Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
January 1, 2021
Emmanuelle A. D. Schindler, R Andrew Sewell, Christopher Gottschalk et al.
138 citations
In a small exploratory double-blind, placebo-controlled, cross-over study, ten adults with migraine received a single oral dose of psilocybin (0.143 mg/kg) or placebo, with sessions two weeks apart. Over the two weeks following administration, psilocybin reduced weekly migraine days by an average of 1.65 days (95% CI: -2.53 to -0.77), significantly more than placebo, which reduced them by 0.15 days (95% CI: -1.13 to 0.83). The reduction in migraine frequency was not linked to the intensity of acute psychedelic effects. Psilocybin was well-tolerated with no serious adverse events. The findings suggest a lasting therapeutic benefit from a single dose, independent of acute psychological effects.
Journal of Psychoactive Drugs
October 20, 2015
Emmanuelle A. D. Schindler, Christopher Gottschalk, Marsha J. Weil et al.
104 citations
Cluster headache is one of the most debilitating pain syndromes, and many patients do not respond to standard treatments. A survey of 496 people with cluster headache, recruited from websites and clinics, found that the indoleamine hallucinogens psilocybin, lysergic acid diethylamide, and lysergic acid amide were rated as comparable to or more effective than most conventional medications for aborting attacks and preventing them. These substances were also perceived to shorten or abort a cluster period and bring chronic cluster headache into remission more often than conventional medications. Even infrequent, non-hallucinogenic doses were reported as effective. The findings reinforce the need for further controlled studies of these compounds.
Headache The Journal of Head and Face Pain
November 1, 2022
Christina Luddy, Yutong Zhu, Hayley Lindsey et al.
75 citations
In an exploratory randomized, double-blind, placebo-controlled trial, a pulse regimen of three doses of psilocybin (0.143 mg/kg) given about five days apart did not significantly reduce cluster headache attack frequency compared to placebo. Over three weeks, attack frequency changed by −3.2 attacks per week with psilocybin (baseline 9.6) and 0.03 attacks per week with placebo (baseline 8.9), a difference that was not statistically significant. The overall effect size was moderate (d = 0.69), but large in chronic participants (d = 1.25) and small in episodic participants (d = 0.35). Changes in attack frequency were not linked to the intensity of acute psychedelic effects. Psilocybin was well-tolerated with no serious adverse events.
Psychopharmacology
October 1, 2010
Anthony G Romano, Jennifer L Quinn, Luchuan Li et al.
42 citations
Lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhances Pavlovian eyeblink conditioning in rabbits. Acute injections of LSD, whether given parenterally or directly into the dorsal hippocampus, produced a 5-HT(2A)-mediated head-bob behavior. Chronic administration of LSD (3 or 10 nmol per side) during conditioning increased conditioned responses compared to vehicle controls. After repeated LSD infusions, subsequent infusion of another hallucinogen (DOI) elicited fewer head bobs, indicating desensitization of the 5-HT(2A) receptor. The slight, short-lived learning enhancement appears to result from this receptor desensitization within the hippocampus.
Journal of the Neurological Sciences
May 15, 2024
Emmanuelle A. D. Schindler, R Andrew Sewell, Christopher Gottschalk et al.
37 citations
In a blinded extension of a prior randomized trial, ten people with cluster headache received a second round of three doses of psilocybin (10 mg/70 kg, five days apart) at least six months after their first round. Attack frequency dropped significantly from a baseline of 18.4 attacks per week to 9.8 attacks per week in the three weeks after the first dose, a reduction of about 50%. This benefit occurred regardless of whether the participant had responded to psilocybin in the first round. No serious or unexpected adverse events occurred. The findings suggest that repeating a pulse of psilocybin can substantially reduce cluster headache attacks and that prior response does not predict the effect of retreatment.
