Compositions Containing Cannabinoids and Methods of Use

Abstract

The present disclosure relates to the use of compositions and their use in pain relief and treatment.Provided herein is a method for reducing acute migraine pain, photophobia, phonophobia, and / or nausea in a subject, comprising administering a pharmacologic effective amount of at least one minor cannabinoid to a subject in need thereof, alone or in combination with tetrahydrocannabinol (THC), cannabidiol (CBD), or both, so that at least one biomarker of central and peripheral sensitization is modulated, and migraine pain, photophobia, phonophobia, and / or nausea is reduced in the subject.In some embodiments, the subject is a human.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 167,448, entitled "COMPOSITIONS COMPRISING CANNABINOIDS AND METHODS OF USE," filed March 29, 2021, which is incorporated by reference in its entirety.

[0002] Field of Disclosure The present disclosure relates to the use of compositions comprising cannabinoids and their use in the relief of pain. [Background technology]

[0003] Background of the disclosure Migraines affect more than 38 million people in the United States. This represents approximately 13% of the adult U.S. population, or slightly more than 1 in 10. Of these, 2 to 3 million migraine sufferers are considered chronic.

[0004] Fibromyalgia is a common chronic pain disorder. It affects an estimated 10 million people in the United States and an estimated 3-6% of the world's population. It is most common in women (75-90% of people diagnosed with fibromyalgia are women), but it also occurs in men and children of all ethnic groups.

[0005] Treatment of migraine pain, frequency, and fibromyalgia pain includes the use of FDA-approved treatments and non-FDA approved alternative treatments, such as cannabinoids.For example, current treatments may include the triptan class of drugs that exert their effects via 5HT-1B / 1D receptor agonism, ergotamines, NSAIDs, opioids, simple analgesics, barbiturates, antiepileptic drugs, tricyclic antidepressants, COX-2 inhibitors, CGRP inhibitors, beta and calcium channel blockers, antihypertensive drugs, antihistamines, onabotulinumtoxinA (Botox®), and the like. However, such treatments often fail to help those diagnosed with either disorder.Therefore, there is a need in the art for effective treatment of the pain associated with migraine attacks with and / or without aura, migraine frequency, or fibromyalgia pain, as well as related disorders such as familial hemiplegic migraine, isolated hemiplegic migraine, and complex regional pain syndrome. Summary of the Invention [Means for solving the problem]

[0006]

[0001] overview Provided herein is a method for reducing acute migraine pain, photophobia, phonophobia, and / or nausea in a subject, comprising administering to a subject in need thereof a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with tetrahydrocannabinol (THC), cannabidiol (CBD), or both, such that at least one biomarker of central and peripheral sensitization is modulated and migraine pain, photophobia, phonophobia, and / or nausea is reduced in the subject.In some embodiments, the subject is a human.

[0002] In some embodiments, the at least one biomarker is selected from the group consisting of N-methyl-D-aspartate (NMDA), glutamate, calcitonin gene-related peptide (CGRP), fatty acid amide hydrolase (FAAH), substance P, 5-hydroxytryptamine (5-HT), nitric oxide (NO), gamma-aminobutyric acid (GABA), nerve growth factor (NGF), serotonin, dopamine, N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG).

[0003] In some embodiments, the at least one minor cannabinoid is cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinol (CBN), cannabinolic acid (CBNA), Δ 9-Tetrahydrocannabivarin (THCV), Tetrahydrocannabinolic acid (THCA), Cannabichromene (CBC), Cannabichromene acid (CBCA), Cannabidivarin (CBDV), and Δ 8 -tetrahydrocannabinol (D8-THC). In some embodiments, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, and the subject is further administered THC and CBD.

[0004] Further provided herein is a method for reducing migraine frequency in a subject, comprising administering to a subject in need thereof a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that at least one biomarker of central and peripheral sensitization is modulated and the frequency of migraine headaches is reduced in the subject.In some embodiments, the subject has chronic migraine.In some further embodiments, the subject has high-frequency migraine.In some embodiments, the subject is a human.

[0005] In some embodiments, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0006] In some embodiments, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC. In some aspects, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, and the subject is further administered THC and CBD.

[0007] Further provided herein is a method for reducing fibromyalgia pain in a subject, comprising administering to a subject in need thereof a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that at least one biomarker of central and peripheral sensitization is modulated and the pain of fibromyalgia is reduced in the subject.In some embodiments, the subject is a human.

[0008] Further provided herein is a pharmaceutical composition comprising at least one isolated minor cannabinoid and THC, wherein the ratio of at least one isolated minor cannabinoid to THC modulates at least one biomarker of central and peripheral sensitization.In some embodiments, the composition further comprises CBD.In some embodiments, the composition further comprises terpenoid.In some embodiments, the composition further comprises an analgesic agent.

[0009] In some embodiments, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0010] In some embodiments, the at least one isolated minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0011] In some embodiments, the composition comprises at least one cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, THC, and CBD.

[0012] Further provided herein is a pharmaceutical composition comprising at least one isolated minor cannabinoid and CBD, wherein the ratio of at least one isolated minor cannabinoid to CBD modulates at least one biomarker of central and peripheral sensitization.In some embodiments, the composition further comprises THC.In some embodiments, the composition further comprises terpenoid.In some embodiments, the composition further comprises an analgesic agent.

[0013] In some embodiments, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0014] In some embodiments, the at least one isolated minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0015] In some embodiments, the composition comprises at least one cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, THC, and CBD.

[0016] Further provided herein is a method for reducing acute migraine pain, comprising administering to a subject in need thereof a pharmacologic amount of a composition comprising THC and CBD, such that at least one biomarker of central and peripheral sensitization is modulated and migraine pain is reduced in the subject while reducing undesirable side effects or risk factors of THC. In some embodiments, the subject is a human.

[0017] In some embodiments, the composition further comprises at least one minor cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0018] Further provided herein is a method for reducing migraine frequency in a subject, comprising administering a pharmacologic effective amount of a composition comprising THC and CBD, such that at least one biomarker of central and peripheral sensitization is modulated and migraine frequency is reduced in the subject, while reducing undesirable side effects or risk factors of THC.In some embodiments, the subject has chronic migraine.In some embodiments, the subject has high frequency migraine.

[0019] In some embodiments, the composition further comprises at least one minor cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0020] Further provided herein is a pharmaceutical composition comprising THC and CBD, wherein the ratio of THC to CBD modulates at least one biomarker of central and peripheral sensitization while mitigating undesirable side effects or risk factors of THC.

[0021] In some embodiments, the composition further comprises a minor cannabinoid. In some aspects, the minor cannabinoid is selected form the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0022] In some embodiments, the at least one biomarker is selected from the group consisting of NMDA, glutamate, and CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0023] In some embodiments, the composition further comprises a terpenoid.

[0024] In some embodiments, the composition further comprises a pain relieving agent.

[0025] In some embodiments, the at least one biomarker is selected from the group consisting of NMDA, glutamate, or CGRP.

[0026] Further provided herein is a method for treating acute migraine pain, photophobia, phonophobia, and / or nausea, comprising administering to a subject in need thereof a pharmacologic effective amount of a composition comprising at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that migraine pain, photophobia, phonophobia, and / or nausea is alleviated in the subject.In some embodiments, the subject is a human.

[0027] In some embodiments, the administering is accomplished by injection.

[0028] In some embodiments, the treatment is effective within at least 2 hours after administration, hi some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0029] In some embodiments, migraine pain is measured by a pain scale.

[0030] In some embodiments, photophobia is measured by the Utah Photophobia Symptom Impact Scale, the Korean Photophobia Questionnaire, or self-report from the subject.

[0031] In some embodiments, phonophobia is measured by self-report from the subject.

[0032] In some embodiments, nausea is measured by subject self-report. In some additional embodiments, nausea is measured by visual analog scale.

[0033] In some embodiments, the composition comprises THC and CBD, wherein the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0034] In some embodiments, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0035] In some embodiments, the at least one minor cannabinoid, THC (if present), and CBD (if present) are at least 90% pure by weight. In some preferred embodiments, the at least one minor cannabinoid, THC (if present), and CBD (if present) are at least 99% pure by weight.

[0036] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0037] Further provided herein is a method for treating migraine frequency, comprising administering to a subject in need thereof a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that migraine frequency is reduced in the subject.In some embodiments, the subject is a human.

[0038] In some embodiments, the subject has chronic migraines, hi some embodiments, the subject has high frequency migraines.

[0039] In some embodiments, the administering is accomplished by injection.

[0040] In some embodiments, the treatment is effective within at least 2 hours after administration. In some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0041] In some embodiments, the composition comprises THC and CBD, wherein the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0042] In some embodiments, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0043] In some embodiments, the at least one minor cannabinoid, THC (if present), and CBD (if present) are at least 90% pure by weight. In some preferred embodiments, the at least one minor cannabinoid, THC (if present), and CBD (if present) are at least 99% pure by weight.

[0044] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0045] Further provided herein is a method for reducing acute migraine pain, comprising administering to a subject in need thereof a pharmacologic amount of a composition comprising THC and CBD, such that the migraine pain is reduced in the subject while reducing undesirable side effects or risk factors of THC. In some embodiments, the subject is a human.

[0046] In some embodiments, the subject has chronic migraines, hi some embodiments, the subject has high frequency migraines.

[0047] In some embodiments, the administering is accomplished by injection.

[0048] In some embodiments, the treatment is effective within at least 2 hours after administration. In some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0049] In some embodiments, the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0050] In some embodiments, the THC and CBD are at least 90% pure by weight. In some preferred embodiments, the THC and CBD are at least 99% pure by weight.

[0051] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0052] Further provided herein is a method for reducing fibromyalgia pain, comprising administering a pharmacologic effective amount of a composition comprising THC and CBD to a subject in need thereof, such that the pain of fibromyalgia is reduced in the subject while reducing the undesirable side effects or risk factors of THC.In some embodiments, the subject is a human.

[0053] In some embodiments, the administering is accomplished by injection.

[0054] In some embodiments, the treatment is effective within at least 2 hours after administration, hi some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0055] In some embodiments, the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0056] In some embodiments, the THC and CBD are at least 90% pure by weight. In some preferred embodiments, the THC and CBD are at least 99% pure by weight.

[0057] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0058] Further provided herein is a method of reducing CGRP-induced photoaversion, the method comprising administering to a subject in need thereof a composition comprising a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both.

[0059] Further provided herein is a method of reducing SNP-induced photoaversion, the method comprising administering to a subject in need thereof a composition comprising a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both.

[0060] Further provided herein is a method for treating acute migraine pain, photophobia, phonophobia, and / or nausea, comprising administering a pharmacologic effective amount of a composition comprising THC and CBD to a subject in need thereof, such that migraine pain, photophobia, phonophobia, and / or nausea is alleviated in the subject.In some embodiments, the subject is a human.

[0061] In some embodiments, the administering is accomplished by injection.

[0062] In some embodiments, the treatment is effective within at least 2 hours after administration. In some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0063] In some embodiments, migraine pain is measured by a pain scale.

[0064] In some embodiments, photophobia is measured by the Utah Photophobia Symptom Impact Scale, the Korean Photophobia Questionnaire, or self-report from the subject.

[0065] In some embodiments, phonophobia is measured by self-report from the subject.

[0066] In some embodiments, nausea is measured by subject self-report. In some additional embodiments, nausea is measured by visual analog scale.

[0067] In some embodiments, the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0068] In some embodiments, the composition further comprises at least one minor cannabinoid. In some aspects, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0069] In some embodiments, the THC, CBD, and at least one minor cannabinoid (if present) are at least 90% pure by weight. In some preferred embodiments, the THC, CBD, and at least one minor cannabinoid (if present) are at least 99% pure by weight.

[0070] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0071] Further provided herein is a method for reducing migraine frequency, comprising administering to a subject in need thereof a pharmacologic effective amount of a composition comprising THC and CBD, such that the frequency of migraine headaches is reduced in the subject. In some embodiments, the subject is a human.

[0072] In some embodiments, the subject has chronic migraines, hi some embodiments, the subject has high frequency migraines.

[0073] In some embodiments, the administering is accomplished by injection.

[0074] In some embodiments, the treatment is effective within at least 2 hours after administration. In some aspects, the treatment is effective within at least 1 hour after administration, within at least 30 minutes after administration, or within at least 15 minutes after administration.

[0075] In some embodiments, the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0076] In some embodiments, the composition further comprises at least one minor cannabinoid. In some aspects, the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0077] The THC, CBD, and at least one minor cannabinoid (if present) are at least 90% pure by weight. In some preferred embodiments, the THC, CBD, and at least one minor cannabinoid (if present) are at least 99% pure by weight.

[0078] In some embodiments, at least one biomarker of central and peripheral sensitization is modulated as a result of administration. In some aspects, the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG. [Brief description of the drawings]

[0079] [Figure 1A]1A-1B show the effect of CBD:THC ratio on motor function using the rotarod assay. The top panel of each figure shows the latency to fall from the rod over three consecutive 5-minute trials. The bottom panel of each figure shows the average latency to fall from the rod over the three trials. [Figure 1B] 1A-1B show the effect of CBD:THC ratio on motor function using the rotarod assay. The top panel of each figure shows the latency to fall from the rod over three consecutive 5-minute trials. The bottom panel of each figure shows the average latency to fall from the rod over the three trials.

[0080] [Diagram 2] FIG. 2 shows the experimental design of the light aversion experiment.

[0081] [Figure 3A] Figures 3A-D show the effect of different ratios of CBD and THC on light aversion. The left panel of each figure shows light aversion measured as a function of time over 30 min. The right panel of each figure shows the average time spent in the light compartment per 5 min during the entire test period. Figures 3A-B show the results of the light aversion experiment for all mice tested. Figure 3C shows the results of the light aversion experiment for female mice. Figure 3D shows the results of the light aversion experiment for male mice. [Figure 3B] Figures 3A-D show the effect of different ratios of CBD and THC on light aversion. The left panel of each figure shows light aversion measured as a function of time over 30 min. The right panel of each figure shows the average time spent in the light compartment per 5 min during the entire test period. Figures 3A-B show the results of the light aversion experiment for all mice tested. Figure 3C shows the results of the light aversion experiment for female mice. Figure 3D shows the results of the light aversion experiment for male mice. [Figure 3C]Figures 3A-D show the effect of different ratios of CBD and THC on light aversion. The left panel of each figure shows light aversion measured as a function of time over 30 min. The right panel of each figure shows the average time spent in the light compartment per 5 min during the entire test period. Figures 3A-B show the results of the light aversion experiment for all mice tested. Figure 3C shows the results of the light aversion experiment for female mice. Figure 3D shows the results of the light aversion experiment for male mice. [Figure 3D] Figures 3A-D show the effect of different ratios of CBD and THC on light aversion. The left panel of each figure shows light aversion measured as a function of time over 30 min. The right panel of each figure shows the average time spent in the light compartment per 5 min during the entire test period. Figures 3A-B show the results of the light aversion experiment for all mice tested. Figure 3C shows the results of the light aversion experiment for female mice. Figure 3D shows the results of the light aversion experiment for male mice.

[0082] [Figure 4] Figure 4 shows the effect of different ratios of CBD and THC on light aversion without CGRP trigger. The left panel shows light aversion measured as a function of time over a 30-minute period. The right panel shows the average time spent in the light compartment per 5 minutes during the entire test period.

[0083] [Figure 5A] Figures 5A-C show the effect of different ratios of CBD and THC on the time that mice spent resting in the dark compartment during the light aversion test. The left panel of each figure shows the time that mice spent in the dark compartment over a 30-minute period. The right panel of each figure shows the average time spent in the dark compartment per 5 minutes during the entire test period. Figure 5A shows the results of all mice tested. Figure 5B shows the results of female mice. Figure 5C shows the results of male mice. [Figure 5B]Figures 5A-C show the effect of different ratios of CBD and THC on the time that mice spent resting in the dark compartment during the light aversion test. The left panel of each figure shows the time that mice spent in the dark compartment over a 30-minute period. The right panel of each figure shows the average time spent in the dark compartment per 5 minutes during the entire test period. Figure 5A shows the results of all mice tested. Figure 5B shows the results of female mice. Figure 5C shows the results of male mice. [Figure 5C] Figures 5A-C show the effect of different ratios of CBD and THC on the time that mice spent resting in the dark compartment during the light aversion test. The left panel of each figure shows the time that mice spent in the dark compartment over a 30-minute period. The right panel of each figure shows the average time spent in the dark compartment per 5 minutes during the entire test period. Figure 5A shows the results of all mice tested. Figure 5B shows the results of female mice. Figure 5C shows the results of male mice.

[0084] [Figure 6] Figure 6 shows the effect of different ratios of CBD and THC on the resting time in the light compartment during the light aversion test. The left panel shows the time spent resting in the light compartment for every 5 minutes during the 30 minutes assay. The right panel shows the average time spent resting in the light compartment per 5 minutes.

[0085] [Figure 7] Figure 7 shows the effect of different ratios of CBD and THC on the light aversion produced by CGRP administration. The left panel shows the time spent resting in the light compartment for every 5 minutes during the 30 minutes assay. The right panel shows the average time spent resting in the light compartment per 5 minutes.

[0086] [Figure 8] Figure 8 shows the effect of different ratios of CBD and THC on the light aversion produced by CGRP administration. The left panel shows the time spent resting in the light compartment for every 5 minutes during the 30 minutes assay. The right panel shows the average time spent resting in the light compartment per 5 minutes.

[0087] [Figure 9] Figure 9 shows the effect of different ratios of CBD and THC on the light aversion induced by SNP administration for the two cohorts. Panels A and C show the time spent resting in the light compartment for every 5 minutes during the 30 minute assay for the two cohorts. Panels B and D show the average time spent resting in the light compartment per 5 minutes for the two cohorts.

[0088] [Figure 10] FIG. 10 shows the experimental design of the rotarod assay.

[0089] [Figure 11] Figure 11 shows the effect of different ratios of CBD and THC on locomotor activity assessed by rotarod. Panel A shows the results in all mice. Panel B shows the results in female mice. Panel C shows the results in male mice.

[0090] [Figure 12] FIG. 12 shows the experimental design of the Y-maze assay.

