What’s Old Is New Again — Taming Migraine Pain With Cannabis

The medicinal properties of cannabis for migraine and other conditions have been well known since ancient times. In the 19th century, cannabis was introduced to Western medicine and quickly became a widely used and respected patent medication and for a century was a mainstay of treatment of migraine in Europe and North America.1 Cannabis’ status as a treatment of choice for migraine during this time is reflected in comments made by Dr. William Osler, who founded Johns Hopkins Hospital and who’s considered the father of internal medicine. In 1892, he wrote in “The Principles and Practice of Medicine” that “Cannabis indica is probably the most satisfying remedy [for migraines].”2

Unfortunately, the Marihuana Tax Act in 1937 essentially deemed cannabis illegal, discontinuing its therapeutic use and research into its medical potential, resulting in limited clinical evidence to support its role in migraine treatment.

More recently, as cannabis restrictions have loosened, a growing number of studies demonstrate efficacy and provide support for Osler’s view of cannabis as a preferred treatment option for migraine.

Migraine Symptoms
Migraine is a genetic neurological disorder that causes symptoms far more severe than those of a typical headache. Migraine sufferers typically experience an intense pulsing headache on one side of the head that’s often accompanied by other symptoms such as nausea and vomiting, visual disturbances, and an increased sensitivity to light, sounds, or smells.

Migraine attacks can last from four to 72 hours or longer. Roughly one-third of persons who experience migraine experience “aura” before an attack, with associated visual problems such as blurred vision, blind spots, flashes of light, hemianopia or loss of half of the field of vision, or a zigzag pattern moving from the central field of vision towards the edge. Other aura symptoms may include tingling sensations and numbness in the face, lips, and tongue or in the arms and legs; speech problems such as slurred speech; dizziness; a stiff neck; and, rarely, loss of consciousness. Migraines with aura are referred to as complicated migraines, while migraines without aura are known as common migraines.3

Migraines are also categorized according to the frequency of attacks, with episodic migraine defined as migraine headaches occurring one to 14 days per month, whereas chronic migraine is diagnosed in those who experience migraine headache on more than 15 days per month.4

Prevalence and Burden
Migraine is the second most disabling disease in the world, affecting 1 in 7 adults globally and nearly 40 million people in the United States.5 Migraine can diminish a person’s quality of life, reducing their ability to provide self-care and undertake normal activities while destroying dreams, destabilizing families, and disrupting careers.

On an annual basis, women suffer from migraine three times as often as men (18% of females vs 6% of males), and during the reproductive years, up to 43% of women suffer, likely related to hormonal changes. Of women who suffer from migraine, 50% experience more than one attack per month, and 25% have four or more severe attacks per month. Eighty-five percent of chronic migraine sufferers are women, and 92% of women with severe migraine become disabled.6 Migraine costs the nation an estimated $78 billion per year, and women account for about 80% of direct medical and lost labor costs.7

Migraine Treatments
Current migraine treatments focus on managing the number of episodes and symptom improvement. However, migraine treatment is challenging and available treatment options are frequently ineffective or inadequate. Complicating treatment are associated medication-related side effects, which can limit or discourage drug use and lead to a high incidence of medication nonadherence.

Migraine treatments are classified as being abortive or prophylactic. Abortives work acutely to reduce the severity of an attack once a migraine has started, while prophylactics work to prevent an attack from occurring and obviate the need for the use of acute therapies.

Abortive Treatments
Abortives include triptans (eg, sumatriptan), nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen, celecoxib), acetaminophen, ergots (eg, ergotamine), opioids (eg, oxycodone, hydrocodone), and antiemetics (eg, prochlorperazine, ondansetron).

A discouraging reality is that current abortive treatments result in sustained and complete relief of pain within two hours for only a portion of patients and have been associated with medication overuse headache (MOH) when used frequently (more than 10 days per month). Effectiveness varies significantly among agents. In one study, triptans relieved migraine headaches for 42% to 76% of participants within two hours and prevented pain for another two hours in 18% to 50% of participants. The study found triptans to be more effective than ergotamines and equally or more effective than NSAIDs, acetaminophen, and acetylsalicylic acid (ASA). Participants reported less pain and prolonged pain relief with a combination of triptans and acetaminophen or ASA.8 It’s important to note that treatment discontinuation due to tolerability issues or contraindications due to the presence of cardiovascular disease or significant risk can hinder the use and effectiveness of abortive treatments.