Neuropharmacology
June 16, 2022
Emmanuelle A. D. Schindler
29 citations
Psychedelic drugs may offer lasting therapeutic benefits for headache and chronic pain disorders after limited dosing, a feature that distinguishes them from conventional treatments. A recent controlled trial of psilocybin in migraine is reviewed, though its limitations are noted. Several neurobiological targets of psychedelics related to headache and chronic pain are highlighted, but separating acute from lasting effects is key to understanding their unique clinical actions. Considerable research is still needed to determine the effects, safety, and mechanisms of psychedelics in these conditions.
Int J Neuropsychopharmacol
April 1, 2025
Jacob S. Aday, Otto Simonsson, Emmanuelle A. D. Schindler et al.
25 citations
Classic psychedelics show promise for treating neuropsychiatric disorders, but weak blinding integrity in clinical trials limits the interpretability of therapeutic effects, making alternative active placebos necessary. This review describes drawbacks of current placebos, proposes criteria for suitable active placebos—including acute psychoactive and physiological effects, matched onset and duration, safety, and lack of therapeutic effects for the target disease—and identifies several pharmacological agents that may serve as active placebos for moderate-to-high doses of short- and long-acting psychedelics, as well as low-dose and microdosing regimens. Future research should apply a thoughtful selection process and ancillary strategies to improve blinding.
Pharmacology Biochemistry and Behavior
December 15, 2011
Emmanuelle A. D. Schindler, Kuldip D. Dave, Elaine M. Smolock et al.
18 citations
The hallucinogens DOI and LSD both require activation of serotonin 2A (5-HT2A) and dopamine D1 receptors to produce head-bob behavior in rabbits, while serotonin 2B/2C receptors are not involved. In vitro, LSD and the antagonist ritanserin bound to frontocortical 5-HT2A receptors pseudo-irreversibly, whereas DOI and ketanserin bound reversibly. LSD showed modest D1 receptor binding affinity, but DOI had negligible affinity for D1 receptors. Despite these differences in binding properties, activation of both 5-HT2A and D1 receptors is a common mechanism for the behavioral effects of these hallucinogens.
Current Pain and Headache Reports
June 27, 2022
Sakari Santeri Rusanen, Suchetana De, Emmanuelle A. D. Schindler et al.
12 citations
A systematic review of nine retrospective surveys involving 5,419 respondents found that oxygen and subcutaneous triptan injections were most often reported as effective abortive treatments for cluster headache, while psilocybin and lysergic acid diethylamide (LSD) were most commonly reported as effective prophylactic treatments. The reported efficacy of most substances was consistent across different surveys, and the order of efficacy generally agreed with clinical studies. The findings suggest that retrospective surveys can provide supporting information on treatment effects and generate hypotheses about novel therapies. The consistently reported efficacy of psilocybin and LSD in prophylactic treatment indicates a need for clinical studies.
Frontiers in Neurology
June 29, 2023
Benjamin N. Blond, Emmanuelle A. D. Schindler
11 citations
A person with refractory right temporal lobe epilepsy who had an implanted responsive neurostimulation (RNS) system experienced a large increase in typical seizure frequency after ingesting a large dose of psychedelic mushrooms. This is the first reported case with electrographic confirmation of seizures linked to classic psychedelic drug use. The findings indicate that the risk of drug-induced seizures should be considered in the context of the re-emerging clinical use of classic psychedelics, particularly for individuals with a history of epilepsy and depending on drug doses and regimens.
Current Pain and Headache Reports
September 1, 2023
Emmanuelle A. D. Schindler
7 citations
A review of existing literature proposes a framework for using psychedelic drugs as therapeutic agents in episodic migraine. In the only clinical trial of a psychedelic drug for migraine, a single low dose of psilocybin reduced weekly migraine days and pain intensity for two weeks in episodic subjects. Transitional effects, along with abortive effects in two subjects and findings in cluster headache, suggest potential medicinal use. Evidence supports continued investigation of psilocybin and other psychedelics as transitional treatments, though acute and preventive applications may have risks that outweigh benefits. Future research should be tailored for migraine, not modeled after other conditions.
