Cannabis extracts for the treatment of pain, cancer, and epilepsy in animals

Abstract

The present disclosure relates to methods of treating epilepsy, cancer, and post-operative pain in veterinary subjects using pharmaceutical compositions and dosage forms comprising cannabis extracts.

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 870,043, filed July 2, 2019, and No. 62 / 962,114, filed January 16, 2020, the disclosures of each of which are incorporated herein by reference in their entireties.

[0002] A recent survey by the American Holistic Veterinary Medical Association found that approximately 60% of people who purchase cannabis products online use these products on their dogs. Industrial hemp products, which are low in THC (0.3%) and high in other cannabinoids, are reported to have health benefits including painkillers, anti-inflammatory agents, anti-anxiety agents, and anti-epileptic agents, and are legal according to the Industrial Hemp Act. Numerous online companies selling cannabis products, including CBD oil, claim that they are safe and effective for a variety of medical conditions in both pets and people. There is very little published data to support these claims, and no data exists showing the safety of using CBD oil concurrently with chemotherapy in veterinary patients. In the absence of optimal treatments for these dogs for pain, epilepsy, or cancer, other potentially effective agents, including cannabinoids, are often sought. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Provisional Patent Application No. 62 / 870,043 [Patent Document 2] U.S. Provisional Patent Application No. 62 / 962,114 Summary of the Invention [Problem to be solved by the invention]

[0004] The present disclosure is directed to compositions comprising cannabidiol and their use for the treatment of pain, epilepsy, or cancer in an animal. 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, The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6; The carrier comprises the biopolymer NF-971P and / or lecithin. [Means for solving the problem]

[0005] In another embodiment, the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, and Contains cannabichromene, The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6, and the carrier comprises the biopolymer NF-971P and / or lecithin.

[0006] 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 Contains alpha-bisabolol.

[0007] In one embodiment, the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect. In one embodiment, the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:25. In one embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0 mg / mL.

[0008] In one 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0009] In another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0010] In one 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0011] In one embodiment the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0012] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0013] In one embodiment, the composition is incorporated in a carrier.In one embodiment, the carrier is selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil and grapeseed oil.In one embodiment, the carrier is grapeseed oil.In another embodiment, the carrier is catnip oil.

[0014] In one embodiment, the composition comprises lecithin. In one embodiment, the lecithin is sunflower lecithin. In one embodiment, the sunflower lecithin is up to 40%. In one embodiment, the composition further comprises NF-971P, hi one embodiment, the NF-971P is at up to 2% weight / volume.

[0015] 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 Contains α-bisabolol, The composition includes one of the biopolymers NF-971P and / or lecithin.

[0016] In one embodiment the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, and Contains cannabichromene, The carrier comprises grape seed oil and one of the biopolymers NF-971P and lecithin.

[0017] In one embodiment, 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 another embodiment, the ratio of cannabidiol to cannabidiolic acid is about 1:1.

[0018] In one embodiment, the cannabis extract comprises cannabidiol and cannabidilic acid, without other components typically found in cannabis oil. In some embodiments, the cannabis extract does not comprise cannabigerophosphate, Δ9-tetrahydrocannabinol, or cannabichromene. In some embodiments, the cannabis extract does not comprise terpenes. In some embodiments, the cannabis extract consists of cannabidiol and cannabidilic acid. In some embodiments, 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 another embodiment, the ratio of cannabidiol to cannabidiol acid is about 1:1.

[0019] In some embodiments, the disclosure provides a purified pharmaceutical composition comprising cannabidiol and cannabidilic acid, and free of other components typically found in cannabis oil. In some embodiments, the purified pharmaceutical composition does not comprise cannabigerophosphate, Δ9-tetrahydrocannabinol, or cannabichromene. In some embodiments, the purified pharmaceutical composition does not comprise terpenes. In some embodiments, the purified pharmaceutical composition consists of cannabidiol and cannabidilic acid. In some embodiments, 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 another embodiment, the ratio of cannabidiol to cannabidiol acid is about 1:1.

[0020] In one aspect, provided herein is a dosage form comprising a therapeutically effective amount of the cannabis extract described above. In one embodiment, the dosage form comprises the pharmaceutical composition described above and one or more pharma- ceutically acceptable additives, flavoring agents, surfactants, and adjuvants. In one embodiment, the flavoring agent is selected from the group consisting of peppermint oil, mango extract, beef, chicken, and seafood.

[0021] In one embodiment, the dosage form is formulated as a sublingual spray. In another embodiment, the dosage form is formulated as a water-soluble or alcohol-soluble solution, or a cream for transdermal application. In another embodiment, the dosage form is formulated as a gel for buccal or intramucosal administration. In another embodiment, the dosage form is formulated as a powder. In another embodiment, the dosage form is formulated as a solution for subcutaneous injection. In another embodiment, the dosage form is formulated as a tablet. In another embodiment, the dosage form is formulated as a capsule. In another embodiment, the dosage form is formulated as a hard chew. In another embodiment, the dosage form is formulated as a soft chew. In another embodiment, the dosage form is formulated for administration using a nebulizer. In another embodiment, the dosage form is formulated for administration using a pet collar. In another embodiment, the dosage form is formulated for inhalation.

[0022] In one embodiment, the dosage form is formulated as a chew for oral administration. In one embodiment, the chew is manufactured using cold extrusion. In one embodiment, the chew weighs about 0.5-10 g. In another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In one embodiment, the chew weighs about 4 g.

[0023] In one embodiment, the chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerophosphate, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0024] In one embodiment, the dosage form is incorporated in a carrier for oral administration.In one embodiment, the carrier is selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil and grapeseed oil.In one embodiment, the carrier is grapeseed oil.In another embodiment, the carrier is catnip oil.

[0025] 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 Contains water.

[0026] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0027] In 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, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0028] 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 Contains water.

[0029] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0030] In one 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, Approximately 5.8% sunflower lecithin, and Contains approximately 5.8% water.

[0031] In another embodiment, the dosage form comprises: cannabis extract, Peanut butter, Rice bran, Glucosamine, Sweet potato, molasses, Brewer's yeast, sugar, water, Glycerin, and Contains rice starch.

[0032] In one embodiment, the flavoring agent is selected from the group consisting of chicken liver powder, chicken extract, maltodextrin, butter, and bacon, hi one embodiment, the flavoring agent is chicken liver powder.

[0033] In one aspect, provided herein is a method for treating or reducing pain in a veterinary subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the above-mentioned compositions or dosage forms, hi one embodiment, the pain is associated with arthritis, post-operative pain, acute pain, joint pain, or polyarticular pain.

[0034] In one aspect, provided herein is a method for treating epilepsy in a veterinary subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the above-mentioned compositions or dosage forms. In one embodiment, the method comprises treating epilepsy in a subject receiving phenobarbital, zonisamide, potassium bromide, and / or levetiracetam as an anti-epileptic treatment, comprising administering to the veterinary subject a pharmaceutical composition or dosage form comprising about 2 mg / kg of cannabis extract per day. In one embodiment, the veterinary subject is not receiving other anti-epileptic treatments. In one embodiment, the cannabis extract is administered about every 12 hours. In another embodiment, the veterinary subject has previously experienced generalized motor seizures or focal seizure episodes. In another embodiment, the veterinary subject has a reduction in seizure frequency and / or duration.

[0035] In one embodiment the cannabis extract present in the subject is a therapeutically effective amount of any of the compositions or dosage forms described above.

[0036] In one aspect, provided herein is a method for treating cancer in a veterinary subject in need thereof comprising administering about 5 mg / kg of cannabis extract to the subject.

[0037] In one aspect, provided herein is a method for improving quality of life in a veterinary subject with cancer comprising administering to the subject a therapeutically effective amount of any of the above-described compositions or dosage forms.

[0038] In one embodiment, the veterinary subject is undergoing L-CHOP or CHOP chemotherapy. In one embodiment, the cannabis extract, composition or dosage form is administered about every 12 hours starting on the 4th or 5th week of doxorubicin treatment.

[0039] In one embodiment, the cancer is lymphoma. In another embodiment, the lymphoma is intermediate to high grade multicentric lymphoma. In another embodiment, following treatment, the veterinary subject experiences resolution of lymphoma-associated abnormalities or a decrease in lymph node size.

[0040] In one embodiment, the veterinary subject has a body weight greater than 15 kg.

[0041] In one embodiment, the veterinary subject is at the end of the first cycle of L-CHOP chemotherapy.

[0042] In one aspect, provided herein is a method for treating post-operative pain in a veterinary subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the above-described compositions or dosage forms.

[0043] In one aspect, provided herein is a method for treating post-operative pain in a subject in need thereof comprising administering a cannabis extract to a veterinary subject about every 12 hours the night before surgery and for 12 days following surgery, along with a 5 day course of Rimadyl.

[0044] In one embodiment, the veterinary subject has undergone a tibial plateau leveling osteotomy, hi another embodiment, the veterinary subject has been treated with fentanyl and / or a nerve block.

[0045] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.1-8.0 mg / kg.

[0046] In one embodiment, the pharmaceutical composition or dosage form is administered at twice the therapeutically effective dose for one week, followed by administration of the therapeutically effective dose.

[0047] In one embodiment, the therapeutically effective dose is about 0.1-0.5 mg / kg. In another embodiment, the therapeutically effective dose is about 2 mg / kg. In another embodiment, the therapeutically effective dose is about 8 mg / kg.

[0048] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 1 mg / kg for one week, followed by a dose of about 0.1-0.5 mg / kg thereafter.

[0049] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 4 mg / kg for one week, followed by a dose of about 2 mg / kg thereafter.

[0050] In one embodiment, the method results in a median maximum therapeutically effective serum concentration of cannabidiol. In one 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 590 ng / mL.

[0051] In one embodiment, the veterinary subject is a dog, a cat, a cow, a pig, or a horse. In one embodiment, the veterinary subject is a dog. In another embodiment, the veterinary subject is a cat.

[0052] In one aspect, provided herein is a method of achieving an area under the curve for cannabidiol from 0 hours to 24 hours of 42.4 to 3048 ng hr / ml in a veterinary subject comprising administering to the subject an effective amount of a cannabis extract.

[0053] In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract: Cannabidiol, and Contains cannabidiol acid,

[0054] The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6. In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is Cannabidiol, and Contains cannabidiol acid, The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6.

[0055] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is Cannabidiol, and Contains cannabidiol acid, The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6.

[0056] In one aspect, provided herein is a method of improving quality of life in a veterinary subject with cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is Cannabidiol, and Contains cannabidiol acid, The ratio of cannabidiol to cannabidiol acid is about 0.6:1 to about 1:0.6.

[0057] In one embodiment the cannabis extract comprises: Cannabigerophosphate, Δ9-tetrahydrocannabinol, and Contains cannabichromene.

[0058] In another embodiment, the cannabis extract further 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, and α-Bisabolol.

[0059] In another 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 1:25. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0 mg / mL.

[0060] In one 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0061] In another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0062] 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0063] In one embodiment the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0064] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0065] In one embodiment the cannabis extract comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 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.

[0066] In one embodiment, the composition is incorporated in a carrier.In another embodiment, the carrier is selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil and grapeseed oil.In another embodiment, the carrier is grapeseed oil.In another embodiment, the carrier is catnip oil.

[0067] In one embodiment, the composition comprises nepetalactone, hi another embodiment, the composition comprises taurine.

[0068] In one embodiment, the composition is formulated for administration using a nebulizer. In another embodiment, the composition is formulated for administration using a diffuser. In another embodiment, the composition is formulated for administration using a pet collar. In another embodiment, the composition is formulated as a pet food for oral administration.

[0069] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew weighs about 0.5-10 g. In another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In another embodiment, the chew weighs about 4 g.

[0070] In another embodiment, the chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerophosphate, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0071] In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract: α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Contains four or more of the following α-bisabolols:

[0072] In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Contains four or more of the following α-bisabolols:

[0073] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Contains four or more of the following α-bisabolols:

[0074] In one aspect, provided herein is a method of improving quality of life in a veterinary subject with cancer comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a cannabis extract and a carrier, wherein the cannabis extract is α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and Contains four or more of the following α-bisabolols:

[0075] In one 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0076] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0077] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0078] In one embodiment the cannabis extract comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 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.

[0079] In one embodiment, the composition is incorporated in a carrier.In another embodiment, the carrier is selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil and grapeseed oil.In another embodiment, the carrier is grapeseed oil.In another embodiment, the carrier is catnip oil.

[0080] In one embodiment, the composition comprises nepetalactone, hi another embodiment, the composition comprises taurine.

[0081] In one embodiment, the composition is formulated for administration using a nebulizer. In another embodiment, the composition is formulated for administration using a diffuser. In another embodiment, the composition is formulated for administration using a pet collar.

[0082] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew weighs about 0.5-10 g. In another embodiment, the chew weighs about 4 g, about 6 g, about 9 g, or about 10 g. In another embodiment, the chew weighs about 4 g. In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof, comprising: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, Cannabichromene, and This includes administering a dosage form that includes one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0083] In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof, comprising: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, Cannabichromene, and This includes administering a dosage form that includes one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0084] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof, comprising: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, Cannabichromene, and This includes administering a dosage form that includes one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0085] In one aspect, provided herein is a method of improving the quality of life of a veterinary subject with cancer, comprising: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, Cannabichromene, and This includes administering a dosage form that includes one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0086] In one embodiment, 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 another embodiment, the ratio of cannabidiol to cannabidiolic acid is about 1:1. In another 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 1:25. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.5 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.3 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.2 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is less than about 0.1 mg / mL. In another embodiment, the concentration of Δ9-tetrahydrocannabinol is about 0 mg / mL.

[0087] In one 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0088] In another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0089] 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, and α-Bisabolol.

[0090] 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0091] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0092] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0093] In one embodiment the cannabis extract comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 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.