Prophylactic Treatments
Prophylactics include antidepressants (eg, amitriptyline, venlafaxine, duloxetine), calcium channel blockers (eg, verapamil), beta-blockers (eg, atenolol), anticonvulsants (eg, valproic acid, topiramate), corticosteroids (eg, dexamethasone), and, more recently, anti-calcitonin gene-related peptide agents (eg, erenumab).9 Poor tolerability and safety concerns are implicated as contributors to poor adherence to preventive treatments, and their underutilization is common. It’s believed that an estimated 38% of persons with episodic migraines would benefit from preventive therapy, yet less than 13% take prophylactic medications.10

Endocannabinoid System Dysfunction
The human body’s endocannabinoid system (ECS) mitigates migraine through several pathways (glutamine, inflammatory, opiate, and serotonin) both centrally and peripherally.11 However, in those with migraine, it’s thought that endocannabinoid deficiency with lower-than-normal levels of the endocannabinoid anandamide contributes to ECS dysfunction and migraine.12

Rationale for Cannabis to Treat Migraine
The use of exogenous cannabinoids may help balance ECS tone and normalize ECS dysfunction in persons with migraine. Active constituents found in cannabis, including THC, CBD, flavonoids, and terpenes, produce effects within the ECS that can help decrease nociception and symptom frequency. More specifically, cannabinoid activity at CB1 receptors may reduce nociperception via a serotonin-mediated pathway, and activity at CB2 receptors produces analgesic effects.11 Also, cannabinoids’ ability to inhibit platelet serotonin release and peripheral vasoconstriction may contribute to cannabis’ prophylactic effect in migraine.13 By acting similarly to the endocannabinoid anandamide, THC can inhibit two of the many mechanisms believed to contribute to migraine, including vasodilation of dural blood vessels and decreased release of calcitonin gene-related peptide from trigeminal neurons. Cannabinoids also have anti-inflammatory effects and cause dopamine blockade, which are beneficial in mitigating migraine.14

Current Evidence
While clinical evidence supporting the use of cannabis for migraines is limited, there’s an accumulation of information supporting the benefits and effectiveness of medical cannabis use in migraine.

Cannabis Use for Migraine Is Common
The use, whether physician recommended or self-selected, of cannabis for migraine is common, with users reporting good efficacy. A survey of 1,429 people using medical cannabis reported the most common conditions for its use to be pain (61.2%), anxiety (58.1%), depression (50.3%), headache/migraine (35.5%), nausea (27.4%), and muscle spasticity (18.4%). Participants reported an 86% reduction in symptoms, and 59.8% of medical cannabis users reported using it as an alternative to prescriptions. Those using for cannabis for migraine reported an average 3.6-point decrease (based on a 10-point scale) in headache severity after cannabis use. 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.15

Preclinical Study
In a preclinical animal study, the effectiveness of THC for migraine was demonstrated using a rat model of migraine; sumatriptan, morphine, and THC each prevented migraine-suppressed wheel-running.16

Cannabis vs Amitriptyline
In another research, scientists conducted a two-phase study. Phase one included 48 medical cannabis patients and sought to determine an effective analgesic dose. It found that an oral dose of 200 mg THC and CBD in 200 mL 50% fat emulsion led to a 55% reduction in acute pain severity. Phase two was a follow-up three-month pilot clinical trial involving 79 medical cannabis patients who were given a daily prophylactic dose of 200 mg THC and CBD in 200 mL 50% fat emulsion, which reduced migraine frequency by 49.4% compared with 40.1% when patients were given 25 mg daily amitriptyline, an antidepressant used for migraine treatment.17

Long-Term Reduction in Migraine Frequency
In 2020, researchers conducted a questionnaire-based study in 145 migraine patients (67% female) licensed for medical cannabis treatment with a median treatment duration of three years. Patients were retrospectively classified as responders if there was a 50% or greater reduction in monthly migraine attack frequency or as nonresponders if they experienced less than a 50% reduction in migraine attack frequency following treatment initiation. Comparative statistics found responders (n=89, 61% of the sample) reported better migraine symptom reduction, less severe headache impact, better sleep quality,
and decreased medication (opioid and triptan) consumption.18

Cannabis: An Abortive and Prophylactic
In another study, researchers conducted a retrospective chart review of 120 adults with the primary diagnosis of migraine headache who were recommended migraine treatment or prophylaxis with medical cannabis between January 2010 and September 2014 and who had at least one follow-up visit. Most patients used more than one form of cannabis and used it daily for migraine prevention. Medical cannabis use decreased headache frequency from 10.4 to 4.6 headaches per month. Forty-eight patients (39.7%) reported prevention of migraine headache, 24 (19.8%) experienced decreased migraine frequency, and 14 (11.6%) reported that medical cannabis aborted their migraine. Inhaled cannabis was commonly used for acute treatment and was reported to abort migraine headache. Fourteen patients (11.6%) reported negative effects, the most common of which were somnolence (two patients [1.7%]) and difficulty controlling the effects of cannabis related to timing and intensity of the dose (two patients [1.7%]). These effects were experienced only in patients using edible cannabis, which was reported to cause more negative effects than did other forms.19

