Response of cluster headache to psilocybin and LSD

Cluster headache is described as an intensely painful primary headache disorder that predominantly affects men and typically begins after age 20. The condition occurs in episodic and chronic forms: episodic cluster headache arises in discrete periods of attacks separated by pain-free remissions, whereas chronic cluster headache features attacks continuing for more than one year without remissions longer than one month. Acute treatments such as high-flow oxygen and subcutaneous sumatriptan are standard for aborting individual attacks, and prophylactic agents including verapamil, lithium and corticosteroids are used to suppress attacks during cluster periods. However, no medications had been reported to reliably terminate an ongoing cluster period or to extend remission periods prior to this study. Sewell and colleagues report a case-series investigation prompted by a patient’s account that recreational use of LSD and later psilocybin produced lasting remissions of his episodic cluster periods. The study aimed to characterise the experiences of people with cluster headache who had used psilocybin-containing mushrooms or LSD specifically to treat their condition, focusing on three outcomes: aborting individual attacks, terminating cluster periods, and extending remission periods. The investigators collected structured self-reports from a sample of confirmed cluster headache patients to explore whether these substances showed signals of efficacy that might merit further research.

The study used a case-series design based on a standardised questionnaire administered to individuals who reported using psilocybin or LSD to treat cluster headache. Participants were recruited via cluster headache support groups and an Internet-based survey after an initial motivating case was identified. The protocol and consent were approved by the McLean Hospital institutional review board. Inclusion required that subjects 1) agreed to be contacted for telephone or e-mail evaluation and 2) met International Classification of Headache Disorders-2 criteria for cluster headache, with medical-record documentation of diagnosis by an MD or DO; participants whose records did not support the diagnosis were excluded. The final analysed sample comprised 53 individuals from the United States, Great Britain, The Netherlands and South Africa. The extracted text does not present a detailed age distribution but notes no significant sex differences on demographic indices or headache features. Data were principally retrospective self-reports of three outcome domains: aborting an attack (operationalised as ending the attack within 20 minutes), terminating a cluster period (prophylactic use resulting in total cessation of attacks during a cluster period), and extending a remission period (delay or prevention of the next expected cluster period). Some respondents reported route and dosing details: several episodic users took sublingual psilocybin for acute attacks, and a minority used subhallucinogenic doses of LSD or psilocybin. If medical records failed to confirm the diagnosis, subjects were excluded. The investigators also noted that six participants provided headache diaries that corroborated recall, and three participants tried psilocybin for the first time after consent but before interview, yielding prospective reports; nine additional psilocybin users and two LSD users had taken drugs for remission extension but were not yet due for another cluster period, so efficacy for them could not be scored. No controlled or blinded procedures were used; analysis consisted of descriptive tabulation of reported responses. The extracted text does not describe inferential statistical testing beyond reporting counts and percentages.

Fifty-three subjects meeting diagnostic confirmation were included. Thirty-two had episodic cluster headache and 21 had chronic cluster headache. Thirty-one (58%) reported they had never used psilocybin or LSD except to treat their cluster headache, and a further 13 (25%) had only remote adolescent recreational use. Episodic cluster headache: Of the 32 episodic subjects, 19 had used sublingual psilocybin during acute attacks; 17 of these 19 reported that psilocybin aborted attacks when defined as ending the attack within 20 minutes. Only one subject reported using sublingual LSD for an acute attack and described it as effective. Twenty-nine episodic subjects used psilocybin prophylactically during a cluster period: 15 (52%) reported total cessation of attacks (cluster period termination), and a further 12 (41%) reported partial efficacy (reduced intensity or frequency but not complete cessation). Among six episodic LSD users who used it prophylactically, five reported cluster period termination. Twenty episodic subjects ingested psilocybin during a remission period; 19 reported extension of the remission (delay or prevention of the next expected cluster period). Four of five subjects reported similar remission extension with LSD. Chronic cluster headache: Among the 21 chronic subjects, seven had used psilocybin acutely and five of those seven reported that psilocybin aborted a cluster attack. Twenty chronic subjects used psilocybin prophylactically: 10 of 20 reported complete termination of cluster attacks and an additional eight reported partial efficacy. Two chronic patients used LSD at subhallucinogenic doses; one reported no attacks for 10 days and the other reported no attacks for 2 months. Subhallucinogenic dosing and corroboration: Overall, 22 (42%) of the 53 subjects reported partial or complete efficacy from subhallucinogenic doses of psilocybin or LSD. Six participants (11%) provided detailed headache diaries that corroborated their retrospective reports. Three participants tried psilocybin for the first time after consenting but before being questioned; two reported complete efficacy and one reported partial efficacy, a prospective response pattern consistent with the retrospective reports. Nine additional individuals who had taken psilocybin and two additional who had taken LSD for remission extension were not yet due for a cluster period at evaluation and so could not be scored for efficacy.

Sewell and colleagues interpret their findings as notable for three main reasons. First, they report that participants described termination of cluster periods, an effect not previously attributed to any medication. Second, the investigators emphasise that a single dose of LSD was described by some subjects as sufficient to induce remission and that psilocybin rarely required more than three doses, which contrasts with other ergot-derived medications that require daily dosing. Third, because many respondents reported benefit from subhallucinogenic doses, the authors suggest the mechanism of action might be unrelated to the classic psychoactive effects of these compounds. The authors acknowledge several important limitations. The study relies mainly on retrospective self-report and is therefore subject to recall bias, although six participants supplied headache diaries that corroborated aspects of recall. Selection bias is possible because recruitment via support groups and the Internet may attract younger, more educated and more motivated individuals and those with positive outcomes; participants with good responses may have been more likely to come forward. Lack of blinding and the uncontrolled design raise the possibility of placebo effects, but the investigators note that cluster headache has shown very low placebo responses in controlled trials of both prophylactic and abortive medications and argue it is unlikely that placebo alone would account for the large number of reported responses. Sewell and colleagues emphasise that the uncontrolled, unblinded nature of the series likely leads to overestimation of efficacy and therefore their observations should be regarded as preliminary and not an endorsement of self-treatment with illegal substances. On balance, the authors conclude that given the high reported rates of benefit in this refractory condition and the signal observed even at subhallucinogenic doses, further controlled research into psilocybin and LSD as treatments for cluster headache is warranted.