The Use of Cannabis for Headache Disorders
Department of Psychiatry, Center for Medicinal Cannabis Research, University of California, San Diego, La Jolla, California.
* Address correspondence to: Igor Grant, MD, Department of Psychiatry, Center for Medicinal Cannabis Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, E-mail: [email protected]
This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
Headache disorders are common, debilitating, and, in many cases, inadequately managed by existing treatments. Although clinical trials of cannabis for neuropathic pain have shown promising results, there has been limited research on its use, specifically for headache disorders. This review considers historical prescription practices, summarizes the existing reports on the use of cannabis for headache, and examines the preclinical literature exploring the role of exogenous and endogenous cannabinoids to alter headache pathophysiology. Currently, there is not enough evidence from well-designed clinical trials to support the use of cannabis for headache, but there are sufficient anecdotal and preliminary results, as well as plausible neurobiological mechanisms, to warrant properly designed clinical trials. Such trials are needed to determine short- and long-term efficacy for specific headache types, compatibility with existing treatments, optimal administration practices, as well as potential risks.
Headache is a major public health concern, with enormous individual and societal costs (estimated at $14.4 billion annually) due to decreased quality of life and disability. 1 Each year, ∼47% of the population experience headache, including migraine (10%), tension-type headache (38%), and chronic daily headache (3%). 2 A sexual dimorphism exists for headache disorders, with women 2–3 times more likely to experience migraine 3 and 1.25 times more likely to experience tension-type headache than men. 4
The present review will focus largely on migraine, tension-type headache, trigeminal autonomic cephalalgias (specifically cluster headache), and medication-overuse headache (MOH). Migraine is classified as a 4–72 h headache that is typically unilateral, pulsating, of moderate-to-severe intensity, and associated with photophobia and phonophobia. 5,6 Tension-type headache is classified as frequent, infrequent, or chronic, typically presenting with bilateral tightening pain of mild-to-moderate intensity and lasting minutes to days. 6,7 Cluster headache is defined as severe unilateral pain in orbital, temporal, and/or supraorbital locations, lasting 15–180 min and typically occurring frequently and at regular intervals. 6,8 MOH is a chronic condition (occurs more than 15 days per month) that develops from frequent use of anti-headache medications. 6,9
The pathophysiology of headache disorders is still under investigation. However, it is believed that migraine and cluster headaches are initiated in the brain in areas such as the hypothalamus, brainstem, or possibly cortex. 6 Tension-type headaches can not only originate in the central nervous system but may also be triggered by myofascial tissue, often developing in response to stress. 10 Regardless of origin, headaches usually involve overactivation of the trigeminovascular pathway, resulting in the release of vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P, as well as vasoactive mediators such as nitrous oxide (NO), which can lead to further sensitization of nociceptive receptors in the head and neck. 11 Serotoninergic signaling, parasympathetic efferents, inflammation, and increased intracranial pressure also play important roles in headache disorders. 12,13
Treatment depends on the underlying headache condition; however, some popular options include NSAIDs for mild headaches and triptans, anti-depressants, verapamil, or ergotamine for more severe or chronic headaches. 14 These may be complemented by nonpharmacological interventions such as cognitive-behavioral therapy or relaxation training. 15 Despite many treatment options, less than half of headache sufferers experience remission, and many continue to develop more severe or chronic headaches throughout their lifetime. 16 Moreover, headache disorders are often underrecognized and undertreated. 17 This current situation warrants an exploration of additional treatment options for headache disorders, with favorable side-effect profiles and efficacy in refractory patients.
One such option, cannabis, has been ignored in the United States for the past several decades but has an established history in the treatment of headaches. Assyrian manuscripts from the second millennium BCE recommended cannabis to “bind the temples,” 18 and Ayurvedic preparations in the third and fourth centuries BCE were indicated for “diseases of the head” such as migraines. 19 The prescription of cannabis was even recommended in ancient Greece, with Pedanius Dioscorides describing its use in his De Maternia Medica as a treatment for “pain of the ears.” 20 Other citations documenting the use of cannabis for headache disorders arise from the ninth century in the Al-Aq-rabadhin Al-Saghir, the earliest known document of Arabic pharmacology. 19 Further recommendations are found in Persian texts from the 10th 21 and 17th centuries. 22 Prominent physicians of the Middle Ages, including John Parkinson 23 and Nicholas Culpeper, 24 also recommended the use of cannabis for headache.