[0094] In one embodiment, the flavoring agent is selected from the group consisting of catnip oil, peppermint oil, mango extract, beef, chicken, and seafood, hi one embodiment, the flavoring agent is catnip oil.

[0095] In one embodiment, the dosage form comprises nepetalactone, hi another embodiment, the dosage form comprises taurine.

[0096] In one embodiment, the dosage form is formulated as a chew for oral administration. In another embodiment, the chew is manufactured using cold extrusion. In another embodiment, the dosage form is formulated as a sublingual spray. In another embodiment, the dosage form is formulated as a water-soluble or alcohol-soluble solution, gel, or cream for transdermal application. In another embodiment, the dosage form is formulated as a gel for buccal or intramucosal administration. In another embodiment, the dosage form is formulated as a powder. In another embodiment, the dosage form is formulated as a solution for subcutaneous injection. In another embodiment, the dosage form is formulated as a tablet. In another embodiment, the dosage form is formulated as a capsule. In another embodiment, the dosage form is formulated as a hard chewable. In another embodiment, the dosage form is formulated as a soft chewable.

[0097] In one embodiment, the dosage form is formulated in a carrier for oral administration.In another embodiment, the carrier is selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil.In another embodiment, the dosage form is a carrier in grapeseed oil.In another embodiment, the dosage form is a carrier in catnip oil.

[0098] In another embodiment, the dosage form is formulated for inhalation. In another embodiment, the dosage form is formulated for administration using a nebulizer. In another embodiment, the dosage form is formulated for administration using a diffuser. In another embodiment, the dosage form is formulated for administration using a pet collar. In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof, comprising: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0099] In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof, comprising: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0100] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof, comprising: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0101] In one aspect, provided herein is a method of improving the quality of life of a veterinary subject with cancer, comprising: Glucosamine HCl, Chondroitin sulfate (76%), Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0102] In one 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0103] In 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, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0104] In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof, comprising: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0105] In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof, comprising: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0106] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof, comprising: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0107] In one aspect, provided herein is a method of improving the quality of life of a veterinary subject in need thereof, comprising: Glucosamine HCl, Hyaluronic acid, Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Administering a dosage form that includes water.

[0108] In one 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water. In 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, Approximately 5.8% sunflower lecithin, and Contains approximately 5.8% water.

[0109] In one aspect, provided herein is a method of treating or reducing pain in a veterinary subject in need thereof, comprising: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid Brewer's yeast, sugar, water, Glycerin, Potato starch, dry peanut butter, Rice starch, and Administering a dosage form comprising guar gum.

[0110] In one aspect, provided herein is a method of treating epilepsy in a veterinary subject in need thereof, comprising: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid Brewer's yeast, sugar, water, Glycerin, Potato starch, dry peanut butter, Rice starch, and Administering a dosage form comprising guar gum.

[0111] In one aspect, provided herein is a method of treating cancer in a veterinary subject in need thereof, comprising: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid Brewer's yeast, sugar, water, Glycerin, Potato starch, dry peanut butter, Rice starch, and Administering a dosage form comprising guar gum.

[0112] In one aspect, provided herein is a method of improving the quality of life of a veterinary subject in need thereof, comprising: cannabis extract, Peanut butter, Rice bran, Glucosamine HCl, Sweet potato, dried molasses, Sorbic acid Brewer's yeast, sugar, water, Glycerin, Potato starch, dry peanut butter, Rice starch, and Administering a dosage form comprising guar gum.

[0113] In one 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0114] In one 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%; dry molasses, about 9.0%; 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0115] In one 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% dry peanut butter, Approximately 1.0-5.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0116] In one embodiment, the dosage form comprises about 5.0% cannabis extract.

[0117] In one embodiment, the flavoring agent is selected from the group consisting of 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 catnip oil.

[0118] In one embodiment, the dosage form comprises nepetalactone, hi another embodiment, the dosage form comprises taurine.

[0119] In one embodiment, the dosage form is formulated as a chew for oral administration. In one embodiment, the chew is manufactured using cold extrusion.

[0120] In one embodiment, a veterinary subject is treated for pain using the above method in combination with gabapentin. In one embodiment, the pain is post-operative. In another embodiment, the veterinary subject is undergoing spinal surgery. In another embodiment, the spinal surgery is a hemi-laminectomy. In one embodiment, the veterinary subject is administered 8-12 mg / kg gabapentin and 6-10 mg / kg cannabis extract every 6-10 hours. In another embodiment, the veterinary subject is administered about 10 mg / kg gabapentin and about 8 mg / kg cannabis extract every 8 hours. [Brief description of the drawings]

[0121] [Figure 1] Figure 1 shows box plots of serum alkaline phosphatase (ALP) activity at each time point for treatment and placebo oils. Boxes represent the mean and 25th and 75th percentiles, and whiskers represent the 99th and 1st percentiles. [Diagram 2] Figure 2 shows the serum concentration (ng / mL) of CBD oil at oral administration times (minutes) of 2 mg / kg and 8 mg / kg. [Diagram 3]Figure 3A is a box plot of the total CBPI score at each time point for the treatment oil and placebo oil. The boxes represent the mean and the 25th and 75th percentiles, and the whiskers represent the 99th and 1st percentiles. Figure 3B is a box plot of the sum of the Hudson scores at each time point for the treatment oil and placebo oil. The boxes represent the mean and the 25th and 75th percentiles, and the whiskers represent the 99th and 1st percentiles. [Figure 4] FIG. 4 is a box plot of the sum of veterinary pain ratings at each time point for treatment oil and placebo oil. [Figure 5A] 5A-5F are graphs showing trot stance % gait cycle symmetry (FIG. 5A), trot stance % gait cycle (FIG. 5B), trot step / stride ratio (FIG. 5C), walking stance % gait cycle symmetry (FIG. 5D), walking stance % gait cycle (FIG. 5E), and walking step / stride ratio (FIG. 5F) for five dogs treated with CBD oil. [Figure 5B] Same as above. [Figure 5C] Same as above. [Figure 5D] Same as above. [Figure 5E] Same as above. [Figure 5F] Same as above. [Figure 6] Figure 6 is a graph showing the survival rate of cancer cell lines treated with CBD oil. [Figure 7A] Figures 7A and 7B are graphs and blots showing caspase activity as a marker of apoptosis in cancer cell lines treated with CBD oil. Caspase activity was measured by fold increase in luminescence using Apo-glo (Figure 7A) and by caspase western blot (Figure 7B). [Figure 7B] Same as above. [Figure 8] Figure 8 is a plot of the combination index of CBD oil and doxorubicin on D17 cells. [Figure 9] FIG. 9 is a graph showing the viability of cancer cell lines treated with doxorubicin. [Figure 10] 10A-10D are graphs showing serum concentrations of CBD (FIG. 10A), CBDA (FIG. 10B), THC (FIG. 10C), and THCA (FIG. 10D) in dogs treated with Oil A, Oil B, and a chewable CBD formulation. Bars with an asterisk represent significant differences at that time point. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0122] The endocannabinoid receptor system is known to play a role in pain modulation and attenuation of 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 have prevented 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 on 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, and anti-inflammatory properties, making it an attractive treatment option for dogs with OA cancer, epilepsy, or postoperative pain.

[0123] cancer Lymphoma is one of the most commonly diagnosed hematopoietic cancers in dogs. The most common chemotherapy protocol used for this disease is a doxorubicin-based multidrug 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.). The availability of intensive treatment methods and increased willingness of clients to pursue treatment have led to improved survival rates for veterinary cancer patients. However, more intensive treatments also increase the risk of associated morbidity, making the balance between quality and quantity of life a key role for veterinary oncologists. Owners of terminally ill pets tend to value quality of life (QoL) over longevity and are willing to trade survival time to maintain QoL (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.).

[0124] The use of marijuana and cannabis products, including cannabidiol (CBD), for medical conditions is becoming much more common for both people and pets. Cannabidiol (CBD) is chemically and phytogenetically related to cannabis-derived phenolic terpenes. CBD oil has been proposed to have many beneficial health effects that may lead to improved QoL. A recent survey by the American Holistic Veterinary Medical Association found that approximately 60% of people who purchase cannabis products online use these products on their dogs. Industrial hemp products, which are low in THC (0.3%) and high in other cannabinoids, have reported health benefits including analgesic, anti-inflammatory, anti-anxiety, and anti-epileptic properties, and are legal according to the Industrial Hemp Act. Numerous online companies selling cannabis products, including CBD oil, claim that they are safe and effective for a variety of medical conditions in both pets and people. There is very little published data to support these claims, and no data exists showing the safety of using CBD oil concurrently with chemotherapy in veterinary patients.

[0125] There are no clinical trials that have specifically studied the risk of interactions between cannabinoids and anticancer drugs. As with any drug that is metabolized through the liver, CBD may exhibit inhibition of the metabolism of other drugs (Bouque et al. (2018) Fund Clin Pharm. 32: 462-484). In addition, it may alter the distribution of drugs through the interaction of transmembrane pumps. Therefore, it is necessary to evaluate the safety and tolerability of the use of CBD oil during chemotherapy for lymphoma, as well as its effect on health-related quality of life (HRQL).

[0126] Epilepsy The use of cannabinoid derivatives in the treatment of various neurological disorders in humans has been explored recently, particularly in the treatment of chronic pain and epilepsy. Full-spectrum cannabinoid-rich industrial hemp products containing less than 0.3% THC have been shown to have no psychoactive effects and moderate activity through non-cannabinoid receptor pathways affecting serotonergic, glycinergic, and GABAergic neurotransmitter pathways. Recent studies using full-spectrum cannabinoid-rich HBN have revealed the efficacy of these products in dogs with chronic pain (Wakshlag et al., Front Vet Sci, 2018). Furthermore, human epilepsy studies, and the launch of Epidiolex as a viable treatment, indicate the benefits of cannabidiol in the treatment of epilepsy, but there are no published studies evaluating the efficacy of HBN in canine epilepsy models. It remains to be evaluated whether treatment of refractory canine epilepsy with HBN reduces seizure number or duration, and whether it alters the metabolism of other drugs commonly used for seizure control in dogs.

[0127] Post-operative pain relief The use of cannabinoid derivatives in the treatment of various neurological disorders in humans has been recently explored, especially in the treatment of chronic pain and epilepsy. Industrial hemp-based dietary supplements (HBN), rich in full-spectrum cannabinoids with less than 0.3% THC, have been shown to have no psychoactive effects and moderate activity through non-cannabinoid receptor pathways affecting serotonergic, glycinergic, and GABA neurotransmitter pathways, potentially reducing pain as well as inflammation. Recent studies in chronic pain have demonstrated their efficacy. HBN has been shown to reduce chronic osteoarthritis pain based on objective client-based validated surveys, but has not yet been explored for postoperative pain relief. The use of HBN should help reduce postoperative pain and improve outcomes for dogs undergoing tibial plateau leveling osteotomy for cranial cruciate fractures.

[0128] In addition, cannabinoids may be useful in reducing postoperative pain after spinal cord injury and hemi-laminectomy. Postoperative pain after spinal cord injury and hemi-laminectomy is complex and involves inflammatory nociceptive and neuropathic pain mechanisms. The complexity of postoperative pain after hemi-laminectomy requires diverse analgesic protocols. The current standard of care in patients after hemi-laminectomy is parenteral opioids, and adjunctive analgesic protocols vary among institutions. While opioid use is effective in controlling postoperative pain, it may be associated with undesirable adverse effects such as vomiting, anorexia, dysphoria, central nervous system and respiratory depression, constipation, and sedation. The goal of adjunctive analgesia in patients after hemi-laminectomy is twofold: to reduce the amount of opioids required for pain control and to target multiple pain mechanisms. Typical adjunctive analgesics include gabapentin, diazepam, and nonsteroidal anti-inflammatory or steroidal agents. Gabapentin, the gold standard for neuropathic pain, is generally well tolerated by patients and is commonly used in postoperative patients following neurosurgery. A potential alternative treatment is cannabidiol. Combined gabapentin and cannabidiol therapy reduces postoperative pain following spinal cord injury and hemi-laminectomy.

[0129] The present disclosure is directed to compositions comprising cannabis extracts and their use for the treatment of pain in animals. Also provided herein are methods for treating pain in veterinary subjects. The efficacy of these compositions and treatments has not been demonstrated to date. Clinical trials and pharmacokinetic data regarding administration are also provided herein.

[0130] 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.

[0131] Unless otherwise defined, all technical and scientific terms used herein generally 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 those well known and commonly employed in the art.

[0132] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., 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" is not limiting, as are other forms such as "include," "includes," and "included." 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. As used herein, when referring to a measurable value such as an amount, duration, etc., the term "about" is meant to encompass a ±5% variation from the specified value as a suitable variation for carrying out the disclosed method.

[0133] As used herein and in the claims, the term "comprising" can include "consisting of" and "consisting essentially of" embodiments. As used herein, the terms "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 components / steps and permit the presence of other components / steps. However, such descriptions should be construed to describe compositions or processes as "consisting" and "consisting essentially of" the recited compounds, which permit the presence of only the specified compounds, together with any pharma- ceutically acceptable carriers, and exclude other compounds.

[0134] 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, and all intermediate values). The endpoints of the ranges and any values ​​disclosed herein are not intended to be limited to the exact ranges or values, but are sufficiently imprecise to include values ​​that are approximations of these ranges and / or values.

[0135] 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 (alone or in combination with another pharmaceutical agent), to a patient, or to a tissue or cell line isolated from a patient (e.g., for diagnostic or ex vivo uses), for the purpose of curing, healing, 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 gained from the field of pharmacogenomics.

[0136] In certain embodiments, the compositions described herein reduce pain in subjects.Pain can be measured using any measurement standard known in the art.For example, pain can be measured using the Canine Brief Pain Inventory (CBPI), Hudson Activity Scale, flexion and extension measurement, and gait analysis.The reduction of any of these indicators indicates the treatment or reduction of pain.