[0091] [Figure 13] Figure 13 shows the effect of different ratios of CBD and THC on spatial memory. Panel A shows the number of entries in novel arms during trials in all mice. Panel B shows the time spent in novel arms during trials in all mice. Panel C shows the number of entries in novel arms during trials in female mice. Panel D shows the number of entries in novel arms during trials in male mice. Panel E shows the time spent in novel arms during trials in female mice. Panel F shows the time spent in novel arms during trials in male mice.

[0092] [Figure 14]Figure 14 shows the effect of different ratios of CBD and THC and CGRP on spatial memory. The upper panel shows the number of entries in novel arms over time. The lower panel shows the average number of entries in novel arms for mice in each cohort.

[0093] [Figure 15-1] FIG. 15 shows the effect of CBD:THC on CSD characteristics including threshold, DC characteristics, and velocity at baseline, after administration of vehicle, and after administration of a composition containing 100:1 CBD / THC. [Figure 15-2] FIG. 15 shows the effect of CBD:THC on CSD characteristics including threshold, DC characteristics, and velocity at baseline, after administration of vehicle, and after administration of a composition containing 100:1 CBD / THC. [Figure 15-3] FIG. 15 shows the effect of CBD:THC on CSD characteristics including threshold, DC characteristics, and velocity at baseline, after administration of vehicle, and after administration of a composition containing 100:1 CBD / THC.

[0094] [Figure 16] FIG. 16 shows the effect of CBD:THC on CSD thresholds 1 hour and 30 minutes post-injection.

[0095] [Figure 17] FIG. 17 shows the effect of CBD:THC on CSD threshold and propagation velocity both 1 hour and 30 minutes post-injection.

[0096] [Figure 18A] FIG. 18A and FIG. 18B show the effects of CBD:THC on CSD half-width and amplitude both 1 hour and 30 minutes post-injection in the motor and visual cortices, respectively. [Figure 18B] FIG. 18A and FIG. 18B show the effects of CBD:THC on CSD half-width and amplitude both 1 hour and 30 minutes post-injection in the motor and visual cortices, respectively.

[0097] [Figure 19A] Figures 19A-B show the effect of CBD:THC on CSD-related pain behavior. Figure 19A shows the pain behavior 30 minutes after induction of associated CSD compared to baseline. Figure 19B shows the effect of 100:1 and 30:1 CBD:THC 30 minutes after CSD induction compared to vehicle. [Figure 19B] Figures 19A-B show the effect of CBD:THC on CSD-related pain behavior. Figure 19A shows the pain behavior 30 minutes after induction of associated CSD compared to baseline. Figure 19B shows the effect of 100:1 and 30:1 CBD:THC 30 minutes after CSD induction compared to vehicle.

[0098] [Figure 20] FIG. 20 shows the effect of CBD:THC on allodynia from hindpaw withdrawal threshold testing in wild-type and FHM1 KI mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0099] Detailed Description Before the present invention is disclosed and described, it is to be understood that the invention is not limited to the particular methods, compositions, or materials disclosed herein but extends to equivalents thereof, as would be recognized by one of ordinary skill in the art. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0100] Concentrations, amounts, and other numerical data may be expressed or presented in a range format herein. It is to be understood that such range formats are used merely for convenience and brevity, and should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were explicitly recited. By way of illustration, the numerical range "about 2 to about 50" should be interpreted to include not only the explicitly recited values ​​of 2 to 50, but also all individual values ​​and subranges within the stated range. This numerical range therefore includes individual values ​​such as 2, 2.4, 3, 3.7, 4, 5.5, 10, 10.1, 14, 15, 15.98, 20, 20.13, 23, 25.06, 30, 35.1, 38.0, 40, 44, 44.6, 45, 48, and subranges such as, for example, 1-3, 2-4, 5-10, 5-20, 5-25, 5-30, 5-35, 5-40, 5-50, 2-10, 2-20, 2-30, 2-40, 2-50, etc. This same principle also applies to ranges reciting only one numerical value as the minimum or maximum value. Moreover, such an interpretation should be applied regardless of the broadness of the range or the characteristic being described.

[0101] As used herein, the term "about" is used to provide flexibility to the endpoints of a numerical range by suggesting that a given value may be "a little above" or "a little below" the endpoint. For example, the endpoints may be within 10%, 8%, 5%, 3%, 2%, or 1% of the recited value. Furthermore, for convenience and brevity, a numerical range of "about 50 mg / mL to about 80 mg / mL" should also be understood to provide support for the range of "50 mg / mL to 80 mg / mL". The endpoints may also be based on variations permitted by appropriate regulatory agencies, such as the FDA, USP, etc.

[0102] In this disclosure, "comprises," "comprising," "containing," "having," and the like may have the meanings ascribed to them in U.S. Patent Law, and may mean "includes," "including," and the like, and are generally construed to be open-ended terms. The terms "consisting of" or "consists of" are closed terms, including only those components, structures, steps, and the like specifically recited with such terms, and in accordance with U.S. Patent Law. "consisting essentially of" or "consists essentially of" have the meanings generally ascribed to them by U.S. Patent Law. In particular, such terms are generally closed terms, except to allow for the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel properties or functions of the item(s) with which they are used. For example, trace elements that are present in a composition but do not affect the properties or characteristics of the composition would be acceptable when present in the words "consisting essentially of," even if they are not explicitly recited in a list of items following such terms. It is understood that when open-ended terms such as "comprising" or "including" are used herein, direct support should be given to the words "consisting essentially of" and "consisting of," as if they were explicitly stated, and vice versa.

[0103] The present disclosure details a composition comprising at least one cannabinoid.For example, in some embodiments, the present disclosure details a method of using a composition comprising at least one minor cannabinoid for the pain associated with migraine attacks with and / or without aura, migraine frequency, and fibromyalgia pain, as well as related disorders such as familial hemiplegic migraine, isolated hemiplegic migraine, and complex regional pain syndrome.Furthermore, such compositions may be used to reduce other symptoms associated with migraine, such as photophobia, phonophobia, and nausea.

[0104] In a further aspect, the present disclosure details a composition comprising THC and CBD.Specifically, the composition of the present disclosure may comprise THC and an amount of CBD to reduce any undesirable side effects of THC or risk factors associated with THC, or to increase the effectiveness of THC or the composition.Non-limiting examples of side effects or risk factors include mental activity, psychosis, anxiety, paranoia, dizziness, confusion, cardiovascular risk, memory impairment, or combinations thereof.Furthermore, the present disclosure details the use of such compositions for the pain associated with migraine attacks with and / or without aura, migraine frequency, and fibromyalgia pain, as well as related disorders such as familial hemiplegic migraine, isolated hemiplegic migraine, and complex regional pain syndrome. I. Minor cannabinoid composition

[0105] The minor cannabinoid compositions of the present disclosure include at least one minor cannabinoid. In some embodiments, the compositions may further include a major cannabinoid, a terpenoid, an additional compound, or a combination thereof.

[0106] The minor cannabinoid composition of the present disclosure, when administered to a subject in need thereof, modulates biomarkers of central and peripheral sensitization. As used herein, the term "modulate" in relation to biomarkers of central and peripheral sensitization generally means a decrease in serum concentration of the biomarker, unless otherwise specified. As used herein, the phrase "peripheral sensitization" refers to hypersensitivity in peripheral nociceptors, which causes phenomena such as lowering of stimulation threshold (allodynia), increased response and long-term sequelae (hyperalgesia), and expansion of receptive field to undamaged tissue, and hypersensitivity of peripheral ocular and auditory nerve pathways, which causes phenomena such as photophobia and phonophobia. As used herein, "central sensitization" refers to hyperexcitatory activity of central nociceptive nerve pathways and central ocular and auditory pathways, which causes phenomena such as photophobia and phonophobia.

[0107] The minor cannabinoid compositions of the present disclosure may modulate biomarkers of central and peripheral sensitization by binding as agonists, antagonists or inverse agonists to one or more receptors from the group consisting of CB1, CB2 (in the dorsal horn, spinal cord), TRPV-1, TRPV-2, TRPV-3, TRPV-4, TRPV-8, TRPA-1, TRPM-8, 5HT-1A, 5HT-2A, type 3 5HT, alpha-2 adrenergic receptors, PPAR-gamma, GAPDH, PPAR, GPCR-92 NK1, EP, trkB, mGlu1, mGlu4, mGlu5 mGlu6, mGlu7, mGlu8, FAAH, NMDA and its subunits NR1 and NR2A.

[0108] In some embodiments, the minor cannabinoid compositions of the present disclosure may modulate 5-HT receptors (including 5HT-1B / 1D receptors), inhibit glutamatergic release via CB1 receptor-mediated inhibition of NMDA, activate TRPV receptors to modulate CGRP release, affect vasomotor tone, increase AEA levels in the cerebrospinal fluid and PAG, or decrease CGRP and NO. In preferred embodiments, the minor cannabinoid compositions of the present disclosure may modulate biomarkers of central and peripheral sensitization by binding as an agonist, antagonist, or inverse agonist to one or more receptors from the group consisting of CB1, CB2, TRPV1, TRPV2, NMDA, and glutamate receptors.

[0109] Biomarkers of central and peripheral sensitization may include NMDA, CGRP, FAAH, substance P, glutamate, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc. In some embodiments, biomarkers of peripheral sensitization may include neurogenic CGRP, nitric oxide, or other compounds that inhibit dural vasodilation.

[0110] In certain embodiments, the minor cannabinoid compositions of the present invention may reduce the activity of enzymes that act as biomarkers, such as cyclooxygenase, lipoxygenase, and P450 enzymes, e.g., CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP3A4, CYP3A5, CYP2A6, CYP2D6, CYP1B1, and / or CYP3A7. Reduction in the activity of one or more of these enzymes may modulate the anti-inflammatory effects involved in migraine pain.

[0111] In certain embodiments, the minor cannabinoid compositions of the present invention may exhibit other forms of antinociception by inhibiting NF-kB activity, iNOS, corticotropin-releasing factor binding protein, cysteine ​​protease ATGB4, photoreceptor-specific nuclear receptor NR2E3, or diacylglycerol lipase. In further specific embodiments, the minor cannabinoid compositions of the present invention may modulate the levels of NMDA, alpha amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid, and kainate receptor modulated neuro-toxicity via CB1, or inhibit CB1-mediated modulation of NMDA, suppress glutamatergic release, or increase endopioid pre-curser gene expression involved in pain perception. In preferred embodiments, the compositions of the present disclosure may affect sensitization by modulating the levels of NMDA and / or glutamate. (a) Minor cannabinoids

[0112] The minor cannabinoid compositions of the present disclosure include at least one minor cannabinoid. The minor cannabinoids used in the present disclosure may be isolated from natural sources or may be synthetically produced. Non-limiting examples of minor cannabinoids may include CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabiditriol, and cannabiolcol. In one embodiment, the minor cannabinoid composition of the present disclosure may comprise one or more of the group of minor cannabinoids consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabidiol, and cannabiolcol.In another embodiment, the minor cannabinoid composition of the disclosure is selected from the group consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), It may comprise two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more of the group of minor cannabinoids consisting of CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabidiol, and cannabiolcol.In yet another embodiment, the minor cannabinoid composition of the disclosure is selected from the group consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBD. The cannabinoids may comprise at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21 or at least 22 or more of the group of minor cannabinoids consisting of V (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabidiol, and cannabiolcol.

[0113] In some embodiments, at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC. In certain embodiments, the minor cannabinoid composition of the present invention comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 minor cannabinoids selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC. In certain embodiments, the minor cannabinoid composition of the present invention may comprise any combination of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC.

[0114] The minor cannabinoid compositions of the present disclosure may comprise from about 1% to about 100% of one or more minor cannabinoids. For example, the minor cannabinoid compositions may comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% of one or more minor cannabinoids. In some embodiments, the minor cannabinoid composition may contain from about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 100% of one or more minor cannabinoids. (b) Major cannabinoids

[0115] The minor cannabinoid composition of the present disclosure may include major cannabinoids. Non-limiting examples of major cannabinoids may include cannabinoids D-9 THC (THC) and CBD. In one embodiment, the minor cannabinoid composition of the present disclosure includes THC. In another embodiment, the minor cannabinoid composition of the present disclosure includes CBD. In a preferred embodiment, the minor cannabinoid composition of the present disclosure may include both THC and CBD.

[0116] The minor cannabinoid compositions of the present disclosure may comprise from about 1% to about 99% of one or more of the major cannabinoids. For example, the compositions may comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% of one or more of the major cannabinoids. In some embodiments, the minor cannabinoid compositions may comprise from about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% of one or more of the major cannabinoids. (c) Terpenoids

[0117] In certain embodiments, the minor cannabinoid composition of the present invention may comprise terpenoids.Non-limiting examples of terpenoids may include myrcene, β-caryophyllene, limonene, α-terpineol, linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, nerolidol, phytol, caryophyllene oxide and α-humule.In some embodiments, the minor cannabinoid composition of the present disclosure may comprise 1, 2, 3, 4, 5 or more terpenoids selected from the group consisting of myrcene, β-caryophyllene, limonene, α-terpineol, linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, nerolidol, phytol, caryophyllene oxide and α-humule.

[0118] Generally speaking, the at least one terpenoid may comprise from 0% to about 99% by weight of the compositions of the present disclosure. For example, the minor cannabinoid composition may comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% by weight of the at least one terpenoid. In some embodiments, the minor cannabinoid composition may contain, by weight, about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% of at least one terpenoid. (d) Other compounds

[0119] In certain embodiments, the minor cannabinoid composition of the present invention may include one or more additional compounds.Non-limiting examples of additional compounds may include simple analgesics such as paracetamol and / or acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), 5-HT (serotonin) receptor agonists, calcitonin gene-related peptide (CGRP) receptor antagonists, N-methyl D-aspartic acid (NMDA) inhibitors, glutamate receptor antagonists, substance P inhibitors, GABA inhibitors, FAAH inhibitors, nerve growth factor (NGF) inhibitors, brain-derived neurotrophic factor (BDNF) inhibitors, extracellular signal-regulated kinase (ERK) antagonists, NO inhibitors, or other compounds. In some embodiments, the minor cannabinoid compositions of the present disclosure may comprise 1, 2, 3, 4, 5, or more than 5 additional compounds selected from the group consisting of a simple analgesic such as paracetamol or acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), a 5-HT (serotonin) receptor agonist, a calcitonin gene-related peptide (CGRP) receptor antagonist, an N-methyl D-aspartate (NMDA) inhibitor, a glutamate receptor antagonist, a substance P inhibitor, a GABA inhibitor, a FAAH inhibitor, a nerve growth factor (NGF) inhibitor, a brain-derived neurotrophic factor (BDNF) inhibitor, an extracellular signal-regulated kinase (ERK) antagonist, an NO inhibitor, or another compound.

[0120] Generally speaking, the at least one additional compound may comprise from 0% to about 99% by weight of the minor cannabinoid compositions of the present disclosure. For example, the minor cannabinoid compositions may contain about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% of one or more additional compounds. In some embodiments, the minor cannabinoid composition may comprise from about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% of one or more additional compounds. (e) Quantity

[0121] Generally speaking, the minor cannabinoid compositions of the present disclosure may be used to deliver greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 180 mg of THC per day. In certain embodiments, up to 40 mg of THC per day is delivered. In other embodiments, up to about 120 mg of THC per day is delivered. These amounts may be included in a single dose or in more than one dose (e.g., two, three, or more than three doses).

[0122] The minor cannabinoid compositions of the present disclosure may be used to deliver about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, or 2400 mg / day of CBD. These amounts may be included in a single dose or in more than one dose (e.g., two, three, or more than three doses). In certain embodiments, a greater amount of CBD is included in the minor cannabinoid composition to treat the inflammatory component in migraine, to counteract the psychoactive or undesirable side effects of THC or minor cannabinoids, or combinations thereof.

[0123] In certain embodiments, the minor cannabinoid compositions of the present disclosure may be used to deliver greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 180 mg / day of THC and greater than about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, or 2400 mg / day of CBD. These amounts may be included in a single dose or in more than one dose (e.g., two, three, or more than three doses).

[0124] In some embodiments, the minor cannabinoid compositions of the present disclosure may be used to deliver greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 180 mg / day of minor cannabinoids. These amounts may be contained in a single dose or in more than one dose (e.g., two, three, or more than three doses). In each of the embodiments in which the compositions of the present disclosure include a minor cannabinoid, the composition may further be used to deliver greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 180 mg / day of THC, or about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, or 2400 mg / day of CBD, or a combination thereof.

[0125] In some embodiments, CBD and THC may be present in the minor cannabinoid composition in a weight ratio (CBD:THC) of about 10:1 to about 300:1. In some aspects, CBD and THC are present in a weight ratio of about 10:1 to about 20:1, about 10:1 to about 30:1, about 10:1 to about 40:1, about 10:1 to about 50:1, about 10:1 to about 60:1, about 10:1 to about 70:1, about 10:1 to about 80:1, about 10:1 to about 90:1, about 10:1 to about 100:1, about 10:1 to about 150:1, about 10:1 to about 200:1, about 10:1 to about 250:1, about 10:1 to about 300:1, about 20:1 to about 300:1, about 30:1 to about 300:1, about 40: They may be present in a weight ratio of about 1 to about 300:1, about 50:1 to about 300:1, about 60:1 to about 300:1, about 70:1 to about 300:1, about 80:1 to about 300:1, about 90:1 to about 300:1, about 100:1 to about 300:1, about 110:1 to about 300:1, about 120:1 to about 300:1, about 130:1 to about 300:1, about 140:1 to about 300:1, about 150:1 to about 300:1, about 20:1 to about 130:1, about 20:1 to about 100:1, or about 30:1 to about 100:1. In some further embodiments, the THC and CBD may be present in a weight ratio of about 10:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, 105:1, 110:1, 115:1, 120:1, 125:1, 130:1, 135:1, 140:1, 145:1, 150:1, 200:1, 250:1, or about 300:1. In some examples, the THC and CBD may be present in a weight ratio of about 20:1, about 25:1, about 30:1, about 100:1, about 130:1, or about 300:1.

