The results from the first randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache has been published in the scientific journal Headache. The initial study provides useful information for creating bigger and more conclusive studies in the future.
A cluster headache is a neurological condition that causes extremely painful headaches, similar to a severe migraine, and effects about 0.1% of the population. It is characterized by sudden, intense, and excruciating pain that comes and goes in cycles or “clusters.” Due to the intensity of the pain caused by cluster headaches, many doctors consider it to be one of the most painful conditions in existence.
Anecdotal reports have circulated for years that psilocybin, the psychoactive compound found in “magic mushrooms,” can help to alleviate cluster headaches. But there has been little scientific evidence to back up these claims.
“Cluster headache patients have been self-managing their disease with psilocybin-containing mushrooms and other similar substances for decades now,” said lead researcher Emmanuelle A. D. Schindler, an assistant professor of neurology at Yale School of Medicine and medical director at the Headache Center of Excellence at VA Connecticut Healthcare System.
“Interestingly, patients report long-lasting effects after limited drug dosing. I wanted for this knowledge to be shared with the medical and scientific communities in their own language, namely through carrying out a randomized controlled trial.”
The researchers recruited a sample of 16 adults (aged 21–65 years) who experienced cluster headache but were otherwise free of other serious medical or psychiatric conditions. Participants were randomized to receive three doses of psilocybin (0.143 mg/kg) or placebo in sessions separated roughly five days apart. The study utilized an enhanced blinding procedure in which drug dose was unknown to both the participants and research staff. Participants filled out headache diaries starting two weeks before and continuing through eight weeks after the first session.
Those who received psilocybin tended to experience a lessening of their cluster headache symptoms, but this reduction did not reach statistical significance when compared to placebo.
“In this small preliminary study, there is evidence for therapeutic effects of psilocybin in cluster headache,” Schindler told PsyPost. “While the ~30% reduction in the number of headache attacks per week was not statistically significant, it was apparent that some subjects in the study responded and others did not. So while the average reduction in weekly attacks was ~30%, in those who responded, the average reduction was closer to 75%.”
The lack of statistical significant might be a result of the exploratory nature of the research and small sample size. The cyclic and unpredictable nature of cluster headaches can also make it difficult to observe an effect.
“The sample size was quite small (only 14 in the final analysis), the treatment regimen (3 doses, 5 days apart each) was only given once (results of a repeat round will be reported this year), and responses were variable (some responded and some frankly did not),” Schindler explained. “These factors would affect the statistical significance of any preventive cluster headache medication study.”
Despite the lack of significant results, the preliminary data can be used to direct larger and more definitive studies. “A lot more work is still needed,” Schindler said. “This study only scratches the surface. We need larger studies with hundreds of patients, studies that look out over a longer time (years), and protocols that allow for adjustments to the dosing regimen depending on how patients respond (standard in headache management).”
Interestingly, the intensity of acute psychedelic effects, such as feelings of oneness with the universe and changes in visual perception, were not associated with changes in cluster attack frequency.
“This study, as well as my previously published migraine study, showed that there was no relationship between the reduction in weekly headache attacks over time and how intense the psychedelic experience was on the days drug was administered,” Schindler told PsyPost. “This is different from studies in mental health conditions, where there does appear to be a relationship.”
“Since headache disorders are not mental health disorders, this lack of a relationship makes sense. The protocol in my cluster headache and migraine studies does not include some of the procedures in mental health studies, such as psychotherapy, again because headache disorders are not psychiatric conditions.”
The exact cause of cluster headaches is not fully understood, but it is thought to be related to abnormalities in the hypothalamus, a part of the brain that regulates the body’s internal clock and controls various bodily functions, including sleep and the autonomic nervous system. Psilocybin has been found to decrease cerebral blood flow to the hypothalamus — although whether this influences headache symptoms remains unknown.
“It’s important to recognize that the way in which psychedelics may be applied as therapeutics will be different in different conditions,” Schindler said. “It’s also interesting to note that psychedelics have overlap with headache medicines, both in their chemistry and pharmacology.”
“In fact, when Albert Hofmann created LSD in 1938, he was looking for a medication with vaso- and broncho-spastic properties, something that could be used in migraine. A compound later built off the LSD molecule, methysergide, was a very effective headache preventive. Methysergide was taken daily for headache prevention, which led to side effects and the drug being taken off the market. This experience serves as a lesson for considering how psychedelics should be applied in headache, or any other condition.”
The study, “Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial“, was authored by Emmanuelle A. D. Schindler, R. Andrew Sewell, Christopher H. Gottschalk, Christina Luddy, L. Taylor Flynn, Yutong Zhu, Hayley Lindsey, Brian P. Pittman, Nicholas V. Cozzi, and Deepak C. D’Souza.