[0137] As used herein, the term "prevent" or "prevention" refers to the absence of onset of a disorder or disease if none occurs, or the absence of further onset of a disorder or disease if onset of a disorder or disease has already occurred. Also considered is the ability to prevent some or all of the symptoms associated with a disorder or disease.

[0138] As used herein, the term "use" includes any one or more of the following embodiments of the invention respectively: use in the treatment of pain, use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, e.g. use in the manufacture of medicaments, methods of using compounds of the invention in the treatment of these diseases, medicaments having compounds of the invention for the treatment of these diseases, and compounds of the invention for use in the treatment of these diseases, where appropriate and expedient unless otherwise stated.

[0139] As used herein, the term "patient", "individual", or "subject" is intended to include organisms, e.g., prokaryotes and eukaryotes, that suffer from or can be afflicted with a disease, disorder, or condition associated with the activity of a protein kinase. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is, e.g., a human suffering from, at risk of, or likely to suffer from, schizophrenia. In another embodiment, the subject is a cell.

[0140] When used in relation to the methods of treatment / prevention and the use of the compounds and pharmaceutical compositions thereof 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 the condition, lifestyle factors indicative of risk for the 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.

[0141] 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 primate is a human. In some embodiments, the individual is a human, including an adult, a child, and a premature infant. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate, such as a chimpanzee or other ape or monkey species. The term "individual" does not denote a particular age or sex.

[0142] As used herein, the term "pharmaceutical acceptable" refers to a material, such as a carrier or diluent, that does not destroy the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components contained in the composition.

[0143] As used herein, the term "pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two, generally in non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are 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.

[0144] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of a pharma- ceutical 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 for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0145] 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 filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, involved in carrying or transporting a compound useful in the present invention or to a patient so that it can 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, including the compound useful in the present invention, and not harmful to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; excipients such as powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar, buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water, 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" includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds can also be incorporated into the compositions. A "pharmaceutically acceptable carrier" or "carrier" can further include pharmaceutically acceptable salts of the compounds useful within the invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice 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.

[0146] 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.

[0147] As used herein, the term "adjuvant" may include, for example, preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, 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, etc. Isotonic agents, such as sugars, sodium chloride, etc., 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, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

[0148] 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, 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.

[0149] As used herein, the term "weight percent" is meant to refer to the amount by weight of a compound and / or ingredient in a composition as the amount by weight of the component of the composition as a percentage of the weight of the entire composition. Weight percent can also be calculated by multiplying the mass fraction by 100. "Mass fraction" is calculated as follows: weight percent = (ml / m T )*100, the mass m of the entire composition T is the ratio of the mass of one substance m1 to

[0150] "Aqueous buffer" refers to an aqueous solution that resists changes in hydronium ion and hydroxide ion concentration (and resulting pH) upon addition of small amounts of acid or base or upon dilution. Buffers consist of a weak acid and its conjugated base (more common), or a weak base and its conjugated acid (less common). Buffers are prepared by methods well known in the art with an appropriate buffering agent 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 commercially available and can be used in the preparation of the compositions of the present invention without further processing.

[0151] As used herein, the term "cannabis extract" refers to a composition of cannabinoids and terpenes isolated from a cannabis plant. The terms "cannabis extract" and "CBD 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 may be performed as 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 by passive extraction with stirring at room temperature (ambient temperature), heating to a temperature above room temperature, or under reflux, as known in the art, to provide a cannabis extract. In another embodiment, cannabis extract from butanol extraction is used as starting material for the method disclosed herein.

[0152] Suitable methods for measuring cannabinoid and terpene content in cannabis extracts are known in the art.In one embodiment, cannabinoid content is determined using liquid chromatography with mass spectrometry detection (LC-MS).In another embodiment, terpene content is determined using gas chromatography with flame ionization detector analysis of headspace (GC-FID).

[0153] As used herein, the term "flavoring agent" refers to an ingredient added to a composition to impart a particular flavor, aroma, or other organoleptic property.

[0154] 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. 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 promote chewing of the article by a target animal. Generally, a chewable matrix exhibits sufficient ductility to be at least slightly malleable when chewed by a target animal, and sufficient palatability that the target animal is not deterred by its taste when chewed multiple times. In contrast, "chewable" does not simply mean that the article can be chewed by an animal (i.e., it does not simply mean that a portion of the article fits sufficiently in the animal's mouth to permit engagement of the animal's teeth against that portion). As used herein, the "maximum serum concentration value" of a substance refers to the maximum value of the substance present in a plasma sample following a single dose.

[0155] As used herein, the term "cold extrusion" refers to a process for producing edible food products that involves several unit operations, including mixing, kneading, shearing, shaping, and forming, all of which are carried out at or near ambient temperature. As used herein, the term "psychotropic effect" refers to alterations in brain function that result in changes in perception, mood, consciousness, or behavior.

[0156] As used herein, a "chemotherapeutic agent" is any compound used to treat a proliferative disorder. Examples of chemotherapeutic agents include, but are not limited to, the following classes of agents: Nitrogen mustards, such as cyclophosphamide, trophosphamide, ifosfamide, and chlorambucil; Nitrosoureas, such as carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), and nimustine (ACNU); Ethylenimines and methyl-melamines, such as Thiotepa; Folic acid analogues, e.g., methotrexate; Pyrimidine analogues, such as 5-fluorouracil and cytarabine; Purine analogues, such as mercaptopurine and azathioprine; Vinca alkaloids, such as vinblastine, vincristine, and vindesine; Epipodophyllotoxins, such as etoposide and teniposide; Antibiotics, such as dactinomycin, daunorubicin, doxorubicin, epirubicin, bleomycin a2, mitomycin c, and mitoxantrone; Estrogens, such as ethylstilbestrol; Gonadotropin-releasing hormone analogues, such as leuprolide, buserelin, and goserelin; Antiestrogens, such as tamoxifen and aminoglutethimide; Androgens, such as testerolactone and drostanolone proprionate; Platinates, such as cisplatin and carboplatin; and Interferon - Interferons including alpha, beta and gamma.

[0157] As used herein, the term "quality of life," or "QoL," is generally considered a multidimensional concept that is a subjective assessment of factors that contribute to overall health, with recent publications suggesting fatigue, anxiety, and gastrointestinal function. The Likert scale system appears to be an appropriate assessment of QoL (Giuffrida et al. (2018) J Amer Vet Med Assoc. 252:1073-1083) and was used in this study.

[0158] 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.

[0159] In another embodiment, the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, and 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.

[0160] 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 A9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0161] 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 Δ9-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 about 0 mg / mL.

[0162] 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 to 0.5 mg / mL of cannabigerophosphate; about 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0163] 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0164] In yet another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0165] In one embodiment, provided herein is a pharmaceutical composition comprising a cannabis extract and a carrier, wherein 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.

[0166] 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0167] 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, Approximately 0.02-0.09% nerolidol 2, and It contains approximately 0.01-0.06% guaiol.

[0168] 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, Approximately 0.01 to 0.50% caryophyllene oxide, and Contains approximately 0.01-0.50% α-bisabolol.

[0169] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0170] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0171] 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, Approximately 0.01-0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0172] 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, Approximately 0.01-0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0173] In one embodiment the cannabis extract is terpene-free.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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-osimeroxidase, α-octyldodecyl ester ...

[0178] These include benzoyl persulfate, eucalyptol, isopulegol, and nerolidol1. 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.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] In one embodiment, the cannabis extract 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] In one embodiment the cannabis extract comprises 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. In one embodiment, the composition is formulated as oil.In another embodiment, the carrier is selected from the group consisting of 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.

[0190] In one embodiment, the dosage form comprises nepetalactone.

[0191] In one embodiment, the dosage form comprises taurine.

[0192] In one embodiment, the pharmaceutical composition comprises lecithin. In another embodiment, the lecithin is sunflower lecithin. In another embodiment, the lecithin is about 5 w / v%, about 10 w / v%, about 15 w / v%, about 20 w / v%, about 25 w / v%, about 30 w / v%, about 35 w / v%, about 40 w / v%, about 45 w / v%, or 50 w / v% of the pharmaceutical composition. In other embodiments, the pharmaceutical composition comprises lecithin mixed with another oil. In some embodiments, the other oil is sesame oil. In some embodiments, the lecithin and the other oil are mixed in a ratio of about 1:4, 1:2, 1:1, 2:1, or 4:1. In some embodiments, the pharmaceutical composition comprises a cannabis extract and a carrier oil. In some embodiments, the carrier oil is substantially all lecithin. In other embodiments, the carrier oil is 100% lecithin.

[0193] 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% of the pharmaceutical composition.

[0194] In one embodiment, the pharmaceutical composition is formulated as a sublingual spray. In yet another embodiment, the pharmaceutical composition is formulated as an aqueous or alcoholic solution, a gel, or a cream for transdermal application. In one embodiment, the pharmaceutical composition is formulated as a gel for buccal or intramucosal 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 chew. In one embodiment, the pharmaceutical composition is formulated as a soft chew.

[0195] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew is manufactured 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.

[0196] In one embodiment, a 4g chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerophosphate, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0197] The pharmaceutical compositions of the present disclosure may be manufactured by processes well known in the art, e.g., by conventional mixing, dissolving, granulating, milling, comminuted, sugar-coating, gelling, emulsifying, encapsulating, entrapping, or lyophilizing processes.

[0198] Thus, compositions for use according to the present disclosure may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers that include excipients and adjuvants that facilitate processing of the active compounds into pharma- ceutically usable preparations. Appropriate formulations will vary depending on the selected route of administration.

[0199] Dosage form In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: Cannabidiol, and Cannabidiolic acid, and Dosage forms are provided that include one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0200] In another embodiment, the dosage form comprises: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, Cannabichromene, and Including one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

[0201] 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.

[0202] 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 A9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0203] 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 Δ9-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 about 0 mg / mL.

[0204] 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 to 0.5 mg / mL of cannabigerophosphate; about 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0205] 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0206] In yet another embodiment, the dosage form comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0207] 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 Contains alpha-bisabolol.

[0208] 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0209] 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, Approximately 0.02-0.09% nerolidol 2, and It contains approximately 0.01-0.06% guaiol.

[0210] 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, Approximately 0.01 to 0.50% caryophyllene oxide, and Contains approximately 0.01-0.50% α-bisabolol.

[0211] In another embodiment, the dosage form comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0212] In another embodiment, the dosage form comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0213] 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, Approximately 0.01-0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0214] 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, Approximately 0.01-0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0215] In one embodiment the cannabis extract is terpene-free.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] In one embodiment, the dosage form contains 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.

[0227] In one embodiment, the dosage form includes 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.

[0228] In one embodiment, the dosage form contains 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.

[0229] In one embodiment, the dosage form contains 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.

[0230] In one embodiment, the dosage form contains 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.

[0231] In one embodiment, the dosage form includes 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.

[0232] In one embodiment, the flavoring agent is selected from the group consisting of catnip oil, peppermint oil, mango extract, beef, chicken, and seafood. In one embodiment, the dosage form is formulated as a sublingual spray. In yet another embodiment, the dosage form is formulated as an aqueous or alcoholic solution, a gel, or a cream for transdermal application. In one embodiment, the dosage form is formulated as a powder. In one embodiment, the dosage form is formulated as a gel for buccal or intramucosal administration. 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 hard chewable. In one embodiment, the dosage form is formulated as a soft chewable.

[0233] In some embodiments, the invention includes infusing an edible product with a cannabis extract. In another embodiment, the edible product is an extruded food, a baked food, a nut butter, a spread, a pelleted feed, or a processed food. In another embodiment, the edible product is a pet food. In another embodiment, the pet food is in a dry, shelf-stable form, such as dry meal, dried fish, dried dairy, fish meal, fish meal, cereals, flour, carbohydrates, dried fruit, etc. In another embodiment, the pet food is moist or semi-moist. In another embodiment, the pet food includes food additives or supplements, such as vitamins, minerals, drugs, such as chemicals, enzymes, etc., that can remove plaque or tartar from the animal's teeth. In one embodiment, the cannabis extract is administered with catnip oil. In another embodiment, any of the dosage forms described may also include catnip.

[0234] 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 nebulized drugs to animals. In another embodiment, the nebulizer system can be easily used on animals without removing them from their natural environment. In another embodiment, the nebulizer delivery device and system can easily treat animals once 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 training levels.

[0235] 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, such as natural convection, forced convection, heating a wick or pad that holds the cannabis extract, using a pump, or by a fan.

[0236] In one embodiment, the cannabis extract is administered by a pet collar. The pet collar may include a belt with a buckle on one side, a free end on the other side, and an attachment means such as an opening located longitudinally within a central portion of the belt, or a quick release clasp mechanism for securing the collar in a closed loop configuration. The pet 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 pet collar at night. In one embodiment, the collar is infused with cannabis extract.

[0237] Kiss In one embodiment, the dosage form is formulated as a chew for oral administration. In another embodiment, the chew is manufactured 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.

[0238] In one embodiment, the dosage form comprises: Brewer's yeast, Gum arabic, Guar gum, Flavoring agents, Verdilox, Previon, cannabis extract, Glycerin, Sunflower lecithin, and Contains water.

[0239] 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 Contains approximately 1-10% water.

[0240] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0241] 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, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0242] 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 Contains water.

[0243] 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 Contains approximately 1-10% water.

[0244] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0245] 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, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0246] 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 Contains water.

[0247] 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 Contains approximately 1-10% water.

[0248] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0249] 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, Approximately 5.7% sunflower lecithin, and Contains approximately 5.7% water.

[0250] 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 Contains water.

[0251] 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 Contains approximately 1-10% water.