[0126] In some embodiments, CBD and THC may be present in the minor cannabinoid composition in a molar ratio (CBD:THC) of about 10:1 to about 300:1. In some embodiments, CBD and THC may be present in a molar ratio (CBD:THC) of about 10:1 to about 20:1, about 10:1 to about 30:1, about 10:1 to about 40:1, about 10:1 to about 50:1, about 10:1 to about 60:1, about 10:1 to about 70:1, about 10:1 to about 80:1, about 10:1 to about 90:1, about 10:1 to about 100:1, about 10:1 to about 150:1, about 10:1 to about 200:1, about 10:1 to about 250:1, about 10:1 to about 300:1, about 20:1 to about 300:1, about 30:1 to about 300:1, about 40: They may be present in a molar ratio of about 1 to about 300:1, about 50:1 to about 300:1, about 60:1 to about 300:1, about 70:1 to about 300:1, about 80:1 to about 300:1, about 90:1 to about 300:1, about 100:1 to about 300:1, about 110:1 to about 300:1, about 120:1 to about 300:1, about 130:1 to about 300:1, about 140:1 to about 300:1, about 150:1 to about 300:1, about 20:1 to about 130:1, about 20:1 to about 100:1, or about 30:1 to about 100:1. In some further embodiments, the CBD and THC may be present in a molar ratio of about 10:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, 105:1, 110:1, 115:1, 120:1, 125:1, 130:1, 135:1, 140:1, 145:1, 150:1, 200:1, 250:1, or about 300:1. In some examples, the CBD and THC may be present in a weight ratio of about 20:1, about 25:1, about 30:1, about 100:1, about 130:1, or about 300:1. II. THC and CBD Composition

[0127] The THC and CBD composition of the present disclosure comprises THC and CBD. Specifically, the THC and CBD composition of the present disclosure comprises THC and an amount of CBD to reduce any undesirable side effects of THC or risk factors associated with THC, or to increase the effectiveness of THC or the composition. Non-limiting examples of side effects or risk factors include psychoactivity, psychosis, anxiety, paranoia, dizziness, confusion, cardiovascular risk, memory impairment, or combinations thereof. In some embodiments, the THC and CBD composition may further comprise at least one minor cannabinoid, terpenoid, additional compound, or combinations thereof.

[0128] The THC and CBD compositions of the present disclosure, when administered to a subject in need thereof, modulate the biomarkers and behavioral indicators of central and peripheral sensitization.As used herein, the term peripheral sensitization refers to hypersensitivity in peripheral nociceptors, which causes phenomena such as lowering of stimulation threshold (allodynia), increased response and long-term sequelae (hyperalgesia), and expansion of receptive field to undamaged tissue.As used herein, "central sensitization" refers to the hyperexcitatory activity of central nociceptive neural pathways.

[0129] The THC and CBD compositions of the disclosure may modulate biomarkers of central and peripheral sensitization by binding as agonists, antagonists or inverse agonists to one or more receptors from the group consisting of CB1, CB2 (in the dorsal horn, spinal cord), TRPV-1, TRPV-2, TRPV-3, TRPV-4, TRPV-8, TRPA-1, TRPM-8, 5HT-1A, 5HT-2A, type 3 5HT, alpha-2 adrenergic receptor, PPAR-gamma, GAPDH, PPAR, GPCR-92 NK1, EP, trkB, mGlu1, mGlu4, mGlu5 mGlu6, mGlu7, mGlu8, FAAH, NMDA and its subunits NR1 and NR2A.

[0130] In some embodiments, the THC and CBD compositions of the present disclosure may indirectly modulate 5-HT receptors (including 5HT-1B / 1D receptors), inhibit glutamatergic release via CB1 receptor-mediated inhibition of NMDA, activate TRPV receptors to modulate CGRP release, affect vasomotor tone, increase AEA levels in the cerebrospinal fluid and PAG, or decrease CGRP and NO. In preferred embodiments, the compositions of the present disclosure may modulate biomarkers of central and peripheral sensitization by binding as an agonist, antagonist, or inverse agonist to one or more receptors from the group consisting of CB1, CB2, TRPV1, TRPV2, NMDA, and glutamate receptors.

[0131] Biomarkers of central and peripheral sensitization may include NMDA, CGRP, FAAH, substance P, glutamate, NO, GABA, NGF, serotonin, dopamine, NO, AEA, 2-AG, etc. In some embodiments, biomarkers of peripheral sensitization may include neurogenic CGRP, nitric oxide, or other compounds that inhibit dural vasodilation.

[0132] In certain embodiments, the THC and CBD compositions of the present invention may reduce the activity of enzymes that act as biomarkers, such as cyclooxygenase, lipoxygenase, and P450 enzymes, e.g., CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP3A4, CYP3A5, CYP2A6, CYP2D6, CYP1B1, and / or CYP3A7. Reduction in the activity of one or more of these enzymes may modulate the anti-inflammatory effects involved in migraine pain.

[0133] In certain embodiments, the THC and CBD compositions of the present invention may exhibit other forms of antinociception by inhibiting NF-kB activity, iNOS, corticotropin-releasing factor binding protein, cysteine ​​protease ATGB4, photoreceptor-specific nuclear receptor NR2E3, or diacylglycerol lipase. In further specific embodiments, the THC and CBD compositions of the present invention may modulate the levels of NMDA, alpha amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid, and kainate receptor modulating neurotoxicity via CB1, or inhibit glutamatergic release by inhibiting CB1-mediated modulation of NMDA, or increase endopioid pre-curser gene expression involved in pain perception. In preferred embodiments, the THC and CBD compositions of the present disclosure may affect sensitization by modulating the levels of NMDA and / or glutamate.

[0134] Behavioral indices may include behavioral responses in animal or human models of trigeminovascular nociception, animal models of spontaneous nociceptive responses in the craniofacial or plantar regions, models of associated neurological conditions, models of migraine or associated symptoms of sensitization such as photophobia, phonophobia, odour phobia, allodynia, or other conditions, or other animal or human models. (a) THC and CBD

[0135] The THC and CBD composition of the present disclosure comprises THC (cannabinoid D-9THC) and CBD.Specifically, the composition of the present disclosure comprises THC and an amount of CBD to reduce any undesirable side effects of THC or risk factors associated with THC, or to increase the effectiveness of THC.Non-limiting examples of side effects or risk factors include psychoactivity, psychosis, anxiety, paranoia, dizziness, confusion, increased cardiovascular risk, memory impairment, or a combination thereof.

[0136] As used herein, THC refers to tetrahydrocannabinol, whether synthetically produced or isolated from the plant. THC is (-)-trans-Δ 9 -tetrahydrocannabinol or its isomers. As used herein, CBD refers to cannabidiol or its isomers, whether produced synthetically or isolated from the plant.

[0137] For example, the THC and CBD compositions of the present disclosure may contain about 0.1% to about 99% THC. For example, the THC and CBD compositions may contain about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% THC. In some embodiments, the THC and CBD compositions may contain about 0.1 to about 0.5, about 0.5 to about 1, about 1 to about 2, about 2 to about 5, about 5 to about 10, about 5 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% THC.

[0138] In each of the above embodiments, the THC and CBD compositions of the present disclosure further comprise CBD. For example, the THC and CBD compositions of the present disclosure may comprise about 1% to about 99.9% CBD. For example, the compositions may comprise about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98, 98.5, 99, 99.5, 99.7, or 99.9% CBD. In some embodiments, the THC and CBD compositions may contain from about 1 to about 25, from about 15 to about 35, from about 20 to about 40, from about 25 to about 45, from about 30 to about 50, from about 35 to about 55, from about 40 to about 60, from about 45 to about 65, from about 50 to about 70, from about 55 to about 75, from about 60 to about 80, from about 65 to about 85, from about 70 to about 90, from about 75 to about 95, from about 80 to about 95, from about 95 to about 98, or from about 98 to about 99.9% CBD.

[0139] In certain embodiments, the THC and CBD compositions of the present disclosure include from about 80% CBD to about 99.9% CBD, and from about 0.1% THC to about 20% THC. In certain embodiments, the THC and CBD compositions of the present disclosure include from about 90% CBD to about 97% CBD and from about 3% THC to about 10% THC. In preferred embodiments, the THC and CBD compositions may include at least about 90% CBD and no more than about 10% THC. For example, the THC and CBD compositions may include at least about 90, 91, 92, 93, 94, 95, 96, 97, or 98% CBD and no more than about 10, 9, 8, 7, 6, 5, 4, 3, or 2% THC. In other preferred embodiments, the THC and CBD compositions may include at least about 95% CBD and no more than about 5% THC. For example, a THC and CBD composition may contain at least about 95, 96, 97, 98.5, 99, 99.5, or 99.9% CBD and no more than about 5, 4, 3, 2, 1.5, 1, 0.5, or 0.1% THC.

[0140] In some embodiments, CBD and THC may be present in the composition in a weight ratio (CBD:THC) of about 10:1 to about 300:1. In some aspects, CBD and THC are present in a weight ratio of about 10:1 to about 20:1, about 10:1 to about 30:1, about 10:1 to about 40:1, about 10:1 to about 50:1, about 10:1 to about 60:1, about 10:1 to about 70:1, about 10:1 to about 80:1, about 10:1 to about 90:1, about 10:1 to about 100:1, about 10:1 to about 150:1, about 10:1 to about 200:1, about 10:1 to about 250:1, about 10:1 to about 300:1, about 20:1 to about 300:1, about 30:1 to about 300:1, about 40: They may be present in a weight ratio of about 1 to about 300:1, about 50:1 to about 300:1, about 60:1 to about 300:1, about 70:1 to about 300:1, about 80:1 to about 300:1, about 90:1 to about 300:1, about 100:1 to about 300:1, about 110:1 to about 300:1, about 120:1 to about 300:1, about 130:1 to about 300:1, about 140:1 to about 300:1, about 150:1 to about 300:1, about 20:1 to about 130:1, about 20:1 to about 100:1, or about 30:1 to about 100:1. In some further embodiments, the CBD and THC may be present in a weight ratio of about 10:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, 105:1, 110:1, 115:1, 120:1, 125:1, 130:1, 135:1, 140:1, 145:1, 150:1, 200:1, 250:1, or about 300:1. In some examples, the CBD and THC may be present in a weight ratio of about 20:1, about 25:1, about 30:1, about 100:1, about 130:1, or about 300:1.

[0141] In some embodiments, CBD and THC may be present in the composition in a molar ratio (CBD:THC) of about 10:1 to about 300:1. In some aspects, CBD and THC are present in a molar ratio of about 10:1 to about 20:1, about 10:1 to about 30:1, about 10:1 to about 40:1, about 10:1 to about 50:1, about 10:1 to about 60:1, about 10:1 to about 70:1, about 10:1 to about 80:1, about 10:1 to about 90:1, about 10:1 to about 100:1, about 10:1 to about 150:1, about 10:1 to about 200:1, about 10:1 to about 250:1, about 10:1 to about 300:1, about 20:1 to about 300:1, about 30:1 to about 300:1, about 40: They may be present in a molar ratio of about 1 to about 300:1, about 50:1 to about 300:1, about 60:1 to about 300:1, about 70:1 to about 300:1, about 80:1 to about 300:1, about 90:1 to about 300:1, about 100:1 to about 300:1, about 110:1 to about 300:1, about 120:1 to about 300:1, about 130:1 to about 300:1, about 140:1 to about 300:1, about 150:1 to about 300:1, about 20:1 to about 130:1, about 20:1 to about 100:1, or about 30:1 to about 100:1. In some further embodiments, the CBD and THC may be present in a molar ratio of about 10:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1, 105:1, 110:1, 115:1, 120:1, 125:1, 130:1, 135:1, 140:1, 145:1, 150:1, 200:1, 250:1, or about 300:1. In some examples, the CBD and THC may be present in a weight ratio of about 20:1, about 25:1, about 30:1, about 100:1, about 130:1, or about 300:1.

[0142] CBD in the compositions of the present disclosure may reduce psychoactive side effects or risk factors of THC or other cannabinoids as measured by prolactin, c-Fox expression, serum and / or cerebrospinal fluid (CSF) levels of anandamide (AEA), GABA, glutamate, FAAH, ethanolamide (palmitoylethanolamide and oleoylethanolamide), FLAT (FAAH-like anandamide transporter), or other fatty acid binding proteins (FABPs).

[0143] CBD may exert its antipsychotic effects as measured by acting as an antagonist, agonist, or inverse agonist on the CB1, CB2, and TRPV1 receptors in the prefrontal cortex, amygdala, and / or hippocampus, GABAergic neurons in the nucleus accumbens, 5HT-1A, D2, PPARγ (peroxisome proliferator-activated receptor gamma), or by interacting with ion channels or enzymes as described herein, contributing to its anti-inflammatory, antioxidant, and / or neuroprotective properties.

[0144] The antipsychotic effects of CBD may be measured in the striatum and temporal cortex, ventral tegmental area (VTA), nucleus accumbens, ventral pallidum, dorsomedial thalamic nucleus, prefrontal cortex, anterior cingulate gyrus, parahippocampal gyrus, amygdala, right posterior temporal gyrus and right temporal lobe, middle occipital gyrus, cerebellum, left caudate nucleus, or dopaminergic mesolimbic pathways.

[0145] The antipsychotic effects of CBD may be measured by reducing psychotomimetic symptoms, amorphine-induced stereotypy, amphetamine-, D-amphetamine-, and ketamine-induced hyperlocomotion, social withdrawal in animal models, reduced scores on the Brief Psychotic Symptoms Rating Scale (BPRS), Parkinson's Disease Psychotic Symptoms Questionnaire, Positive and Negative Syndrome Scale (PANSS), apomorphine stereotypy, catalepsy, MK-801 prepulse inhibition (PPI), hyperlocomotion, or social withdrawal, and a variety of other behavioral and neurochemical techniques in animal models such as c-Fos immunohistochemistry, or other techniques.

[0146] Methods for isolating, synthesizing, or purifying THC and CBD are known in the art. (b) Minor cannabinoids

[0147] The THC and CBD compositions of the present disclosure may include at least one minor cannabinoid. The minor cannabinoids used in the present disclosure may be isolated from natural sources or may be synthetically produced. Non-limiting examples of minor cannabinoids may include CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabiditriol, and cannabiolcol. In one embodiment, the THC and CBD compositions of the disclosure may comprise one or more of the group of minor cannabinoids consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabiditriol, and cannabiolcol.In another embodiment, the THC and CBD compositions of the disclosure are selected from the group consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBD (cannabinolic ... It may comprise two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more of the group of minor cannabinoids consisting of BDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabiditriol, and cannabiolcol.In yet another embodiment, the THC and CBD compositions of the disclosure are selected from the group consisting of CBGV (cannabigerovarin), CBGVA (cannabigerovarinic acid), CBG (cannabigerol), CBGA (cambigerolic acid), cannabinerolic acid, cannabinol, CBN (cannabinol), CBNA (cannabinolic acid), THCV (tetrahydrocannabivarin), THCA (tetrahydrocannabinolic acid), D8-THC (delta-8-tetrahydrocannabinol), CBDA (cannabidiolic acid), CBC (cannabichromene), CBCA, (cannabichromene acid), CBDV (cannabivarin), CBL (cannabicyclol), CBLA (cannabicyclol acid), cannabicyclovaline, CBE (cannabielsoin), CBF (cannabifuran), cannabicitran, cannabiditriol, and cannabiolcol, or more.

[0148] In some embodiments, the minor cannabinoids may be selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC. In certain embodiments, the THC and CBD compositions of the present invention may contain at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 minor cannabinoids selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC. In certain embodiments, the THC and CBD compositions of the present invention may contain any combination of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, or D8-THC.

[0149] The THC and CBD compositions of the present disclosure may contain from about 1% to about 99.9% of one or more minor cannabinoids. For example, the minor cannabinoid composition may contain about 0.1, 0.5, 1.5, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5, 99.7, 99.9% of one or more minor cannabinoids. In some embodiments, the THC and CBD compositions may contain from about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% of one or more minor cannabinoids.

[0150] In some embodiments, the THC and CBD compositions may comprise a ratio of minor cannabinoids to THC of about 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 22:1, 25:1, 28:1, 30:1, 32:1, 35:1, 38:1, 40:1, 50:1, 75:1, 90:1, 100:1, 110:1, 125:1, 150:1, 200:1, 250:1, 400:1, or 500:1. In other embodiments, the THC and CBD compositions may include a ratio of minor cannabinoids to D8-THC of about 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 22:1, 25:1, 28:1, 30:1, 32:1, 35:1, 38:1, 40:1, 50:1, 75:1, 90:1, 100:1, 110:1, 125:1, 150:1, 200:1, 250:1, 400:1, or 500:1. In still other embodiments, the THC and CBD compositions may comprise a ratio of minor cannabinoids to THCV of about 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 22:1, 25:1, 28:1, 30:1, 32:1, 35:1, 38:1, 40:1, 50:1, 75:1, 90:1, 100:1, 110:1, 125:1, 150:1, 200:1, 250:1, 400:1, or 500:1. In preferred embodiments, the THC and CBD compositions may comprise a ratio of CBC, CBL, CBN, CBG, CBDV, CBC to THC, D8-THC, or THCV of about 5:1, 8:1, 10:1, 12:1, 15:1, 18:1, 20:1, 22:1, 25:1, 28:1, 30:1, 32:1, 35:1, 38:1, 40:1 50:1, 75:1, 90:1, 100:1, 110:1, 125:1, 150:1, 200:1, 250:1, 400:1, or 500:1.

[0151] In certain embodiments, the THC and CBD compositions may include a ratio of D8-THC to D9-THC of about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In other embodiments, the THC and CBD compositions may include a ratio of THCV to D9-THC of about 1:1, 2:1, 3:1, 4:1, 5:1 6:1, 7:1, 8:1, 9:1, or 10:1. (c) Terpenoids

[0152] In certain embodiments, the THC and CBD compositions of the present invention may include terpenoids. Non-limiting examples of terpenoids may include myrcene, β-caryophyllene, limonene, α-terpineol, linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, nerolidol, phytol, caryophyllene oxide, and α-humule. In some embodiments, the THC and CBD compositions of the present disclosure may include 1, 2, 3, 4, 5, or more than 5 terpenoids selected from the group consisting of myrcene, β-caryophyllene, limonene, α-terpineol, linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, nerolidol, phytol, caryophyllene oxide, and α-humule.

