Psilocybin’s Migraine-Suppressing Effects: An Exploratory Controlled Study

Controlled studies are sparse, although anecdotal data suggest that certain 5-hydroxytryptamine 2A receptor ligands, such as psilocybin, may have long-lasting therapeutic effects after low doses in headache disorders.

According to this experimental article, psilocybin has a long-lasting therapeutic impact on migraine headache after just one dose. An interesting discovery that calls for more research into the mechanism underlying the clinical effects of certain 5-HT2A receptor drugs in migraine and other neuropsychiatric diseases is the distinction between transient psychotropic effects and long-lasting therapeutic effects.

Introduction

With a prevalence of 15%, migraines are one of the most prevalent headache illnesses and is one of the three most incapacitating diseases in the world. There are numerous migraine treatments available, but their ineffectiveness and unfavorable side effects could make them unsuccessful in the long run.

• It has been known for more than 50 years that certain 5-hydroxytryptamine 2A (5-HT2A) receptor agonists, including psilocybin and lysergic acid diethylamide (LSD), may have therapeutic effects on migraine. These specific 5-HT2A agonists are claimed to induce long-lasting decreases in headache load after a single or few oral doses, despite chemically and pharmacologically being identical to other migraine treatments (such as dihydroergotamine (DHE), methysergide).

Even though there isn’t any conclusive research, this clinical effect is fresh and intriguing. The demonstration of such effects in headache disorders would suggest that this distinct benefit of the drug class seen across different diseases is affected through a shared neurobiological mechanism, especially considering numerous controlled studies with specific 5-HT2A agonists in mental health disorders and addiction also suggesting long-lasting therapeutic effects after limited dosing (s).

This exploratory proof-of-concept study used a double-blind, placebo-controlled, cross-over design to examine the effects of psilocybin on migraine. In the controlled experimental context, we anticipated that a single low-dose oral psilocybin treatment would safely reduce migraines over a 2-week period in migraine sufferers. Additionally, we were ready for unexpected results and tried to incorporate all we learned in the planning and creation of subsequent research.

Primary Findings

The change in migraine frequency during the two weeks following medication administration was the main end measure. It was calculated as the variation in weekly migraine days from baseline.

Changes in the frequency of migraine attacks, light and sound sensitivity, motion sickness, and attack-related functional impairment were some other major end measures. Acute changes in vital signs, time until the next migraine episode, general medication effects, psychotropic ratings, and adverse events were some of the secondary end measures.

Two-Weeks Post Administration: Migraine Frequency

After using psilocybin, the weekly migraine days changed much less from their initial value. The percentages of participants who experienced weekly migraine days that were reduced by at least 25%, 50%, and 75% were as follows: 80%, 50%, and 30% after psilocybin, and 20%, 20%, and 0% after placebo, respectively. Significant differences between the placebo and psilocybin were found, with at least a 25% reduction.

Two-Weeks Post Administration: Additional Outcomes

Psilocybin significantly reduced weekly migraine attacks, pain intensity, attack-related functional impairment, and weekly migraine abortive days compared to placebo. There were no appreciable variations in the length of the migraine attacks or the assessments of the accompanying symptoms (photophobia, phonophobia, and nausea/vomiting).

Time-Until-Next Migraine

The intervals between the first and second migraine bouts were timed because psilocybin is known to acutely produce headache attacks. The time to the first attack was statistically inconclusive, however psilocybin significantly increased the time to the second attack compared to placebo.

Discussion

The results of this study confirm anecdotal claims of migraine treatment benefits and add to earlier studies showing long-lasting therapeutic benefits for depression, anxiety, alcoholism, and smoking from psilocybin and other specific 5-HT2A receptor agonists.

To our knowledge, the therapeutic impact shown over a period of two weeks following a single oral drug dose and described in this study is a novel result in the treatment of migraines. Contrary to current preventative migraine medicines, which often require daily administration (like topiramate) or contain medications that stay in the body for a long time after delivery (e.g., anti-calcitonin gene-related peptide or receptor monoclonal antibodies).

Traditional transitional migraine treatments like corticosteroids, which are given orally in pulses of varying duration, and DHE, which is given as a thrice-daily, 5-day intravenous or subcutaneous injection regimen, are both known to have long-lasting clinical effects after relatively minimal drug administration.

Summation

The current study did not discover a correlation between psychotropic effects and the change in migraine frequency over a 2-week period, in contrast to some earlier psilocybin studies for other neuropsychiatric conditions. This finding suggests that the therapeutic effect of psilocybin in migraine is independent of acute changes in sensation and perception. In fact, the study’s participants with the highest 5D-ASC scale scores experienced some of the smallest decreases in migraine burden. These findings are in line with survey studies that found prophylactic treatment for headache disorders with sub-hallucinogenic doses of psilocybin and LSD.

Additionally, 2-bromo-lysergic acid diethylamide (BOL-148 or BOL), a relative of LSD with significantly diminished psychotropic effects, is said to provide medical benefits for cluster headaches as well as other types of headaches. Collectively, these results point to a separation between psilocybin’s short-term psychoactive effects and its long-term therapeutic effects in treating headache problems. This raises the exciting potential that the therapeutic effects of these specific chemicals might not necessitate their eponymous “psychedelic” properties if this is proven.

Future Implications

They have shown migraine-suppressing effects in the two weeks measured following the single administration of a low oral dose in the first controlled study of psilocybin in migraine. The frequency of migraine attacks changed without regard to the immediate psychotropic effects. This exploratory study validates the efficacy of psilocybin as an investigational agent in migraine and demonstrates that low-dose psilocybin can be safely administered orally to migraine patients in the experimental research setting with careful recruitment, screening, preparation, monitoring, and follow-up procedures.

This research also adds a fresh perspective on the special properties of this class of medications in the realm of specific 5-HT2A receptor drugs.

• Although the results of this exploratory trial are encouraging, more controlled studies must be carried out before this strategy can be applied in the clinic to fully comprehend psilocybin’s ability to suppress migraines as well as its long-term safety and tolerability. It will be necessary to duplicate the findings of this study in a bigger sample with a completely randomized design to confirm the current findings.

Studies with a range of doses will show whether psilocybin’s effects on migraine are dose-dependent. The effectiveness of psilocybin as a transitional and/or preventive treatment will be demonstrated by studies examining repeated dosing, either closely spaced apart or separated by predetermined intervals. Studies examining the mechanisms of psilocybin’s effects will provide information on the biological target of this substance and its potential for drug development, including chemical alterations that can minimize unneeded side effects while maximizing reductions in migraine parameters. These studies will be conducted concurrently with clinical investigations.

• For instance, it has been suggested that interactions among serotonin, sigma-1, and toll-like receptors, all of which are connected to migraine, which is a chronic inflammatory condition, are responsible for the immunomodulatory and anti-inflammatory effects shared by these specific 5-HT2A receptor compounds. Sleep and neuroendocrine systems also have a role in the pathogenesis of migraines and the known effects of 5-HT2A receptor agonists.