[0252] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0253] 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, Approximately 5.8% sunflower lecithin, and Contains approximately 5.8% water.

[0254] 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 Contains water.

[0255] 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 Contains approximately 1-10% water.

[0256] 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, Approximately 0.5 to 1.5% Previon, Approximately 3-6% cannabis extract, Approximately 13-17% glycerin, Approximately 3-7% sunflower lecithin, and Contains approximately 3-7% water.

[0257] 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, Approximately 5.8% sunflower lecithin, and Contains approximately 5.8% water.

[0258] In yet another 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, dry peanut butter, Rice starch, and Contains guar gum.

[0259] In yet 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0260] 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%; dry molasses, about 9.0%; 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0261] 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 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% dry peanut butter, Approximately 1.0-5.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0262] In yet 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0263] 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%; dry molasses, about 9.0%; 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% dry peanut butter, Approximately 2.0% rice starch, and Contains approximately 2.0% guar gum.

[0264] 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% dry peanut butter, Approximately 1.0-5.0% rice starch, and Contains approximately 1.0-5.0% guar gum.

[0265] In another embodiment, the dosage form further comprises chondroitin sulfate.

[0266] 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.

[0267] In one embodiment the cannabis extract comprises: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, and Contains cannabichromene.

[0268] 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.

[0269] 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 A9-tetrahydrocannabinol to other cannabinoids is about 1:20.

[0270] 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 Δ9-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 yet another embodiment, the concentration of A9-tetrahydrocannabinol is about 0 mg / mL.

[0271] 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 to 0.5 mg / mL of cannabigerophosphate; about 0.01-0.5 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.01-0.5 mg / mL of cannabichromene.

[0272] 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 of cannabigerophosphate; about 0.1-0.3 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.1-0.4 mg / mL of cannabichromene.

[0273] In yet another embodiment, the cannabis extract comprises: Approximately 5mg / mL cannabidiol, Approximately 5 mg / mL cannabidiolic acid, Approximately 0.11 mg / mL cannabigerophosphate; about 0.25 mg / mL Δ9-tetrahydrocannabinol, and Contains approximately 0.27 mg / mL of cannabichromene.

[0274] 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 Contains alpha-bisabolol.

[0275] 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, Approximately 0.04-0.08% caryophyllene oxide, and Contains approximately 0.01-0.04% α-bisabolol.

[0276] 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, Approximately 0.02-0.09% nerolidol 2, and It contains approximately 0.01-0.06% guaiol.

[0277] 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, Approximately 0.01 to 0.50% caryophyllene oxide, and Contains approximately 0.01-0.50% α-bisabolol.

[0278] In another embodiment, the cannabis extract comprises: Camphene, β-ocimene, Eucalyptol, Isopulegol, and / or Further contains nerolidol 1.

[0279] In another embodiment, the cannabis extract comprises: Approximately 0.02% camphene, Approximately 0.02-0.03% β-ocimene, Approximately 0.02-0.05% eucalyptol, Approximately 0.02% isopulegol, and / or Contains approximately 0.02-0.04% nerolidol1.

[0280] 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, Approximately 0.01-0.04% isopulegol, and / or Contains approximately 0.01-0.05% nerolidol1.

[0281] 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, Approximately 0.01-0.50% isopulegol, and / or Contains approximately 0.01-0.50% nerolidol1.

[0282] In one embodiment, the composition is formulated as oil.In another embodiment, the carrier is selected from the group consisting of 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.

[0283] In one embodiment, the flavoring agent is selected from the group consisting of catnip oil, chicken liver powder, chicken extract, maltodextrin, butter, and bacon, hi another embodiment, the flavoring agent is chicken liver powder.

[0284] In one embodiment, the composition is formulated as a chew for oral administration. In another embodiment, the chew is manufactured 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.

[0285] In one embodiment, a 4g chew comprises: Approximately 7mg of cannabidiol, Approximately 6mg of cannabidiol acid, Approximately 0.12 mg of cannabigerophosphate, approximately 0.32 mg of Δ9-tetrahydrocannabinol, and Contains approximately 0.36 mg of cannabichromene.

[0286] Treatment method In one aspect, provided herein is a method for treating or reducing pain in a veterinary subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the above-described compositions or dosage forms.

[0287] In one embodiment, the pain is associated with arthritis, post-operative pain, acute pain, dental pain, pain associated with gingivitis, arthralgia, or polyarticular pain.

[0288] In one embodiment, the veterinary subject has cancer. In one embodiment, the cancer is a solid tumor, such as lung cancer, prostate cancer, colorectal cancer, thyroid cancer, renal cancer, adrenal cancer, liver cancer, pancreatic cancer, breast cancer, and central and peripheral nervous system cancer. In another embodiment, the cancer is a hematopoietic tumor, such as lymphoma and leukemia.

[0289] In one embodiment, the veterinary subject is undergoing chemotherapy, hi one embodiment, the chemotherapy is L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisolone (L-CHOP), or cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP).

[0290] In one embodiment, the method results in a reduction in tumor burden. In another embodiment, the method results in apoptosis of tumor cells. In another embodiment, the method results in a reduction in proliferation of tumor cells.

[0291] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.1-15.0 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.1-10.0 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.1 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.2 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.3 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.4 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.5 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.6 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.7 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.8 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 0.9 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 1 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 1.5 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 2 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 3 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 4 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 5 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 6 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 7 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 8 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 9 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 10 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 11 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 12 mg / kg.In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 13 mg / kg. In yet another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 14 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 15 mg / kg. In another embodiment, the pharmaceutical composition or dosage form is administered at twice the therapeutically effective dose for one week, followed by administration of the therapeutically effective dose. 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.

[0292] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 1 mg / kg for one week, followed by a dose of about 0.1-0.5 mg / kg thereafter.In another embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 4 mg / kg for one week, followed by a dose of about 2 mg / kg thereafter.

[0293] In one embodiment, the pharmaceutical composition or dosage form is administered at a dose of about 2 mg / kg every 12 hours for two weeks, followed by a dose of about 1 mg / kg every 12 hours for two weeks, followed by a dose of about 2 mg / kg every 12 hours for four weeks.

[0294] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 1.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 1.0 mg / kg.

[0295] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 2.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 2.0 mg / kg.

[0296] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 3.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 3.0 mg / kg.

[0297] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 4.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 5.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 5.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 5.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 5.0 mg / kg.

[0298] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 6.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 6.0 mg / kg.

[0299] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 7.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 7.0 mg / kg.

[0300] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 8.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 8.0 mg / kg.

[0301] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 9.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 9.0 mg / kg.

[0302] In one embodiment, the pharmaceutical composition or dosage form is administered once daily at a dose of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered twice daily at a dose of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered three times daily at a dose of about 10.0 mg / kg. In one embodiment, the pharmaceutical composition or dosage form is administered four times daily at a dose of about 10.0 mg / kg.

[0303] In one embodiment, the method results in a median therapeutically effective 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.

[0304] 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.

[0305] In one aspect, provided herein is a method of treating or reducing arthritis associated pain, post-operative pain, acute pain, dental pain, gingivitis associated pain, arthritic pain, or polyarticular pain in a veterinary subject in need thereof, comprising administering a therapeutically effective amount of a cannabis extract to the subject. In one embodiment, the cannabis extract is administered at a dose of about 0.1-15.0 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 0.1-10.0 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.1 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.2 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.3 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 0.4 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 0.5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.6 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.7 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 0.8 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 0.9 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 1 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 1.5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 2 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 3 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 4 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 5 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 6 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 7 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 8 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 9 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 10 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 11 mg / kg. In another embodiment, the cannabis extract is administered at a dose of about 12 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 13 mg / kg. In yet another embodiment, the cannabis extract is administered at a dose of about 14 mg / kg. In one embodiment, the cannabis extract is administered at a dose of about 15 mg / kg.

[0306] In another embodiment, the cannabis extract is administered at twice the therapeutically effective dose for one week, followed by administration of the therapeutically effective dose. 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.

[0307] In one embodiment, the cannabis extract is administered at a dose of about 1 mg / kg for one week, followed by a dose of about 0.1-0.5 mg / kg thereafter.In another embodiment, the cannabis extract is administered at a dose of about 4 mg / kg for one week, followed by a dose of about 2 mg / kg thereafter.

[0308] In one embodiment, the method results in a median therapeutically effective 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.

[0309] In one embodiment, the veterinary subject is administered gabapentin in combination with a dose of the cannabis extract provided herein. In another embodiment, the veterinary subject is administered about 1, 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg / kg of gabapentin in combination with a dose of the cannabis extract provided herein. In another embodiment, the veterinary subject is administered about 10 mg / kg of gabapentin in combination with a dose of the cannabis extract provided herein.

[0310] In another embodiment, the veterinary subject is administered a dose of gabapentin between 1 mg / kg and 50 mg / kg together with a dose of a cannabis extract provided herein. In another embodiment, the veterinary subject is administered a dose of gabapentin between 10 mg / kg and 40 mg / kg together with a dose of a cannabis extract provided herein. In another embodiment, the veterinary subject is administered a dose of gabapentin between 1 mg / kg and 20 mg / kg together with a dose of a cannabis extract provided herein. In another embodiment, the veterinary subject is administered a dose of gabapentin between 5 mg / kg and 15 mg / kg together with a dose of a cannabis extract provided herein. In another embodiment, the veterinary subject is administered a dose of gabapentin between 12 mg / kg and 14 mg / kg together with a dose of a cannabis extract provided herein.

[0311] In some embodiments, the veterinary subject is administered gabapentin along with a dose of cannabis extract provided herein about every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In one embodiment, the veterinary subject is administered gabapentin along with a dose of cannabis extract provided herein about every 8 hours. The cannabis extract can be administered at a different time and / or schedule with the gabapentin or differently.

[0312] In another embodiment, the veterinary subject is administered gabapentin along with a dose of cannabis extract provided herein 1, 2, 3, 4, 5 or 6 times per day. The cannabis extract can be administered with the gabapentin or at a different time and / or on a different schedule. In one embodiment, the veterinary subject is administered about 10 mg / kg of gabapentin about every 8 hours along with a dose of cannabis extract provided herein. The cannabis extract can be administered with the gabapentin or at a different time and / or on a different schedule. In another embodiment, the veterinary subject is administered 10 mg / kg of gabapentin and 8 mg / kg of cannabis extract every 8 hours. The cannabis extract can be administered with the gabapentin or at a different time.

[0313] 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.

[0314] 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 linings (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 local pain. In another embodiment, the local pain is joint pain. In one embodiment, the veterinary subject is an animal over 100 kg (e.g., horse, cow, or pig).

[0315] The therapeutic compositions of the present invention are administered with suitable carriers, excipients, and other agents that are incorporated into the formulation to provide improved transport, delivery, tolerance, and the like. Numerous suitable formulations can be found in the formularies known to all pharmaceutical scientists: 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, water-in-oil and oil-in-water 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.

[0316] The dosage may vary depending on the age and weight of the subject to be administered, the target disease, condition, route of administration, etc. A variety of delivery systems are known and can be used to administer the pharmaceutical composition of the present invention, such as encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis, etc. (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, transdermal, oral, sublingual, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), or may be administered together with other biologically active agents. Administration may be systemic or local.

[0317] The pharmaceutical preparation for oral use can be made using solid excipients, and the resulting mixture can be milled as necessary, and after adding suitable auxiliary agents as required, the mixture of granules can be processed to obtain tablets or dragee cores.Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gums, cellulose preparations such as methylcellulose, hydroxypropylmethylcellulose, sodium carbomethylcellulose, and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).If desired, disintegrants can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.

[0318] Dragee cores are provided with suitable coatings. 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.

[0319] The injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, local injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, for example, by dissolving, suspending, or emulsifying the pharmaceutical composition or dosage form 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 auxiliary agents, and these may be used in combination with suitable solubilizers such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. As oily media, for example, sesame oil, soybean oil, etc. may be employed, and these 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.

[0320] The pharmaceutical composition that can be used orally includes the push-fit capsule made of gelatin, and the soft sealed capsule made of gelatin and plasticizer such as glycerol or sorbitol.The push-fit capsule may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer.In the soft capsule, the active ingredient can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol.

[0321] 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, administration 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 the condition is abated. Advantageously, the above-mentioned pharmaceutical composition for oral or parenteral use is prepared in dosage form with a unit dose suitable for the dosage of active ingredient.Such dosage forms in unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, chews, pet food, etc.In certain embodiments, the dosage provided above is administered in a serving of pet food, such as 1mg / kg of cannabis extract provided in a serving of pet food.

[0322] According to the methods disclosed herein, the pharmaceutical formulation can be administered to the patient using any acceptable device or mechanism. For example, administration can be achieved using a syringe and needle, or using a reusable pen and / or autoinjector. The methods of the present invention include the use of multiple reusable pens and / or autoinjectors to administer the pharmaceutical formulation.

[0323] In non-human animal administration embodiments, the term "pharmaceutical" as used herein may be substituted for "veterinary." EXAMPLES

[0324] Example 1: CBD Oil and Protocol Approval The industrial hemp strain used in this study was a proprietary cannabis strain utilizing ethanol and heat extraction, and the final dried product was reconstituted in an olive oil base containing approximately 10 mg / ml CBD, 0.24 mg / ml tetrahydrocannabinol (THC), 0.27 mg / ml cannabichromene (CBC), and 0.11 mg / ml cannabigerol (CBG) dehydrated as an equivalent mixture of CBD and CBD carboxylic acid (CBDa), with all other cannabinoids less than 0.01 mg / ml. Analysis of five different manufacturing runs using a commercial analytical laboratory (MCR Laboratories, Framingham, MA) shows less than 9% variation between batches for each of the detected cannabinoids listed above. This study was conducted after the Cornell University Institutional Animal Care and Use Committee (IACUC) approved the study in line with the guidelines for animal use in accordance with the IACUC. Client-owned dogs were enrolled after informed consent in accordance with the Declaration of Helsinki.