The reintroduction of cannabis to the West in 1839 25 began a century of its use as an effective treatment for headache disorders 26 until its illegalization in 1937. 27 Notable physicians who espoused the benefits of cannabis for headache disorders included John Russell Reynolds, the personal physician of Queen Victoria, 28 American neurologist Silas Weir Mitchell, 29 the president of the New York Neurological Society Edouard C. Seguin, 19 William Gowers, a founding father of modern neurology, 30 and Sir William Osler, often considered the father of modern medicine. 31
When cannabis was deemed illegal by the U.S. government, its therapeutic use and research into its medical potential was largely discontinued. To this day, there are few clinical investigations of the use of cannabis for headache; however, the studies that have emerged demonstrate potential efficacy. In addition, numerous pre-clinical investigations 18 have validated the role of endocannabinoids in preventing headache pathophysiology, which suggests a mechanistic role of cannabis in the treatment of these disorders. Although the cannabis plant comprises more than 100 cannabinoids, there has been little study of the individual effects of these cannabinoids on headache disorders; therefore, the present review will focus largely on the clinical potential of the cannabis plant as a whole.
The present review has four unique aims: (1) Highlight common historical trends in the use of cannabis in the treatment of headache to inform future clinical guidelines. (2) Briefly present the current clinical literature on this topic, with a focus on more recent publications that have not been discussed in past reviews. (3) Compile various preclinical studies into a prospective integrated model outlining the role of cannabinoids in the modulation of headache pathogenesis. (4) Outline several 19,32–35 future directions that warrant exploration based on the limited, but promising findings on this topic.
Materials and Methods
The material presented was drawn from standard searches of the PubMed/National Library of Medicine database, influential sources of current medical literature, and past review articles. Search keywords included cannabis; cannabinoids; headache; migraine; cluster headache; medication-overuse headache; tetrahydrocannabinol; cannabidiol; clinical trial; placebo; and double blind. CliniacalTrials.gov was also queried for studies that have not yet been published. Individual articles were selected based on historical, clinical, or preclinical relevance to cannabinoids or cannabis as a treatment for headaches.
Historical Use of Cannabis for Headache
Historical reports, though not ideal forms of evidence, are important resources for understanding the potential use of cannabis in the treatment of headache disorders. Clinical publications between 1839 and 1937 provide valuable insights into the most effective practices, challenges, and benefits during an era when cannabis was commonly used to treat headache. A summary of historical treatment practices using cannabis for migraines can be seen in Table 1 . Historical sources indicate that cannabis was used as an effective prophylactic and abortive treatment for headache disorders. Although dosing varied among physicians, most prescribed alcohol extractions of the drug in the range of ¼ to ½ grain (16–32 mg). 28,32,36–40 This dose was likely chosen to minimize the effects of intoxication while also providing effective therapeutic relief. Other providers suggested that doses should be progressively increased until modest effects of intoxication were felt. 19 For prophylactic treatment, these doses were usually administered two to three times daily for weeks or even months. 28,32,36–38 Acute treatment often involved higher doses taken as needed and, in some cases, smoked cannabis was recommended. 19,41–42
Historical Reports of the Use of Cannabis as a Treatment for Headache (19th and Early 20th Century)
|Migraine||A: 0.03 fluid ounce of alcohol extract 1 h before pain onset||4 Case studies||Distinct termination of migraine. All patients experienced improvement, some were cured.||Donovan 41|
|Migraine||A: 21.6 mg||2 Case studies||Immediate relief and elimination of headache for 14 months after treatment. No lasting harm.||Reynolds 27|
|P: 21.6 mg—three times daily|
|Migraine/headache||P: 21.6 mg, 1–2 times per day (can increase to 43.2 mg)||9 Case studies and clinical experience||Responses in majority of cases. Usually lasting relief, sometimes curative. Palliative during headache.||Greene 35 ; Russo 18|
|Clavus hystericus and migraine||P: 21.6 mg to 43.2 mg every night||Textbook||Palliation even in severe cases.||Waring 36|
|Migraine or sick headache||P: Taken before each meal (Women: 21.6 mg increased to 32.4 after 2–3 weeks; Men: 32.4 increased to 48.6)||Clinical experience||Majority of patients reported migraine relief for months.||Seguin (1878) cited in Russo 18|
|Migraine or sick headache||A: 21.6–32.4 mg at beginning of attack.||Clinical experience||Found to be the most effective drug for migraine. Can abort attacks in some cases.||Ringer 37|
|P: 21.6–32.4 mg, 2–3 times daily, for weeks or months continuously.|
|Migraine||P: 8.1–16.2 mg of solid extract twice a day.||Clinical experience||Helpful prophylactically and abortively, even in cases of migraine refractory to other treatments.||Hare 40|
|A: Take as needed|
|Chronic daily headache||P: 21.6–32.4 mg (increasing if necessary), 2–3 times per day for weeks to months.||4 Case studies||Cured complaints in a majority of cases.||Mackenzie 38|
|Migraine||P: 16.2 mg twice a day continuously||Short report||Given immediately will stop attack, given periodically will reduce severity and frequency.||Suckling 39|
|A: Take 16.2 mg during onset of attack|
A, abortive; P, prophylactic.
