Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers, Matthew W. Johnson et al., 2012

Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers

Matthew W. Johnson, R. Andrew Sewell, and Roland R. Griffiths

Drug and Alcohol Dependence, 2012, 123, (1-3), 132–140.

doi: 10.1016/j.drugalcdep.2011.10.029



Background—Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious in treatment of cluster headache, little is known about the relationship between psilocybin and headache.
Methods—This double-blind study examined a broad range of psilocybin doses (0, 5, 10, 20, and 30 mg/70 kg) on headache in 18 healthy participants.
Results—Psilocybin frequently caused headache, the incidence, duration, and severity of which increased in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration.
Conclusions—Possible mechanisms for these observations are discussed, and include induction of delayed headache through nitric oxide release. These data suggest that headache is an adverse event to be expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research.

Keywords : psilocybin; headache; cluster headache; migraine; classic hallucinogen; LSD; psychedelic


1. Introduction

Psilocybin is a relatively well-characterized hallucinogen that has a long history of religious use by indigenous cultures of Mesoamerica and South America in the form of Psilocybe mushrooms. These mushrooms have also been used for recreational and spiritual purposes in industrialized societies. Psilocybin exerts its effects via its active metabolite, psilocin. Psilocybin, like mescaline from the peyote cactus and lysergic acid diethylamide (LSD), is considered a “classic” hallucinogen, producing psychoactive effects that are similar and primarily mediated by 5-HT2A receptor agonism. Psilocybin and LSD belong to a subclass of classic hallucinogens that, like the neurotransmitter serotonin, are structurally based on a tryptamine chemical backbone (Nichols, 2004). Other tryptamine-based compounds such as sumatriptan and ergotamine constitute the primary and most effective class of acute migraine treatment for migraine and related primary headaches (Brandes et al., 2010); in fact, chemist Albert Hofmann discovered LSD while searching for novel treatments for migraine, among other disorders (Hofmann, 1980). A recent case series also provided preliminary evidence that psilocybin and LSD may treat cluster headache (Sewell et al., 2006), and evidence suggests that the non-hallucinogenic LSD analog 2-bromo-LSD (BOL-148) may share similar efficacy (Sicuteri, 1963; Karst et al., 2010).

In a previous study, 36 hallucinogen-naïve volunteers received 30 mg/70 kg psilocybin and a comparison drug (40 mg/70 kg methylphenidate; a psychoactive “active placebo” used to maintain study blinding) in different sessions (Griffiths et al., 2006; Griffiths et al., 2008). Although reduction or induction of cephalic pain was not specifically assessed, it was our impression that more participants spontaneously reported headache after psilocybin study days than after methylphenidate days. Although reports of headache following psilocybin use were few, our reliance on spontaneous self-report likely underestimated the true incidence. A subsequent literature search uncovered several reports of headache following classic hallucinogen use.

The first such report came nearly a hundred and twenty years ago, when Prentiss and Morgan reported that one of their experimental subjects given mescaline experienced a three-day headache severe enough to be debilitating on the second day (Prentiss and Morgan, 1895). Other healthy volunteers reported “persistent ache and feeling of exhaustion in the occipital region, that persisted for several days” (Prentiss and Morgan, 1896). The pharmacologist Arthur Heffter’s account of his personal experience with mescaline on June 5, 1887 reads: “Nausea, occipital headache, intense dizziness, and clumsiness in moving began about half an hour after the last dose” (Heffter, 1898). The American neurologist Weir Mitchell described his own experience with mescaline in an 1896 talk to the American Neurological Society as characterized by “left frontal pain (not severe) and soon after a dull occipital ache felt on both sides and at or about the occipital bosses” (Mitchell, 1896). The headache persisted for two days, prompting Mitchell to editorialize that the mescaline experience was “worth one such headache… but not worth a second.” The psychologist Havelock Ellis also reported a “slight headache which passed off in the course of the morning” in his detailed description of the effects he experienced after taking mescaline. He also reported that a poet friend who also took it complained of “a very slight headache, which came and went” as the only negative side effect (Ellis, 1902).