[0325] Example 2: Terpene Profile Terpene profiles were determined using gas chromatography with flame ionization detection (GC-FID) of the headspace for four separate oil extractions. All oils contained 0.09-0.13% α-pinene, 0.23-0.44% β-myrcene, 0.04-0.09% β-pinene, 0.05-0.09% δ-limonene, 0.03-0.06% linalool, 0.04-0.07% β-caryophyllene, 0.02-0.04% α-humulene, 0.04-0.07% nerolidol 2, 0.02-0.04% guaiol, 0.04-0.08% caryophyllene oxide, and 0.01-0.04% α-bisabolol. Additionally, some of the oils tested contained 0.02% camphene, 0.02–0.03% β-ocimene, 0.02–0.05% eucalyptol, 0.02% isopulegol, and / or 0.02–0.04% nerolidol 1. Total terpenes ranged from 0.73–1.10%.

[0326] Example 3: Pharmacokinetics An initial investigation of the oral pharmacokinetics of a single dose was conducted in four beagles (3.5-7 years old, castrated males, 10.7-11.9 kg). Each dog was orally administered 2 mg / kg and 8 mg / kg CBD oil with a 2-week washout period between each experiment. The dogs were fed 2 hours after dosing. Physical examinations were performed at 0, 4, 8, and 24 hours after dosing. Attitude, behavior, proprioception, and gait during free running / walking and navigation around a standard traffic cone (weaving) were subjectively evaluated at each time point. 5 ml of blood was collected at 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after oil administration. Blood samples were obtained via jugular vein puncture and transferred to coagulation tubes for 20 minutes. Samples were centrifuged at 3,600 × g for 10 min (VWR, clinical centrifuge), serum was removed, and stored at −80°C until analysis using liquid chromatography-mass spectrometry (LC-MS) at the Colorado State University Core Mass Spectrometry Facility.

[0327] Example 4: Extraction and mass spectrometry of CBD from dog serum CBD was extracted from dog serum using a combination of protein precipitation and liquid-liquid extraction with n-hexane, with minor modifications to microflow ultra-high pressure liquid chromatography (UHPLC). Briefly, 0.05 ml of dog serum was subjected to protein precipitation in the presence of ice-cold acetonitrile (final concentration 80%), and deuterated CBD was added as an internal standard (0.06 mg / ml, CDB-d3Cerilliant, Round Rock, TX, USA). 0.2 ml of water was added to each sample before the addition of 1.0 ml of hexane to enhance liquid-liquid phase separation. The hexane extract was removed and concentrated to dryness under laboratory nitrogen. Samples were resuspended in 0.06 mL of 100% acetonitrile prior to LC-MS analysis. A standard curve using the CBD analytical standard was constructed with serum from dogs not exposed to CBD, extracted as described above. Cannabidiol concentrations in serum were quantified using a chromatography-coupled triple quadrupole mass spectrometer (UHPLC-QQQ-MS).

[0328] Example 5: CBD serum concentration data analysis From the UHPLC-QQQ-MS data, peak areas of CBD detected in biological samples were extracted and normalized to the peak area of ​​the internal standard CBD-d3 for each sample using Skyline and an in-house R script (www.r-project.org). CBD concentrations were calculated to nanograms per mL of serum as determined by the regression line of the standard curve (r2=0.9994, 0-1000ng / mL). In this assay, the limit of detection (LOD) and limit of quantification (LOQ) represent the lower limit of detection and quantification for each compound in the matrix of this study. Pharmacokinetic variables were estimated by non-compartmental analysis utilizing a pharmacokinetic software package (PK Solution, version 2.0, Montrose, CO, USA).

[0329] Example 6: Clinical Trial Inclusion and Exclusion Criteria The study population consisted of client-owned dogs presenting to Cornell University Animal Hospital for evaluation and treatment of lameness due to OA. Dogs were considered for inclusion in the study if they had radiographic evidence of OA, signs of pain as assessed by their owner, lameness detectable on visual gait assessment, and painful joints on palpation. Each dog initially underwent a complete blood count ([CBC] Bayer Advia 120, Siemens Corp., New York, NY, USA) and serum chemistry analysis (Hitachi 911, Roche Diagnostics, Indianapolis, IN, USA) to rule out underlying diseases that might preclude enrollment. Elevations in alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were allowed if previous liver ultrasound was deemed within normal limits, except for potential nonprogressive nodules (possible hepatic nodular hyperplasia).

[0330] All owners completed a brief questionnaire to define the affected limb, duration of lameness, and duration of taking analgesics or other medications.

[0331] All dogs underwent radiographic examination of affected joints by a radiologist to confirm the presence or absence of OA and to exclude those with complications that might preclude enrolment (i.e. lytic lesions).

[0332] During the study, dogs were only allowed to receive NSAIDs, fish oil, and / or glucosamine / chondroitin sulfate for 4 weeks prior to or during the 10-week study period, without any changes to these medications, as standard treatment for the disease process. Other pain medications, such as gabapentin and tramadol, were also discontinued at least 2 weeks prior to enrollment. Dogs were excluded if they had evidence of renal disease, uncontrolled endocrine, neurological, or neoplastic disease, or if they had a temperament unsuitable for walking on a lead, or if they were undergoing physical therapy. All dogs were fed a normal diet, and no changes were allowed during the study.

[0333] Example 7: Clinical Trials The study was a placebo-controlled, double-blind, crossover clinical trial. Dogs received either CBD, 2 mg / kg, every 12 hours, or a placebo (same volume of olive oil with 10 parts per thousand of anise oil and 5 parts per thousand of peppermint oil added to provide a similar herbal aroma) every 12 hours, in a randomized order (randomization iPhone application). Each treatment was administered for 4 weeks with a 2-week washout period between treatments. Blood was drawn and complete blood counts and chemistry analyses were repeated at weeks 2 and 4 for each treatment.

[0334] At each visit, each dog was assessed by a veterinarian based on a scoring system, as well as by its owner (Canine Brief Pain Inventory [CBPI], Hudson Activity Scale) before treatment began and at 2 and 4 weeks thereafter.

[0335] Example 8: Statistical Analysis An initial power analysis was performed to assess the number of dogs needed for the study as a crossover design with a power of 0.80 and an alpha of 0.05, using prior data suggesting a baseline CBPI or Hudson score change of approximately 15 points (2-sided) with a standard deviation of 20. In calculating, it was assumed that 14 dogs would be needed to find significance.

[0336] Statistical analysis was performed using a commercially available software package (JMP 12.0, Cary, NC, USA). All data were assessed for normality using the Shapiro-Wilks test. Given that the majority of blood, serum and scoring data were normally distributed, a mixed model of analysis of variance was used. Crossover study variables included in the model were treatment, time, oil order, sex, age, NSAID use, treatment x time fixed effects, and random effects of observation period, period nested in dog, and time point nested within period nested in dog. Fixed effects of initial CPBI or Hudson score were also included in these analyses to control for differences and relative changes in CBPI pain and activity disability assessments and Hudson scores between dogs. Dunnett's test was performed post-hoc for any significant effects of time x treatment to assess differences with week 0 of CBD oil or placebo oil as the baseline time point for comparison. A p-value of less than 0.05 was determined to be significant for all analyses.

[0337] Example 9: Pharmacokinetic Results Pharmacokinetics showed that the median elimination half-life of CBD was 4.2 hours (3.8-6.8 hours) for the 2 mg / kg dose and 4.2 hours (3.8-4.8 hours) for the 8 mg / kg dose (Table 1). The median maximum concentrations of CBD oil (Figure 2) were 102.3 mg / mL (60.7-132.0 ng / mL, 180 nM) and 590.8 ng / mL (389.5-904.5 ng / mL, 1.2 uM), reached after 1.5 and 2 hours for the 2 and 8 mg / kg doses, respectively. No overt psychoactive properties were observed at any of the time points assessed when 2 and 8 mg / kg were administered over 24 hours. These results led to a practical dosing during clinical trials of 2 mg / kg body weight every 12 hours. [Table 1]

[0338] Example 10: Dogs included in clinical trials Twenty-two client-owned dogs with clinical and radiographic evidence of osteoarthritis were recruited. Sixteen of these dogs completed the study and were included in the analysis; their breed, weight, age, sex, deteriorated limb, radiographic findings, NSAID use, and treatment sequence are summarized in Table 2. Dogs were removed due to osteosarcoma at enrollment, gastric volvulus (placebo), past aggression issues (CBD oil), pyelonephritis / renal failure (CBD oil), recurrent pododermatitis (placebo oil), and diarrhea (placebo oil). [Table 2]

[0339] Example 11: Clinical Trial Results CBPI and Hudson scores (Figure 3A and Figure 3B) showed a significant reduction in pain and an increase in activity (p<0.01) during weeks 2 and 4 of CBD treatment compared to baseline week 0, whereas placebo treatment showed no difference between the scores before the start of treatment and the CBPI and Hudson scores (Table 3). Veterinarian-assessed lameness (Figure 4) showed an increase in lameness with age (p<0.01), whereas lameness was significantly reduced with the use of NSAIDs (p=0.03). Veterinary pain scores showed a significant reduction in pain in dogs administered NSAIDs (p<0.01). CBD oil significantly reduced pain compared to baseline at both week 2 and week 4 assessments (p<0.03), whereas placebo treatment showed no significant difference at 24. No changes were observed in weight-bearing ability when assessed using the Veterinary Lameness and Pain Scoring System (Table 3). [Table 3]

[0340] Chemistry analyses and CBC were performed at each visit. No significant changes were observed in the measured CBC values ​​in either CBD oil or placebo treated dogs (data not shown). Serum chemistry values ​​did not differ between placebo compared to CBD oil (Table 4) with the exception of alkaline phosphatase (ALP), which increased significantly over time from baseline by the fourth week of CBD oil treatment (p=0.005), with 9 of 16 dogs showing increases over time (Figure 1). Glucose increased in dogs receiving placebo oil at each time point (p=0.04) and creatinine values ​​increased over time in both dogs receiving CBD oil and dogs receiving placebo oil (p<0.01), but all values ​​remained within reference ranges. Other notable significance in serum chemistry values ​​was primarily associated with age or NSAID use. Increasing age was associated with significantly higher blood urea nitrogen (BUN; p<0.001), calcium (p=0.014), phosphorus (p=0.001), alanine aminotransferase (ALT; p=0.028), ALP (p=0.012), gamma glutamine transferase (GGT; p=0.018), globulin (p=0.021), and cholesterol (p=0.002) levels. NSAID use was associated with significantly higher BUN (p=0.003) and creatinine (p=0.017), and significantly lower total protein (p<0.001) and serum globulin (p<0.001). [Table 4]

[0341] Example 12: Safety study in dogs A 12-week safety study was conducted in dogs to evaluate the safety of soft chews containing CBD.

[0342] Animals and study design Eight purebred beagle dogs aged 11 months to 5 years and weighing 7.39 to 11.95 kg at the start of the study were selected as study subjects, as shown in Table 5. [Table 5]

[0343] Dogs were housed singly in cages of animal welfare act compliant size with a 12-h light / 12-h dark cycle and target conditions of 50°-85°F. Cages and food bowls were cleaned and disinfected daily in accordance with the animal welfare act. Fresh tap water suitable for human consumption was available ad libitum via an automated watering system. There were no known contaminants that could reasonably be expected to be present in the dietary materials that are known to have the potential to interfere with the purpose or conduct of the study. During the study, the control diet, Purina Dog Chow, was the only food source provided to each animal once per day for approximately 1 hour. Dogs were fed according to ideal body condition and fasted for a minimum of 12 hours prior to blood collection. CBD was administered via soft chew provided twice daily at a dose of approximately 2 mg / kg. Doses are shown in Table 6. [Table 6]

[0344] CBC and serum chemistry Prior to the start of the study, 5 milliliters of blood was drawn from each dog and used to determine eligibility for the study. During the study, 5 milliliters of blood was drawn weekly (± 2 days). Blood was collected by jugular vein puncture with a sterile syringe. Samples were split into two tubes: a red top serum separator tube and a lavender top EDTA tube. The red top tube was allowed to clot and then centrifuged in a refrigerated centrifuge at 3000 RPM for 15 minutes. The lavender top tube was placed on a rocker to allow the blood to mix properly with the anticoagulant. Blood samples were packaged and sent overnight with priority to Antech Diagnostics for analysis.

[0345] Pharmacokinetic (PK) blood sampling On the first day of dosing, blood for PK analysis was collected from 6 of the 8 dogs. The most cooperative dog was selected for PK analysis. Approximately 6 milliliters of blood was collected by jugular vein puncture with a sterile syringe at 0, 30, 60 minutes, 2, 4, 8, 12, and 24 hours after treatment. Samples were placed into red-top coagulation tubes without serum separator. Serum was collected by centrifuging the tubes at 3000 RPM for 15 minutes. Collected serum was placed in silo vials and stored at -70°C. Each tube was labeled with dog ID, collection date, and collection time point. Samples were shipped overnight on dry ice to the Colorado State University Proteomics & Metabolomics Facility.

[0346] Clinical findings A veterinarian performed a complete physical examination of all dogs prior to the start of the study and upon completion. Each dog was evaluated for general health, body and coat condition. Qualified personnel performed clinical observations twice daily in accordance with the Summit Ridge Farms veterinary care program and SOP VC-003 (observation rounds). All animals were evaluated twice daily with reference to SOP VC-016 (recognition of pain, stress, and / or distress). Clinical laboratory diagnostic procedures were performed as necessary. Appropriate veterinary care was provided to each individual in accordance with the veterinary care program.

