Medical Cannabis for Migraine & Pain

Neurologists have more tools than ever before for acute and preventive migraine treatment, with novel disease-specific treatments based on our expanding understanding of migraine pathogenesis.¹ Nonetheless, many people with migraine self-treat with over-the-counter medications, integrative treatments, physical modalities, and more—including cannabis. In this article, we review the history, evidence, and current research and make suggestions for counseling patients who ask about cannabis.

Historical Perspective

There is a long history of relatively safe use of cannabis as a botanical medicine, as early as 2900 BC in China and 1000 BC in India.² Cannabis was a mainstay for treatment of migraine in Europe and North America between 1843 and 1943 and reported to have benefit for both migraine prevention and acute treatment.^3,4 Sir William Osler, considered by many as the father of modern medicine, wrote in his 1916 textbook that cannabis was “probably the most satisfactory remedy” for migraine.⁵ In the last 25 years, the scientific discovery of an endocannabinoid system (ECS), a homeostatic biochemical network found in mammals, has triggered interest in targeting this system for health and disease.⁶ Despite the psychoactive effects associated with higher doses, both historical and contemporary data suggest that therapeutic benefit can be reached at subintoxicating doses.⁷ The National Academies Committee on the Health Effects of Marijuana concluded that there is “conclusive or substantial evidence” that cannabis is effective for the treatment of chronic pain in adults.⁸

Cannabinoids for Treatment of Pain

The term cannabis may be confusing because there are many chemotypes of the Cannabis plant specifically related to Δ⁹-tetrahydrocannabinol (THC) content. THC, a partial agonist at cannabinoid 1 and 2 receptors (CB_1/2), is the primary antinociceptive compound in cannabis, reputed to have opioid-sparing effects.⁹ The pain-relieving effects are primarily caused by THC agonist activity on binding to CB₁, involved in pain processing in the central and peripheral nervous systems.¹⁰Cannabis plants contain many other cannabinoids and chemical classes. For example, there is much interest in cannabidiol (CBD), a nonintoxicating cannabinoid, with unsubstantiated claims by industry that can be misleading.

The primary drawback of THC is the psychoactive effects that can affect cognitive function in a dose-dependent manner. Cognitive effects include decreased working memory (ie, the ability to focus on and use information in the short term) and executive function (ie, the ability to organize tasks, remember details, and manage time). However, dosing of THC at subintoxicating doses, in combination with CBD and a gradual up-titration may help to decrease these side effects.⁷ In fact, we are learning that “less is more” when it comes to dosing THC, meaning that lower doses of THC are likely more effective for pain and that higher doses may actually be hyperalgesic.¹¹

Hemp contains chiefly CBD but, by legal definition, can have trace amounts of THC (<0.3% by US federal designation). There is scant evidence for analgesic effects of CBD, which has very different pharmacology from THC, and is only now being studied in humans for the treatment of migraine.¹² A recent study showed that a single oral dose of CBD adjunctive to standard care was ineffective for low back pain in the emergency department compared with adjunctive placebo.¹³ Even though CBD may not provide strong analgesia, however, there are other mechanisms by which CBD could beneficially affect migraine, including anti-inflammatory and anxiolytic effects and modulation of the serotonin 5HT_1A receptor.^14,15

Cannabis and Migraine

It is estimated that 1 billion people worldwide experience migraine, associated with high cost of health care and significant effects on quality of life.¹⁶ In a cross-sectional survey of 1,429 people who used medical cannabis, 35.5% of responders reported using medical cannabis for headache or migraine. Inhalation, which allows for rapid delivery of THC to the brain, was the most common method of administration, used by 81.4% of survey respondents.¹⁷

There is evidence supporting the role of the ECS in migraine through activation of the CB₁ receptor.¹⁸ Preclinical research shows the endocannabinoid anandamide (also known as N-arachidonoylethanolamine [AEA]), inhibits trigeminovascular neurons via the CB₁ receptor (also known as the transient receptor potential vanilloid subtype 1 [TRPV1] receptor), and the triptan-responsive serotonin 5HT_1B and 5HT_1D receptors. This suggests that THC may modulate the activity of the trigeminovascular system, a key player in migraine pathogenesis.^19-22 It is also hypothesized that low ECS function may be associated with chronic migraine.³ AEA levels in cerebrospinal fluid of people with chronic migraine and probable migraine or medication-overuse headache were significantly reduced (0.21±0.06 and 0.22±0.05 pmol/mL, respectively) compared with people without headache disorders (0.39±0.09 pmol/mL; P<.001) reflecting what could be a failure of the ECS to inhibit activation of the trigeminovascular system.²³ ECS modulation of migraine could be through effects on pain perception and transmission, neurotransmitter release, dural blood vessel dilation, or inflammation.

Clinical evidence supporting cannabis for migraine treatment is still limited, however. A case series from 1974 reported that inhaled cannabis provided benefit for 3 people with headache and migraine.²⁴ More recently, a cross-sectional survey of 145 people with medical cannabis authorization who were self-treating with cannabis, showed 61% reported a 50% or more reduction in monthly migraine attacks. The survey also suggested there was a long-term reduction in migraine frequency and reduced medication intake.²⁵ A retrospective chart review of 121 people who obtained cannabis from 2 cannabis specialty clinics had a mean reduction from 10.4 to 4.6 (P<.001) migraine headaches per month.²⁶ Most participants in this study used a combination of inhaled and oral forms daily, with inhalation preferred for acute treatment. An observational study of cannabis use for migraine or headache using data collected from a smartphone application reported that people with migraine who used inhaled cannabis flower had mean headache pain benefit of -3.3 points on a 0- to 10-point scale within 2 hours of administration.²⁷ The only randomized controlled trial of cannabis for headache to date is a crossover study of oral nabilone (synthetic THC) 0.5 mg/ day vs ibuprofen 400 mg/day for the treatment of medication-overuse headache. Participants had reduced daily analgesic use with either, but this was statistically significant only for nabilone.²⁸

