While clinical psychedelic research largely utilizes a psychotherapeutic framework and implicates a role for acute psychedelic effects, several lines of evidence suggest that the benefits of the drug class in headache disorders stem from direct action on the neurological condition itself (i.e., migraine, cluster headache). Recognition of distinct therapeutic frameworks is still lacking, however, which hinders the advancement of psychedelic medicine.

In three clinical trials of psilocybin in migraine (n=10) and cluster headache (n=24) carried out by the authors, subjects maintained headache diaries, rated acute psychedelic effects (5 dimensional altered states of consciousness [5D-ASC] scale), and completed the Centers for Disease Control Health-related Quality of Life questionnaire, which begins with a ‘general health’ rating and includes questions related to mental health (poor mental health, depression, anxiety, poor sleep). In a secondary analysis, pooled outcomes were compared between placebo and psilocybin groups (ANOVA), and correlations with headache frequency carried out (Spearman rank).

The percent total 5D-ASC score was not correlated with change in headache frequency after drug administration (p=0.453). ‘General health’ was the only rating with significant group x time interaction (p=0.016), with post-hoc analysis showing worsening after placebo (p=0.037) and non-significant improvement after psilocybin (p=0.167). There was no correlation between change in ‘general health,’ or any mental health rating, and headache frequency change after drug administration.

In these preliminary migraine and cluster headache clinical trials, headache frequency changes after psilocybin administration were independent from either acute psychedelic effects or measures of mental health. Further rigorous scientific investigation of psilocybin in headache disorders is needed, though must incorporate thoughtful designs and outcomes that are relevant for the disorder and patient population being examined.