of doxorubicin or vincristine. The concentration of doxorubicin varies between cell lines to achieve 20%-80% growth inhibition. Cell lines are treated with serial dilutions of doxorubicin as follows: CMT12 and D17 (0.067-2 μM) and 17-71 (0.0167-0.5 μM). Methanol is used as a vehicle control for all CBD treatments, and sterile water for doxorubicin and vincristine at the highest dose is used to represent vehicle control treated wells. The cells are then incubated for 48 hours before performing the MTT assay as described above.

[0365] Vehicle control treated wells were considered to represent 100% proliferating cells in triplicate across three experiments. The percentage of viable cells for each particular combination was averaged and reported as the mean proliferation rate + / - SD for further CI evaluation.

[0366] 5. Trypan Blue Exclusion Assay for Cell Viability Trypan blue exclusion assays were performed on primary canine dermal fibroblasts (CDF), excluding the productive MTT assay, due to the slow proliferation rate and low metabolic activity of these normal canine cells. The effect of CBD treatment is compared to the results obtained with 17-71, CMT12, and D17 cell lines for comparative purposes. For CDF cells, applied cellular extracellular matrix (ABM) is applied overnight to 24-well tissue culture treated plates (Applied Biological Materials [ABM], Richmond, BC, Canada). For all cell lines, cells were plated at 5 × 10 per well. 3After seeding at a cell density of 1000 x g / mL and incubating to 60% confluence, cells are treated with methanol vehicle control, 3.75, 7.5, and 15 μg / mL CBD for 48 hours. Cells are then trypsinized, harvested, and centrifuged at 1900 g for 10 minutes. Except for the 17-71 cell line, cells are separated with Accumax (Invitrogen, Carlsbad, California). Cell pellets are resuspended in 0.1% trypan blue (Sigma Aldrich, St Louis, Missouri) in PBS solution, placed on Cell Countess disposable cell counting slides, and all positively stained cells are automatically counted in a Countess II Cell Counter (Invitrogen; ThermoFisher Scientific, Carlsbad, California) under identical settings for each cell line, using the same parameters for each cell line.

[0367] All treatments are performed in triplicate and the percentage of viable cells is averaged.

[0368] 6. MTT and Trypan Blue Data Management and Calculation

[0369] Raw data (individual optical density of each well) from the MTT proliferation assay and trypan blue exclusion assay are normalized to the vehicle control treatment (single or combined treatment) of each cell line, which is considered to represent 100% proliferating cells. The percentage of proliferating cells is determined by comparing the optical density measurements or viability counts of each of the treated wells at each concentration compared to the vehicle control wells for each cell line.

[0370] The concentrations required to obtain 50% inhibition of cell proliferation (IC50) for CBD, CBDA, and cannabis extracts are then calculated between experiments by probit analysis using XLFit5 software (IDBS, Guildford, United Kingdom) to report the results for each cell line.

[0371] To determine CI values ​​according to formula I, the compound interactions of chemotherapy and CBD treatments in the CI study are calculated using Compusyn software (v.2; Compusyn Inc, Paramus, New Jersey) using the median equation principle according to the method described by Chou and Talalay (Chou TC, Drug combination studies and their synergy quantification using the Chou-Talalay method, Cancer Res., 2010, 70(2), pp. 440-446, which is incorporated herein by reference in its entirety).

number

[0372] 7. Annexin V-FITC Apoptosis Assay Apoptosis after 4 and 8 hours of treatment is measured using Annexin-V staining (Invitrogen Annexin V-FITC staining kit, Carlsbad, California). Briefly, cells are detached with Accumax (Innovative Cell Technologies, San Diego, California), harvested, and centrifuged at 1000 g for 10 minutes at 4° C. The pellet is washed once with PBS and then diluted with approximately 1×10 6 cells in Annexin Binding Buffer (ABB; 10 mM HEPES, 140 mM NaCl, 2.5 mM CaCl2, pH 7.4). 6Cells are resuspended at a density of 1000 cells / mL. Annexin V-FITC conjugate is added to the cell suspension as suggested by the manufacturer and incubated for 15 min at room temperature. After incubation, ABB is added to the cell suspension and kept on ice until fluorescence is measured using a BD FACScalibur flow cytometer (BD Biosciences, Ashland, Oregon) using an argon laser. Ten thousand events are collected per sample. Analysis is performed using FlowJo software (version 10.7.1. Becton, Dickinson, Ashland, Oregon) by gating first on each cell line, then on forward and side scatter properties for Annexin V-FITC positive cells.