[0153] Generally speaking, the at least one terpenoid may comprise from 0% to about 99.9% by weight of the THC and CBD compositions of the present disclosure. For example, the THC and CBD compositions may contain about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 97, 98, 99, 99.5 or 99.9% by weight of the at least one terpenoid. In some embodiments, the THC and CBD compositions may contain about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 90%, about 90 to about 95, or about 95 to about 99.9% by weight of at least one terpenoid. (d) Other compounds

[0154] In certain embodiments, the THC and CBD compositions of the present invention may include one or more additional compounds. Non-limiting examples of additional compounds may include simple analgesics such as paracetamol and / or acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), 5-HT (serotonin) receptor agonists, calcitonin gene-related peptide (CGRP) receptor antagonists, N-methyl D-aspartate (NMDA) inhibitors, glutamate receptor antagonists, substance P inhibitors, GABA inhibitors, FAAH inhibitors, nerve growth factor (NGF) inhibitors, brain-derived neurotrophic factor (BDNF) inhibitors, extracellular signal-regulated kinase (ERK) antagonists, NO inhibitors, or another compound. In some embodiments, the THC and CBD compositions of the disclosure may include 1, 2, 3, 4, 5, or more than 5 additional compounds selected from the group consisting of a simple analgesic such as paracetamol or acetaminophen, a nonsteroidal anti-inflammatory drug (NSAID), a 5-HT (serotonin) receptor agonist, a calcitonin gene-related peptide (CGRP) receptor antagonist, an N-methyl D-aspartate (NMDA) inhibitor, a glutamate receptor antagonist, a substance P inhibitor, a GABA inhibitor, a FAAH inhibitor, a nerve growth factor (NGF) inhibitor, a brain-derived neurotrophic factor (BDNF) inhibitor, an extracellular signal-regulated kinase (ERK) antagonist, an NO inhibitor, or another compound.

[0155] Generally speaking, the at least one additional compound may comprise 0% to about 99% by weight of the THC and CBD compositions of the present disclosure. For example, the compositions may include about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% of one or more additional compounds. In some embodiments, the THC and CBD compositions may include about 1 to about 25, about 15 to about 35, about 20 to about 40, about 25 to about 45, about 30 to about 50, about 35 to about 55, about 40 to about 60, about 45 to about 65, about 50 to about 70, about 55 to about 75, about 60 to about 80, about 65 to about 85, about 70 to about 90, about 75 to about 95, or about 80 to about 99% of one or more additional compounds. (e) Quantity

[0156] Generally speaking, the THC and CBD compositions of the present disclosure may be used to deliver greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, or 180 mg of THC per day. These amounts may be contained in a single dose or in more than one dose (e.g., two, three, or more than three doses).

[0157] In each of the above embodiments, the THC and CBD compositions of the present disclosure may further be used to deliver about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, or 2400 mg / day of CBD. These amounts may be included in a single dose or in more than one dose (e.g., two, three, or more than three doses). In certain embodiments, a larger amount of CBD is included in the composition to reduce undesirable side effects of THC or risk factors associated with THC, or to increase the effectiveness of THC. Non-limiting examples of side effects or risk factors include mental activity, psychosis, anxiety, paranoia, dizziness, confusion, cardiovascular risk, memory impairment, or a combination thereof. III. Pharmaceutical Compositions

[0158] The present disclosure also provides a pharmaceutical composition. The pharmaceutical composition comprises a minor cannabinoid composition (described in detail in section I above) or a THC and CBD composition (described in detail in section II above) and at least one pharma- ceutically acceptable excipient. The pharma-ceutically acceptable excipient may be a diluent, binder, filler, buffer, pH adjuster, disintegrant, dispersant, preservative, lubricant, taste masking agent, flavoring agent, or coloring agent. The amount and type of excipient utilized to form the pharmaceutical composition may be selected according to known principles of pharmacy.

[0159] In each of the embodiments described herein, the composition of the present invention may optionally contain one or more additional compounds.Therefore, in addition to the treatment described herein, other treatments known to be effective in treating disease, disorder, or condition or to reduce side effects may be provided to the subject.In some embodiments, the additional drug or therapeutic active induces anti-inflammatory effect. (i) Diluent

[0160] In one embodiment, excipient may be diluent. Diluent may be compressible (i.e., plastically deformable) or abrasively fragile. Non-limiting examples of suitable compressible diluent may include microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose ester (i.e., mixed ester of acetate and butyrate), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, corn starch, phosphorylated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, and trehalose. Non-limiting examples of suitable abrasively brittle diluents include dicalcium phosphate (anhydrous or dihydrate), tricalcium phosphate, calcium carbonate, and magnesium carbonate. (ii) Binder

[0161] In another embodiment, the excipient may be a binder.Suitable binders may include, but are not limited to, starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C12-C18 fatty acid alcohol, polyethylene glycol, polyol, sugar, oligosaccharide, polypeptide, oligopeptide, and combinations thereof. (iii) Filler

[0162] In another embodiment, excipient may be filler.Suitable filler may include, but is not limited to, carbohydrate, inorganic compound, and polyvinylpyrrolidone.As a non-limiting example, filler may be calcium sulfate, both dibasic and tribasic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starch, lactose, sucrose, mannitol, or sorbitol. (iv) Buffer

[0163] In yet another embodiment, the excipient may be a buffer.Representative examples of suitable buffers may include, but are not limited to, phosphate, carbonate, citrate, Tris buffer, and buffered saline salts (e.g., Tris buffered saline or phosphate buffered saline). (v) pH adjuster

[0164] In various embodiments, the excipient may be a pH adjusting agent. By way of non-limiting example, the pH adjusting agent may be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid. (vi) disintegrant

[0165] In further embodiments, excipient may be a disintegrant.Disintegrant may be non-effervescent or effervescent.Suitable examples of non-effervescent disintegrants include, but are not limited to, starch, such as corn starch, potato starch, its pregelatinized and modified starch, sweeteners, clays, such as bentonite, microcrystalline cellulose, alginates, sodium starch glycolate, gums, such as agar, guar, carob, karaya, pectin and tragacanth.Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid. (vii) Dispersants

[0166] In yet another embodiment, the excipient may be a dispersant or dispersion enhancer.Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, refined wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose. (viii) excipients

[0167] In another alternative embodiment, excipient may be a preservative.Non-limiting examples of suitable preservatives may include antioxidants such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate;chelating agents such as EDTA or EGTA;and antibacterial agents such as paraben, chlorobutanol, or phenol. (ix) Lubricants

[0168] In a further embodiment, the excipient may be a lubricant. Non-limiting examples of suitable lubricants include minerals such as talc or silica; fats such as vegetable stearin, magnesium stearate, or stearic acid. (x) Flavoring agent

[0169] In yet another embodiment, the excipient may be a flavoring agent. The flavoring material may include cellulose ethers; polyethylene glycol; polyvinyl alcohol; polyvinyl alcohol and polyethylene glycol copolymers; monoglycerides or triglycerides; acrylic polymers; mixtures of acrylic polymers and cellulose ethers; cellulose acetate phthalate; and combinations thereof. (xi) Flavoring agents

[0170] In an alternative embodiment, the excipient may be a flavoring agent, which may be selected from synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. (xii) Coloring agent

[0171] In yet further embodiments, the excipient may be a colorant.Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).

[0172] The weight fraction of the excipient or combination of excipients in the composition may be about 99% or less, about 97% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1% or less of the total weight of the composition.

[0173] The agents and compositions described herein can be formulated by any conventional method using one or more pharma- ceutically acceptable carriers or excipients, for example, as described in Remington's Pharmaceutical Sciences (ed. AR Gennaro), 21st ed., ISBN: 0781746736 (2005), which is incorporated herein by reference in its entirety. Such formulations contain a therapeutically effective amount of the biologically active agent described herein, which may be in purified form together with a suitable amount of carrier, so as to provide the form for proper administration to a subject.

[0174] The term "formulation" refers to preparing a drug in a form suitable for administration to a subject, such as a mammal, including but not limited to a human. Thus, a "formulation" can include a pharma- ceutically acceptable excipient, including a diluent or carrier.

[0175] The term "pharmaceutical acceptable" as used herein may refer to a substance or ingredient that does not cause unacceptable loss of pharmacological activity or unacceptable adverse side effects. Examples of pharmaceutical acceptable ingredients may be those listed in the United States Pharmacopeia (USP29) and National Formulary (NF24), United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 ("USP / NF"), or those with monographs in more recent editions, and in the FDA's continuously updated Inactive Ingredient Search online database. Other useful ingredients not listed in USP / NF etc. may also be used.

[0176] The term "pharmaceutically acceptable excipient" used herein may include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, or absorption retardants. The use of such media and agents for pharmaceutical active substances is well known in the art (see generally Remington's Pharmaceutical Sciences (A.R. Gennaro, ed.), 21st edition, ISBN: 0781746736 (2005)). Except where any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Auxiliary active ingredients can also be incorporated into the composition.

[0177] A "stable" formulation or composition can refer to a composition that has sufficient stability to permit storage at a convenient temperature, e.g., from about 0° C. to about 60° C., for a commercially reasonable period of time, e.g., at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years.

[0178] The formulation should be suitable for the mode of administration. The agents used in the present disclosure can be formulated by known methods for administration to a subject using several routes, including but not limited to parenteral, pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, ocular, buccal, and rectal. Individual agents may also be administered in combination with one or more additional agents, or in combination with other biologically active or inactive agents. Such biologically active or inactive agents may be in fluid or mechanical communication with the agent(s), or may be bound to the agent(s) by ionic, covalent, van der Waals, hydrophobic, hydrophilic, or other physical forces.

[0179] Controlled release (or sustained release) preparations may be formulated to extend the activity of the drug(s) and reduce the frequency of administration. Controlled release preparations can also be used to effect time of onset of action or other characteristics, such as blood levels of the drug, and consequently affect the occurrence of side effects. Controlled release preparations may be designed to initially release an amount of drug(s) that produces the desired therapeutic effect, and slowly and continuously release other amounts of the drug to maintain the level of therapeutic effect over an extended period of time. To maintain a near constant level of drug in the body, the drug may be released from the dosage form at a rate that replaces the amount of drug metabolized or excreted from the body. Controlled release of the drug may be stimulated by various triggers, such as changes in pH, changes in temperature, enzymes, water, or other physiological conditions or molecules. IV. Administration (a) Dosage form

[0180] The compositions of the present disclosure may be formulated into various dosage forms and administered by several different means that deliver a therapeutically effective amount of the active ingredient. Such compositions may be administered orally (e.g., inhalation), parenterally, or topically in dosage unit formulations containing conventional non-toxic pharma- ceutically acceptable carriers, adjuvants, and vehicles, as desired. Topical administration may also include the use of transdermal administration, such as transdermal patches or iontophoretic devices. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, or intrasternal injection, or infusion techniques. Drug formulations are described, for example, in Gennaro, AR, Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (18th ed., 1995), and Liberman, HA, and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Dekker Inc., New York, NY (1980). In certain embodiments, the composition may be a food supplement, or the composition may be a cosmetic.

[0181] Solid dosage forms for oral administration may include capsules, tablets, caplets, pills, powders, pellets, and granules. In such solid dosage forms, the active ingredient is usually combined with one or more pharma- ceutically acceptable excipients, examples of which are detailed above. Oral preparations may also be administered as aqueous suspensions, elixirs, or syrups. For these, the active ingredient may be combined with various sweeteners or flavoring agents, coloring agents, and emulsifying and / or suspending agents, if desired, as well as diluents such as water, ethanol, glycerin, and combinations thereof. For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0182] For parenteral administration (including subcutaneous, intradermal, intravenous, intramuscular, intraarticular and intraperitoneal), the preparation may be an aqueous or oily solution. Aqueous solutions may contain a sterile diluent, such as water, saline solution, pharma- ceutically acceptable polyols, such as glycerol, propylene glycol, or other synthetic solvents; antibacterial and / or antifungal agents, such as benzyl alcohol, methylparaben, chlorobutanol, phenol, thimerosal, and the like; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and / or agents for adjusting tonicity, such as sodium chloride, dextrose, or polyhydric alcohols, such as mannitol or sorbitol. The pH of the aqueous solution may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Oily solutions or suspensions may further contain sesame, peanut, olive, or mineral oil. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a ready-made sterile liquid, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0183] For topical (e.g., transdermal or transmucosal) administration, penetrants appropriate for the barrier to be permeated are generally included in the formulation. Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. In some embodiments, the pharmaceutical composition is applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes. Transmucosal administration may be accomplished by the use of nasal sprays, aerosol sprays, tablets, or suppositories, and transdermal administration may be accomplished via ointments, salves, gels, patches, or creams as generally known in the art.

[0184] In certain embodiments, the composition may be formulated for sublingual delivery. Sublingual delivery forms (films, tablets, or sprays) are designed to dissolve very quickly. Examples of such formulations may include ergotamine tartrate, isosorbide dinitrate, isoproterenol HCl, or combinations thereof. The components required for pharmaceutical dosage units may be processed according to known methods, using or incorporating coatings and additives as necessary. By way of example only, in addition to the pharmaceutical active ingredient, the dosage unit may contain effective amounts of binders, fillers, disintegrants, sustained release agents, diluents, anti-adherents, glidants, flow aids, plasticizers, and lubricants, which are well known in the field of pharmaceutical processing for sublingual delivery. For example, these tablet formulations may contain, in addition to the active agent, a limited number of soluble excipients including binders such as povidone or hydroxypropylmethylcellulose (HPMC), diluents such as lactose, mannitol, starch or cellulose, disintegrants such as pregelatinized or modified starches, lubricants such as magnesium stearate, stearic acid or hydrogenated vegetable oils, sweeteners such as saccharin or sucrose, and suitable flavors and colorants. A method for producing a sublingual dosage form may include, for example, wetting the blended powdered ingredients with an alcohol-water solvent system containing about 60% alcohol and 40% water and pressing the mixture into a tablet.

[0185] In certain embodiments, the compositions of the present disclosure may be encapsulated in a suitable vehicle to aid in the delivery of the compound to target cells, to enhance the stability of the composition, or to minimize the potential toxicity of the composition. As will be understood by those skilled in the art, a variety of vehicles are suitable for delivering the compositions of the present invention. Non-limiting examples of suitable structured fluid delivery systems may include nanoparticles, liposomes, microemulsions, micelles, dendrimers, and other phospholipid-containing systems. Methods for incorporating compositions into delivery vehicles are known in the art.

[0186] In an alternative embodiment, liposome delivery vehicles may be utilized. Generally speaking, liposomes are spherical vesicles with phospholipid bilayer membranes. The lipid bilayer of liposomes can fuse with other bilayers (e.g., cell membranes), thus delivering the contents of liposomes to cells. In this way, the composition of the present disclosure can be selectively delivered to cells by encapsulation in liposomes that fuse with the membrane of target cells.

[0187] Liposomes may be composed of a variety of different types of phospholipids with various hydrocarbon chain lengths. Phospholipids generally contain two fatty acids linked to one of various polar groups via glycerol phosphate. Suitable phospholipids include phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). The fatty acid chains comprising the phospholipids may range in length from about 6 to about 26 carbon atoms, and the lipid chains may be saturated or unsaturated. Suitable fatty acid chains include (common names in parentheses) n-dodecanoate (laurate), n-tetradecanoate (myristate), n-hexadecanoate (palmitate), n-octadecanoate (stearate), n-eicosanoate (arachidate), n-docosanoate (behenate), n-tetracosanoate (lignocerate), cis-9-hexadecenoate (palmitoleate), cis-9-octadecanoate (oleate), cis,cis-9,12-octadecane dienoate (linoleate), all-cis-9,12,15-octadecatrienoate (linolenate), and all-cis-5,8,11,14-eicosatetraenoate (arachidonate). The two fatty acid chains of the phospholipids may be the same or different. Acceptable phospholipids include dioleoyl PS, dioleoyl PC, distearoyl PS, distearoyl PC, dimyristoyl PS, dimyristoyl PC, dipalmitoyl PG, stearoyl, oleoyl PS, palmitoyl, linolenyl PS, and the like.

[0188] Phospholipids may be derived from any natural source and therefore may comprise a mixture of phospholipids. For example, egg yolk is rich in PC, PG, and PE, soybean contains PC, PE, PI, and PA, and animal brain or spinal cord is rich in PS. Phospholipids may also be derived from synthetic sources. A mixture of phospholipids with various ratios of individual phospholipids may be used. A mixture of different phospholipids may result in a liposome composition with advantageous activity or stability of activity properties. The phospholipids may be cationic lipids, such as N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, 3,3'-deheptyloxacarbocyanine iodide, 1,1'-dedodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, perchloarate), 1,1'-dioleyl-3,3,3',3'-tetramethylindocarbocyanine methanesulfonate, N-4-(delinooleylaminostyryl)-N-methylpyridinium iodide, or 1,1-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchloarate in an optimal ratio.

[0189] The liposomes may optionally include sphingolipids, in which sphingosine is the structural counterpart of glycerol and one of the fatty acids of phosphoglycerides or cholesterol, which are major components of animal cell membranes. The liposomes may optionally contain pegylated lipids, which are lipids covalently linked to polymers of polyethylene glycol (PEG). The PEGs may range in size from about 500 to about 10,000 daltons.

[0190] Liposome may further comprise a suitable solvent.The solvent may be an organic solvent or an inorganic solvent.Suitable solvents include, but are not limited to, dimethylsulfoxide (DMSO), methylpyrrolidone, N-methylpyrrolidone, acetonitrile, alcohol, dimethylformamide, tetrahydrofuran, or combinations thereof.

[0191] Liposomes can be prepared by any known method of preparing liposomes for drug delivery, for example, as detailed in U.S. Patent Nos. 4,241,046, 4,394,448, 4,529,561, 4,755,388, 4,828,837, 4,925,661, 4,954,345, 4,957,735, 5,043,164, 5,064,655, 5,077,211 and 5,264,618 (the disclosures of which are incorporated herein by reference in their entirety).For example, liposomes can be prepared by ultrasonicating lipids in aqueous solution, solvent injection, lipid hydration, reverse evaporation, or freeze-drying by repeated freezing and thawing. In a preferred embodiment, liposomes are formed by sonication. Liposomes may be multilamellar, with many layers like an onion, or unilamellar. Liposomes may be large or small. Continued high shear sonication tends to form smaller unilamellar liposomes.

[0192] As will be apparent to one of skill in the art, all parameters governing liposome formation may be varied, including but not limited to temperature, pH, concentration of active ingredient (e.g., minor cannabinoids, major cannabinoids, terpenoids, combinations thereof, etc.), lipid concentration and composition, concentration of polyvalent cations, rate of mixing, presence and concentration of solvent.