Expert Review of Neurotherapeutics
January 1, 2023
Emmanuelle A. D. Schindler, Peter S. Hendricks
5 citations
Most current psychedelic research targets depression and substance use disorders, but reports also indicate benefits for headache disorders and chronic pain. This perspective reviews conventional treatments for these conditions and describes historical, recent, and ongoing investigations of psychedelics' therapeutic effects, including the first two clinical trials of psilocybin in headache disorders and case reports of psilocybin mushroom self-administration in chronic pain patients. It highlights challenges when applying the standard psychedelic-assisted psychotherapy model—featuring larger doses, emphasis on subjective effects, and required adjunctive psychotherapy—to headache and chronic pain disorders. Flexibility in protocols is needed to evaluate different treatment paradigms and mechanisms.
Neurology
April 7, 2025
Emmanuelle A. D. Schindler, Christopher Gottschalk, Deepak Cyril D’souza
2 citations
In clinical trials of psilocybin for migraine and cluster headache, the strength of acute psychedelic effects did not predict reductions in headache frequency. Improvements in mental health measures were also not consistently linked to headache relief. The findings suggest that the therapeutic benefits of psilocybin on headache disorders may operate through mechanisms separate from its psychedelic or mood-altering properties.
CNS Drugs
September 1, 2024
Emmanuelle A. D. Schindler
2 citations
Interest in using psychedelics and other psychoactive compounds to treat headache disorders is increasing. Although people have long reported therapeutic benefits from these substances, formal clinical trials have only recently begun. The effectiveness of any treatment depends on the specific headache disorder, the particular drug, and how it is used; no single protocol works for all headaches or drugs. This article discusses the careful considerations needed when evaluating classic psychedelics, ketamine, and cannabinoids as potential headache medicines.
Headache The Journal of Head and Face Pain
December 29, 2025
Emmanuelle A. D. Schindler, Christopher Gottschalk, Brian Pittman et al.
1 citation
In an exploratory randomized, double-blind, placebo-controlled trial, adults with migraine received either two doses of diphenhydramine placebo, one dose of psilocybin (10 mg) plus one dose of diphenhydramine, or two doses of psilocybin, each separated by 7 days. Over the two weeks after the sessions, the reduction in migraine days per week did not differ significantly among groups, though large effect sizes were seen for those receiving psilocybin. Over eight weeks, all groups showed similar reductions in migraine frequency of about 50%. Diphenhydramine partially mimicked psilocybin's acute effects, but blinding was incomplete. No serious adverse events occurred.
Neurology
June 9, 2026
Emmanuelle A. D. Schindler, Kevin Lenaburg, Robert Wold
A survey of adults with cluster headache found that many use N,N-dimethyltryptamine (DMT) to treat their condition, with some reporting benefits. The text does not provide specific numbers or effect sizes.
Headache
February 1, 2026
Faraidoon Haghdoost, Dilara Bahceci, Candice Delcourt et al.
Many people with cluster headache lack effective treatments. An online survey of 202 Australian adults with cluster headache found that 35% rated their treatments as not at all or somewhat ineffective, and 27% reported only partial effectiveness. The main treatment challenges were ineffectiveness (74%), side effects (54%), cost (53%), and access difficulties (39%). Among participants, 62% expressed interest in joining future clinical trials, with psilocybin being the highest-ranked treatment (66% very interested), followed by combination therapies (84% very interested or interested). The findings highlight inadequate treatment options and a strong patient interest in research, particularly on psilocybin and combination therapies.
Journal of Military Veteran and Family Health
December 1, 2023
Emmanuelle A. D. Schindler, Jason J. Sico
Patients with headache disorders like migraine or cluster headache often have poor quality of life, and military members and Veterans are at high risk, especially due to head trauma. Available treatments may not work, have side effects, or be unaffordable. Psychedelics have been discussed as a treatment for over 50 years; patients report that LSD and psilocybin provide long-lasting relief for weeks or months after just a single or few doses. Formal studies are beginning, and first results for psilocybin in migraine and cluster headache are encouraging but small and not conclusive. Veterans have been active in the re-emergence of psychedelics but may not all be able or willing to participate in studies due to health conditions or military viewpoints.