Cannabinoids and Psychedelics for Headache Management

People with headache disorders that persist despite treatment with available medications may attempt self-treatment using alternative substances. Secondary plant metabolites have established biological activity and molecular mechanisms. Among these are cannabis and typical and atypical psychedelics (Figure). This article will cover 2 plants with therapeutic potential for migraine that are US Drug Enforcement Agency (DEA) Schedule 1 drugs: cannabis and psilocybin. We will also discuss ketamine, a dissociative anesthetic.

Cannabis

The plant cannabinoid Delta-9-tetrahydrocannabinol (THC) has analgesic, antiemetic, and anti-inflammatory potential. Preclinical studies have found that the endocannabinoid anandamide and the phytocannabinoid THC have effects on structures and processes involved with migraine pathogenesis, including inhibition of the trigeminovascular system and cortical spreading depression.^1-3 Cannabis has long been used to treat migraine, with Sir William Osler, a founder of the discipline of internal medicine, writing that cannabis was “probably the most satisfactory remedy” for migraine.⁴ Retrospective and survey studies suggested that cannabis may have benefits for preventive and acute treatment of migraine. A cross-sectional survey of medical cannabis users in Israel reported that among those self-treating migraine with cannabis, 61% reported a greater than 50% reduction in monthly migraine attacks.⁵ A retrospective chart review from 2 cannabis specialty clinics revealed a decrease in migraine frequency from 10.4 to 4.6 episodes per month (P<.0001).⁶ An observational study using real-time (app-collected) data from cannabis users revealed migraine pain benefit at 2 hours after inhalation of cannabis, with a mean reduction of 3.3 points on a 0- to 10-point scale.⁷

Data from randomized controlled trials (RCTs) of cannabis for headache are limited. Oral nabilone (synthetic THC) 0.5 mg/day was compared with ibuprofen (400 mg) for the treatment of medication overuse headache.⁸ Nabilone was found to be safe and well-tolerated and was more effective than ibuprofen. Results from the first RCT of vaporized cannabis for the acute treatment of migraine presented at the 2023 American Headache Society annual scientific meeting revealed positive 2-hour results from THC 6% + CBD 11% vs placebo.⁹ Inhalation delivers cannabinoids more rapidly to the brain compared with oral administration. No RCTs have been performed to study cannabis for migraine prevention, and additional studies are needed to evaluate whether cannabis use contributes to medication overuse headache in some individuals.⁶ Well-designed studies are needed to evaluate the benefits and risks of cannabinoid use for acute and preventive migraine treatment.

Psilocybin

Psilocybe is a genus of mushroom (“magic mushrooms”) that grows worldwide and contains the active ingredient psilocybin, an indole amine, responsible for its psychedelic, or hallucinogenic, effects.¹⁰ Activity at the 5-HT receptor family is reported, with highest affinities at receptors 7, 2B, 1D, 5, and 2C.^11,12 Serotonin signaling may beneficially affect neuroplasticity in the setting of pain, and additional details regarding this pathway may be found elsewhere.^17-19 Among the first reports of the analgesic potential of psychedelics in 1896,¹⁴ a tincture of mescaline was reported to be effective for “nervous headache,” and in 1964,¹³ lysergic acid diethylamide (LSD) was reputed to alter pain perception and attention. People with uncontrolled cluster headache and migraine have reported using psychedelic substances with success as detailed in a qualitative inquiry on this topic.^15,16 These reports have led to survey studies followed by placebo-controlled studies evaluating the efficacy of psilocybin for migraine and cluster headache prevention.

Sewell et al²⁰ administered a standardized questionnaire to 53 people with cluster headache self-treating with psilocybin or LSD who were identified through cluster headache support groups and an online survey. Twenty-two of 26 psilocybin users reported that psilocybin aborted cluster headache attacks, 25 of 48 psilocybin users reported cluster period termination, and 18 of 19 psilocybin users reported extension of the remission period. A more recent survey studied 170 individuals with any of 5 painful disorders, including 63 participants with migraine and 44 participants with tension headache (no individuals with cluster headache were included in this study), who used psilocybin microdose (15.4%), full dose (9.2%), or both (74%).²¹ Self-reported effects included same-day pain reduction (33%) and benefits beyond day 3 with full doses (19%). Full dose had more significant benefit (P<.001) than microdose; microdose had significantly better effect than conventional medications (P<.005). A microdose of psilocybin is defined as 1/10th to 1/20th of a recreational or macrodose (or full dose) and does not result in alteration of consciousness. Macrodose is intended to induce a non-ordinary consciousness state and has been linked to alterations in functional connectivity in brain regions associated with pain processing.

Cluster Headache Prevention

The therapeutic effects of psilocybin on primary headache disorders have been studied recently in RCTs for cluster headache and migraine.