[0373] Negative fluorescent controls are unstained cells. For each treatment, three independent replicates are examined.

[0374] 8. Western Blot Assessment of Signaling Pathways and Autophagy Cells are seeded onto 100 mm tissue culture treated plates and incubated overnight in complete medium until 60% confluence is reached. Cells are treated with methanol vehicle control or 10 μg / mL CBD for 2, 4, or 8 hours. Cells are harvested and lysed at each time point for control and CBD treated cells using mammalian lysis buffer (25 mM Tris, 100 mM NaCl, 1 mM EDTA, 1% Triton X-100, pH 7.4) and then centrifuged at 12000 g for 5 minutes at 4° C. Supernatants are harvested and protein concentrations are determined using the Bradford assay (Coomassie dye; ThermoFisher Scientific Pierce, Waltham, Massachusetts). Samples are equilibrated to a common volume (µg / µL) in lysis buffer and 5x laemmili loading buffer (300 mM Tris-HCl pH 6.8, 10% sodium dodecyl sulfate, 50% glycerol, 12.5% ​​β-mercaptoethanol, 0.025% bromophenol blue). For each protein of interest, 30 µg of total protein is subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) on a gel ranging from 6% to 15% based on the molecular weight of the protein of interest. Proteins are then transferred to a 0.45 µm pore size polyvinylidene difluoride membrane (Immobilon-P Membrane, EMD Millipore, Billerica, Massachusetts) for 1 h at 333 mA and then diluted with Tris-buffered saline / 0.5% CO.Block in 5% milk in 0.5% Tween 20 solution (TBST). Incubate membranes overnight in primary antibody solution at a dilution of 1:1000 in TBST at 4° C. on a rocking platform. Primary antibodies that have been confirmed to be cross-reactive with canine cells or tissues include mouse extracellular regulated kinase (ERK) (R&D Biosciences, Boston, Massachusetts); rabbit anti-protein kinase B (AKT), Ser473 phosphorylated AKT, stress-activated protein kinase / jun-amino-terminal kinase (SAPK / JNK), Thr183 / Tyr185 phosphorylated SAPK / JNK, mammalian target of rapamycin (mTOR), Ser2448 phosphorylated mTOR, anti-Thr202 / Tyr204 phosphorylated p44 / 42 MAPK (ERK1 / 2), anti-p38, anti-phospho-p38, anti-p62, and anti-LC3 A / B (Cell Signalling Technology, Danvers, Massachusetts) (see e.g., Syrja P, Anwar T, Jokinen T, Kyostila K, Jaderlund KH, Cozzi F, Rohdin C, Hahn K, Wohlsein P,Baumgartner W,Henke D,Oevermann A,Sukura A,Leeb T,Lohi H,and Eskelinen EL,Basal Autophagy Is Altered in Lagotto Romagnolo Dogs with an ATG4D Mutation,Vet Pathol,2017 Nov,54(6),pp.953-963,doi:10.1177 / 0300985817712793, Gordon IK,Ye F,and Kent M,Evaluation of the mammalian target of rapamycin pathway and the effect of rapamycin on target expression and cellular proliferation insar osteocoma cells from dogs,Amer J Vet Res,2008,69,pp.1079-1084, Ikari A, Atomi K, Kinjo Y, and Sugatani J, Magnesium deprivation inhibits a MEK-ERK cascade and cell proliferation in epithelial Madin-Darby canine kidney cells, Life Sci, 2010, 86, pp. 766-773, and Levine CB, Bayle J, Biourge V, and Wakshlag JJ, Effects and synergy of feed ingredients on canine neoplastic cell proliferation, BMC Vet Res, 2016, 12(1), 159, which are incorporated by reference in their entirety. The membranes are washed three times with TBST and incubated in the corresponding secondary anti-rabbit IgG or anti-mouse IgG horseradish peroxidase-conjugated antibodies (Cell Signalling Technology, Danvers, MA) at a dilution of 1:2000 for 1 hour at room temperature. Membranes are washed three times with TBST and visualized with a chemiluminescence reagent (Clarity Western ECL Substrate; Bio-Rad, Hercules, California). Digital images are taken using an imaging system (Biospectrum 410; UVP, Upland, California or FluorChem E; Cell Biosciences, San Jose, California).

[0375] Each blot is performed twice from two different experiments to confirm findings.