Washington State University Study
Strainprint is a Canadian data application used by medical cannabis patients to journal their use. The app allows users to learn which strains work best for their conditions and which strains are working for other users treating similar symptoms/conditions. Researchers from Washington State University analyzed anonymous self-reported data entered into Strainprint over a 16-month period. They found that patients using medical cannabis for migraine experienced a 49.6% reduction in symptoms and recurrence. Furthermore, persons identified as suffering the most reported the greatest amount of relief. In other words, cannabis use helped to make the pain more tolerable in the toughest cases that were almost impossible to treat with traditional prescription pain medication. No risk for overdose was detected.20

MOH
MOH or rebound headaches are caused by regular, long-term use of medication to treat headaches, such as migraines. Risk factors include a history of migraine and frequent use of headache medications. MOH risk increases with the use of combination analgesics (eg, acetaminophen/caffeine, butalbital/ASA/caffeine), ergotamine, or triptans 10 or more days a month, or simple analgesics (eg, acetaminophen, ibuprofen) more than 15 days a month.21

Opioid use also increases risk for MOH, which has been seen in animals and humans. In an animal study, rats given morphine repeatedly showed tolerance to morphine’s antimigraine effect and increased sensitivity to further migraine induction, echoing the tolerance and MOH phenomena observed in humans with migraines.16 In contrast, rats didn’t develop tolerance to THC’s antimigraine effect.

A randomized, double-blind, crossover trial in patients with treatment-refractory MOH found that the synthetic cannabinoid nabilone was more effective than ibuprofen in reducing daily analgesic intake, pain intensity, level of medication dependence, and improved quality of life in these patients.22

Researchers from the Washington State University Strainprint study also found that repeat use of cannabis is associated with tolerance to its effects, making tolerance a risk factor for the use of cannabis to treat headache and migraine.20 However, based on their findings, cannabis didn’t appear to lead to the MOH that’s associated with other conventional treatments, meaning that cannabis use doesn’t worsen headaches or migraines over time.

Antiemetic Benefits
Beyond the pain associated with migraine, nausea and vomiting are common and can be disabling for many. The analgesic and antiemetic benefits associated with THC are well documented. In fact, two synthetic forms of THC—dronabinol and nabilone23—have been approved by the FDA for the treatment of chemotherapy-related nausea and vomiting. In a 2018 study, researchers conducted a literature review to determine the medicinal benefits of cannabinoid for the treatment migraines, facial pain, and chronic pain. They found that medicinal cannabis provided a significant advantage in improving migraine-related nausea and vomiting.24

Reduced Opioid Risks
In the American Migraine Prevalence and Prevention study, approximately 30% of community-residing respondents reported opioid use for migraine.25 In 2010, 59% of emergency department visits for migraine-involved opioid administration or prescription.26 Despite the potential for short-term benefits, opioids are associated with only modest initial efficacy, increased risk for migraine chronification, and potential for misuse, abuse, and dependence. While opioids can help block pain, they’re also highly addictive and don’t affect the underlying migraine process. In some cases, opioids can also reduce the efficacy of some preventive treatments.

There’s some evidence that cannabis compounds may be less risky alternatives to opioids and lessen the burden of opioid addiction. The “opioid-sparing effect” of cannabinoids could be a significant benefit for many migraine patients, as combining cannabis with opiates has been shown to decrease opiate dose requirements.27 The benefits of cannabis in helping to reduce use of opioids and other prescription medicines was identified in an electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain. It was found that 41.2% to 59.5% of medical cannabis patients substitute prescription medications with cannabis, the most commonly replaced being opiates/opioids (40.5% to 72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), antidepressant/antianxiety medications (39%), NSAIDs (21%), triptans (8.1%), anticonvulsants (7.7%), muscle relaxers (7%), and ergots (0.4%).24

Final Thoughts
Despite the lack of large clinical studies, the existing evidence is encouraging and supports further evaluation of medical cannabis as a potential preferred option for migraine. Of additional interest is the possibility that cannabis may also help mitigate the risk of opioids in migraine and other pain conditions, which could play a positive role in fighting the opioid crisis.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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