The Use of Marijuana or Synthetic Cannabinoids for the Treatment of Headache

Uri Napchan, MD; Dawn C. Buse, PhD; Elizabeth W. Loder, MD, MPH

Disclosures

Headache. 2011;51(3):502-505. 

In This Article

Commentary

Cannabis, also known as "marijuana," refers to any preparation of the cannabis plant, most of which are intended for use as a psychoactive substance. The major psychoactive compound in cannabis is Δ9-tetrayhydrocannabinol (THC), which has partial agonist activity at the 2 known cannabinoid receptors in humans – CB1 and CB2. CB1 receptors are principally located on peripheral and central nerve terminals, while CB2 receptors are mainly expressed in peripheral tissues. A variety of endogenous and exogenous compounds exist that may have agonist, antagonist, or mixed effects on these receptors. Anandamide and 2-arachidonoyl glycerol, for example, are endogenous compounds with activity at both CB1 and CB2 receptors.[1,2] CB1 and CB2 receptors and naturally occurring cannabinoids are sometimes referred to as the "endocannabinoid system." THC and the synthetic cannabinoid drug dronabinol also are both active at the CB1 and CB2 receptors. The Table summarizes the location and characteristics of cannabinoid receptors in humans.

Although marijuana is principally used as a psychoactive substance, it has also been used for medical and religious purposes for over 2000 years.[3] A recent systematic review and meta-analysis summarized existing evidence regarding the use of cannabis for the treatment of chronic pain. This review concluded that there was evidence of a positive and moderate short-term trend toward a reduction of pain.[4] However, the authors found a high number of central nervous system adverse events that could partially or completely offset any reduction in pain.

In the USA, marijuana is currently classified as a Schedule I substance by the Drug Enforcement Administration (DEA). The DEA maintains that marijuana meets the 3 criteria required for placement in the Schedule I category – (1) high potential for abuse, (2) no current accepted medical use, and (3) lack of accepted safety for use under medical supervision. However, voters in a number of US states have approved the use of medical marijuana for specific diseases, even though the medical value of marijuana for many conditions is a matter of dispute among experts.[5]

There are a number of reasons why naturally occurring cannabis or cannabinoid drugs might have a pharmacologic effect on headache. Cannabinoids are active in areas of the brain known to be involved in migraine pathophysiology, including areas suspected of being involved in the generation of migraine. The endogenous compound anandamide appears to modulate pain signaling in the central nervous system. It also potentiates 5-HT1A and inhibits 5-HT2A receptors, so effects on serotonergic pain transmission also may be involved in any therapeutic effects on headache.[6]

It has been suggested that one explanation for migraine and other headache disorders, at least in some patients, may be an underlying endocannabinoid deficiency.[6] Levels of anadamide are decreased in the cerebrospinal fluid of individuals with chronic migraine compared with normal controls.[7] Because experimental data suggest that endocannabinoids may have anti-nociceptive action by modulating the trigeminovascular system,[8] these low levels imply that depletion of anadamide may reflect increased activation of the trigeminal vascular system and play a role in more frequent migraine attacks. Cannabinoid receptors have been found in several areas of the brain identified as potential migraine generators. These include the periacqueductal gray matter, rostral medulla, and nucleus trigeminal caudalis.[9,10] Anandamide was also found to attenuate neurogenic, calcitonin gene-related peptide, and nitric oxide-induced dural vasodilation.[2] Cannabinoids may also exert an effect on headache through mechanisms that do not involve cannabinoid receptors, for example through effects on glutamatergic or other systems. Anandamide, for example, has been shown to activate the transient receptor potential vanilloid receptor (TRPV1) on trigeminal ganglion neurons and affect the release of calcitonin gene-related peptide.[11]

At present, there are few published reports in the medical literature regarding the possible therapeutic benefits of naturally occurring cannabis or cannabinoid drugs such as dronabinol for the treatment of migraine, cluster headache, or other headache types. Robbins et al. reported a case study of an individual with chronic cluster headaches whose attacks were unresponsive to multiple trials of acute and preventative treatments. This patient reported that cluster headache attacks were relieved within 5 minutes by the inhalation of marijuana. Subsequent treatment with dronabinol 5 mg orally also provided the patient relief within 15 minutes.

An older report by Schnelle et al. presented data from 128 subjects who completed an anonymous survey on the use of cannabis and cannabis products for the treatment of a wide variety of medical conditions, many of which involve pain or other chronic symptoms; 6.6% reported the use of cannabis for the treatment of migraine and 3.6% for headache. Of participants, 72.2% reported that symptoms were "much improved" after using cannabis, 60.8% reported that they were "very satisfied" with the therapeutic use, and 70.8% reported that they did not experience any side effects but the remainder experienced moderate or severe side effects.

The 2 studies discussed above both suggest benefits of cannabis use for several headache types based upon subjective patient self-report. However, a PubMed search using the terms "headache," "cannabis," and "cannabinoids" did not identify any methodologically rigorous studies that support a possible benefit of cannabis or cannabinoids in the treatment of primary headache disorder. Despite the paucity of high-quality evidence, a possible benefit of cannabis for headache is plausible given our understanding of its mechanism of action.

A recent survey of 113 patients with chronic cluster headaches in France found that 26% regularly consumed cannabis, although no data are available on whether cannabis was used for treatment of cluster headache or for recreational reasons.[12] This is a much higher percentage than the overall rate of marijuana use in the USA, which was found to be 6.6% among those aged 12 or older in 2009.[13] It is unclear whether this is due to cultural differences or whether individuals with cluster headaches are more likely to use marijuana for other reasons.

A higher level of marijuana use in cluster headache sufferers would not be surprising, however, because cluster headache sufferers are more likely than the general population to use other substances. For example, the majority of individuals with cluster headaches are current or ex-cigarette smokers.[14,15] However, unlike tobacco use, the use of marijuana in individuals with cluster headache may potentially have a therapeutic effect, as suggested the Robbins et al. case report. This might explain any higher prevalence of marijuana use in individuals with cluster headaches compared with non-sufferers. In addition, patients with cluster headaches report feeling "restless" during an attack,[14,15] and cannabis use may induce a sense of well-being and relaxation which may ameliorate symptoms of an attack. Somewhat paradoxically, cannabis has also been suggested as a possible trigger for cluster attacks, although evidence for this is much less firm than that for alcohol, nitroglycerin,[16] and histamine.[17] The potential mechanism of any such action is not clear. It is difficult to distinguish cause and effect in these reports, because patients may be using cannabis early in an attack to relieve feelings of dread or anxiety.

In summary, a small number of case reports and survey studies suggest a possible benefit of cannabis for the treatment of acute headache. Such benefit is plausible in view of the pharmacological effects of THC and synthetic cannabinoids. Methodologically rigorous studies to support this view, however, are lacking. Further research in this area seems warranted, especially as more US states legalize the use of marijuana for medical purposes. Novel compounds with cannabinoid-like mechanisms of action may hold promise for patients with headaches that are refractory to currently available treatment options. It will be important to carefully quantify the harm to benefit balance of such treatments. Many potential users are young people, including women of childbearing potential, and the primary headache disorders are conditions of long duration. Such treatments must be held to the same standards of proof applied to other pharmacological interventions for headache. At present, it is premature to make strong clinical recommendations for the use of marijuana or cannabinoid drugs for headache disorders.

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