[0193] In another embodiment, the compositions of the present invention may be delivered to cells as microemulsions. Microemulsions are generally clear, thermodynamically stable solutions that include an aqueous solution, a surfactant, and an "oil." The "oil" in this case is a supercritical fluid phase. The surfactant resides at the oil-water interface. Any of a variety of surfactants are suitable for use in microemulsion formulations, including those described herein or otherwise known in the art. Aqueous microdomains suitable for use in the present invention generally have characteristic structural dimensions of about 5 nm to about 100 nm. Aggregates of this size are poor scatterers of visible light, and therefore these solutions are optically clear. As will be appreciated by those skilled in the art, microemulsions can and do have a number of different microstructures, including spherical, rod-like, or disc-like aggregates. In one embodiment, the structures may be micelles, which are the simplest microemulsion structures that are generally spherical or cylindrical objects. Micelles resemble oil-in-water droplets, while reverse micelles resemble water-in-oil droplets. In an alternative embodiment, the microemulsion structure is a lamellar. It comprises successive layers of water and oil separated by a layer of surfactant. The "oil" of the microemulsion optimally comprises a phospholipid. Any of the phospholipids detailed above for liposomes are suitable for the embodiments directed to microemulsions.

[0194] In yet another embodiment, the compositions of the present disclosure may be delivered in dendritic macromolecules, i.e. dendrimers. Generally speaking, dendrimers are branched dendritic molecules, where each branch is a linked chain of molecules that splits into two new branches (molecules) after a certain length. This branching continues until the branches (molecules) are so densely packed that the canopy forms a sphere. In general, the properties of a dendrimer are determined by the functional groups on its surface. For example, hydrophilic end groups such as carboxyl groups will typically result in water-soluble dendrimers. Alternatively, phospholipids may be incorporated into the surface of the dendrimer to facilitate absorption across the skin. Any of the phospholipids detailed for use in liposome embodiments are suitable for use in dendrimer embodiments. Any method generally known in the art may be utilized to create dendrimers and encapsulate the compositions of the present invention therein. For example, dendrimers may be produced by a repetitive sequence of reaction steps where each additional iteration results in a higher order dendrimer. As a result, they have a regular, highly branched 3D structure with nearly uniform size and shape. Furthermore, the final size of the dendrimer is typically controlled by the number of iterative steps used during synthesis. A variety of dendrimer sizes are suitable for use in the present invention. In general, the size of a dendrimer may range from about 1 nm to about 100 nm.

[0195] Generally, the safe and effective amount of the composition of the present disclosure is the amount that will cause the desired therapeutic effect in the subject while minimizing undesirable side effects.In various embodiments, the effective amount of the composition of the present disclosure can reduce the pain associated with migraine attacks with and / or without aura, reduce the frequency of migraine headaches, reduce the pain of fibromyalgia or the pain associated with related disorders such as familial hemiplegic migraine, isolated hemiplegic migraine, and complex regional pain syndrome.

[0196] The amount of the composition described herein that can be combined with pharmaceutically acceptable carrier to produce a single dosage form varies according to the subject to be treated and specific mode of administration.It is understood by those skilled in the art that the unit content of the drug contained in each dosage form does not have to constitute a therapeutically effective amount by itself, because the required therapeutically effective amount can be achieved by administering a large number of individual doses.

[0197] The toxicity and therapeutic efficacy of the compositions described herein are measured using LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects can be determined by standard pharmaceutical procedures in cell cultures or experimental animals to determine the dose that is therapeutically effective in 50% of the population. The dose ratio between toxic and therapeutic effects is called the LD ratio. 50 / ED 50 The therapeutic index can be expressed as:

[0198] The specific therapeutically effective dose level for any particular subject will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition used; the duration of treatment; drugs used in combination with or simultaneously with the specific compound used; and similar factors well known in the medical arts (see, for example, Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4th Edition, Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of a person skilled in the art to start administering the composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.If desired, the effective daily dose may be divided into multiple doses for the purpose of administration.As a result, a single dose composition may contain such amounts or submultiples thereof to make up the daily dose.However, it will be understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment.

[0199] Again, each of the conditions, diseases, disorders, and conditions described herein, as well as others, can benefit from the compositions and methods described herein. In general, treating a condition, disease, disorder, or condition includes preventing or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the condition, disease, disorder, or condition, but has not yet experienced or exhibited clinical or subclinical symptoms thereof. Treating can also include inhibiting the condition, disease, disorder, or condition, e.g., arresting or alleviating the onset of the disease or at least one of its clinical or subclinical symptoms. Furthermore, treating can include alleviating the disease, e.g., causing the regression of the condition, disease, disorder, or condition, or at least one of its clinical or subclinical symptoms. The benefit to the subject being treated can be either statistically significant or at least perceptible to the subject or the physician.

[0200] The administration of the compositions of the present disclosure may occur as a single event or over a time course of treatment. For example, the compositions of the present disclosure may be administered daily, weekly, biweekly, or monthly. In the treatment of acute conditions, the time course of treatment may be at least one day to at least several days. Certain conditions may extend the treatment from several days to several weeks. For example, the treatment may extend for one week, two weeks, or three weeks. In more chronic conditions, the treatment may extend for several weeks to several months, or even a year or more.

[0201] Treatment with the methods described herein can be administered prior to, simultaneously with, or following a conventional treatment modality. (b) Purity

[0202] Generally speaking, compounds included in the compositions of the present disclosure, such as minor or major cannabinoids, should be of high purity and consistent quality regardless of source. For example, the minor or major cannabinoids used in the compositions of the present disclosure are at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% pure by weight. In certain embodiments, the minor or major cannabinoids used in the compositions of the present disclosure are at least 95, 96, 97, 98 or 99% pure by weight. In a preferred embodiment, the minor or major cannabinoids used in the compositions of the present disclosure are at least 97% pure by weight. In a more preferred embodiment, the minor or major cannabinoids used in the compositions of the present disclosure are at least 99% pure by weight. Unless otherwise stated, purity percentages are by weight.

[0203] Furthermore, the THC and / or CBD contained in the composition of the present disclosure should be of high purity and consistent quality regardless of source. For example, the THC and / or CBD used in the composition of the present disclosure is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% pure by weight. In certain embodiments, the THC and / or CBD used in the composition of the present disclosure is at least 95, 96, 97, 98 or 99% pure by weight. In a preferred embodiment, the THC and / or CBD used in the composition of the present disclosure is at least 97% pure by weight. In a more preferred embodiment, the THC and / or CBD used in the composition of the present disclosure is at least 99% pure by weight.

[0204] The manufacture of the compounds for the compositions of the present disclosure preferably meets GLP requirements. In certain embodiments, the manufacture of the compounds for the compositions of the present disclosure meets GMP requirements to ensure consistent quality.

[0205] Quantitative / qualitative methods to confirm quality and purity include the use of high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC), nuclear magnetic resonance (NMR) spectroscopy, gas chromatography (GC), thin layer chromatography (TLC), and standard methods to test for contamination of microbiological contaminants, heavy metal contaminants, pesticide contaminants, or other contaminants.

[0206] Generally speaking, the compositions of the present disclosure have at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% fewer side effects than those that are not at least 90% pure in minor and major cannabinoids. As used herein, side effects refer to any effect of the compositions other than reducing pain, photophobia, phonophobia, or nausea associated with migraine attacks with and / or without aura, migraine frequency, and fibromyalgia pain, and associated disorders such as familial hemiplegic migraine, sporadic hemiplegic migraine, and complex regional pain syndrome. V. Method

[0207] Another aspect of the present disclosure is a method of using the compositions described in the above paragraphs.

[0208] The terms "treat", "treating" or "treatment" as used herein refer to both therapeutic treatment and prophylactic or preventative measures, the purpose being to prevent or slow down (alleviate) undesirable physiological changes or diseases / disorders. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, stabilized (i.e., not worsening) status of disease, delay or slowing of disease progression, improvement or mitigation of disease status, and remission (whether partial or complete remission). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with the disease, condition, or disorder, as well as those prone to have the disease, condition, or disorder, or those in whom the disease, condition, or disorder is to be prevented. (a) Methods for reducing migraine pain with minor cannabinoid compositions

[0209] The minor cannabinoid composition of the present disclosure may be used in a method for reducing migraine pain.Generally speaking, such a method would include administering a pharmacologic effective amount of at least one minor cannabinoid alone or in combination with THC, CBD, or both, such that migraine pain is reduced in a subject.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0210] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. As used herein, the term "phytocannabinoid" refers to a cannabinoid isolated from a non-synthetic source.

[0211] In certain embodiments, the migraine pain is acute migraine pain. Generally speaking, the methods of the present invention are used in subjects suffering from acute migraine headaches. Methods for diagnosing acute migraine headaches are known in the art.

[0212] In some embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc. (b) A method for reducing migraine pain with a THC and CBD composition

[0213] The THC and CBD compositions of the present disclosure may be used in a method for reducing migraine pain while reducing undesirable side effects of THC or risk factors associated with THC. Non-limiting examples of side effects or risk factors include mental activity, psychosis, anxiety, paranoia, dizziness, confusion, increased heart rate, memory impairment, or a combination thereof. Generally speaking, such a method would include administering a pharmacologic effective amount of THC and CBD such that migraine pain is reduced in a subject while minimizing undesirable side effects or risk factors of THC. In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0214] In certain embodiments, the migraine pain is acute migraine pain. Generally speaking, the methods of the present invention are used in subjects suffering from acute migraine headaches. Methods for diagnosing acute migraine headaches are known in the art. In some embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc. (c) Reducing migraine frequency with minor cannabinoid compositions

[0215] The minor cannabinoid composition of the present disclosure may be used in a method for reducing migraine frequency.Generally speaking, such a method would include administering a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that migraine frequency is reduced in a subject.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0216] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. In certain embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0217] In certain embodiments, the subject may be diagnosed with chronic migraine or high-frequency migraine.As used herein, chronic migraine is defined as headache more than 15 days per month.High-frequency migraine is defined as headache 7-14 days per month.Methods for diagnosing chronic migraine or high-frequency migraine are known in the art. (d) A method for reducing migraine frequency with a THC and CBD composition

[0218] The THC and CBD compositions of the present disclosure may be used in a method for reducing migraine frequency. Generally speaking, such a method would include administering a pharmacologic effective amount of THC and CBD such that the frequency of migraine headaches is reduced in a subject while minimizing the undesirable side effects or risk factors of THC. In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0219] In certain embodiments, at least one biomarker is NMDA. In other embodiments, at least one biomarker is glutamate. In still other embodiments, at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0220] In certain embodiments, the subject may be diagnosed with chronic migraine or high-frequency migraine.As used herein, chronic migraine is defined as headache more than 15 days per month.High-frequency migraine is defined as headache 7-14 days per month.Methods for diagnosing chronic migraine or high-frequency migraine are known in the art. (e) A method for reducing pain in fibromyalgia with a minor cannabinoid composition

[0221] The minor cannabinoid composition of the present disclosure may be used in a method for reducing fibromyalgia pain.Generally speaking, such a method may include administering a pharmacologic effective amount of at least one minor cannabinoid alone or in combination with THC, CBD, or both, such that fibromyalgia pain is reduced in a subject.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0222] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. In certain embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0223] In certain embodiments, the subject may have been diagnosed with fibromyalgia pain. Methods for diagnosing fibromyalgia pain are known in the art. (f) Methods for reducing fibromyalgia pain with THC and CBD compositions

[0224] The THC and CBD compositions of the present disclosure may be used in a method for reducing fibromyalgia pain. Generally speaking, such a method would include administering a pharmacologic effective amount of THC and CBD such that fibromyalgia pain is reduced in a subject while minimizing the undesirable side effects or risk factors of THC. In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0225] In certain embodiments, at least one biomarker is NMDA. In other embodiments, at least one biomarker is glutamate. In still other embodiments, at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0226] In certain embodiments, the subject may have been diagnosed with fibromyalgia pain. Methods for diagnosing and measuring fibromyalgia pain are known in the art and may include pain scales and self-report by the subject. (g) Methods for treating acute migraine pain, photophobia, phonophobia, and / or nausea

[0227] The minor cannabinoid composition of the present disclosure may be used in a method for treating acute migraine pain, photophobia, phonophobia, and / or nausea. Generally speaking, such a method would include administering a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, to a subject in need thereof, such that migraine pain, photophobia, phonophobia, and / or nausea is alleviated in the subject. In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0228] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. As used herein, the term "phytocannabinoid" refers to a cannabinoid isolated from a non-synthetic source.

[0229] In certain embodiments, the migraine pain is acute migraine pain. Generally speaking, the methods of the present invention are used in subjects suffering from acute migraine headaches. Methods for diagnosing acute migraine headaches are known in the art.

[0230] Methods for measuring migraine pain are generally known in the art and may include the use of a pain scale. For example, the pain scale may include a numeric rating scale (NRS) or a visual analog scale (VAS) (e.g., Likert or Wong-Baker). In some embodiments, pain may be self-reported by the subject on a pain scale of 0 to 10, with 0 indicating no pain and 10 indicating a high level of pain. In some embodiments, a four-point scale of 0 to 3 may be used, with 0 indicating no pain and 3 indicating a high level of pain, with the subject self-reporting their level of pain. Migraine pain may be reported prior to administration, with pain on a scale of 2 or 3 indicating the need for treatment. After administration, pain may improve to a scale of 1 or 0 within at least 2 hours of administration. In some examples, pain may improve within at least 2 hours of administration, at least 1.5 hours of administration, at least 1 hour of administration, at least 30 minutes of administration, or at least 15 minutes of administration. In a preferred embodiment, migraine pain is improved to 0 within at least 2 hours of administration.

[0231] Methods for measuring photophobia are generally known in the art and may include the Utah Photophobia Symptom Impact Scale and the Korean Photophobia Questionnaire. In some embodiments, photophobia may be self-reported by the subject on a pain scale. Photophobia may be reported by the subject prior to administration. After administration, reduction in photophobia may be self-reported by the subject. In other embodiments, reduction in photophobia may be determined by the methods described above.

[0232] Methods for measuring nausea are generally known in the art and may include self-report by the subject or may include a visual analog scale.

[0233] In some embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc. (h) Methods of Treating Migraine Pain with THC and CBD Compositions

[0234] The THC and CBD compositions of the present disclosure may be used in a method for treating migraine pain while reducing undesirable side effects of THC or risk factors associated with THC. Non-limiting examples of side effects or risk factors include mental activity, psychosis, anxiety, paranoia, dizziness, confusion, increased heart rate, memory impairment, or a combination thereof. Generally speaking, such a method would include administering a pharmacologic effective amount of THC and CBD such that migraine pain is reduced in a subject while minimizing undesirable side effects or risk factors of THC. In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0235] In certain embodiments, the migraine pain is acute migraine pain. Generally speaking, the methods of the present invention are used in subjects suffering from acute migraine headaches. Methods for diagnosing acute migraine headaches are known in the art. In some embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc. (i) Treating Migraine Frequency with Minor Cannabinoid Compositions

[0236] The minor cannabinoid composition of the present disclosure may be used in a method for treating migraine frequency.Generally speaking, such a method includes administering a pharmacologic effective amount of at least one minor cannabinoid alone or in combination with THC, CBD, or both, and the frequency of migraine will be reduced in a subject.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0237] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. In certain embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0238] In certain embodiments, the subject may be diagnosed with chronic migraine or high-frequency migraine.As used herein, chronic migraine is defined as headache more than 15 days per month.High-frequency migraine is defined as headache 7-14 days per month.Methods for diagnosing chronic migraine or high-frequency migraine are known in the art. (j) Methods of Treating Fibromyalgia Pain with Minor Cannabinoid Compositions

[0239] The minor cannabinoid composition of the present disclosure may be used in a method for treating fibromyalgia pain.Generally speaking, such a method will include administering a pharmacologic effective amount of at least one minor cannabinoid alone or in combination with THC, CBD, or both, so that fibromyalgia pain is alleviated in a subject.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0240] In some embodiments, the at least one minor cannabinoid detailed in section I above may be a phytocannabinoid. In certain embodiments, the at least one biomarker is NMDA. In other embodiments, the at least one biomarker is glutamate. In still other embodiments, the at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0241] In certain embodiments, the subject may have been diagnosed with fibromyalgia pain. Methods for diagnosing fibromyalgia pain are known in the art and may include pain scales and self-report by the subject. (k) Methods of Treating Fibromyalgia Pain with THC and CBD Compositions

[0242] The THC and CBD compositions of the present disclosure may be used in a method for treating fibromyalgia pain.Generally speaking, such a method would include administering a pharmacologic effective amount of THC and CBD so that fibromyalgia pain is alleviated in a subject while minimizing the undesirable side effects or risk factors of THC.In some embodiments, at least one biomarker of central and peripheral sensitization may be modulated as a result of administration.

[0243] In certain embodiments, at least one biomarker is NMDA. In other embodiments, at least one biomarker is glutamate. In still other embodiments, at least one biomarker may include CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG, etc.

[0244] In certain embodiments, the subject may have been diagnosed with fibromyalgia pain. Methods for diagnosing fibromyalgia pain are known in the art and may include pain scales and self-report by the subject. Exemplary embodiments

[0245] Embodiment 1: A method of treating acute migraine pain, photophobia, phonophobia, and / or nausea comprising administering to a subject in need thereof a pharma- ceutically effective amount of a composition comprising at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that migraine pain, photophobia, phonophobia, and / or nausea are alleviated in the subject.

[0246] Embodiment 2: The method of embodiment 1, wherein the subject is a human.

[0247] Embodiment 3: The method of embodiment 1, wherein said administering is accomplished by injection.

[0248] Embodiment 4: The method of embodiment 1, wherein the treatment is effective within at least 2 hours after administration.

[0249] Embodiment 5: The method of embodiment 4, wherein the treatment is effective within at least 1 hour after administration.

[0250] Embodiment 6: The method of embodiment 5, wherein the treatment is effective within at least 30 minutes after administration.

[0251] Embodiment 7: The method of embodiment 6, wherein the treatment is effective within at least 15 minutes after administration.

[0252] Embodiment 8: The method of embodiment 1, wherein the migraine pain is measured by a pain scale.

[0253] Embodiment 9: The method of embodiment 1, wherein said photophobia is measured by the Utah Photophobia Symptom Impact Scale, the Korean Photophobia Questionnaire, or self-report from the subject.

[0254] Embodiment 10: The method of embodiment 1, wherein said phonophobia is measured by self-report from the subject.