[0347] blood analysis Blood was analyzed for white blood cell count, red blood cell count, hemoglobin, hematocrit, MCV, MCHC, MCH, and platelet count with complete differential. In addition, a 22-test chemistry screen was performed consisting of glucose, urea nitrogen, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, ALT, AST, CPK, cholesterol, calcium, phosphorus, sodium, potassium, chloride, A / G ratio, BUN / creatinine ratio, globulin, triglycerides, GGTP, and magnesium. Measurements were performed prior to the start of the study and then weekly during the course of the study.

[0348] PK analysis Blood concentration values ​​and pharmacokinetic analyses of test substances were performed as described in Gamble et al. (2018) Front Vet Sci. 165:1-9.

[0349] result body weight The mean change in dog weight during the 12-week study was 0.04 kg (-0.43%).

[0350] food consumption The average weekly food consumption of the dogs during the study was 204 g.

[0351] Test substance consumption Five of the eight dogs accepted the chews 100% of the time. Three dogs required occasional dosing during the study: Dog ID No. 13644 (dosed 6.5% of the time), Dog ID No. 13513 (dosed 2.4% of the time), and Dog ID No. 2784123 (dosed 17.3% of the time).

[0352] Hematology and serum chemistry Starting from week 1, the group mean alkaline phosphatase (ALP) values ​​increased slightly. These values ​​remained stable until week 7, when the group mean ALP values ​​increased increasingly. The highest group mean values ​​were observed in the last week of the study, but did not exceed the normal reference range. The increase in the group mean values ​​appeared to be due to three dogs (dog ID numbers 13536, 2753822, and 2808987). By the end of the study, dog ID numbers 13536 and 2753822 were above 100 U / L, but did not exceed the normal maximum of 131 U / L. Their values ​​therefore remained within the normal reference range. The increase observed in only a few animals in the group may indicate individual sensitivity to the product. All other blood parameters were within normal ranges, with no clear trends.

[0353] Clinical findings Occasional loose stools and vomiting were recorded during the study. Dog ID #13536 had five cases of vomiting of food or bile and six cases of loose stool. Dog ID #13513 had two cases of loose stool. Dog ID #27583822 had two cases of vomiting of food and eight cases of loose stool. Dog ID #13644 had 12 cases of loose stool. Dog ID #13490 had two cases of loose stool. Dog ID #2808987 had four cases of loose stool. Dog ID #2963028 had six cases of loose stool. Dog ID #2784123 had six cases of loose stool. Occasional loose stool and vomiting of bile are not uncommon in dog colonies and were not considered related to the test article. Clinical findings are listed in Table 7. [Table 7]

[0354] conclusion There were no adverse effects on body weight or food consumption. Group mean alkaline phosphatase values ​​showed mild elevations during the study without exceeding the normal reference range. The remaining hematology and serum chemistry results were within normal ranges throughout the study, and no obvious trends were observed over time. No clinical findings considered related to test article administration were observed in any dog ​​during the course of the study. Overall acceptance of the treats was 96.7%, with 5 of 8 dogs consuming treats 100% of the time during the study.

[0355] Example 13: Pilot study in dogs A pilot study was conducted to evaluate the effectiveness of ElleVet Mobility Oil for the treatment of arthritis in dogs.

[0356] method Five dogs suffering from end-stage arthritis, arthralgia, and geriatric pain were selected for the study, as shown in Tables 8 and 9.

[0357] Following the manufacturer's instructions, dogs were given a loading dose of 2 mg / kg every 12 hours for the first 2 weeks, then tapered to 1 mg / kg every 12 hours for 2 weeks, then returned to a dose of 2 mg / kg every 12 hours for the final 4 weeks of the study.

[0358] On days 0, 14, 30, and 60, dogs were evaluated with flexion and extension measurements, muscle histology measurements, the Brief Canine Pain Inventory, and gait analysis using a pressure-sensing walkway. [Table 8] [Table 9]

[0359] result Three out of five owners (60%) reported significant improvements in pain severity scores and pain interference scores. Gait analysis revealed that total pressure index (TPI%), step / stride ratio, and stance percentage did not show significant improvement or decline throughout the study, as shown in Figures 5A-5F. Flexion improved in three out of five dogs and decreased by more than 5 degrees in two out of five dogs. Extension improved in two out of five dogs and decreased in one out of five dogs. After completing the study, three out of four owners who completed the questionnaire expressed a desire to continue using the supplement. Improvements observed by owners included improved function and comfort in lying down, getting up, resting, walking, energy, playing, and overall health.

[0360] Example 14: Safety study in cats A 12-week safety study was conducted in cats to evaluate the safety of oil containing CBD.

[0361] Animals and study design As shown in Table 10, eight cats aged 2 to 6 years and weighing 3.33 to 5.17 kg at the start of the study were selected as study subjects. [Table 10]

[0362] Cats were housed singly in cages sized to comply with the Animal Welfare Act and maintained on a 12-h light / 12-h dark cycle and target conditions of 50°-85°F. Cages, food bowls, water bowls, and litter boxes were cleaned and disinfected daily in accordance with the Animal Welfare Act. Fresh tap water suitable for human consumption was available ad libitum via stainless steel bowls. There were no known contaminants that could reasonably be expected to be present in the dietary materials that are known to have the potential to interfere with the purpose or conduct of the study.

[0363] During the study, the control diet, Purina Cat Chow, was the only food source provided to each animal once per day for approximately 4 hours. Cats were fed according to ideal body condition and fasted for a minimum of 12 hours before blood collection. CBD oil was administered orally twice daily at a dose of 2 mg / kg using a 1 ml syringe. The total dose per 24-hour period was 4 mg / kg. Doses are shown in Tables 11 and 12. [Table 11] [Table 12]

[0364] CBC and serum chemistry Prior to the start of the study, 5 milliliters of blood was drawn from each cat and used to determine eligibility for the study. During the study, 5 milliliters of blood was drawn weekly (± 2 days). Blood was collected by jugular vein puncture with a sterile syringe. Samples were split into two tubes: a red-top serum separator tube and a lavender-top EDTA tube. The red-top tube was allowed to clot and then centrifuged in a refrigerated centrifuge at 3000 RPM for 15 minutes. The lavender-top tube was placed on a rocker to allow the blood to mix properly with the anticoagulant. Blood samples were packaged and sent overnight on priority to Antech Diagnostics for analysis.

[0365] Pharmacokinetic (PK) blood sampling On the first day of dosing, blood for PK analysis was collected from 6 of the 8 cats. The most cooperative cat was selected for PK analysis. Approximately 4 milliliters of blood was collected by jugular vein puncture with a sterile syringe one day prior to treatment (time point 0), then 1, 4, 8, and 24 hours after treatment. Samples were placed into red-top coagulation tubes without serum separator. Serum was collected by centrifuging the tubes at 3000 RPM for 15 minutes. Collected serum was placed into silo vials stored at -70°C. Each tube was labeled with cat ID, collection date, and collection time point. Samples were shipped overnight on dry ice to the Colorado State University Proteomics & Metabolomics Facility.

[0366] Clinical findings A veterinarian performed a complete physical examination of all cats prior to the start of the study and upon completion. Each cat was evaluated for general health, body and coat condition. Qualified personnel performed clinical observations twice daily in accordance with the Summit Ridge Farms veterinary care program and SOP VC-003 (observation rounds). All animals were evaluated twice daily with reference to SOP VC-016 (recognition of pain, stress, and / or distress). Clinical laboratory diagnostic procedures were performed as necessary. Appropriate veterinary care was provided to each individual in accordance with the veterinary care program.

[0367] blood analysis Blood was analyzed for white blood cell count, red blood cell count, hemoglobin, hematocrit, MCV, MCHC, MCH, and platelet count with complete differential. In addition, a 22-test chemistry screen was performed consisting of glucose, urea nitrogen, creatinine, total protein, albumin, total bilirubin, alkaline phosphatase, ALT, AST, CPK, cholesterol, calcium, phosphorus, sodium, potassium, chloride, A / G ratio, BUN / creatinine ratio, globulin, triglycerides, GGTP, and magnesium. Measurements were performed prior to the start of the study and then weekly during the course of the study.

[0368] PK analysis Extraction of cannabidiol from feline serum for LC-MS Aliquots of feline serum were delivered to the facility on dry ice and stored at -80°C upon receipt. For cannabidiol (CBD) extraction, serum was thawed on ice and 50μL of each sample was placed into a 2.0ml glass extraction vial (VWR ROBO Unassembled Autosampler Vial) chilled on ice. 200μL of cold (-20C) 100% acetonitrile (spiked with 60ng / mL d3-CBD) was added to each sample and vortexed for 5 minutes at room temperature. 200μL of water was added and vortexed for an additional 5 minutes. 1ml of 100% hexane was then added to each sample and vortexed for a final 5 minutes. Phase separation was enhanced by centrifugation at 3000rpm for 15 minutes at 4C. The top hexane layer was transferred to a new labeled glass vial (approximately 900uL per sample), carefully avoiding the middle and bottom layers. Samples were concentrated to dryness under N2 and resuspended in 60 μL of 100% acetonitrile (Zgair et al. (2015) J Pharm Biomed Anal. 114:145-51).

[0369] standard curve An 8-point standard curve of CBD was generated in matrix background using blank serum. Concentrations ranged from 0 ng / mL to 1000 ng / mL (3.2X dilution series). 50 uL of each spiked serum sample was extracted as above.

[0370] LC-MS / MS analysis LC-MS / MS was performed on a Waters Acquity M-Class UPLC coupled to a Waters Xevo TQ-S triple quadrupole mass spectrometer. Chromatographic separation was performed on a Waters BEH C18 iKey Separation Device (150 μm×50 mm, 1.7 μm). The mobile phase was acetonitrile 99.9%, formic acid 0.1% (B), and water with 0.1% formic acid (A). The analytical gradient was as follows: time=0 min, 70% B; time=1.0 min, 70% B; time=6 min, 100% B; time=7.0 min, 100% B; time 7.5 min, 70% B. The total run time was 10 min. The flow rate was 3.0 μL / min and the injection volume was 2.0 μL. Samples were kept at 6° C. in the autosampler and the column was operated at 70° C. The MS was operated in selected reaction monitoring (SRM) mode, where parent ions were selected by the first quadrupole and fragmented in the collision cell, followed by fragment ions selected by the third quadrupole. Product ions, collision energy, and cone voltage were optimized for each analyte by direct injection of individual synthetic standards. Interchannel delay was set to 3 ms. The MS was operated in positive ionization mode, with the capillary voltage set to 3.6 kV. The source temperature was 120 °C, and the desolvation temperature was 992 °C. The desolvation gas flow rate was 1 L / h, the cone gas flow rate was 150 L / h, and the collision gas flow rate was 0.2 mL / min. The nebulizer pressure (nitrogen) was set to 7 Bar. Argon was used as the collision gas.

[0371] Data Analysis and Statistics All raw data files were imported into the Skyline open source software package (MacLean et al. (2010) Bioinformatics. 26(7):966-8). Each target analyte was visually inspected for retention time and peak area integration. Peak areas of target compounds detected in biological samples were extracted and normalized to the peak area of ​​the appropriate internal standard in each sample using an in-house R script (TQS Tools). CBD concentrations were calculated in nanograms per milliliter of extract (0.06 mL) and then back-calculated to nanograms per mL of serum (0.05 mL of serum).

[0372] Calculating variance with QC pooling 50uL of all serum samples (cat and dog) were pooled into a single quality control sample and 50uL was extracted as described above. The QC pool was injected every 10 samples and the CBD concentration was used to measure technical variation over the course of data acquisition.

[0373] Limit of detection (LOD) and limit of quantification (LOQ) The LOD and LOQ represent the lower limit of detection and quantification for each compound in the matrix of this study. The LOD is calculated based on the standard deviation (Sy) of the response of the zero-point calibration standard (i.e., 0 ng / mL CBD as an estimate of the noise) and the slope (S) of the calibration curve of values ​​that approximate the LOD according to the following formula: LOD = 3*(Sy / S). LOQ = 10*(Sy / S). Sy in y is the standard deviation used for LOD and LOQ calculations (Shrivastava (2011) Chronicles of Young Scientists. 2:21-5; Broccardo et al. (2013) Chromatogr B Analyt Technol Biomed Life Sci. 934:16-21).

[0374] result body weight The mean change in cat weight during the 12-week study was 0.06 kg (1.04%).

[0375] food consumption The average weekly food consumption of cats during the study was 62 g.

[0376] Receipt of test substances Overall, all cats exhibited behaviors such as licking, salivating, pacing, head shaking, biting, and unwillingness to take the test substance (uncooperative behavior) at various intervals throughout the study, indicating that the test substance was disliked.

[0377] Hematology and serum chemistry Beginning at week 2, the mean alanine aminotransferase (ALT) values ​​for this group increased. These values ​​continued to increase from baseline until the end of the study. Mild elevations in individual ALT values ​​were observed in most cats throughout the study. The cat with the largest increase in ALT (above the normal reference range of 100 U / L) and a concomitant increase in aspartate aminotransferase (AST) was cat ID number 13CNL3. Beginning at week 4, this cat's ALT and AST values ​​began to decrease but remained higher than baseline. ALT values ​​remained above the normal reference ranges shown in Table 70 throughout the study. Also at week 2, cat ID numbers 13IRD3 and 13CPJ7 had ALT values ​​increased by 23-31 U / L from baseline values, respectively. Cat ID number 13CPJ7's ALT value returned to baseline by week 10. At week 4, cat ID number 13CCL1's ALT increased by 32 U / L from baseline. Values ​​returned to baseline by week 10. The test article appeared to cause mild ALT changes in the majority of cats, with one cat maintaining an elevated ALT level above normal throughout the study. All other blood parameters were within normal ranges, with no clear trends observed.

