While anecdotal evidence suggests that select 5-hydroxytryptamine 2A receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking.
This exploratory article suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions.
Migraine is one of the most common headache disorders with a prevalence of approximately 15% and is among the top three disabling diseases worldwide. A range of treatment options for migraine exists, though limited efficacy and unpleasant side effects may preclude long-term success. Evidence suggesting that select 5-hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin and lysergic acid diethylamide (LSD), have clinical effects in migraine has existed for over half a century. While chemically and pharmacologically similar to other migraine medications (e.g., dihydroergotamine (DHE), methysergide), these particular 5-HT2A agonists are reported to produce long-lasting reductions in headache burden after a single or few oral doses. Such a clinical effect is novel and intriguing, though definitive studies are lacking. In the setting of numerous controlled studies with select 5-HT2A agonists in mental health disorders and addiction also suggesting long-lasting therapeutic effects after limited dosing, the demonstration of such effects in headache disorders would suggest that this unique benefit of the drug class seen among different diseases is effected through a shared neurobiological mechanism(s).
The goal of this exploratory, proof-of-concept study was to investigate the effects of psilocybin in migraine in a double-blind, placebo-controlled, cross-over design. We hypothesized that a single administration of low-dose oral psilocybin in migraine patients would suppress migraine over a 2-week period and be safe in the controlled experimental setting. We were also prepared for unanticipated findings and sought to use all information learned in the design and development of future studies.
1.2 Outcome Measures
The primary outcome measure was the change in migraine frequency, measured as the change in weekly migraine days compared to baseline in the 2 weeks after drug administration. Other primary outcome measures included change in weekly migraine attacks, light sensitivity, sound sensitivity, nausea/vomiting, and attack-related functional impairment in the 2 weeks after drug administration. Secondary outcome measures included change in the use of migraine abortive(s), time to the next migraine attack, acute changes in vital signs, general drug effects, psychotropic ratings, and adverse events.
1.3 Findings & Outcomes Two-Weeks Post Drug Administration
The change from baseline in weekly migraine days showed a significantly greater reduction after psilocybin. The percentages of subjects who had at least 25%, 50%, and 75% reductions in weekly migraine days were as follows: 80%, 50%, 30% after psilocybin, and 20%, 20%, 0% after placebo, respectively. Psilocybin and placebo significantly differed at the level of at least 25% reduction.
Other Migraine Outcomes
Reductions from baseline were significantly greater after psilocybin compared to placebo in weekly migraine attacks, pain severity, attack-related functional impairment, and weekly migraine abortive days. There were no significant differences on migraine attack duration or associated symptom (photophobia, phonophobia, nausea/vomiting) ratings.
Time to Next Migraine Attacks
Given that psilocybin is known to acutely induce headache attacks, the times to both the first and second migraine attack were measured. The time to the first attack was statistically equivocal, but the time to the second attack was significantly greater after psilocybin, relative to placebo.
The findings from this study validate the previous anecdotal reports of therapeutic effects in migraine and complement research in past decades with psilocybin and other select 5-HT2A receptor agonists demonstrating lasting beneficial effects in treating depression, anxiety, alcohol addiction and cigarette smoking.
To our knowledge, the therapeutic effect over 2 weeks after the single administration of an oral agent reported in this study is a novel finding in migraine therapy. This contrasts with existing preventive migraine therapies that necessitate repeated, daily administration (e.g., topiramate) or include treatments that remain in the body long after administration (e.g., anti-calcitonin gene-related peptide or receptor monoclonal antibodies). Lasting clinical effects after relatively limited drug administration are seen with such conventional transitional migraine treatments as corticosteroids, which are administered in oral pulses of various duration, and DHE, which is administered as a thrice daily, 5-day intravenous or subcutaneous injection regimen. It is notable that DHE also has agonist activity at the 5-HT2A receptor, in addition to several other receptors. Whether a shared mechanism of action in migraine exists between psilocybin and DHE or psilocybin and corticosteroids will require further study.
- In contrast to some previous psilocybin studies for other neuropsychiatric conditions, the current study did not find that psychotropic effects correlated with the migraine frequency change over 2 weeks, suggesting that the therapeutic effect of psilocybin in migraine is independent of acute changes in sensation and perception. In fact, subjects in the present study with the highest 5D-ASC scale scores had some of the smallest reductions in migraine burden. These observations are consistent with survey studies reporting that sub-hallucinogenic doses of psilocybin and LSD provide prophylactic relief in headache disorders.
- Furthermore, a relative of LSD, 2-bromo-lysergic acid diethylamide (BOL-148 or BOL), which has greatly reduced psychotropic effects, is also reported to have medicinal effects in cluster and other headache disorders. Collectively, these findings suggest dissociation between the acute psychotropic effects and the sustained therapeutic action of psilocybin and other select 5-HT2A receptor compounds in headache disorders. If confirmed, this raises the intriguing possibility that the therapeutic effects of these particular compounds may not require their namesake “psychedelic” effects.
While encouraged by the findings in this exploratory study, before this approach could be used clinically, it is imperative that additional controlled investigations be completed in order to understand psilocybin’s full capacity to suppress migraine, as well as its long-term safety and tolerability. To verify the present findings, it will be necessary to replicate the results of this study in a larger sample under a fully randomized design. Studies with a dose range will inform on whether the effects of psilocybin in migraine are dose dependent. Studies investigating repeated administration either in close succession or separated by specified intervals will help illustrate psilocybin’s abilities as a transitional and/or preventive treatment. In parallel with clinical investigations, studies determining the mechanisms of psilocybin’s effects will inform on the biological target of this agent and potential for drug development, including chemical modifications that can minimize unnecessary effects while maximizing reductions in migraine parameters. For instance, it has been proposed that the immunomodulatory and anti-inflammatory effects common to these select 5-HT2A receptor compounds involve interactions among serotonin, sigma-1, and toll-like receptors, all of which are implicated in migraine, itself a chronic inflammatory condition. Neuroendocrine systems and sleep also underlie both migraine pathophysiology and the known actions of 5-HT2A receptor compounds.
In the first controlled investigation of psilocybin in migraine, we have demonstrated migraine-suppressing effects in the 2 weeks measured after the single administration of a low oral dose. The change in migraine frequency was independent from acute psychotropic effects. This exploratory study supports the viability of psilocybin as an investigational agent in migraine and shows that with careful recruitment, screening, preparatory, monitoring, and follow-up procedures, low-dose psilocybin can safely be administered orally to migraine patients in the experimental research setting. This study also represents a new arm in the field of select 5-HT2A receptor compounds, offering a new perspective on the unique abilities of this drug class.