G Model DAD-4291; No. of Pages 9 ARTICLE IN PRESS Drug and Alcohol Dependence xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Drug and Alcohol Dependence jo urnal homepage: www.elsevier.com/locate/drugalcdep Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers a,∗ b,c a,d Matthew W. Johnson , R. Andrew Sewell , Roland R. Griffiths a Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, MD, United States b Yale University School of Medicine, Department of Psychiatry, New Haven, CT, United States c VA Connecticut Healthcare System, West Haven, CT, United States d Johns Hopkins University School of Medicine, Department of Neuroscience, Baltimore, MD, United States a r t i c l e i n f o a b s t r a c t Article history: Background: Psilocybin is a well-characterized classic hallucinogen (psychedelic) with a long history of Received 26 July 2011 religious use by indigenous cultures, and nonmedical use in modern societies. Although psilocybin is Received in revised form 3 October 2011 structurally related to migraine medications, and case studies suggest that psilocybin may be efficacious Accepted 31 October 2011 in treatment of cluster headache, little is known about the relationship between psilocybin and headache. Available online xxx 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. Keywords: Results: Psilocybin frequently caused headache, the incidence, duration, and severity of which increased Psilocybin Headache in a dose-dependent manner. All headaches had delayed onset, were transient, and lasted no more than a day after psilocybin administration. Cluster headache Migraine Conclusions: Possible mechanisms for these observations are discussed, and include induction of delayed Classic hallucinogen headache through nitric oxide release. These data suggest that headache is an adverse event to be LSD expected with the nonmedical use of psilocybin-containing mushrooms as well as the administration Psychedelic of psilocybin in human research. Headaches were neither severe nor disabling, and should not present a barrier to future psilocybin research. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction (Brandes et al., 2010); in fact, chemist Albert Hofmann discov- ered LSD while searching for novel treatments for migraine, among Psilocybin is a relatively well-characterized hallucinogen that other disorders (Hofmann, 1980). A recent case series also provided has a long history of religious use by indigenous cultures of preliminary evidence that psilocybin and LSD may treat cluster Mesoamerica and South America in the form of Psilocybe mush- headache (Sewell et al., 2006), and evidence suggests that the rooms. These mushrooms have also been used for recreational and non-hallucinogenic LSD analog 2-bromo-LSD (BOL-148) may share spiritual purposes in industrialized societies. Psilocybin exerts its similar efficacy (Sicuteri, 1963; Karst et al., 2010). effects via its active metabolite, psilocin. Psilocybin, like mesca- In a previous study, 36 hallucinogen-naïve volunteers received line from the peyote cactus and lysergic acid diethylamide (LSD), 30 mg/70 kg psilocybin and a comparison drug (40 mg/70 kg is considered a “classic” hallucinogen, producing psychoactive methylphenidate; a psychoactive “active placebo” used to main- effects that are similar and primarily mediated by 5-HT2A recep- tain study blinding) in different sessions (Griffiths et al., 2006, tor agonism. Psilocybin and LSD belong to a subclass of classic 2008). Although reduction or induction of cephalic pain was not hallucinogens that, like the neurotransmitter serotonin, are struc- specifically assessed, it was our impression that more partici- turally based on a tryptamine chemical backbone (Nichols, 2004). pants spontaneously reported headache after psilocybin study days Other tryptamine-based compounds such as sumatriptan and ergo- than after methylphenidate days. Although reports of headache tamine constitute the primary and most effective class of acute following psilocybin use were few, our reliance on spontaneous migraine treatment for migraine and related primary headaches 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 Corresponding author at: Johns Hopkins University, Department of Psychiatry ago, when Prentiss and Morgan reported that one of their experi- and Behavioral Sciences, Behavioral Biology Research Center, 5510 Nathan Shock mental subjects given mescaline experienced a three-day headache Drive, Suite 3000, Baltimore, MD 21224-6823, United States. Tel.: +1 410 550 0056. E-mail address: [email