[0376] 9.D17 and CMT12 Immunofluorescence

[0377] CMT12 and D17 adherent cell lines are split into Nunc chamber slides (ThermoFisher Scientific, Rochester, New York) and cells at 70% confluence are treated with either methanol control or 10 μg / mL CBD for 6 hours. Cells are fixed with 4% paraformaldehyde for 1 hour and then permeabilized with PBS containing 0.1% Triton X-100 for 30 minutes. Cells are then washed with PBS and incubated with bovine serum albumin (Sigma Aldrich, St. Louis, Missouri) for 30 minutes, then goat antiserum (Vector Labs, Burlingame, California) for 1 hour, then washed twice with PBS for 10 minutes with rocking at room temperature. Equivalent concentrations of rabbit polyclonal nonspecific antibody (Vector Labs, Burlingame, California) or polyclonal rabbit anti-LC3A / B antibody (Cell Signalling, Danvers, Massachusetts) are used at the same concentrations as described by Syrja and coworkers (Syrja P, Anwar T, Jokinen T, Kyostila K, Jaderlund KH, Cozzi F, Rohdin C, Hahn K, Wohlsein P, Baumgartner W, Henke D, Oevermann A, Sukura A, Leeb T, Lohi H, and Eskelinen EL, Basal Autophagy Is Altered in Lagotto Romagnolo Dogs with an ATG4D Mutation, Vet Pathol, 2017 Nov, 54(6), pp.953-963, doi:10.1177 / 0300985817712793 (which is incorporated herein by reference in its entirety). The cells are incubated overnight at 4°C and then washed twice with PBS. The cells are then incubated with a 1:400 dilution of Oregon Green 488-conjugated secondary goat anti-rabbit antibody (Invitrogen, Carlsbad, California) for 2 hours at room temperature.Coverslips are mounted using Vectrashield DAPI mounting medium (Vector Labs, Burlingame, California) and images are taken at 400 or 600 magnification with the same fluorescent intensity for each image and processed using an Olympus fluorescent microscope and DP controller software (Olympus Corp., Center Valley, Pennsylvania).

[0378] 10.Statistical analysis

[0379] All statistical analyses for the percentage of proliferating cells measured by MTT and Annexin-FITC assays are performed using JMP Pro (v.11.2.1; SAS Institute Inc., Cary, North Carolina). Residuals from statistical models were assessed for normality and found not to be normally distributed in most analyses. Therefore, nonparametric Kruskal-Wallis tests are used to compare differences in the percentage of proliferating cells for each treatment dose used within each cell line, across experiments. Comparisons between each treatment group and the vehicle control group are performed using the Steele method, which adjusts for alpha risk for multiple comparisons.

[0380] For viability outcomes determined by trypan blue exclusion assay, residuals from statistical models were found to be normally distributed and therefore will be analyzed using analysis of variance with Dunnett's test for comparisons with vehicle control, controlling for multiple comparisons. Differences are considered statistically significant at P<.05 for all statistical tests.

[0381] result

[0382] 1. 48-Hour MTT Assay CBD, CBDA, and Whole Cannabis Extract Examination of the probit analysis of CBD against the five cell lines revealed that the IC50 for 17-71 cells was 2.5 μg / mL, with concentrations ≥ 2.5 μg / mL causing a significant decrease in proliferation. The CMT12 cell line shows a similar profile, with a slightly higher probit IC50 of 3.5 μg / mL, with a significant decrease in proliferation at ≥ 2.5 μg / mL. Abrams, D17, and HMPOS showed similar probit analysis concentrations of 4.1, 4.1, and 3.6 μg / mL, respectively, with concentrations ≥ 5 μg / mL being significant in slowing cell proliferation compared to vehicle control treated cells (Figure 1A).

[0383] In conjunction with other cannabinoids and terpenes, the total cannabis extract, using a CBD concentration in the extract of 20 μg / mL or less, indicates that lower CBD concentrations are required across all cell lines. The cannabis extract shows a probit IC50 of approximately 0.8 μg / mL for the 17-71 cell line, with the first significantly different concentration slowing proliferation being 0.67 μg / mL or more. Probits for CMT12, Abrams, D17, and HMPOS cells reveal IC50s of 1.5, 1.3, 1.6, and 1.7 μg / mL, respectively, with these cell lines showing a significant reduction in proliferation of 1.25 μg / mL or more compared to vehicle control treated cells (Figure 1B).