Early reports of cannabis for the treatment of headache appear to be largely positive, with many patients experiencing a decrease in the frequency and intensity of their headache episodes. In some cases, headache was cured entirely even after cannabis discontinuation. 28,32,36–42 Furthermore, these early clinical reports praise the apparent safety of long-term cannabis use, as well as its added benefits of mollifying the nausea and anxiety that often accompany headaches. A common emphasis was placed on the importance of specific purity, preservation, and administration of the cannabis as well as patient adherence in the efficacy of treatment.
Clinical Studies on Cannabis Use for Headache
The schedule 1 classification of marijuana in 1970 has made rigorous clinical studies on the treatment efficacy of this substance difficult. Currently, there are no placebo-controlled clinical studies examining the use of cannabis for headache; nevertheless, there have been a number of other studies published that give insight into its therapeutic efficacy ( Table 2 ). 19,43–58 However, care should be taken when interpreting the findings from these studies. With one exception, 53 these studies did not include a control group, and given that the placebo effect can be altered by the context of treatment, 59 it is reasonable to expect a significant placebo response given the pre-existing public popularity and notoriety of cannabis. Moreover, self-reports and case studies may have a bias toward immediate improvement without awareness of possible dependence, rebound, or withdrawal responses, which are important concerns in headache treatment. 60 In fact, studies show that headache can be induced in 23.2% patients undergoing cannabis withdrawal. 61
Clinical Reports of the Use of Cannabis or Exogenous Cannabinoids as a Treatment for Headache
|Subject population||Type of study||Significant findings||Source|
|3 Chronic smokers||Case series||Migraines after cannabis cessation. Remission of headache with return to use in one patient.||El-Mallakh 42|
|Patient with migraine||Case report||Women found superior relief of migraine with cannabis compared with beta-blockers, opiates, and ergots.||Petro (1997) cited in Russo 18|
|Patient with migraine||Case report||18 years of treatment failure with standard pharmaceuticals, found success with smoked cannabis.||Grinspoon and Bakalar 45|
|Patient with migraine||Case report||Successful treatment with cannabis that did not produce inebriation.||Terwur (1997) cited in Russo 18|
|121 Patients prescribed cannabis for migraine||Retrospective study||Migraine occurrences decreased from 10.4 to 4.6 per month; 39.7% had a positive effect, 19.8% had decreased frequency, and 11.6% had aborted pain.||Rhyne et al. 46|
|5 Cases of chronic migraine headache||Case series||All cases successfully treated with dronabinol or cannabis. In one case, cannabis improved response more than dronabinol. In three cases, cannabis was used to abort headache in the prodromal phase.||Mikuriya 48|
|1655 Patients seeking physician recommendation for medical cannabis||Survey||40.8% of applicants reported improvement of headache symptoms with cannabis.||Nunberg et al. 49|
|3 Subjects with chronic headaches||Case series||Smoking cannabis caused relief similar or greater than ergotamine and aspirin.||Noyes Jr. and Baram 50|
|30 Outpatients with medication-overuse headache||Clinical Trial (RDAC—Crossover)||Nabilone was superior to ibuprofen in reducing pain intensity, analgesic intake, and medication dependence while improving quality of life.||Pini et al. 52|
|Patient with refractory cluster headache||Case report||Smoked cannabis or dronabinol at the beginning of cluster headache provided complete immediate headache relief.||Robbins et al. 53|
|113 Patients with chronic cluster headache||Survey||26% regularly used cannabis. Use as treatment unknown.||Donnet et al. 54|
|139 Patients with chronic cluster headache||Survey||Overall, 45.3% had used cannabis, and 19.4% had used it to treat cluster headache; 25.9% found efficacy, and the remainder found variable or negative effects.||Leroux et al. 55|
|Patient with pseudotumor cerebri||Case report||Complete resolution of headache with smoking cannabis in||Evans and Ramadan 56|
|112 Patients with MS-associated trigeminal neuralgia||Survey||Overall, 70% found relief from trigeminal neuralgia, and 90% found chronic pain relief.||Consroe et al. 57|
MS, multiple sclerosis.