protected] (M.W. Johnson). severe enough to be debilitating on the second day (Prentiss and 0376-8716/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2011.10.029 Please cite this article in press as: Johnson, M.W., et al., Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers. Drug Alcohol Depend. (2011), doi:10.1016/j.drugalcdep.2011.10.029 G Model DAD-4291; No. of Pages 9 ARTICLE IN PRESS 2 M.W. Johnson et al. / Drug and Alcohol Dependence xxx (2011) xxx–xxx Morgan, 1895). Other healthy volunteers reported “persistent ache participants who regularly suffered from migraine or other and feeling of exhaustion in the occipital region, that persisted “essential” (idiopathic or primary) headaches showed increased for several days” (Prentiss and Morgan, 1896). The pharmacol- psychoactive effects from very low doses of psilocybin and ogist Arthur Heffter’s account of his personal experience with LSD compared to age-matched controls (Fanciullacci et al., mescaline on June 5, 1887 reads: “Nausea, occipital headache, 1974). intense dizziness, and clumsiness in moving began about half an In order to more rigorously characterize the headaches that hour after the last dose” (Heffter, 1898). The American neurolo- had been spontaneously reported in the first study, our second gist Weir Mitchell described his own experience with mescaline psilocybin administration study specifically examined this poten- in an 1896 talk to the American Neurological Society as charac- tial side effect. Our informed consent process described headache terized by “left frontal pain (not severe) and soon after a dull on or after the session day as a possible adverse effect of psilocybin occipital ache felt on both sides and at or about the occipital bosses” administration. We explicitly asked participants about headache, (Mitchell, 1896). The headache persisted for two days, prompting and carefully characterized those reported. This study is therefore Mitchell to editorialize that the mescaline experience was “worth the first to prospectively assess the dose-dependent incidence of one such headache. but not worth a second”. The psychologist headache following psilocybin administration. Havelock Ellis also reported a “slight headache which passed off 2. Methods in the course of the morning” in his detailed description of the effects he experienced after taking mescaline. He also reported 2.1. Participants that a poet friend who also took it complained of “a very slight Participants were 10 female and 8 male medically and psychiatrically healthy headache, which came and went” as the only negative side effect volunteers (Griffiths et al., 2011). Only one had previously used hallucinogens; he (Ellis, 1902). had taken psilocybin on two occasions more than 20 years before study screening. The next report of headache from classic hallucinogen use Demographics, including self-reported headache history, are presented in Table 1. came sixty years later, in a report of 16 individual administrations Participants were not paid for participation, and generally reported being moti- of psilocybin (across 13 participants in doses ranging from 5 to vated by curiosity about psilocybin’s effects, altered states of consciousness, and the opportunity for self-reflection. Study conduct, including participant selection, 14 mg). 50% resulted in reports of headache, but further details followed the safety guidelines for human hallucinogen research recommended by were not provided (Delay et al., 1958). Two years later a study our laboratory (Johnson et al., 2008). in which psilocybin was given in doses ranging from 8 to 36 mg reported headache in 5 of 14 volunteers (Malitz et al., 1960). How- 2.2. Procedure ever, Malitz did not characterize the headaches further, or state at Experimental methods, inclusion and exclusion criteria are described in detail what dose they occurred. Another description of psilocybin pub- elsewhere (Griffiths et al., 2011). Psilocybin was administered in doses of 0, 5, 10, 20, lished the same year listed “headache” under “later effects” (i.e., and 30 mg/70 kg in five 8-h drug sessions conducted at approximately one-month more than 12 h post drug administration) but gave no further intervals in a double-blind, crossover design. Psilocybin doses increased sequen- details (Hollister et al., 1960). The same author measured the after tially in nine randomly selected participants and decreased sequentially in the other nine. The single placebo session was intermixed among the four active doses as effects of 37–209 ␮g/kg psilocybin in 17 subjects, and