[0255] Embodiment 11: The method of embodiment 1, wherein the nausea is measured by self-report from the subject.

[0256] Embodiment 12: The method of embodiment 1, wherein said nausea is measured by a visual analog scale.

[0257] Embodiment 13: The method of embodiment 1, wherein the composition comprises THC and CBD, and the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0258] Embodiment 14: The method of embodiment 1, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0259] Embodiment 15: The method of embodiment 1, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 90% pure by weight.

[0260] Embodiment 16: The method of embodiment 15, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 99% pure by weight.

[0261] Embodiment 17: The method of embodiment 1, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0262] Embodiment 18: The method of embodiment 17, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0263] Embodiment 19: A method of treating migraine frequency, comprising administering to a subject in need thereof a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that migraine frequency is reduced in the subject.

[0264] Embodiment 20: The method of embodiment 19, wherein the subject is a human.

[0265] Embodiment 21: The method of embodiment 19, wherein the subject has chronic migraine headaches.

[0266] Embodiment 22: The method of embodiment 19, wherein the subject has high-frequency migraine headaches.

[0267] Embodiment 23: The method of embodiment 19, wherein said administering is accomplished by injection.

[0268] Embodiment 24: The method of embodiment 19, wherein the treatment is effective within at least 2 hours after administration.

[0269] Embodiment 25: The method of embodiment 24, wherein the treatment is effective within at least 1 hour after administration.

[0270] Embodiment 26: The method of embodiment 25, wherein the treatment is effective within at least 30 minutes after administration.

[0271] Embodiment 27: The method of embodiment 26, wherein the treatment is effective within at least 15 minutes after administration.

[0272] Embodiment 28: The method of embodiment 19, wherein the composition comprises THC and CBD, and the ratio of CBD:THC is about 30:1 mg / kg to about 300:1 mg / kg.

[0273] Embodiment 29: The method of embodiment 19, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0274] Embodiment 30: The method of embodiment 19, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 90% pure by weight.

[0275] Embodiment 31: The method of embodiment 30, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 99% pure by weight.

[0276] Embodiment 32: The method of embodiment 19, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0277] Embodiment 33: The method of embodiment 19, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0278] Embodiment 34: A method of treating acute migraine pain, comprising administering to a subject in need thereof a pharma- ceutical effective amount of a composition comprising THC and CBD, such that migraine pain is alleviated in the subject while reducing undesirable side effects or risk factors of THC.

[0279] Embodiment 35: The method of embodiment 34, wherein the subject is a human.

[0280] Embodiment 36: The method of embodiment 34, wherein the subject has chronic migraine headaches.

[0281] Embodiment 37: The method of embodiment 34, wherein the subject has high-frequency migraine headaches.

[0282] Embodiment 38: The method of embodiment 34, wherein said administering is accomplished by injection.

[0283] Embodiment 39: The method of embodiment 34, wherein the treatment is effective within at least 2 hours after administration.

[0284] Embodiment 40: The method of embodiment 39, wherein the treatment is effective within at least 1 hour after administration.

[0285] Embodiment 41: The method of embodiment 40, wherein the treatment is effective within at least 30 minutes after administration.

[0286] Embodiment 42: The method of embodiment 41, wherein the treatment is effective within at least 15 minutes after administration.

[0287] Embodiment 43: The method of embodiment 34, wherein the composition comprises THC and CBD, and the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

[0288] Embodiment 44: The method of embodiment 34, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 90% pure by weight.

[0289] Embodiment 45: The method of embodiment 34, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 99% pure by weight.

[0290] Embodiment 46: The method of embodiment 34, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0291] Embodiment 47: The method of embodiment 46, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0292] Embodiment 48: The method of embodiment 34, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0293] Embodiment 49: A method of reducing fibromyalgia pain, comprising administering to a subject in need thereof a pharmacologic effective amount of a composition comprising THC and CBD, such that fibromyalgia pain is reduced in the subject while reducing undesirable side effects or risk factors of THC. In some embodiments, the subject is a human.

[0294] Embodiment 50: The method of embodiment 49, wherein said administering is accomplished by injection.

[0295] Embodiment 51: The method of embodiment 49, wherein the treatment is effective within at least 2 hours after administration.

[0296] Embodiment 52: The method of embodiment 51, wherein the treatment is effective within at least 1 hour after administration.

[0297] Embodiment 53: The method of embodiment 52, wherein the treatment is effective within at least 30 minutes after administration.

[0298] Embodiment 54: The method of embodiment 53, wherein the treatment is effective within at least 15 minutes after administration.

[0299] Embodiment 55: The method of embodiment 49, wherein the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

[0300] Embodiment 56: The method of embodiment 49, wherein the THC and CBD are at least 90% pure by weight.

[0301] Embodiment 57: The method of embodiment 56, wherein the THC and CBD are at least 99% pure by weight.

[0302] Embodiment 58: The method of embodiment 49, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0303] Embodiment 59: The method of embodiment 58, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0304] Embodiment 60: A method of reducing CGRP-induced photoaversion, comprising administering to a subject in need thereof a composition comprising a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both.

[0305] Embodiment 61: A method for reducing SNP-induced photoaversion, comprising administering to a subject in need thereof a composition comprising a pharmacologic effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both.

[0306] Embodiment 62: A method of reducing acute migraine pain, photophobia, phonophobia, and / or nausea in a subject comprising administering to a subject in need thereof a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with tetrahydrocannabinol (THC), cannabidiol (CBD), or both, such that at least one biomarker of central and peripheral sensitization is modulated and migraine pain, photophobia, phonophobia, and / or nausea is reduced in the subject.

[0307] Embodiment 63: The method of embodiment 62, wherein the subject is a human.

[0308] Embodiment 64: The method of embodiment 62, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0309] Embodiment 65: The method of embodiment 62, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0310] Embodiment 66: The method of embodiment 62, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, and further administering to the subject THC and CBD.

[0311] Embodiment 67: A method of reducing migraine frequency in a subject comprising administering to a subject in need thereof a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that at least one biomarker of central and peripheral sensitization is modulated and migraine frequency is reduced in the subject.

[0312] Embodiment 68: The method of embodiment 67, wherein the subject is a human.

[0313] Embodiment 69: The method of embodiment 67, wherein the subject has chronic migraine headaches.

[0314] Embodiment 70: The method of embodiment 67, wherein the subject has high-frequency migraine headaches.

[0315] Embodiment 71: The method of embodiment 67, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0316] Embodiment 72: The method of embodiment 67, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0317] Embodiment 73: The method of embodiment 67, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, and further administering to the subject THC and CBD.

[0318] Embodiment 74: A method of reducing fibromyalgia pain in a subject comprising administering to a subject in need thereof a pharma- tically effective amount of at least one minor cannabinoid, alone or in combination with THC, CBD, or both, such that at least one biomarker of central and peripheral sensitization is modulated and fibromyalgia pain is reduced in the subject.

[0319] Embodiment 75: The method of embodiment 74, wherein the subject is a human.

[0320] Embodiment 76: The method of embodiment 74, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0321] Embodiment 77: The method of embodiment 74, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0322] Embodiment 78: The method of embodiment 74, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC, and the subject is further administered THC and CBD.

[0323] Embodiment 79: A pharmaceutical composition comprising at least one isolated minor cannabinoid and THC, wherein the ratio of said at least one isolated minor cannabinoid to THC modulates at least one biomarker of central and peripheral sensitization.

[0324] Embodiment 80: The composition of embodiment 79, further comprising CBD.

[0325] Embodiment 81: The composition of embodiment 79, further comprising a terpenoid.

[0326] Embodiment 82: The composition of embodiment 79, further comprising an analgesic agent.

[0327] Embodiment 83: The composition of embodiment 79, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0328] Embodiment 84: The composition of embodiment 79, wherein the at least one isolated minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0329] Embodiment 85: The composition of embodiment 79, wherein the composition comprises at least one cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC; THC; and CBD.

[0330] Embodiment 86: A pharmaceutical composition comprising at least one isolated minor cannabinoid and CBD, wherein the ratio of said at least one isolated minor cannabinoid to CBD modulates at least one biomarker of central and peripheral sensitization.

[0331] Embodiment 87: The composition of embodiment 86, further comprising THC.

[0332] Embodiment 88: The composition of embodiment 86, further comprising a terpenoid.

[0333] Embodiment 89: The composition of embodiment 86, further comprising an analgesic agent.

[0334] Embodiment 90: The composition of embodiment 86, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, 2-AG.

[0335] Embodiment 91: The composition of embodiment 86, wherein the at least one isolated minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0336] Embodiment 92: The composition of embodiment 86, wherein the composition comprises at least one cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC; THC; and CBD.

[0337] Embodiment 93: A method of reducing acute migraine pain, comprising administering to a subject in need thereof a pharma- ceutical effective amount of a composition comprising THC and CBD, such that at least one biomarker of central and peripheral sensitization is modulated and migraine pain is reduced in the subject while reducing undesirable side effects or risk factors of THC.

[0338] Embodiment 94: The method of embodiment 93, wherein the subject is a human.

[0339] Embodiment 95: The method of embodiment 93, wherein the composition further comprises at least one minor cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0340] Embodiment 96: A method of reducing migraine frequency in a subject, comprising administering a pharma- ceutically effective amount of a composition comprising THC and CBD such that at least one biomarker of central and peripheral sensitization is modulated and migraine frequency is reduced in the subject while reducing undesirable side effects or risk factors of THC.

[0341] Embodiment 97: The method of embodiment 96, wherein the subject has chronic migraine headaches.

[0342] Embodiment 98: The method of embodiment 96, wherein the subject has high-frequency migraine headaches.

[0343] Embodiment 99: The method of embodiment 96, wherein the composition further comprises at least one minor cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0344] Embodiment 100: A pharmaceutical composition comprising THC and CBD, wherein the ratio of THC to CBD modulates at least one biomarker of central and peripheral sensitization while reducing undesirable side effects or risk factors of THC.

[0345] Embodiment 101: The composition of embodiment 100, further comprising a minor cannabinoid.

[0346] Embodiment 102: The composition of embodiment 101, wherein the minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0347] Embodiment 103: The composition of embodiment 100, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, and CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0348] Embodiment 104: The composition of embodiment 100, further comprising a terpenoid.

[0349] Embodiment 105: The composition of embodiment 100, further comprising an analgesic agent.

[0350] Embodiment 106: A method for treating acute migraine pain, photophobia, phonophobia, and / or nausea, comprising administering a pharmacologic effective amount of a composition comprising THC and CBD to a subject in need thereof, such that migraine pain, photophobia, phonophobia, and / or nausea are alleviated in said subject. In some embodiments, said subject is a human.

[0351] Embodiment 107: The method of embodiment 106, wherein said administering is accomplished by injection.

[0352] Embodiment 108: The method of embodiment 106, wherein the treatment is effective within at least 2 hours after administration.

[0353] Embodiment 109: The method of any of embodiments 108, wherein the treatment is effective within at least 1 hour after administration.

[0354] Embodiment 110: The method of embodiment 109, wherein the treatment is effective within at least 30 minutes after administration.

[0355] Embodiment 111: The method of embodiment 110, wherein the treatment is effective within at least 15 minutes after administration.

[0356] Embodiment 112: The method of embodiment 106, wherein the migraine pain is measured by a pain scale.

[0357] Embodiment 113: The method of embodiment 106, wherein said photophobia is measured by the Utah Photophobia Symptom Impact Scale, the Korean Photophobia Questionnaire, or self-report from the subject.

[0358] Embodiment 114: The method of embodiment 106, wherein the phonophobia is measured by self-report from the subject.

[0359] Embodiment 115: The method of embodiment 106, wherein the nausea is measured by self-report from the subject.

[0360] Embodiment 116: The method of embodiment 106, wherein said nausea is measured by a visual analog pain scale.

[0361] Embodiment 117: The method of embodiment 106, wherein the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

[0362] Embodiment 118: The method of embodiment 106, wherein the composition further comprises at least one minor cannabinoid, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0363] Embodiment 119: The method of embodiment 118, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 90% pure by weight.

[0364] Embodiment 120: The method of embodiment 119, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 99% pure by weight.

[0365] Embodiment 121: The method of embodiment 106, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0366] Embodiment 122: The method of embodiment 121, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

[0367] Embodiment 123: A method for treating migraine frequency, comprising administering to a subject in need thereof a pharma- ceutical effective amount of a composition comprising THC and CBD, such that migraine frequency is reduced in the subject.

[0368] Embodiment 124: The method of embodiment 123, wherein the subject is a human.

[0369] Embodiment 125: The method of embodiment 123, wherein the subject has chronic migraine headaches.

[0370] Embodiment 126: The method of embodiment 123, wherein the subject has high-frequency migraine headaches.

[0371] Embodiment 127: The method of embodiment 123, wherein said administering is accomplished by injection.

[0372] Embodiment 128: The method of embodiment 123, wherein the treatment is effective within at least 2 hours after administration.

[0373] Embodiment 129: The method of embodiment 128, wherein the treatment is effective within at least 1 hour after administration.

[0374] Embodiment 130: The method of embodiment 129, wherein the treatment is effective within at least 30 minutes after administration.

[0375] Embodiment 131: The method of embodiment 130, wherein the treatment is effective within at least 15 minutes after administration.

[0376] Embodiment 132: The method of embodiment 123, wherein the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

[0377] Embodiment 133: The method of embodiment 123, wherein the composition further comprises at least one minor cannabinoid, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

[0378] Embodiment 134: The method of embodiment 133, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 90% pure by weight.

[0379] Embodiment 135: The method of embodiment 134, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 99% pure by weight.

[0380] Embodiment 136: The method of embodiment 123, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administering.

[0381] Embodiment 137: The method of embodiment 136, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG. EXAMPLES

[0382] Example 1: Preclinical Model The biomarkers of the present disclosure and other indicators of activity, including central and peripheral sensitization, may be observed using preclinical in vitro and in vivo models of migraine pain and frequency, fibromyalgia pain, as well as other pain models.

[0383] The migraine model used to observe biomarkers or activity can be in vitro and in vivo, and can be vascular, neuronal, and behavioral models. In vitro vascular models can include models of vasodilation and vasoconstriction in isolated human or animal arteries and veins, or other models. Neurovascular models can include models that target activation and modulation of the trigeminovascular system, such as models of trigeminal nerve stimulation and plasma protein extravasation, models of meningeal stimulation, models of superior sagittal sinus stimulation, models of c-Fos expression in the trigeminal nucleus caudalis (TNC), models of nitric oxide donors, models of cortical spreading depression focusing on other receptors such as 5HT-1B / 1D receptors, CGRP receptors, or NMDA receptors, models of central pain sensitization focusing on the trigeminal nerve, or other models.

[0384] In vivo vascular models may include, for example, models measuring the arterial or veinal diameter of the carotid bed, arteriovenous anastomoses, and pial arteries, models of intravital microscopy, and models of meningeal blood flow, or other models. Anesthesia models may include models of intracranial dural stimulation, models of brainstem dysfunction / modulation, models of cortical spreading depression targeting aura, models of pharmacological induction, or other models.

[0385] Behavioral models may include models of trigeminovascular nociception, models of spontaneous nociceptive responses in the craniofacial region, models of associated neurological conditions, models of migraine or associated conditions of sensitization, such as photophobia, phonophobia, odour phobia, or other conditions, or other models.

[0386] Genetic models may include a CACNA1A mouse model, an ATP1A2 mouse model, a casein kinase 1 delta mouse model, a TRESK mouse model, models targeting familial or sporadic hemiplegic migraine, or other models.

[0387] Models of chronic migraine may include a nitroglycerin model, a model of medication overuse headache, a model of spontaneous trigeminal allodynia, a model of monogenic migraine mutations, or other models.

[0388] Models may be vascular and neuronal models different from those described, incorporating techniques and tools such as laser Doppler flowmetry, micro-iontophoresis and / or microinjection, histology and / or immunohistochemistry, biochemistry, evoked behavioral tests, spontaneous behavioral tests, conditioned placed preference or aversion, elevated plus maze or zero maze, or other models intended to measure desired biomarkers or signs of activity.

[0389] Other pain models that may be used may include models of peripheral inflammation and peripheral neurogenic inflammation such as complete Freund's adjuvant (CFA), models applying carrageenan, mustard oil, bee venom, capsaicin, and formalin, models of chronic post-ischemic pain, models of chronic constriction injury, spinal nerve ligation, phototoxicity, distal nerve injury, complete nerve transection, trigeminal ganglion compression, experimental osteolytic sarcoma, experimental squamous cell carcinoma, experimental melanoma, models of muscle pain, or other models.

[0390] In each of the above models, the compositions of the present disclosure are expected to reduce migraine pain or migraine frequency. Additionally, the other pain models detailed above may be used to demonstrate that the compositions of the present disclosure reduce fibromyalgia pain. Example 2: FHM Test

[0391] This study evaluates cannabinoid combinations that normalize (1) cortical spreading depression (CSD) properties, (2) behavioral responses, and (3) parameters of neuroinflammation in FHM1 or FHM2 mice compared to WT mice.

[0392] The study monitors changes in cortical spreading depression (CSD) properties through experiments inducing CSD. The study also evaluates behavioral and neuroinflammatory responses in relation to allodynia. For example, pain measurements, especially the von Frey filament test in the periorbital area or hind paw, and pain-related behavior using a home-modified version of the Mouse Grimace Scale (MGS) are monitored. Assessment of pain-related behavior by MGS is performed 24, 48 and 72 hours after injection. Neuroinflammation is evaluated using immunohistochemistry (IHC) performed on relevant brain sections using relevant markers for example HMGB1, NF-κB, and microglial activation.

[0393] FHM1 transgenic mice are compared to WT, for example, Thy1-ChR2 (Thy1-driven expression of channelrhodopsin 2) / FHM1 are compared to Thy1-ChR2 / WT mice.

[0394] Different ratios and combinations of cannabinoids are evaluated, including ratios of 100:1 and 30:1 CBD:THC mg / kg. Example 3: Migraine Study

[0395] The cannabinoid combinations will be evaluated using at least two migraine models. First, peripheral injection of the nitric oxide (NO) donor nitroglycerin (NTG), also known as glyceryl trinitrate (GTN), to induce migraine-like symptoms in mice - a widely used and described accepted model to induce evoked and spontaneous pain in rodents. Second, a CGRP-induced migraine model will be evaluated.