[0384] Considering that the cannabis extract used has a significant proportion of CBDA, a 48-hour MTT assay is performed with CBDA. CBDA treatment of 17-71 cells shows an IC50 of 15.1 μg / mL, with concentrations above 5 μg / mL showing a significant slowing of cell proliferation. The CMT12 cell line shows a significant slowing of proliferation starting at 10 μg / mL and above, and an IC50 could not be determined since 50% growth inhibition is not achieved in the assay. Three osteosarcoma cell lines, Abrams, D17, and HMPOS, show significant growth inhibition at 20 μg / mL, but IC50 calculations could not be calculated due to the lack of growth inhibition (Figure 1C).

[0385] Graphs from Figures 1A-1C show assay results at three different time points performed in duplicate. * depicts initial concentrations that are significantly different from vehicle control treated baseline for 17-71, including any higher concentration (P<.05), ^ depicts initial points that are significantly different from vehicle control treated baseline for CMT12, including any higher concentration (P<.05). # depicts initial points that are significantly different from vehicle control treated baseline for D17, HMPOS, and Abrams, including any higher concentration (P<.05).

[0386] 2. Trypan Blue Exclusion Assay for CBD The percentage of trypan blue positive dermal fibroblasts for methanol vehicle control cells is 16±3% of the cell population. This is significantly higher when treated with 15, 7.5, and 3.75 μg / mL CBD for 48 hours at 77±12%, 58±7%, and 32±5%, respectively (FIG. 2). 17-71 cells show a trypan blue positive cell population of 3±1% when treated with methanol as a vehicle control. Trypan blue positive cells at both 15 μg / mL and 7.5 μg / mL are significantly increased at 55%±6% and 27±8%, respectively. 17-71 cells treated with 3.75 μg / mL are unchanged from vehicle control treated cells at 7±4% positive cells. D17 cells show a trypan blue positive cell population of 5±1% when treated with methanol as a vehicle control. At 15 μg / mL, trypan blue positive cells are significantly increased at 35±4%. D17 cells treated with 7.5 and 3.75 μg / mL are unchanged from vehicle control treated cells with 5±2% and 4±2% positive cells, respectively. CMT12 cells show a trypan blue positive cell population of 3±1% when treated with methanol as vehicle control. Trypan blue positive cells are significantly increased at 15 μg / mL with 87%±8% and 7.5 μg / mL with 9±3%. CMT12 cells treated with 3.75 μg / mL show no difference from vehicle control treated cells with 4±2% (Figure 2).

[0387] Each cell line from Figure 2 was assessed for trypan-positive cell death across three experiments, with * indicating a significant increase in trypan-positive cells compared to VC cells (P<.05).

[0388] 3. Combination Index MTT Dual Treatment Assay with CBD and Chemotherapeutic Agents (Doxorubicin / Vincristine)

[0389] When all three cell lines were treated with doxorubicin, the 17-71 lymphoma cell line was most sensitive at inhibitory concentrations of IC20-IC80 between 0.033 and 0.125 μM, while the CMT12 and D17 cell lines required higher concentrations (0.5-2 μM) to disrupt cell proliferation. Regardless of the cell line treated with doxorubicin, synergistic or additive effects are evident at higher concentrations of CBD (10 and 5 μM) with CI values ​​below 1.1, coupled with the IC20-IC80 concentrations of CBD (Table 5). The only universally antagonistic effects (CI values ​​above 1.1) observed across cell lines are with lower concentrations of CBD (2.5 and 1.25 μg / mL) and lower concentrations of doxorubicin. [Table 6]

[0390] When all three cell lines were treated with vincristine, the 17-71 lymphoma cell line again demonstrated the highest sensitivity to treatment with IC20-IC80 values ​​ranging from 0.25 to 1 nM, while the CMT12 and D17 cell lines treated with vincristine required higher concentrations (1.7-6.8 nM) to block cell proliferation. Almost universally, vincristine and CBD treatments demonstrated synergistic or additive effects regardless of the cell line tested, with nearly all CI values ​​below 1.1, suggesting that vincristine and CBD likely potentiate each other's effects in the canine neoplastic cell lines tested (Table 5).