[0378] Clinical findings Occasional loose stools and vomiting were recorded during the study as shown in Table 13. Cat ID No. 13CCL1 was observed to have five cases of food vomiting. Cat ID No. 13CNL3 was observed to have one case of hairball vomiting and one case of hair and bile vomiting. Cat ID No. 13IRD3 was observed to have one case of food vomiting. Cat ID No. 15EGA5 was observed to have three cases of food vomiting and one case of hair and bile vomiting. Cat ID No. GJY3 was observed to have two cases of hairball vomiting and one case of food vomiting. Occasional vomiting of hairballs and food is not uncommon in cat colonies and was not believed to be related to the test article. [Table 13]

[0379] Penalty data Table 14 shows the quantification of cannabidiol in feline serum and Table 15 shows the pharmacokinetics of cannabadiol in cats. [Table 14-1] [Table 14-2] [Table 15]

[0380] The LOD for CBD in feline serum was calculated to be 1.9 ng / mL (ppb in serum). The LOQ for CBD in feline serum was calculated to be 6.2 ng / mL (ppb in serum).

[0381] conclusion There were no adverse effects on body weight or food consumption. Group mean alanine aminotransferase values ​​showed an elevation during the study, peaking at week 2. Values ​​decreased during the following weeks, but did not return to baseline values. The ALT value in one cat (cat ID no. 13CNL3) remained significantly elevated throughout the study and was above the normal reference range during the treatment period. Hematology and serum chemistry mean values ​​for the remaining groups were within normal reference ranges throughout the study, with no obvious trends observed over time. No adverse clinical findings considered to be related to administration of the test article were observed in any of the cats during the course of the study. However, acceptance of the test article was considered poor.

[0382] Example 15: Canine Oncology Safety Study The study will be conducted to 1) evaluate the safety and tolerability of oral CBD administration to dogs undergoing L-CHOP chemotherapy for the treatment of high-grade lymphoma, 2) describe differences in health-related quality of life (HRQL) assessments between patients receiving oral CBD oil versus placebo in addition to L-CHOP / CHOP chemotherapy, and 3) evaluate peak concentrations and excretion kinetics of doxorubicin following chemotherapy (weeks 9 / 10).

[0383] Animals and study design All canine patients had a cytological or histological diagnosis of intermediate- to high-grade multicentric lymphoma and were treated with L-CHOP chemotherapy (weeks 5–11) or CHOP chemotherapy (weeks 4–10). Patients weighed >15 kg (to allow the use of standard dose chemotherapy) and had completed the first cycle of L-CHOP chemotherapy (initial doxorubicin treatment).

[0384] Other exclusion criteria were defined as follows: patients were not expected to survive at least 10 weeks from the date of initiation of L-CHOP treatment, had significant comorbidities that would interfere with the ability to assess response to treatment, and had documented liver dysfunction (defined as total bilirubin >1.5 times the reference interval). Breeds at high risk for multidrug resistance (MDR1) mutations were not included unless the absence of mutations in this gene could be demonstrated.

[0385] The study will be approved by the UF Animal Care and Use Committee (IACUC) and owner signed informed consent will be obtained for all patients on the day of enrollment.

[0386] Patients undergoing chemotherapy for lymphoma will be randomized to receive either placebo or CBD oil starting at week 4 or 5 of their doxorubicin-based chemotherapy protocol and continuing for 5 weeks. Patients will be evaluated with a physical exam, complete blood count (CBC), chemistry panel, and urinalysis (UA) prior to study initiation and will be monitored as described in Table 16. [Table 16]

[0387] Clinical information is collected at the time of diagnosis, including symptoms and clinical signs. Lymph nodes are measured at each visit independently by two experienced clinicians, including oncology residents, oncology specialists, or ACVIM oncology faculty-certified specialists. Lymph node measurements are performed according to published response evaluation criteria for canine peripheral nodal lymphoma. Additional staging tests, including chest radiographs, abdominal ultrasound, urinalysis, immunophenotyping, and bone marrow aspiration, are recommended for all dogs but are not required for enrollment. Dogs are staged as described by the World Health Organization Clinical Staging System for Livestock Lymphoma. In addition to the typical information collected at each chemotherapy appointment, clients are asked to complete a QoL questionnaire as described in Giuffrida et al., 2018 (Giuffrida et al.(2018)J Amer Vet Med Assoc.252:1073-1083.).

[0388] All enrolled dogs will be randomly assigned, using a randomization application, to either receive the control (placebo) or the therapeutic oil. The pharmacy team will provide the supplements (control or treatment) to allow blinding of the clinicians. Dogs will be supplied with CBD equivalent to 5mg / kg body weight every 12 hours for the duration of the study. The placebo will consist of an equal amount of olive oil with 10 parts per thousand of anise oil and 5 parts per thousand of peppermint oil (to provide a similar herbal aroma). The supplement will be given with food every 12 hours.

[0389] Adjunctive medications, including gastrointestinal protectants, antibiotics, anti-nausea medications, musculoskeletal supplements (i.e., glucosamine), and flea / tick and heartworm preventatives, are permitted.

[0390] Owners will be given sufficient treatment for each week of the trial and will be asked to return previous bottles to ensure proper dosing. Missed doses will be recorded. All dogs will undergo CBC, chemistry, and UA at weeks 5, 8, and 10 to more fully evaluate safety during treatment. Additionally, inflammation will be evaluated at weeks 5, 7, and 10 with serum collection for C-reactive protein assessment.

[0391] Response to treatment at each visit is determined as outlined by published response assessment criteria for canine peripheral nodal lymphoma. Complete response (CR) is defined as the complete absence of any identifiable abnormalities associated with lymphoma, including normal lymph node size and consistency, partial response (PR) is characterized by a 30% or greater decrease in the mean sum of the largest measured lymph node diameters, stable disease (SD) is defined as a decrease in lymph node size of less than 30% or an increase of less than 20%, and progressive disease (PD) is defined as a greater than 20% increase in the mean sum of lymph node diameters or an apparent progression of lymphoma elsewhere in the body. Objective response rate is defined as the percentage of patients who achieve a complete or partial response to treatment. Toxicity is graded according to the VCOG-Common Terminology Criteria for Adverse Events one week after vinblastine administration.

[0392] Doxorubicin excretion kinetics Eight dogs from the treatment and placebo groups will undergo doxorubicin pharmacokinetic evaluation. The evaluation will be performed at the 9th / 10th week of doxorubicin treatment, after 4 weeks of CBD oil administration, assuming steady-state concentrations in the bloodstream are reached. The dogs will have blood drawn at the end of IV dosing of doxorubicin to evaluate peak serum concentrations of doxorubicin. The dogs will then have 2cc of blood drawn 5, 45, and 60 minutes after the injection to evaluate both the elimination half-life and doxorubicin exposure. These analyses will be used to better understand whether chronic CBD exposure alters the pharmacokinetics of chemotherapy (Wittenberg et al. (2014) Vet Comp Oncol. 12: 2: 114-119.).

[0393] statistical analysis The clinical data generated from this study provides ordinal data that allows for the assessment of change over time from baseline in each group. A power analysis revealed that if the mean Likert score for a parameter is between 2 and 1.5 points (less severe disease) with a standard deviation within any particular score of 0.7, then 18 dogs per group would be required with a p-value of 0.05 and a desired power of 0.8. Thus, 20 dogs will be enrolled in each arm. Data analysis will be performed in three categories: fatigue, anxiety, and gastrointestinal status, using a generalized linear mixed model approach with fixed effects of time, treatment, time x treatment, sex, age, stage of disease, and a random effect of dog.

[0394] Considering the numerical data generated from doxorubicin elimination kinetics, all data were processed using a two-way ANOVA examining time versus treatment with Tukey's post-hoc analysis with alpha set at 0.05.

[0395] Example 16: Canine epilepsy study The study will be conducted to 1) determine the safety of a cannabis-based dietary supplement (HBN) in dogs receiving antiepileptic drugs (AEDs), 2) evaluate the efficacy of adjunctive therapy with HBN to reduce seizure frequency in dogs with epilepsy, and 3) evaluate serum chemistries on AED serum levels and organ function.

[0396] Animals and study design A recent study by Law et al. suggests that refractory seizures may be improved by medium-chain triglycerides. Based on those methods, 24 dogs will be enrolled in this study. All of these dogs have been diagnosed with refractory epilepsy and will be evaluated for a minimum of 3 months with an initial dose of 2 mg / kg HBN (ELLEVET) every 12 hours. In addition, the dogs will receive their current AED regimen (phenobarbital, zonisamide, potassium bromide, and / or levitiracetam) or an equivalent amount of placebo oil for three months. After the first 3 months of treatment, the dogs will be switched to the second oil and treated for another 3 months. The diagnosis of epilepsy will be based on clinical findings, magnetic resonance imaging, cerebrospinal fluid analysis, and seizure logs (number and duration) from the past three months. Prior to enrollment, all dogs will present with either generalized motor seizures or focal seizure episodes and will be receiving optimal doses of maintenance AEDs with acceptable therapeutic serum values.

[0397] For each dog, the number of seizures per week, the mean duration of seizures, and the number of days on which seizures occurred are compared 3 months before and 3 months after the start of treatment with HBN or placebo oil. Comparisons are also made for an additional 3 months when switched to the second oil. A minimum of 50 percent reduction in the number of seizures per week is interpreted as a good clinical response to HBN and is statistically evaluated by chi-square as responders and non-responders. Side effects are closely monitored (i.e., ataxia and sedation). At weeks 0, 2, 6, 12, 14, 18, and 24, all owners complete a brief seizure survey. In addition, owners keep a seizure diary / log for the frequency and duration of seizures during each arm of the study throughout the 3 months. Blood is drawn for complete blood counts, serum chemistry profile, AED and HBN values ​​before the start of HBN and at weeks 0, 2, 6, 12, 14, 18, and 24.

[0398] statistical analysis Total CBC, chemistry, episodes per month, duration per seizure, and AED change from baseline (numeric and quantitative) will be assessed using mixed model ANOVAs. Analyses will take into account fixed effects including weight, age, sex, neuter status, treatment, time, treatment × time, and period. Time nested within period and dogs within time and period will be treated as random effects with differences over time, and treatment will be assessed using Tukey's post hoc analysis.

[0399] Example 17: Post-operative pain relief study in dogs The study will be conducted to 1) evaluate client-specific outcomes regarding pain relief over 8 weeks following tibial plateau leveling osteotomy; 2) use objective quantitative forcemat analysis at weeks 0, 2, and 8; and 3) evaluate serum chemistry for markers of organ function and chronic inflammation.

[0400] Animals and study design A cohort of 48 dogs will be studied in an owner- and veterinarian-blinded placebo study (24 placebo, 24 therapeutic). Prior to surgery, all dogs will have a complete blood count and serum chemistry. All dogs will receive routine pain control treatment with fentanyl immediately after surgery. Many dogs will also receive nerve blocks, which may be evaluated in the statistical model. The therapeutic or placebo oil will be administered the evening before surgery. The day after surgery, dogs will be treated in the morning and afternoon. Before being discharged on the second postoperative day, dogs will perform forcemat walking. Dogs will receive a standard course of Rimadyl, a nonsteroidal anti-inflammatory drug, for five days and released to their owners. For the next 12 days, dogs will receive placebo or therapeutic oil every 12 hours. All dogs will return two weeks after surgery for suture removal, at the same time serum chemistry, serum collection for inflammatory biomarkers, and forcemat analysis will be performed. Eight weeks after surgery, all dogs will have radiographs taken to determine adequate healing and blood drawn for CBC, chemistry, inflammatory markers, and force mat analysis. At weeks 0, 2, and 8, all owners will complete the Canine Brief Pain Inventory and Hudson Scale scores for their dogs. Dogs will be randomly assigned to treatment and placebo groups in a double-blind fashion. All dogs will undergo a complete veterinary evaluation for lameness, pain, and gait at enrollment, week 2, and follow-up visits at week 8.

[0401] statistical analysis The power of the study will be assessed based on a relative peak vertical force change of approximately 5% between-group difference at either 2 and / or 8 weeks post-surgery, with a standard deviation of 8%, a standard alpha value of 0.05, and a beta value of 0.8. This indicates that at least 21 dogs are required in each group. All numerical and quantitative values ​​will be evaluated using mixed-model analysis of variance. The analysis considered fixed effects including weight, age, sex, neutered status, and dog as random effects, with differences due to time and treatment assessed using Tukey's post-hoc analysis. Significance will be set at p<0.05 for all parameters.

[0402] Example 18: Pharmacokinetics in dogs Oral pharmacokinetics of cannabidiol using industrial hemp has been recently established based on a dose of 2 mg / kg. An average total dose of 20 mg resulted in a peak concentration of approximately 100 ug / kg. This peak concentration, a relative absorption rate of approximately 367 ug / L, and a mean retention time of 6 hours suggest that total absorption was less than 20%. It is possible that absorption could be improved using a different matrix. However, lipid microspheres have not performed better than oil emulsions.

[0403] Previous studies have suggested that lecithin may enhance the absorption of lipid emulsions in vivo and in situ. Thus, the addition of sunflower lecithin to a base oil may provide a more effective vehicle for oral delivery. Additionally, the biopolymer NF-971P, utilized in tablets and suspensions to extend the delivery time of the compound, offers another option for oral delivery. NF-971F may require the product to be formulated in an aqueous suspension rather than an oil base. All dogs completed blood counts, serum chemistry and urinalysis performed at the end of the two-week phase to ensure product safety.

[0404] Study design Phase 1 Dogs are dosed at 2mg / kg on feeding using cannabis extract in grape seed oil. After dosing, a 7-point pharmacokinetic analysis is performed. Dogs are dosed twice daily for two weeks. Blood samples are taken at the end of the first and second week to test for steady-state levels in the bloodstream. Dogs are then washed out for four weeks.