Psilocybin has received much interest as a treatment for cluster headache given unmet need, especially for individuals with chronic cluster headache.²² Fourteen participants with cluster headache were enrolled in an exploratory, randomized, double-blind, placebo-controlled trial of psilocybin (0.143 mg/kg) vs placebo over 3 experimental sessions for the treatment of cluster headache.²³ Eight participants received psilocybin and 6 received placebo. Despite the finding of a moderate effect size and a reduction in frequency of cluster headache attacks (which was greater in those with chronic vs episodic attacks), there were no significant differences on attack duration, pain severity, or frequency.

A feasibility study for the prophylactic effects of psilocybin in individuals with chronic cluster headache in an open-label clinical trial of 10 individuals over 10 weeks was reported.²⁴ Functional connectivity was measured using functional MRI the day before the first dose (.14 mg/kg) and 1 week after the final dose (3 doses total in weeks 5, 6, and 7 of the study). Results included a significant average reduction of 3.6 attacks per week comparing baseline (the first 4 weeks of the study) with 4-week follow-up, a 31% change across participants. Functional MRI demonstrated changes in hypothalamic connectivity associated with regions of the diencephalic cluster, but there was no significant association with these measured changes and the frequency of chronic cluster headaches.

These findings, plus the lack of substantial adverse effects and unmet need for individuals with cluster headache, warrant further research in larger studies.

Migraine Prevention

In an exploratory, double-blind, placebo-controlled, crossover study, participants with chronic migraine received a single oral dose of synthetic psilocybin (0.143 mg/kg [approximately 10 mg for a 65-kg individual]; n=10). Psilocybin was well-tolerated and resulted in a significant reduction in migraine frequency per week (P=.004), pain severity, functional impairment, and weekly migraine abortive medication use days compared with placebo.²⁵ Adverse effects of nausea, lightheadedness, and anxiety were found to be self-limiting and transient. A study assessing repeat dosing of 10 mg of psilocybin compared with placebo (25 mg diphenhydramine) in migraine was completed recently (results are not yet published).²⁶

There are concerns about drug–drug interactions between psilocybin and serotonergic drugs. In studies by Schindler et al,^23,25 participants were required to have discontinued serotonergic antidepressants for at least 6 weeks, serotonergic antiemetics for at least 2 weeks, vasoconstrictive medications for at least 5 elimination half-lives, and triptans no more than twice weekly, and not within 5 half-lives before psilocybin administration and not for 5 psilocybin half-lives (15 hours) after psilocybin administration.

Ketamine

Ketamine is a dissociative anesthetic that has been used since the 1960s for depression and pain management that has a rapid onset and fast recovery time. As an anesthetic, its effects are characterized by amnesia, analgesia, and catatonia with or without actual loss of consciousness. The mechanism of action is attributed to NMDA receptor antagonism, inhibiting glutamatergic signaling. Intranasal Spravato (esketamine; Janssen Pharmaceuticals, Raritan, NJ) has been approved by the Food and Drug Administration for treatment-resistant depression.

A systematic review considered the efficacy of subdissociative and subanesthetic doses of ketamine for treatment of headache or migraine, including 5 articles in a qualitative synthesis and 3 for meta-analysis.²⁷ Quality of the evidence was low (grade 1), and the researchers failed to find a consistent significant benefit of ketamine compared with placebo, concluding that benefits of ketamine in management of headache are unclear. There was a suggestion that intramuscular administration may be more effective than oral intake. A recently published retrospective study by Yuan et al²⁸ studied 242 individuals with refractory chronic migraine treated with intranasal ketamine at a tertiary headache center. Intranasal ketamine was used for a median of 10 spray use days per month, with an average of 6 to 8 sprays per day (10 mg per 0.1 mL; 1 to 2 sprays per each nostril). Intranasal ketamine was reported by 49.1% of participants to be “very effective” and quality of life in 35.5% was reported to be “much better.” Overall, use of intranasal ketamine was found to reduce headache intensity, but 74% of participants reported experiencing adverse events, although none was serious. Well-designed placebo-controlled trials are needed to evaluate the efficacy, safety, and optimal dosing of ketamine for acute or preventive treatment of refractory chronic migraine.

Conclusion

Some individuals with migraine or cluster headache self-treat with cannabis or psychedelics. Results from survey studies have led to RCTs of cannabis for acute migraine and psilocybin for migraine and cluster headache prevention. Cannabis is available medically or for recreational use in 38 US states and the District of Columbia. Psilocybin has been decriminalized in select cities since 2019, and Oregon and Colorado passed ballot measures for statewide decriminalization in 2020 and 2022. Psychedelic practitioners (licensed or not) are using encrypted messaging platforms to distribute information about their practices and educate individuals on how to obtain psychedelic substances. Ketamine is a prescription drug that is administered intravenously in ketamine clinics to treat chronic pain and psychiatric disorders, and retrospective evidence suggests that intranasal ketamine may be useful for the treatment of refractory chronic migraine. The availability of all 3 therapies has expanded in recent years, and regulations around their use continues to evolve across the United States. Neurologists treating individuals with headache disorders should familiarize themselves with the emerging literature around cannabis, psilocybin, and ketamine for headache treatment to inform their counseling of individuals who are self-treating with such treatments or interested in trying them for refractory presentations of migraine or cluster headache.