With funding from the Migraine Research Foundation, we are currently enrolling participants in the first randomized, double-blind placebo-controlled trial^a of inhaled cannabis for acute treatment of migraine. The aim of the study is to learn whether vaporized cannabis with THC or CBD is effective for aborting migraine attacks and associated photophobia, phonophobia, and nausea. Participants will treat 4 separate migraine attacks with 1 of 4 separate treatments consisting of THC (~5%), THC (~5%) mixed with CBD(~12%), CBD (~12%), and sham cannabis with flower provided by the National Institute on Drug Abuse. Inhalation is being used as the route of administration because of the rapid pharmacokinetics desired for acute treatment of migraine as well as less erratic uptake compared with oral cannabinoid administration.²⁹ Other questions (eg, the role of cannabinoids for migraine prevention and whether frequent cannabis use might cause medication-overuse headache) will remain after this trial. Our hope is that this study and others will provide neurologists with scientific evidence they can provide when patients ask about cannabinoids for migraine.

The only cannabinoids that have been approved by the Food and Drug Administration as medical treatments are dronabinol (an artificial THC) and a pharmaceutical preparation of CBD, for chemotherapy-related nausea or seizures related to certain epilepsy syndromes, respectively. Many individuals across the US, however, are reporting that they receive benefit from self-administered cannabis for pain and headache, as well as better sleep, mood improvement, improved ability to function, and better quality of life.¹⁷

Cannabis and Other Painful Neurologic Conditions

Other conditions with pain that may be refractory to existing medications that might benefit from cannabis include multiple sclerosis, neuropathic pain, and fibromyalgia. Single-dose, placebo-controlled studies of inhaled cannabis in people with neuropathic pain arising from spinal cord injury or disease, peripheral neuropathy, and diabetic peripheral neuropathy show significant reductions in pain scores.^31-33 Additionally, individuals with medication-refractory multiple sclerosis using inhaled cannabis had improved scores on the Modified Ashworth Scale for spasticity and Visual Analogue Scale for pain.³⁰ In a prospective study of 367 people with fibromyalgia syndrome (FMS), using either oral or inhaled cannabis, 81.1% reported at least moderate overall improvement and 22.2% of those who also used opioids stopped or reduced opioid doses.³⁴ A systematic review of 10 studies concluded that cannabis may be beneficial for pain processing, reducing inflammation, and buffering stress for some with FMS.³⁵ It is important to note that although the potency of research-grade cannabis is well below that of cannabis flower available in the real world, this less-potent research cannabis has demonstrated efficacy in clinical trials for pain and spasticity.³⁶

Counseling Patients About Cannabis

Patients need to know that, although anecdotal evidence abounds, much more research is needed to answer many of the clinical questions that arise regarding the use of cannabis to treat pain or headache. This is especially true for those with migraine. For people with painful conditions for which there is some evidence of cannabis efficacy, a therapeutic trial of cannabis may be reasonable if pain is refractory to evidence-based and guideline-recommended treatments.^37-40 In clinical practice, the health care practitioner qualified to authorize medical cannabis performs an initial evaluation. Once authorization is granted, a patient may or may not have clear guidance on how to proceed; many who are inexperienced with cannabis appreciate detailed education from a health care practitioner. Referring patients to naturopathic doctors or advanced nurse practitioners with formal training and experience in providing this guidance is the best-case scenario. Several organizations provide curricula and may help locate practitioners in your area who provide patient education. The Medical Cannabis Institute, the Society of Cannabis Clinicians, and the American Cannabis Nurses Association are among the organizations that provide such curricula.

Our clinical experience in California—a state that regulates cannabis and mandates quality-control testing—is that formal consultation with an advanced practitioner who has training and experience in counseling patients on cannabis use vs sending patients directly to a dispensary results in better outcomes and higher patient satisfaction. The consult allows ample time for individualized assessment; education on dosing, administration forms and side effects; and evaluation for any potential drug interactions. It is important that patients access products that have passed quality-control testing for microbial and fungal contamination, heavy metals, and pesticides. It is also important that products have passed potency testing, because these products are not regulated by the FDA or the Dietary Supplement Health and Education Act of 1994 (DSHEA) due to the Schedule 1 designation of cannabis and cannabinoids by the US Drug Enforcement Agency. In states where medical cannabis is legal, products are found at licensed dispensaries and a trained health care provider, acting as a liaison, can help guide patients to appropriate products for therapeutic dosing. For scheduled administration, oral dosing is initiated with low-dose THC (0.5-3.0 mg) and titrated slowly to tolerance.⁴¹ For acute migraine or as-needed use for acute pain or spasticity, inhalation via a medical cannabis vaporizer using dried cannabis flower with THC content of 5% to 10% is suggested.¹¹ Use of inhaled concentrates, oils, or waxes in the form of vape pens or dabbing should never be recommended because of the toxicity, extreme potency, and potential contamination of these products.^42-44

Conclusion

Although our armamentarium of FDA-approved treatments for migraine has expanded since 2018 to include new acute and preventive treatments that are both effective and well-tolerated, there are still individuals with migraine refractory to these treatments. To date there have been few formal investigations into cannabis for migraine, but the few that exist are promising and support the need for further research. The potential for medication-overuse headache from regular cannabis use needs to be further evaluated. The evidence for cannabis in migraine and pain is limited but growing.