[0405] Phase 2 Dogs are dosed with cannabidiol at 2mg / kg using a blend of their current oil and up to 40% sunflower lecithin. After dosing, a 7-point, 24-hour pharmacokinetic study is performed. Dogs are then dosed twice daily for two weeks. Serum is collected at the end of weeks 1 and 2 to examine steady-state levels. Dogs are allowed to wash out for 4 weeks before the next phase of the study.

[0406] Phase 3 The same suspension as in Phase 2 is used with the addition of the biopolymer NF-971P at up to 2% weight / volume. This creates a homogenous suspension that is liquid and delivered in an oil-based delivery system. This mixture allows for a longer digestion time and release of the cannabinoids in the digestive tract. This results in more gradual peaks and troughs during the 24-hour pharmacokinetic study. The emulsion is tested over two weeks with twice-daily (every 12 hours) dosing. Serum is collected at the end of the first and second weeks. The dogs are then washed out for four weeks before the next phase of testing.

[0407] Phase 4 Dogs receive 0.5 cc of oil at 50 mg / ml percutaneously. The oil is administered intraearly every 12 hours for two weeks. Dogs are housed separately during the study to prevent oral exposure through mutual grooming. A seven-point, 24-hour pharmacokinetic analysis is performed after the first treatment. Blood is drawn at the end of the first and second weeks to determine steady-state concentrations in the bloodstream.

[0408] Example 19: In vitro cancer testing In vitro cancer studies were conducted by treating cancer cell lines with CBD oil to examine its effects on cancer cell viability and apoptosis. A combination treatment of CBD oil with doxorubicin was also tested.

[0409] survival rate D17, HMPOS, Abrams, 17-71, and CMT12 cancer cell lines were treated with CBD oil. Cells were treated with CBD oil ranging from 0 to 10 μg / mL for 48 hours. As shown in Figure 6, in all cell types, CBD oil had an IC of 0.8 to 2.9 μg / mL. 50 , which caused a dose-dependent decrease in cell viability.

[0410] Apoptosis To measure cancer cell apoptosis, D17, 17-71, and CMT12 cancer cell lines were treated with vehicle control or CBD oil and incubated for 8 or 16 hours. At 8 hours, caspase activity as a marker of apoptosis was measured using the Apo-glo assay. As shown in Figure 7A, in all cell types, cells treated with CBD oil had a statistically significant increase in caspase activity compared to cells that were not treated or treated with the vehicle control. As shown in Figure 7B, at 8 and 16 hours, caspase activation in the cancer cell lines was visualized using Western blotting. At both time points, caspase activity is seen in cells treated with CBD oil but not in cells treated with the vehicle control.

[0411] Combination Index D17 cells were treated with a combination of CBD oil and doxorubicin at different concentrations. Figure 8 shows the synergistic relationship between CBD oil and doxorubicin when administered together.

[0412] Example 20: Combination Therapy of CBD Oil and Gabapentin for Post-Op Pain Relief in Dogs The study was conducted to 1) evaluate the safety and analgesic efficacy of CBD with gabapentin in the postoperative period after hemi-laminectomy by utilizing a validated pain scoring system and 2) directly compare the analgesic efficacy of CBD + gabapentin (group 1) and gabapentin alone (group 2) in postoperative hemi-laminectomy patients by comparing the time to first relief and the number of rescue opioid injections required within 48 hours.

[0413] Study design and animals Patients will be selected from those with acute onset (duration of clinical symptoms less than 2 weeks), spinal pain, paraparesis, or paraplegia, and a modified Frankel spinal cord injury score of grades 1 to 4. Patients will undergo a hemilaminectomy at the T10-L3 interbody level, and extruded disc material will be identified at the time of surgery. Patients will be excluded from the study if they have a negative deep pain score (modified Frankel spinal cord injury score of 5) pre- or postoperatively, if they have a known food allergy, if their routine preoperative blood tests are abnormal, if their temperament would prevent pain evaluation in a clinical setting, and if they have been using corticosteroids for more than 1 week, or if they are taking immunosuppressants.

[0414] Sample size will be calculated using prior studies in which the pooled standard deviation of time to opioid rescue was 2.85 hours. An a priori sample size calculation will be performed using this standard deviation, 90% power, and α = 0.05, assuming an effect resulting in at least a 2 hour difference between groups. From this calculation and in consultation with the Center for Interdisciplinary Statistical Education and Research (Pullman, WA), it was concluded that 19 dogs should be included in each group. To allow for possible study dropouts, 25 dogs will be assigned to both groups.

[0415] Patients will be randomized using a temporally randomized block design to the following treatment arms: Treatment group 1: 10mg / kg gabapentin and 8mg / kg CBD oil orally administered once every 8 hours. Treatment group 2: 10mg / kg gabapentin or placebo oil given orally every 8 hours. Once treatment group assignment has been made, the drug / placebo appropriate for the patient's weight will be prescribed by an unblinded neurology intern.

[0416] material A liquid formulation of gabapentin (50 mg / ml) (Amneal Pharmaceuticals; Bridgewater, NJ) was used in the study and was dosed based on patient weight. Gabapentin was administered orally at 10 mg / kg every 8 hours. CBD oil was administered orally at 8 mg / kg once every 8 hours. This dose was chosen as the higher of previously evaluated doses of 2 and 8 mg / kg that were demonstrated to be safe in dogs. The placebo CBD oil was olive oil spiked with 10 parts anise oil and 5 parts peppermint oil. Once patients are assigned to treatment groups, CBD oil or placebo oil is placed into glass amber medicine vials and labeled based on patient information and weight. A commercial analytical laboratory (Integrity Labs, WA) analyzes the CBD oil for cannabinoid concentration and evaluates potential variability in concentrations.

[0417] method All dogs undergo a standardized anesthesia protocol consisting of premedication with methadone (0.2 mg / kg) and dexmedetomidine (5 mcg / kg) IM or IV, followed by induction with isoflurane gas and propofol to effect and maintenance with fentanyl constant rate infusion (CRI). Fentanyl CRI (2–5 mcg / kg / min) is started at induction and discontinued when the muscle layer is closed. Breakthrough pain during surgery is addressed with an additional fentanyl bolus (2 mcg / kg). Upon discontinuation of fentanyl, all patients receive an intramuscular dose of methadone (0.2 mg / kg). This dose of methadone is administered to cover pain immediately postoperatively before patients are evaluated for pain or receive oral medications. This protocol of discontinuing fentanyl and administering methadone intraoperatively is similar to other studies evaluating postoperative pain after hemi-laminectomy in dogs.

[0418] All patients will recover in the intensive care unit with routine monitoring and treatment. After extubation, patients will begin oral therapy (as assigned by treatment group) once the physician has confirmed that the gag reflex is intact, that they are alert and responsive, and that they can maintain a sternal decubitus position without assistance.

[0419] Trained blinded observers record pain scores and adverse side effects every 2 hours for the first 24 hours postoperatively and every 4 hours thereafter. Pain scores are recorded using the previously validated Modified Glasgow Composite Scale, scored out of 20. At any time point, patients with a pain score greater than 5 / 20 are rescued with methadone (0.2 mg / kg IV). The 5 / 20 intervention has been previously validated and has been used in similar postoperative studies. Time to first rescue dose, and number of rescue doses over 48 hours are recorded. Other observations recorded include the patient's appetite and the time the patient regularly begins eating, the patient's neurological grade assessed daily, any additional medications post-operatively (e.g., maropitant or trazodone), and any adverse side effects. After testing is completed 48 hours postoperatively, serum chemistry panels will be repeated and liver values ​​will be reassessed. Patients will continue pain medications as prescribed by their primary care physician. Patients will be discharged at the discretion of their primary care clinician.

[0420] statistical analysis Commercially available statistical software is used to analyze the data. Between-group differences in age, sex, and neurological grade are assessed using Pearson chi-square tests. Time to first relief with opioid analgesics is compared via Kaplan-Meier survival curves with Breslow pairwise comparisons. If the data are normally distributed, differences in total number of doses of rescue opioids and pain scores at presentation are assessed using standard one-way analysis of variance. If the data are not normally distributed, Kruskal-Wallis one-way analysis of variance is used. If significant differences in means are observed between groups, post-hoc least significant difference tests are performed. The safety of CBD alone and in combination with gabapentin will be evaluated. This will be done by comparing the incidence of adverse effects between groups using one-way analysis of variance. If there are significant differences in the means observed in the analysis of variance, a post-hoc Tukey's multiple comparison test will be performed. Statistical significance will be considered at p<0.05.

[0421] Example 21: Bioavailability and Metabolism of Cannabinoids The study will compare the absorption of three CBD formulations to that of a chew-based formulation by examining 24-hour pharmacokinetics and one- and two-week steady-state levels.

[0422] Study design Phase 1 Six dogs were dosed with 2mg / kg CBD using sesame oil 25% substituted with purified medium chain triglycerides (Oil A). The dogs consumed half a can of Purina Proplan at the time of dosing and their daily meal at 1 hour later. A 7-point pharmacokinetic analysis was performed on the dogs. The dogs were then dosed twice daily (approximately 11 hours apart) for two weeks. Blood samples were taken at the end of the first and second weeks to test for steady-state levels in the bloodstream. The dogs were then washed out for three weeks before phase two.

[0423] Phase 2 Six dogs were dosed with 2mg / kg CBD using sesame oil substituted with 25% refined sunflower lecithin (Oil B). The dogs consumed half a can of Purina Proplan at the time of dosing and their daily meal at 1 hour later. A 7-point pharmacokinetic analysis was performed on the dogs. The dogs were then dosed twice daily (approximately 11 hours apart) for two weeks. Blood samples were taken at the end of the first and second weeks to test for steady-state levels in the bloodstream. The dogs were then washed out for three weeks before phase 3.

[0424] Phase 3 Six dogs were administered 2mg / kg CBD using a 10mg chewable dosage form. The dogs consumed half a can of Purina Proplan at the time of administration and their daily meal at 1 hour later. A 7-point pharmacokinetic analysis was performed on the dogs. The dogs were then dosed twice daily (approximately 11 hours apart) for two weeks. Blood samples were taken at the end of the first and second weeks to test for steady-state levels in the bloodstream.

[0425] result Table 17 shows data from the 24-hour pharmacokinetic analysis of Oil A, Oil B, and the chewable. Data are presented for the maximum concentration observed in blood (CMax), time to reach maximum concentration (TMax), half-life of the cannabinoids in serum (T1 / 2), area under the curve at 24 hours (AUC-t), total area under the curve versus dose (AUC...), and median retention time (MRT). Additionally, mean predicted serum concentrations were calculated based on the 5 half-lives of each cannabinoid. Kruskal-Wallis non-parametric tests showed that there were few statistically significant differences (post-hoc tests with p-values ​​less than 0.05) across the three treatments for any of the parameters examined. This suggests that the 24-hour pharmacokinetics are similar for the three formulations. However, there were differences in serum concentrations of CBD, CBDA, THC, and THCA concentrations across the 1-week and 2-week time points, as shown in Figures 10A-10D. Two-way ANOVAs across both time and treatment show treatment effects at both week 1 and week 2. Serum CBDA concentrations 6 hours after administration were higher in Oil B than in Oil A and the chewable group at both weeks 1 and 2. THCA concentrations in Oil B and the chewable group were higher than Oil A.

[0426] conclusion These results suggest that all three CBD formulations are absorbed and, based on current information, can achieve physiological concentrations of CBD and CBDA (assuming 100ng of cannabinoids in serum is sufficient). Furthermore, when using lecithin as 25% of the base, there is a clear improvement in the absorption and / or retention in serum of CBDA and THCA, suggesting that this formulation may require a lower dose than oils that do not contain lecithin to achieve similar cannabinoid concentrations. [Table 17]

[0427] The disclosed subject matter should not be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0428] All references (e.g., publications or patents or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition comprising a cannabis extract and a carrier, said cannabis extract comprising: Cannabidiol, and Contains cannabidiol acid, the ratio of cannabidiol to cannabidiolic acid is from about 0.6:1 to about 1:0.6; A pharmaceutical composition wherein the carrier comprises lecithin.

2. The pharmaceutical composition of claim 1, wherein the carrier further comprises biopolymer NF-971P.

3. 1. A pharmaceutical composition comprising a cannabis extract and a carrier, said cannabis extract comprising: Cannabidiol, Cannabidiolic acid, Cannabigerophosphate, Δ9-tetrahydrocannabinol, and Contains cannabichromene, 1. A pharmaceutical composition comprising a ratio of cannabidiol to cannabidiolic acid of about 0.6:1 to about 1:0.6, and said carrier comprises lecithin.

4. The pharmaceutical composition of claim 3, wherein the carrier further comprises biopolymer NF-971P.

5. The cannabis extract, α-pinene, β-myrcene, β-pinene, δ-limonene, Linalool, β-caryophyllene, α-humulene, Nerolidol 2, Guaiol, Caryophyllene oxide, and α-Bisabolol The pharmaceutical composition of claim 1 , further comprising four or more of the following:

6. 6. A pharmaceutical composition according to any one of claims 3 to 5, wherein the concentration of Δ9-tetrahydrocannabinol is insufficient to produce a psychotropic effect.

7. 7. A pharmaceutical composition according to any one of claims 3 to 6, wherein the ratio of Δ9-tetrahydrocannabinol to other cannabinoids is about 1:

25.

8. 8. The pharmaceutical composition of claim 1, wherein the carrier further comprises a substance selected from the group consisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, sesame oil, MCT oil, and grapeseed oil.

9. 9. A formulation comprising any of the pharmaceutical compositions of any one of claims 1 to 8 and one or more pharma- ceutically acceptable excipients, flavoring agents, surfactants, and adjuvants.

10. 10. The formulation of claim 9, wherein the composition is formulated as a chew for oral administration, optionally wherein the chew is manufactured using cold extrusion.

11. The formulation of claim 10, wherein the chew weighs about 0.5 to 10 g.

Images