[0391] 4. Annexin V Apoptosis Assay

[0392] Annexin V apoptosis assays using flow cytometry are performed at 4 and 8 hours after 8 hours of treatment with 15 μg CBD or vehicle control (methanol). Annexin V staining reveals a mean percentage and SD of positively stained cells of 31.0 ± 10.8% and 79.0 ± 6.1% at 4 and 8 hours, respectively, in the 17-71 cell line, showing a significant increase in positive cells at both 4 and 8 hours compared to VC cells and untreated cells (10.1 ± 0.4% and 9.9 ± 1.2%, respectively). D17 cells treated with CBD show a significant increase in Annexin V positive cells only at the 8 hour time point (24.0 ± 3.6%) when compared to VC cells (6.5 ± 0.6%) and untreated cells (3.3 ± 1.0%). D17 cells treated with 15 μg CBD for 4 hours (9.4 ± 1.8%) are higher than VC cells or untreated cells, but this increase is not significant. Similarly, the CMT12 cell line shows a significant increase in positive cells at 8 hours with 21.5±2.5% of cells staining for Annexin V. There is also an increase in Annexin V stained cells at 4 hours in the CMT12 cell line (15.7±2.2%), but this is not significantly increased from VC treated cells (10.9±2.0%) or untreated cells (13.9+0.6%) using a non-parametric conservative statistical test (Figures 3B, 3C, and 3D). Figures 3B, 3C, and 3D are bar graphs showing apoptosis of neoplastic cell lines 17-71, D17, and CMT12 following treatment with 15 μg / mL CBD. In these figures, the Annexin V apoptosis assay represents the relative percentage of Annexin V positive cells identified via flow cytometry. In these figures, results from baseline vehicle control treated cells (VC), untreated cells, and treated cells (4 and 8 hour treatment with 15 μg / mL CBD) are compared, with "*" indicating a significant increase from VC treatment (P<.05).

[0393] 5. Time-course Western Blot Analysis of Pathway Involvement

[0394] Multiple immunoblots are performed after treating cells with methanol vehicle control or 10 μg / mL CBD for 2, 4, and 8 hours. Immunoblots performed using AKT and phosphorylated AKT or mTOR and phosphorylated mTOR show no decrease in signal or increase in intensity over time, regardless of treatment, across two different time course analysis experiments. The lack of change suggests that the PI3 kinase-AKT-mTOR pathway is unchanged in its association with the induction of autophagy or apoptosis. Evaluation of the MAP kinase pathway shows a repeatable increase in both ERK and JNK phosphorylation across all three cell lines in the presence of 10 μg / mL CBD compared to an equivalent amount of methanol vehicle control treatment over an 8 hour time course (Figures 4A and 4B). ERK and phosphorylated ERK expression at 2, 4, and 8 hours shows widespread phosphorylation in 17-71, D17, and CMT12 cell lines at 2, 4, and 8 hours compared to methanol vehicle control treated cells. The presence of baseline ERK and JNK phosphorylation is not evident in 17-71 cells, both of which show abundant phosphorylation peaking at 4 h of treatment with CBD. ERK baseline phosphorylation is more evident in D17 and CMT12 cells, and is rapidly induced to peak at 2-4 h in these cell lines (Figure 4A). JNK phosphorylation status is stable in CMT12 cell lines following CBD treatment, while D17 cells show a more mild induction of phosphorylated JNK. Overall, baseline JNK and ERK protein expression across cell lines is virtually unchanged, regardless of treatment or time. The blots presented are representative of duplicate time-course immunoblot experiments performed.

[0395] In parallel with these time course analyses, assessment of LC3 protein is assessed as part of the autophagy response in cells over 8 hours. Overall, in all three cell lines, there is an increase in the LC3II proportion of LC3 protein, which represents the ethanolamine-conjugated form of the protein found in autophagy vesicles or autophagosomes. This increase in LC3II is notable starting at 2 hours of treatment and persists throughout the entire 8 hours of treatment, which is not observed in vehicle control treated cells. (Figure 5A). Coupled with the LC3II response, a notable decrease is also observed in western blots of the autophagy cargo carrier protein p62, another marker of autophagy that is well discussed in the literature (Yoshi SR and Mizushima N, Monitoring and measuring autophagy, Int J Mol Sci, 2017, 18, 1865, which is incorporated herein by reference in its entirety). These observations were also accompanied by activation of caspase 3, which could be seen at 2 h in 17-71 cells, but was not evident until 8 h in CMT12 and D17 CBD-treated cells, indicating that autophagy appears to precede the apoptotic response in these cells (Figure 5A).