Nabilone, a synthetic cannabinoid mimicking tetrahydrocannabinol (THC), has been shown to decrease analgesic intake while reducing MOH pain in a double-blind, placebo-controlled trial. 53 In this study, 26 patients with treatment refractory MOH completed a course of either nabilone (0.5 mg) or ibuprofen (400 mg) for 8 weeks, then after a week-long washout period, completed a second 8-week course of the previously excluded medication. Oral cannabinoid administration was chosen over an oromusocal THC spray, both because oral administration avoids the concentration peaks that can lead to euphoric effects and because chronic administration better overcomes individual differences in bioavailability. Although both substances showed improvement from baseline, nabilone was significantly more effective than ibuprofen in reducing pain intensity, analgesic intake, and medication dependence, as well as in improving quality of life. This study also examined the safety of nabilone as a treatment for headache and found that patients only experienced mild adverse effects that disappeared after discontinuation of the medication. The results of this study are significant, especially given that MOH is exacerbated by many pharmacological treatments. This study also highlights the potential value of cannabis in combination therapies, as a supplement to traditional treatments, or as a secondary treatment in refractory cases. Currently, a multicenter, double-blind, placebo-controlled study is being performed to examine the safety and efficacy of a dronabinol, or synthetic THC, metered dose inhaler for the treatment of migraine (clincaltrials.gov, NCT Identifier: > NCT00123201). When published, this study could give valuable insights into the efficacy and risks of cannabinoids for the treatment of migraines.
Cannabis and cannabinoids have been studied clinically for other conditions, showing efficacy in the treatment of neuropathic/chronic pain, spasticity, and nausea. 62–66 These three conditions are associated mechanistically and qualitatively with the experience of headache and, although the clinical literature for each of these conditions exceeds the scope of this review, it is plausible that their efficacy will carry over in the treatment of headache disorders as well. For example, the analgesic properties of cannabis seen in the treatment of neuropathic pain will likely apply to chronic headache, the antispasmodic properties seen in the treatment of multiple sclerosis could apply to muscle strain known to induce tension headaches, and the antiemetic properties seen in the treatment of chemotherapy-associated nausea might also palliate migraine-induced nausea.
Many individuals are currently using cannabis for the treatment of migraine and headache with positive results. In a survey of nine California clinics (N=1746), physicians recorded headaches and migraines as a reason for approving a medical marijuana ID card in 2.7% of cases, and 40.7% patients self-reported that cannabis had therapeutic benefits for headaches and migraines. In another California survey of 7525 patients, 8.43% of patients reported that they were using medical cannabis to treat migraines. Another survey of 1430 patients found that 9% of patients were using medical cannabis to treat migraines (subdivided into 7.5% for classical migraines, 1% for cluster headaches, and 0.5% for others). Other studies have reported the use of cannabis for migraine or headache relief, with specific estimates including 5% (N=24,800) and 6.6% (N=128) for migraines and 3.6% (N=128) and 7.4% (N=217) for headache.
Other studies have looked specifically at the change in the occurrence of headache disorders with use of cannabis. 52 One retrospective study described 121 patients who received cannabis for migraine treatment, among whom 85.1% of these patients reported a reduction in migraine frequency. 47 The mean number of migraines at the initial visit was 10.4, falling to 4.6 at follow-up visits after cannabis treatment. Moreover, 11.6% of the patients found that, when smoked, cannabis could effectively arrest the generation of a migraine. These results indicate that cannabis may be an effective treatment option for certain migraine sufferers.
Reports from 139 cluster headache patients 56 indicate that cannabis could have value in treating a portion (25.9%) of these patients as well. However, cannabis was reported to provoke cluster headache attacks in some patients (22.4%) as well. One possible explanation for this provoking effect is that cannabis is known to increase heart rate, increase blood pressure, and cause systemic vasodilation. 67 Cluster headache sufferers seem to be highly sensitive to vasodilation of the carotid tree and increased oxygen demands, findings that are supported by evidence that alcohol is a reliable trigger and supplemental oxygen is an effective abortive therapy. 68 The increased oxygen demand and/or the vasodilation effects of cannabis could theoretically be responsible for this exacerbation in some cluster headache sufferers. Interestingly, cluster headaches appear to show improvement with treatment using hallucinogens such as d-lysergic acid amide (ergine or LSA), psilocybin, and lysergic acid diethylamide (LSD). 33 As such, it is possible that the psychoactive properties of THC could play a role in the treatment of cluster headaches.
Case reports also give insights into the mechanisms behind the anti-headache action of cannabis. Smoking cannabis has been reported to relieve pain associated with pseudotumor cerebri, 57 a condition that is characterized by an increase in the intracranial pressure of an uncertain etiology. This suggests that the therapeutic effect of cannabis in some headache conditions could be a result of reducing intracranial pressure. In fact, dexanabinol, a synthetic cannabinoid, has been found to relieve intracranial pressure and improve outcomes after traumatic brain injury. 69
Cannabinoids and Headache Pathophysiology
The pathophysiological mechanisms of many headache disorders are not entirely understood. Nevertheless, preclinical data examining the effects of endocannabinoids on the neurological and vascular systems demonstrate the influence of endocannabinoids in modulating several major components of migraine pathogenesis ( Table 3 and Fig. 1 ). 35,70–85
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