[0396] Different ratios of CBD:THC are tested to reduce NTG-induced migraine-like phenotype in mice. Migraine-like behaviors in mice (light aversion, periorbital tactile hypersensitivity, and facial signs of discomfort) are evaluated. Animals are injected with NTG or vehicle and one of the following treatments: vehicle, CBD (1-100 mg / kg, ip), THC (1 mg / kg ip fixed dose), or CBD:THC combinations (1:1, 3:1, 10:1, 30:1, 60:1, 100:1, and 300:1 (300:1 is 300 mg / kg CBD and 1 mg / kg THC)). Both male and female mice are tested.

[0397] The adverse effects of different combinations of CBD:THC are also evaluated in mice.The experiments test for depression (tail suspension), activity and motor changes (spontaneous wheel activity), and cognitive changes (Y-maze).Mice are injected (ip) with vehicle, CBD, THC, or the different combinations of CBD:THC listed above. Example 4: Migraine Study

[0398] Locomotor function was assessed using a rotarod (see assay description and related methods in Example 5). Mice are placed on the rotating rod with increasing rotation speed. Latency to fall off the rod is collected. Results are shown in Figure 1A. The top panel shows the latency to fall off the rod over three consecutive 5-minute trials (two-way ANOVA [time and treatment], treatment factor p=0.46, interaction factor p=0.89; N=9-11 per group). The bottom panel shows the average latency to fall off the rod over three trials (one-way ANOVA, treatment factor p=0.46; N=9-11 per group).

[0399] Figure 1A shows that THC alone and the 1:1 ratio appeared to increase motor function (trend only). However, caffeine at 100 mg / kg ip, which was the positive control for this experiment, was shown to induce a decrease in the latency to fall from the rod, but did not produce the expected results. A second cohort was necessary to gain power and resolve the positive control issue.

[0400] FIG 1B shows a rotarod trial in which the positive control was diazepam, which resulted in an increase in the expected time to fall. The top panel shows the latency to fall from the rod over three consecutive 5 min trials (2-way ANOVA [time and treatment], treatment factor p<0.0001; Tukey's multiple comparisons * p<0.05; vs. vehicle group). The lower panel shows the mean latency to fall off the rod over three trials (One-way ANOVA p<0.0001; Tukey's multiple comparisons). * p<0.05 vs. vehicle group). Example 5: Photophobia Experiments method animal

[0401] Sixty-four male and 64 female wild-type CD1 (Charles River, USA) mice were used. Mice were 8-9 weeks old when they arrived at our facility and were allowed to acclimate for 1 week before use. Mice were housed in groups of four per cage with a 12-h light cycle and food and water available ad libitum. Lights were on at 6 am and off at 6 pm. For all experiments, investigators were blinded to drug treatments and animals were randomized (block randomized) to each treatment group before the start of the experiment. For each assay, mice were brought to the laboratory 1 h before the start of the experiment for acclimatization. Animal procedures were approved by the University of Iowa Animal Care and Use Committee and were performed in accordance with the standards set by the National Institutes of Health and the ARRIVE guidelines. Drug administration

[0402] All drugs were administered by intraperitoneal (ip) injection. CGRP and caffeine were administered at 10 μl / g body weight using a 30 g×0.5 needle. CBD, THC and various ratios of CBD:THC were administered at 3.3 μl / g body weight using a 23 g×0.5 needle. Rat a-CGRP (Sigma-Aldrich, USA) was administered at 0.1 mg / kg, caffeine (Sigma-Aldrich, USA) was administered at 100 mg / kg, both diluted in the vehicle, Dulbecco's PBS (Hyclone, GE Healthcare Life Science, USA). CBD was administered at 1 or 100 mg / kg, THC was administered at 1 mg / kg, both diluted in the vehicle sunflower oil (Sigma-Aldrich, USA). Animals were gently held during injection but not anesthetized. Mice were allowed to recover for 30–60 min in their home cages before testing (see figure legends and experimental design for exact details). Light aversion assay

[0403] A light / dark assay was used to measure animals' aversion to bright light (a surrogate for photophobia). Briefly, mice are placed individually into a light / dark box that contains two compartments, one brightly lit and the other unlit, pitch black, and completely enclosed. Mice are allowed to move freely between them. An infrared beam tracking system (Med Associates) monitors and quantifies behavior. Light-averse animals spend more time in the dark compartment than naive animals. Data were collected using Activity Monitor version 7.06 from 12 chambers as previously described. Mice were pre-exposed once to the chamber to reduce exploration (baseline, data not shown) and then tested in bright light (25,000 lux). Data were collected for 30 min and analyzed at subsequent 5 min intervals. Time in the light compartment was reported as the mean + / - SEM of all mice in each interval and as the mean + / - SEM of the average time per interval for each individual mouse. Y-maze assay

[0404] The Y-maze assay was used to measure spatial memory using a three-arm maze. The assay is divided into two trials separated by an intertrial period. During the first trial, one arm (the novel arm) is closed and the mouse is left to explore the two other arms for 5 min. The mouse is then returned to its home cage with a 2 min intertrial period. During the second trial, the mouse is allowed to explore all arms. Mice with good spatial memory enter the previously unexplored (novel) arm more frequently than the other arms. Mice with poor spatial memory show no preference. The number and time of entries in the novel arm during the second trial were reported as the mean + / - SEM of all mice in each interval (30 s) and the mean + / - SEM of the total time of the trial for each individual mouse. Rotarod assay

[0405] The rotarod assay was used to measure motor dysfunction in mice. The assay is divided into three trials of 5 min each separated by a 10 min rest period. For each trial, the mouse is placed on the stationary rod. Once the animal is in position, rod rotation is initiated at a speed of 4 rpm / min and increased to 60 rpm in 5 min. Following this protocol, each animal is trained for 2 days and tested on the third day. Latency to fall off the rod is reported as the mean + / - SEM of all mice for each trial. Experimental design The experimental design of this cohort is shown in Figure 2. The same animals were used to assess light aversion (light-dark assay), spatial memory (Y-maze) and motor function (rotarod). Animals were randomly assigned to six groups: negative control group (vehicle, sunflower oil), positive control group (CGRP 0.1 mg / kg or caffeine 100 mg / kg depending on the assay), CBD (100 mg / kg), THC (1 mg / kg), 1:1 (both CBD and THC at 1 mg / kg), or 100:1 (CBD at 100 mg / kg and THC at 1 mg / kg). Groups remained the same throughout the experiment (i.e., mice injected with 100:1 were always the same in the different assays).

[0406] One week after arrival at the facility, animals were pre-exposed to the light aversion chamber to reduce their desire to explore following exposure (baseline, data not shown). Mice were then tested twice for light aversion, with one week between tests.

[0407] Test 1: Testing the efficacy of CBD and / or THC against CGRP-induced light aversion. Drug administration was performed ip by ASW or AK 60 min before testing. 30 min before testing, animals received a second injection of CGRP (0.1 mg / kg) to induce a migraine-like situation. Only one group received PBS, which represents the negative control in this experiment. The group that received sunflower oil + CGRP represents the positive control. These injections were also performed ip by ASW or AK. After 30 min, animals were placed in the light aversion chamber and tested for 30 min.

[0408] Test 2: Testing the potential effect of CBD and / or THC alone on light aversion. Animals were given one week for recovery. The same groups were then used for test 2, only the second injection was reversed. All groups were administered vehicle 30 min before testing, except for the first group, which received CGRP and was the positive control for this test. The group that received sunflower oil + PBS was the negative control for this test (red line).

[0409] Spatial memory was assessed using the Y-maze one week after test 2. Drugs were administered 60 min before testing, except for CGRP (positive control), which was administered 30 min before testing.

[0410] One week after the Y-maze, motor function was assessed using the rotarod. Drugs were administered 60 min before testing, except for caffeine (positive control), which was administered 30 min before testing. result A. Light aversion A CBD:THC ratio of 100:1 reduces light aversion induced by CGRP administration.

[0411] Light aversion was measured both as a function of time over a 30 min test period (top panels of Figures 3A-B; two-way ANOVA [time and treatment], treatment factor p = 0.0005, interaction factor p = 0.0249; Tukey's multiple comparisons, * p < 0.05; ** p < 0.01; *** p<0.001 vs. vehicle+vehicle group at the corresponding time point; N=18-22 / group), data are also expressed as the average time spent per 5 min during the entire test period (lower panels of Figures 3A-B; one-way ANOVA, treatment factor p=0.0005; Tukey's multiple comparisons, * p < 0.05; ** p<0.01; p<0.001 vs. vehicle+vehicle group; N=18–22 per group).

[0412] Compared to our negative control consisting of mice injected with vehicle (sunflower oil and PBS, black circles), injection of CGRP + vehicle induced a significant decrease in the time spent in the light compartment, representing the positive control in this experiment (red triangles). Co-administration of CBD alone (blue diamonds), THC alone (green squares), or a CBD:THC ratio of 1:1 (purple diamonds) failed to reverse the decrease in time spent in the light compartment induced by CGRP. Co-administration of a CBD:THC ratio of 100:1 (orange squares) almost completely alleviated the CGRP-induced light aversion, which was no longer significantly different from the negative control group.

[0413] Although we were not provided with the power to detect small differences, the data were then analyzed by sex. Lack of power would make these results more difficult to interpret. Results for females are shown in FIG. 3C. The left panel shows the time spent in the light compartment every 5 min during the 30 min assay (2-way ANOVA [time and treatment], treatment factor p=0.21, interaction factor p=0.0069; Tukey's multiple comparisons, p=0.005 vs. vehicle+vehicle group at corresponding time points). *<0.05; N=9-11 per group). The right panel shows the average time spent per 5 min in the lighted compartment (one-way ANOVA, treatment factor p=0.17; N=9-11 per group. Results for males are shown in Figure 3D. The left panel shows the time spent in the lighted compartment for each 5 min period during the 30 min assay (two-way ANOVA [time and treatment], treatment factor p=0.0032, interaction factor p=0.76; Tukey's multiple comparisons, vs. vehicle+vehicle group at corresponding time points). * p<0.05; N=9-11 per group). The right panel shows the average time spent per 5 min in the light compartment (one-way ANOVA, treatment factor p=0.0057; Tukey's multiple comparisons, * p<0.05; N=9–11 per group).

[0414] Unfortunately, the difference between the negative control (vehicle + vehicle) and the positive control (CGRP + vehicle) in females was not as robust as we would have liked (especially at later time points), making further interpretation difficult (Figure 3C).However, based on the first 15 minutes of the assay, it appears that only the 100:1 ratio of CBD:THC reduces light aversion behavior in females, but the others do not.

[0415] The positive and negative controls in males show robust differences from CGRP+vehicle, causing a strong and significant decrease in time spent in the light compartment compared to the vehicle+vehicle group (Figure 3D). Again, the 100:1 group shows the best rescue, but the other treatments do not appear to alleviate the phenotype at all.

[0416] As a control for this experiment, the effect of different ratios of CBD:THC was tested on the same animals in the absence of a CGRP trigger. In this experiment, CGRP+vehicle (black circles) serves as a positive control compared to vehicle+vehicle (red triangles, negative control). The results are shown in Figure 4. The left panel shows the time spent in the light compartment every 5 min during the 30 min assay (2-way ANOVA [time and treatment], treatment factor p=0.0256, interaction factor p=0.0394; Tukey's multiple comparisons, not significant. N=18 per group). * 22). The right panel shows the mean time spent per 5 min in the light compartment (one-way ANOVA, treatment factor p = 0.0256; Tukey's multiple comparisons, not significant; N = 18–22 per group).

[0417] Unfortunately, the negative control group in this experiment yields lower than expected results (not unexpected when animals are tested in this assay for the third time), but nevertheless, CGRP+vehicle mice spend less time in the lighted compartment than vehicle+vehicle mice. All other groups spend an average time in the lighted compartment of 75-125 s, which is within the normal range. Whether these results, which are higher than the vehicle+vehicle group, have biological meaning remains to be determined. This experiment may need to be reevaluated using a new cohort of naïve mice. Effect of different ratios of CBD and THC on CGRP-induced increase in rest time in the dark compartment.

[0418] When migraine sufferers have an attack, it is common for them to seek out a dark compartment and rest. Mice exhibit a similar behavior. In the present study, compared to the negative control (vehicle + vehicle), the positive control (CGRP + vehicle) results in a significant increase in the time spent resting in the dark compartment, both when the data are plotted as a function of time (left panel of Figure 5A) or when plotted as an average (right panel of Figure 5A). The left panel shows the time spent resting in the dark compartment for every 5 min during the 30 min assay (two-way ANOVA [time and treatment], treatment factor p = 0.0004, interaction factor p = 0.0643; Tukey's multiple comparisons, * p < 0.05; ** p < 0.01; *** p<0.001 vs. vehicle+vehicle group at the corresponding time point; N=18-22 per group). The right panel shows the average time spent per 5 min resting in the dark compartment (One-way ANOVA, treatment factor p=0.0004; Tukey's multiple comparisons, * p < 0.05; ** p < 0.01; *** p<0.001 vs. vehicle+vehicle group; N=18–22 per group).

[0419] When co-administered with CGRP, neither CBD alone nor the 1:1 ratio reversed this increase in rest time. Although THC alone and the 100:1 ratio still differed from the vehicle+vehicle group during the first 10 minutes of the assay, these two treatments appeared to attenuate the phenotype, such that the groups were no longer significantly different from vehicle+vehicle when the data were potted as means (Figure 5A, right panel).

[0420] The data were then analyzed by sex, although we were not provided with the power to detect small differences. Lack of power makes these results more difficult to interpret. The results for females are shown in FIG. 5B, and those for males in FIG. 5C. The left panel in FIG. 5B shows the time spent resting in the dark compartment for every 5 min during the 30 min assay (2-way ANOVA [time and treatment], treatment factor p=0.066, interaction factor p=0.16). The right panel in FIG. 5B shows the average time spent per 5 min in the light compartment (1-way ANOVA, treatment factor p=0.0483; * p<0.05; N=9-11 per group). The left panel in Figure 5C shows the time spent resting in the dark compartment every 5 min during the 30 min assay (2-way ANOVA [time and treatment], treatment factor p=0.0077, interaction factor p=0.0805; Tukey's multiple comparisons, * p < 0.05; ** p<0.01 vs. vehicle+vehicle group at the corresponding time point; N=9-11 per group). The right panel in Figure 5C shows the average time spent per 5 min in the light compartment (one-way ANOVA, treatment factor p=0.0078; Tukey's multiple comparisons, ** p < 0.05; ** p<0.01; N=9–11 per group).

[0421] In females, only the 100:1 ratio appeared to attenuate the increased resting in the dark compartment produced by CGRP administration, whereas in males, only THC alone appeared to have an effect. The effect of different ratios of CBD and THC on rest time in the lighted compartment.

[0422] The left panel of Figure 6 shows the time spent resting in the light compartment every 5 min over the 30 min assay (2-way ANOVA [time and treatment], treatment factor p=0.0293, interaction factor p=0.059; Tukey's multiple comparisons, vs. vehicle+vehicle group at the corresponding time point). *p<0.05; N=18–22 per group). The right panel of Figure 6 shows the average time per 5 min spent resting in the light compartment (one-way ANOVA, treatment factor p=0.0084; Tukey's multiple comparisons, not significant; N=18–22 per group).

[0423] As expected from previously published results, CGRP injection does not increase the time spent resting in the light compartment (CGRP + vehicle group, FIG. 6). Only a CBD:THC ratio of 100:1 results in a significant increase in the time spent resting in the light compartment when the data are presented as a function of time. A CBD:THC ratio of 30:1 also reduces the light aversion produced by CGRP administration.

[0424] Light aversion was measured as a function of time over a 30 min test period as described above (Figure 7, top panel: two-way ANOVA [time and treatment], treatment factor p = 0.0117; Tukey's multiple comparisons, dark * p < 0.05; ** p<0.01 vs. vehicle group. * p<0.05; vehicle+CGRP vs. 30:1+CGRP). Data are also expressed as the average time spent per 5 min during the entire test period (Figure 7, lower panel; one-way ANOVA, p=0.0124; Tukey's multiple comparisons, ** p<0.01 vs. vehicle group).

[0425] Compared to our negative control consisting of mice injected with vehicle (sunflower oil and PBS, black circles), injection of CGRP + vehicle induced a significant decrease in the time spent in the light compartment and represents the positive control in this experiment (red triangles). Co-administration of a CBD:THC ratio of 100:1 (orange squares) was included as our control ration that reduced CGRP-induced light aversion. Co-administration of CBD:THC 30:1 reduced CGRP-induced light aversion and was no longer significantly different from the negative control group. CBD:THC ratios of 300:1, 20:1, and 10:1 did not reduce the light aversion produced by CGRP administration.

[0426] Light aversion was tested similarly to the experiment above. The results are shown in FIG. 8. The top panel shows the time spent in the light compartment every 5 min over a 30 min period (2-way ANOVA [time and treatment]; treatment factor p<0.0001; Tukey's multiple comparisons, * p < 0.05; ** p < 0.01; *** p<0.001; **** p<0.0001 vs. vehicle+vehicle group at the corresponding time point), the lower panel shows the average time spent in the light compartment during treatment (one-way ANOVA; p<0.0001; Tukey's multiple comparisons, ** p < 0.01; **** p<0.0001 vs. vehicle+vehicle group).

[0427] Co-administration of CBD:THC ratios of 300:1 (blue circles), 20:1 (avocado green open circles), or 10:1 (grey diamonds) did not reduce CGRP-induced light aversion. CBD:THC (100:1) reduces SNP-induced light aversion

[0428] Light aversion was evaluated. In this experiment, injection of SNP+vehicle (red square) was used as a positive control for light aversion. The results are shown in Figure 9. Panel A shows the time spent in the light compartment every 5 min during test 1 (two-way ANOVA [time and treatment]; treatment factor p=0.0461; Tukey's multiple comparisons against vehicle+vehicle group at corresponding time point; not significant). Panel B shows the average time spent in the light compartment during test 1 (one-way ANOVA; p=0.0461; Tukey's multiple comparisons against vehicle+vehicle group [ns]). Panel C shows the time spent in the light compartment every 5 min over 30 min during test 2 (two-way ANOVA [time and treatment], treatment factor p=0.3112; Tukey's multiple comparisons against vehicle-vehicle group [ns]). Panel D shows the average time spent in the light compartment during trial 2 (one-way ANOVA; p=0.3112; Tukey's multiple comparisons [ns] versus vehicle minus vehicle group).