[0396] 6. Immunofluorescence for LC3I / II

[0397] Cytofluorescence imaging is taken at 400x and 600x magnification for D17 and CMT12 cell lines, respectively. Use of rabbit polyclonal antibody as a control shows mild background fluorescence, which is minimal with or without 10 μg / mL CBD treatment (FIG. 5B). FIG. 5B, row 1 shows control rabbit antibody immunostaining on vehicle control treated cells. FIG. 5B, row 2 shows control rabbit antibody immunostaining on CBD 10 μg / mL treated cells. FIG. 5B, row 3 shows rabbit LC3A / B antibody immunostaining in vehicle control treated cells showing variable staining of the cytoplasm. FIG. 5B, row 4 shows rabbit LC3A / B immunostaining in cells treated with 10 ug / mL CBD showing punctate autophagosomes in the cytoplasm.

[0398] When using LC3A / B rabbit polyclonal antibodies, there is mild diffuse cytoplasmic staining in methanol vehicle control treated cells, regardless of the cell line used. Both CMT12 and D17 cells showed numerous discrete punctate, intensely staining vesicles when treated with 10 μg / mL CBD immunofluorescence with LC3A / B antibodies, consistent with LC3 protein localization to autophagosomes or autophagolysosomes (Figure 5B).

[0399] analysis The aim of this study was to examine whether CBD and its natural acidic form (CBDA) caused similar cytotoxic effects in a selected number of common canine cancers representing mesenchymal, round, and epithelial origins. In a multi-human cell line study, the results indicate that CBD uniformly caused similar canine cancer cell death, while CBDA had limited effects at the concentrations used, except for a mild effect on lymphoma cell lines at the highest concentration. These assays were incubated for 48 hours, similar to other natural product studies that often required more than 24 hours to induce cytotoxicity.

[0400] The results also demonstrate a significant reduction in canine cancer cell proliferation when treated with CBD concentrations ranging from 2.5 to 10 μg / mL with similar effects on all five cell lines tested. The CBD-rich whole cannabis extract used in this study resulted in a significant reduction in cancer cell proliferation at the lowest CBD concentrations ranging from 0.67 to 10 μg / mL. When using whole cannabis extract, select a CBD concentration identical to that used in the pure CBD experiments. The lethality of CBD in the presence of CBDA and / or other phytocannabinoids and terpenes at lower concentrations may be an enhancement of the whole plant extract effect in this study. This synergistic result is commonly reported as the "entourage effect" where a mixture of cannabinoids and terpenes may act in concert to also produce an enhancing effect.

[0401] The cell proliferation response upon treatment of 17-71, CMT12, and D17 cell lines with 10-15 μg / mL CBD results in apoptosis as demonstrated by Annexin V staining and cleaved caspase 3 immunoblot (Figure 3A), occurring within 8 hours of treatment. Figure 3A is an image of an immunoblot for cleaved caspase 3 (17Kda) after 8 and 16 hours of CBD treatment compared to methanol vehicle control, showing cleaved caspases across all cell lines at both time points. Additionally, the autophagy response is observed with a proportional phase shift of LC3-I to the phosphatidyl-ethanolamine LC3-II portion of the protein, p62 degradation and localization of the autophagosome-associated LC3 protein. Accompanying this rise in LC3-II is a concomitant decrease in the autophagy cargo adaptor protein SQSTM1 / p62.

[0402] Evaluation of cell signaling mechanisms reveals no significant changes in signaling pathways through AKT or mTOR signaling, however there is a repeatable and dramatic increase in phosphorylation of the MAP kinase pathway, specifically ERK and JNK signaling, with minimal effects on p38 phosphorylation and activation. The synergistic and antagonistic results of cancer cell growth are significant when treating canine cancer cells with commonly used chemotherapeutic agents in combination with CBD. The combination of vincristine and CBD consistently enhances the reduction of cell viability compared to either treatment alone, demonstrating a significant synergistic response at lethal to sublethal doses of both CBD and vincristine. Significantly, combined treatment with doxorubicin and CBD produces both synergistic and antagonistic results, depending on the specific concentration of each compound used. Based on the results, when more lethal doses of CBD and doxorubicin are utilized, there may be additive to synergistic responses, but at sublethal doses, the effects may be antagonistic. The doses of doxorubicin used in these in vitro assays were higher than those observed in dog serum during IV infusion when treating the CMT12 and D17 cell lines (1-2 μM), while the 17-71 cell line was much more sensitive to doxorubicin treatment at concentrations roughly 10-fold lower. Similarly, the 17-71 cell line was more sensitive to vincristine than the D17 and CMT12 cell lines, with all of the concentrations used being 5-20 fold lower than those observed to be effective in canine clinical use, which is approximately 20-40 nM.

[0403] Example 16 Canine Atopy Research A study was conducted to determine the effectiveness of cannabis extract for the treatment of atopy in dogs.

[0404] The study was a double-blind, prospective, placebo-controlled, randomized study. Client-owned dogs with atopic dermatitis (cAD) were included. Eligible dogs were diagnosed with cAD based on published guidelines. Owner consent was obtained for each case prior to the study. Parasitic and infectious causes of pruritus were excluded by negative combing, skin scraping, and cytological examination. No dog in the study showed improvement on a hydrolyzed diet or a novel protein-free diet 2 months prior. For each case, a skin examination was performed, and lesions and pruritus were assessed using a validated scoring system. Only cases of localized and mild-to-moderate cAD were included. Mild-to-moderate cAD was defined as patients with a pruritus visual analog scale (pVAS) score of 3-7 and a Canine Atopic Dermatitis Extent and Severity Index-4 (CADESI-4) score of 10-35.

[0405] Concomitant administration of cyclosporine (either brand name Atopica or generic microemulsion) is not permitted, and patients who have received this medication within the past 2 months will be excluded. Concomitant administration of allergen-specific immunotherapy, either injectable or sublingual, will be permitted for patients who have received this treatment for at least 1 year prior to the initial study. Concomitant administration of oclacitinib, oral glucocorticoids, ketoconazole, and other imidazoles will be permitted for patients who have received these medications for at least 2 months prior to the initial study. Patients who have received Cytopoint injections within 3 months of the initial study will be excluded. No changes in other treatments, concomitant medications, or medications will be permitted during the study. No changes in patients' typical bathing routine will be permitted during the study. No changes in diet will be permitted during the study.

[0406] The investigators were blinded to group allocation. Group A consisted of patients receiving an oral oil-based CBD:CBDA product in capsule form at a dose of 2 mg / kg twice daily. Group B consisted of patients receiving a corresponding placebo oil in capsule form. Dogs with comorbidities such as renal failure, liver disease, endocrine disease, or other immune dysfunction (ITP, IMHA) were excluded. The study involved 29 dogs with cAD (17 treatment and 12 control). Dosage with the oral CBD:CBDA product was approximately 2 mg / kg twice daily for 28 days. Owners were asked to administer the drug with food.

[0407] During the study, the doses of approved medications that patients were receiving prior to the study remained unchanged. Furthermore, no changes were made to the doses of medications within 21 days prior to the start of the study. procedure

[0408] Clients were asked to sign a consent form. On day (0), each dog underwent an initial consultation by the investigator, including a thorough medical history and physical examination. Treatment was initiated as described above, with follow-up visits at weeks 2 and 4. Changes in owners' perceptions of the extent and severity of atopic dermatitis were assessed using pVAS. Changes in the extent and severity of atopic dermatitis were assessed by veterinarian-based CADESI-4. The benchmarks separating normal / remission from mild, moderate, and severe cAD using CADESI-4 are 10, 35, and 60, respectively, as suggested by validation studies. Prior to the start of the study, all participating investigators were trained on how to assess and interpret the CADESI-4, including the evaluation of clinical cases. 1 cc of serum from visits 0 and 4 was stored at -20°C for future cytokine analysis and serum CBD testing.

[0409] analysis The current power analysis revealed that the population required to find statistical significance was approximately 13 patients with a standard deviation of 2.5 and a change in VAS scoring of 2.0 by owner. Eighteen dogs were enrolled based on a random number generator that assigned a maximum of 36 patients to group A or B to ensure adequate enrollment and completion of the study. After data collection and cleaning, all scores and blood parameters were evaluated using a mixed-model analysis of variance, including the effects of time, treatment, concomitant medication, and random effect of dog with an alpha set below 0.05 as significant. If differences were found, Tukey post-hoc tests were performed to evaluate differences between time points.

[0410] result Figure 6A shows the VAS scores for the treatment and control groups. Figure 6B shows the CADESI scores for the treatment and control groups at zero and four weeks. Significant differences are marked with asterisks at zero and four weeks.

[0411] Figure 7A shows alkaline aminotransferase levels in dogs treated with either CBD or placebo. Values ​​are shown for both zero and four weeks. Figure 7B shows alkaline phosphatase levels in dogs treated with either CBD or placebo. Values ​​are shown for both zero and four weeks.