[0429] Figure 9 shows that SNP + vehicle appears to decrease time in the light compartment (trend only) (Figure 10). A second cohort is required to obtain power for significance. B. Motor function - rotarod

[0430] The experimental design is shown in Figure 10. The animals used in this experiment were also used for light aversion and spatial memory, and were tested a third time in the rotarod assay. Briefly, two weeks after the last Y-maze experiment, the animals were subjected to three subsequent days of rotarod assay. The first two days were used for habituation, and then the animals were divided into six different treatment groups: - negative control group: vehicle (sunflower oil), - Positive control group: diazepam (5mg / kg ip), - CBD (100mg / kg), - THC (1mg / kg), - 1:1 (1mg / kg of both CBD and THC), and - 100:1 (100mg / kg CBD and 1mg / kg THC).

[0431] All treatments were administered 60 min prior to the rotarod assay on day 3, except for diazepam, which was administered 30 min prior to the assay. Effects of CBD, THC and CBD:THC ratio on locomotor activity assessed by rotarod:

[0432] Figure 11 shows the results of locomotor activity. Panel A shows the results for all mice shown as the average across all three trials on the treatment day (day 3) (one-way ANOVA, treatment factor p=0.0408; Tukey's multiple comparisons showed no differences between groups). Panel B shows the results for female mice shown as the average across all three trials on the treatment day (one-way ANOVA treatment factor p=0.132). Panel C shows the results for male mice shown as the average across all three trials on the treatment day (one-way ANOVA treatment factor p=0.452).

[0433] Animals administered vehicle remained on the rod for an average of 120 seconds. Animals administered diazepam (5 mg / kg, ip) showed a robust decrease in the time to fall from the rod, which could become significant if animals were added to this group. Compared to their two control groups, CBD alone and 100:1 treatments produced results similar to the vehicle group. The THC alone and 1:1 groups showed a non-significant increase in the time to fall, probably due to within-group variability. In any case, none of the treatments induced a decrease in motor function; if anything, some induced an increase. When separated by sex, the results show the same trend. C. Spatial memory

[0434] The experimental design is shown in Figure 12. The animals used in this experiment were also used in the light aversion (and later in the rotarod). Briefly, two weeks after the last light aversion experiment, the animals were subjected to two trials in the Y-maze separated by a 2 min intertrial period. The animals were divided into five groups as follows: - negative control group: vehicle (sunflower oil), - CBD (100mg / kg), - THC (1mg / kg), - 1:1 (1mg / kg of both CBD and THC), - 100:1 (100mg / kg CBD and 1mg / kg THC).

[0435] All treatments were administered 55 min before the first 5 min trial and therefore 62 min before the second 2 min trial. The effects of CBD, THC and the CBD:THC ratio on spatial memory were not assessed by Y-maze.

[0436] The results are shown in Figure 12. Panel A shows the number of entries into the novel arms during trial 2 in all mice (one-way ANOVA treatment factor p = 0.66). Panel B shows the time spent in the novel arms during trial 2 in all mice (one-way ANOVA treatment factor p = 0.624). Panel C shows the number of entries into the novel arms during trial 2 in female mice (one-way ANOVA treatment factor p = 0.083). Panel D shows the number of entries into the novel arms during trial 2 in male mice (one-way ANOVA treatment factor p = 0.998). Panel E shows the time spent in the novel arms during trial 2 in female mice (one-way ANOVA treatment factor p = 0.846). Panel D shows

[0437] Animals receiving vehicle entered the novel arm an average of 6 times on the second trial, lasting an average of 66.7 seconds. All other treatment groups showed similar results. There were no sex differences in the number of entries or time spent in the arms.

[0438] A positive control experiment was also performed by adding a composition containing CGRP, and the results are shown in Figure 14. The upper panel shows the number of entries in the novel arm after every 30 seconds over a period of 2 minutes. The lower panel shows the average number of entries in the novel arm for each cohort. D. Additional Experiments to be Conducted

[0439] Conducting experiments aimed at evaluating the effects of CBD and THC on spontaneous pain, tactile allodynia, motor function, object memory, depression, and anxiety.

[0440] Facial signs of discomfort (spontaneous pain): An automated facial grimace assay based on the mouse grimace scale developed in 2010 may be used, which measures spontaneous pain by scoring facial features (eye closure, nose and cheek expansion, ear position and whisker orientation). Several groups have shown that different models of migraine exhibit this phenotype in mice. In the automated version, video monitoring of eyelid closure and assessment of facial features allows the objective characterization of spontaneous pain on a linear scale.

[0441] Tactile allodynia: As an index of evoked pain, tactile allodynia, measured by application of von Frey filaments, is the most accepted pain assay in preclinical practice. Moreover, the perception of touch as a painful stimulus is reported by nearly half of migraine patients. Several groups have reported that mouse models of migraine showed enhanced sensitivity to tactile stimuli.

[0442] Wheel activity (motor function): Wheel activity is used to measure the physical activity and motivation of rodents. Mice are confined to the wheel for 2 hours, during which they are free to remain immobile or run at will. The number of rotations of the wheel, the speed, and the time spent moving are monitored and reflect any sedative or stimulating effects of the drug.

[0443] Novel object recognition (object memory): In this cognitive assay, mice are presented with two similar objects during a first session, and then one of the two objects is replaced with a novel object during a second session. The amount of time it takes to explore the novel object provides an index of recognition memory. Animals with object memory impairment spend the same amount of time exploring the two objects during the second session, while animals without impairment spend more time interacting with the novel object.

[0444] Tail Suspension Assay (Depression): Visually isolated mice are suspended 50 cm above the floor by tape placed approximately 1 cm from the tip of their tail. Immobility time is recorded for 6 min. Mice are considered immobile only if they hang passively and completely motionless.

[0445] Zero Maze (Anxiety): This test relies on two opposing innate behaviors: exploring novel environments and avoiding elevated and open spaces that are considered dangerous. The apparatus consists of two open (anxiety-inducing) and two closed (safe) elevated arms that form a zero or circle. Mice are allowed to explore for 5 minutes, and the time spent exploring the closed arms compared to the open arms indicates the animal's anxiety level. Example 6: CSD Experiments

[0446] The aim of the CSD experiments was to determine whether the combination of CBD and THC in ratios of 100:1 and 30:1 normalizes the altered CSD properties and behavioral responses of FHM1 mice compared to WT mice. At a later stage, we will determine whether the combination of CBD and THC is more effective than CBD (100 mg / kg) and THC (1 mg / kg) alone. All proposed experiments were performed in awake and freely moving mice. Optogenetics was used to induce CSD (Houben et al., J Cereb Blood Flow Metab 2017;37:1641-55), because this method allowed us to evaluate the effect of the treatment on CSD without the negative confounding factor of anesthesia. Aim 1: Effects of CBD / THC on CSD characteristics in WT and FHM1 mice

[0447] The objective was to determine whether acute doses of i.p. injected CBD / THC would normalize CSD characteristics (i.e., threshold, propagation velocity, as well as basic features amplitude, slope, and width) with a potential stronger effect expected in FHM1 compared to WT mice. Mice of both sexes were tested. CSD threshold experiments were performed in Thy1-ChR2 (Thy1-driven expression of channelrhodopsin-2) / FHM1 mice and Thy1-ChR2 / WT mice. In the experiments, optic fibers for optogenetic CSD induction were placed on the skull (left hemisphere) and dura (right hemisphere). It was expected that the most reliable data would be obtained from fibers placed on the dura. However, data obtained from fibers on the skull were expected to directly match data from objective 2 below (also with fibers placed on the skull). To accurately assess CSD propagation velocity, amplitude, slope, and width, recording electrodes were placed intracortically. Due to this configuration of optic fiber and recording electrode placement, a different set of mice was required for objective 1 than for objective 2. For each mouse, we first performed threshold measurements on multiple days (to establish a stable baseline) before we tested a single dose of CBD / THC. To reduce the number of mice and maximize the results of the experiment, we tested two doses and vehicle in each mouse over a two-week period.

[0448] The groups in the experiment included Thy1-ChR2 / FHM1 mice (N=10) and Thy1-ChR2 / WT mice (N=10). Each group had an equal number of males and females. Groups were tested using compositions containing 100:1 CBD:THC ratios (100mg / kg CBD and 1mg / kg THC), 30:1 (CBD:THC, 30mg / kg CBD and 1mg / kg THC), and vehicle.

[0449] Serial CSD threshold assessments were performed in conjunction with CBD:THC administration (2 doses, 100:1 and 30:1) 1 h prior to CSD testing (N = 3 blinded WT and FHM1 mice; 10 experiments per mouse). Serial CSD threshold assessments were also performed in conjunction with CBD:THC administration 30 min prior to CSD testing (N = 2 blinded WT and FHM1 mice; 6 experiments per mouse). The repeated CSD threshold paradigm provides a basis for determining the effects of CBD:THC on CSD characteristics. Expected internal variability in thresholds also warranted the inclusion of repeated baseline measurements between drug tests. In addition to CSD thresholds, CSD velocity, amplitude, and width were measured.

[0450] Exemplary data from the experiment 1 hour post-injection is shown in Figure 15. The data showed that CSD could be successfully induced after CBD:THC administration, with no obvious changes in CSD thresholds for both the 100:1 and 30:1 doses and the 1 hour and 30 minutes pre-administration times. No adverse effects of CBD:THC in exacerbating CSD were observed in either WT or FHM1 mice.

[0451] Long-term recordings in freely moving mice allowed repeated CSD threshold testing. Intra-individual variability over several days necessitated repeated baseline testing before and after drug testing. Since April 2021, the design has been adapted to include both 1 hour and 30 minutes before administration of CBD:THC. Preliminary CSD threshold results 1 hour and 30 minutes after injection are shown in Figures 16 and 17. Preliminary data show no obvious increase or decrease in CSD thresholds after injection of CBD:THC.

[0452] The half-width and amplitude of motor and visual cortex CSD were evaluated. The results are shown in Figure 18A and Figure 18B for motor and visual cortex, respectively. Although analysis of the data is ongoing, preliminary data shows no obvious increase or decrease in CSD half-width or amplitude after injection of CBD:THC. Aim 2: Effects of CBD / THC on CSD-related pain-related behaviors, i.e., mouse grimace score and allodynia

[0453] The aim was to determine whether acute doses of i.p. injected CBD / THC normalize CSD-associated pain-related behaviors with potentially stronger effects in FHM1 mice compared to WT mice. Behavioral measurements were performed using a modified version of the Mouse Grimace Scale (MGS) test (Langford et al. Nat Meth 2010;7:447-9) for headache assessment (part A), and the von Frey filament test in the periorbital area or hind paw for allodynia assessment (part B). To minimize confounding effects of invasive surgery on pain-related behavioral outcomes, both the optical fiber for optogenetic CSD induction and the recording electrodes were placed in one hemisphere on the skull. CSD was induced by light stimulation of suprathreshold intensity.

[0454] Given the nature of the experiment, headache and allodynia assessments could not be performed in the same mice. MGS was measured using a platform placed directly in front of the optogenetic cage, whereas allodynia experiments were performed in a different room. Also, it is not recommended to perform these behavioral tests in the same mice, as one assessment may confound the other. Therefore, in the following, we divided the experiment into (part A) MGS assessment and (part B) allodynia assessment. Note that data from the CSD readout in the two groups can be combined, allowing post-hoc tests for possible male-female differences if the effect size is large enough and / or if the effect of the drug is sex-specific.

[0455] Part A: MGS measurements: The groups in the experiment included Thy1-ChR2 / FHM1 mice (N=6) and Thy1-ChR2 / WT mice (N=6). Each group had an equal number of males and females. Groups were tested with compositions containing 100:1 CBD:THC ratios (100mg / kg CBD and 1mg / kg THC), 30:1 (CBD:THC, 30mg / kg CBD and 1mg / kg THC), and vehicle.

[0456] The results of the MGS measurement experiment are shown in Figure 19A-19B. Figure 19A shows the MGS scores at baseline and CSD. The results show that CSD causes an increase in headache pain behavior measured by MGS. Figure 19B shows the change in MSG scores with different ratios of CBD:THC. As can be seen, administration of 100:1 CBD:THC and 30:1 CBD:THC reduced MSG scores (p=0.0078 and 0.0781, respectively).

[0457] Part B: Allodynia Measurement: The groups in the experiment included Thy1-ChR2 / FHM1 mice (N=6) and Thy1-ChR2 / WT mice (N=6). Each group had an equal number of males and females. Groups were tested with compositions containing 100:1 CBD:THC ratios (100mg / kg CBD and 1mg / kg THC), 30:1 (CBD:THC, 30mg / kg CBD and 1mg / kg THC), and vehicle.

[0458] Preliminary analysis of MGS from four mice suggested no significant effects of either 100:1 or 30:1 CBD:THC administered 1 hour prior to dosing. Furthermore, there was no indication of adverse pain-inducing effects of administration of sunflower oil vehicle and CBD:THC in either WT or FHM1 mice. Aim 3: Effects on timing of allodynia measurements in the baseline setting

[0459] The timing of the effect of treatment in mice that did not undergo CSD was tested. As a result, the animals do not need to express Thy1-ChR2. It was hypothesized that administration of CBD and THC would normalize the enhanced allodynia threshold in FHM1 mice to WT levels. Assessment of allodynia measurements was performed by hind paw withdrawal threshold at 24, 48 and 72 hours after injection. To reduce the number of mice and maximize the outcome of the experiment, two doses and vehicle were tested in each mouse over a two-week period.

[0460] The groups in the experiment included groups of FHM1 mice (N=10) and WT mice (N=10). Each group had an equal number of males and females. Groups were tested using compositions containing 100:1 CBD:THC ratio (100mg / kg CBD and 1mg / kg THC), 30:1 (CBD:THC, 30mg / kg CBD and 1mg / kg THC), and vehicle.

[0461] Preliminary analysis shows variability between untreated and vehicle groups. It is unclear whether variability over repeated measurements is different between WT and FHM1 mice. Therefore, in parallel with drug testing, tests are performed to establish the stability of repeated allodynia measurements over time, even in the absence of treatment. Preliminary results of hind paw withdrawal threshold testing are shown in Figure 20. Although no consistent effect of CBD:THC on allodynia is seen, preliminary data may indicate an effect of 30:1 CBD:THC administered 30 minutes before testing.

Claims

1. A composition for treating acute migraine pain in a subject in need thereof, comprising THC and CBD, wherein administration of the composition relieves migraine pain in the subject while reducing undesirable side effects or risk factors of THC.

2. The composition of claim 1 , wherein the subject is a human.

3. The composition of claim 1 or 2, wherein the subject has chronic migraine headaches.

4. The composition of any of claims 1 to 3, wherein the subject has high frequency migraine headaches.

5. The composition of claim 1, wherein administration of the composition is achieved by injection.

6. 6. The composition of claim 1, wherein the composition is effective within at least 2 hours after administration.

7. The composition of claim 6 , wherein the composition is effective within at least one hour after administration.

8. The composition of claim 7, wherein the composition is effective within at least 30 minutes after administration.

9. The composition of claim 8, wherein the composition is effective within at least 15 minutes after administration.

10. 10. The composition of any of claims 1 to 9, wherein the composition comprises THC and CBD, and the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

11. 11. A composition according to any of claims 2 to 10, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 90% pure by weight.

12. 12. The composition of claim 11, wherein the at least one minor cannabinoid, the THC (if present), and the CBD (if present) are at least 99% pure by weight.

13. The composition of any of claims 1 to 12, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administration.

14. 14. The composition of claim 13, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

15. 15. The composition of any of claims 1 to 14, wherein the at least one minor cannabinoid is selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

16. A composition for relieving acute migraine pain in a subject in need thereof comprising THC and CBD, wherein administration of the composition modulates at least one biomarker of central and peripheral sensitization such that migraine pain is relieved in the subject while reducing undesirable side effects or risk factors of THC.

17. The composition of claim 16 , wherein the subject is a human.

18. 18. The composition of claim 16 or 17, wherein the composition further comprises at least one minor cannabinoid selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

19. A composition comprising THC and CBD for treating acute migraine pain, photophobia, phonophobia, and / or nausea in a subject in need thereof, wherein administration of the composition relieves migraine pain, photophobia, phonophobia, and / or nausea in the subject.

20. 20. The composition of claim 19, wherein administration of the composition is accomplished by injection.

21. 21. The composition of claim 19 or 20, wherein the composition is effective within at least 2 hours after administration.

22. 22. The composition of claim 21, wherein the composition is effective within at least one hour after administration.

23. 23. The composition of claim 22, wherein the composition is effective within at least 30 minutes after administration.

24. 24. The composition of claim 23, wherein the composition is effective within at least 15 minutes after administration.

25. 25. The composition of any of claims 19 to 24, wherein the migraine pain is measured by a pain scale.

26. 26. The composition of any of claims 19-25, wherein the photophobia is measured by the Utah Photophobia Symptom Impact Scale, the Korean Photophobia Questionnaire, a photoaversion assay, or self-report from the subject.

27. 27. The composition of any of claims 19 to 26, wherein the phonophobia is measured by self-report from the subject.

28. 28. The composition of any of claims 19 to 27, wherein the nausea is measured by self-report from the subject.

29. 29. The composition of any of claims 19 to 28, wherein the nausea is measured by a visual analog scale.

30. 30. The composition of any of claims 19 to 29, wherein the ratio of CBD:THC is from about 30:1 mg / kg to about 300:1 mg / kg.

31. 31. The composition of any of claims 19 to 30, wherein the composition further comprises at least one minor cannabinoid, the at least one minor cannabinoid being selected from the group consisting of CBG, CBGA, CBN, CBNA, THCV, THCA, CBC, CBCA, CBDV, and D8-THC.

32. 32. The composition of claim 31, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 90% pure by weight.

33. 33. The composition of claim 32, wherein the THC, the CBD, and the at least one minor cannabinoid (if present) are at least 99% pure by weight.

34. 34. The composition of any of claims 19 to 33, wherein at least one biomarker of central and peripheral sensitization is modulated as a result of said administration.

35. 35. The composition of claim 34, wherein the at least one biomarker is selected from the group consisting of NMDA, glutamate, CGRP, FAAH, substance P, 5-HT, NO, GABA, NGF, serotonin, dopamine, AEA, and 2-AG.

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