[0412] FIG. 8 shows alkaline phosphatase levels in dogs when CBD treatment was combined with various other drugs, as indicated, or when CBD treatment was administered without other drugs (far right column).

[0413] Figure 9A shows serum levels of monocyte chemoattractant protein-1 (MCP-1) for study participants at zero and four weeks. Figure 9B shows serum levels of IL-6 for study participants at zero and four weeks.

[0414] Figure 10A shows serum levels of IL-31 for study participants at zero and four weeks. Figure 10B shows serum levels of IL-34 for study participants at zero and four weeks.

[0415] Those skilled in the art will appreciate further features and advantages of the present invention based on the above-described embodiments. Accordingly, the present invention should not be limited by what has been particularly shown and described, except as indicated by the appended claims. All publications and references cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A composition comprising a cannabis extract for use in a method for treating atopy in a veterinary subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of cannabis extract.

2. The veterinary subject is a dog; and / or the cannabis extract comprises CBD and CBDA; and / or the cannabis extract is administered orally, optionally the cannabis extract is administered via a capsule; and / or the cannabis extract comprises CBD and CBDA, and the cannabis extract is administered such that a dose of about 2 mg / kg of CBD and CBDA is administered; and / or The cannabis extract is administered once every 12 hours; A composition for use according to claim 1.

3. A composition for use in promoting wound healing in a veterinary subject in need thereof, said composition comprising a therapeutically effective amount of a cannabis extract.

4. The cannabis extract is administered topically; and / or the veterinary subject is a dog; and / or the cannabis extract comprises CBG and CBGA, optionally 20 mg of CBG and CBGA are applied to the wound, further optionally the CBG and CBGA are applied to the wound every 12 hours; A composition for use according to claim 3.

5. A composition for use in the treatment of hair plucking in a veterinary subject in need thereof, said composition comprising a therapeutically effective amount of a cannabis extract.

6. The veterinary subject is a bird; and / or the cannabis extract comprises CBD, CBDA, or a combination thereof, optionally the cannabis extract comprises 70 mg / mL total cannabinoids, further optionally the cannabis extract comprises 60 mg / mL CBD and CBDA; and / or said cannabis extract is administered at a dose of 60 mg / kg twice daily for three months; A composition for use according to claim 5.

7. A composition for use in the treatment of lameness in a veterinary subject in need thereof, said composition comprising a therapeutically effective amount of a cannabis extract.

8. The veterinary subject is a horse; and / or The cannabis extract comprises CBD, CBDA, or a combination thereof; and / or said cannabis extract is administered at a dose of 1 mg / kg every 12 hours; A composition for use according to claim 7.

9. A composition for use in a method for treating arthritis in a veterinary subject in need thereof, said composition comprising a therapeutically effective amount of a cannabis extract.

10. The subject is a rabbit; and / or The cannabis extract comprises CBD, CBDA, or a combination thereof; and / or The cannabis extract is administered at a dose of between 10 mg / kg and 25 mg / kg; and / or The cannabis extract is administered at a dose of about 15 mg / kg; and / or The cannabis extract is administered at a dose of about 20 mg / kg; and / or The cannabis extract is administered twice daily; 10. The method of claim 9.

11. The cannabis extract comprising: Cannabidiol; and Cannabidiolic acid Including, the ratio of cannabidiol to cannabidiolic acid is from about 0.6:1 to about 1:0.6; A composition for use according to any one of the preceding claims.

12. A cannabis extract comprising: Cannabigerolic acid; Δ9-tetrahydrocannabinol; and Cannabichromene and / or 4. The cannabis extract comprising: Cannabidiol; Cannabidiolic acid; Cannabigerolic acid; Δ9-tetrahydrocannabinol; and Cannabichromene Including, the ratio of cannabidiol to cannabidiolic acid is from about 0.6:1 to about 1:0.6; and / or 4. The cannabis extract comprising: α-pinene; β-Myrcene; β-pinene; δ-Limonene; Linalool; β-caryophyllene; α-humulene; Nerolidol 2; Guaiol; Caryophyllene oxide; and α-Bisabolol and / or The concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect; and / or The ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25; and / or The concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL; and / or the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL, less than about 0.3 mg / mL, less than about 0.2 mg / mL, less than about 0.1 mg / mL, or about 0 mg / mL; A composition for use according to claim 11.

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