Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey
Methodology: Online survey (retrospective).
Sample: 496 CH patients (global)
Dosage: Self-administered; various doses (illicit use).
Key Findings:
– Respondents reported that psilocybin (along with lysergic acid diethylamide, LSD, and lysergic acid amide, LSA) was “comparable to or more efficacious than most conventional medications” for preventing attacks.
– Notably, patients indicated that even infrequent, non-hallucinogenic (micro) doses of psilocybin could effectively reduce CH burden.
– Many credited these psychedelics with terminating cluster periods or inducing remission in chronic CH more reliably than standard preventives.
Implications:
This seminal survey provided quantitative backing to prior anecdotes and strongly signaled the need for controlled trials.
Citation: Schindler, E. A., Gottschalk, C. H., Weil, M. J., Shapiro, R. E., Wright, D. A., & Sewell, R. A. (2015). Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey. Journal of psychoactive drugs, 47(5), 372–381. https://doi.org/10.1080/02791072.2015.1107664
The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey
Methodology: Online survey (Italy)
Sample: 154 CH patients (Italy)
Dosage: Self-administered; various doses (illicit use)
Key Findings:
– A majority of those trying psilocybin/LSD reported significant relief.
– Intriguingly, 85.7% of participants felt these psychedelics were no less safe than standard therapies, and over half even considered them safer than conventional medicines.
– This indicates that experienced patients not only found psilocybin effective but also tolerated it well, without perceiving serious harms.
Implications:
Such findings underscore why many CH sufferers persist in seeking psychedelics despite legal barriers.
Citation: Di Lorenzo, C., Coppola, G., Di Lorenzo, G., Bracaglia, M., Rossi, P., & Pierelli, F. (2015). The use of illicit drugs as self-medication in the treatment of cluster headache: Results from an Italian online survey. Cephalalgia, 36(2), 194-198. https://doi.org/10.1177/0333102415583145
Use of Prescribed and Non-Prescribed Treatments for Cluster Headache in a Swedish Cohort
Methodology: Online survey (Sweden)
Sample: 8 participants.
Dosage: Self-administered; various doses (illicit use)
Key Findings:
–Only a small subset (3–4% of respondents) had tried psilocybin, since it is illicit in Sweden.
– Nonetheless, the outcomes were striking: 100% (8/8) of those who used psilocybin as an acute abortive reported it was effective in stopping attacks.
– For preventive use, 91.7% (11/12) achieved at least a partial preventive benefit, with 58.3% reporting complete prevention of cluster attacks.
– These patient-reported success rates are extraordinarily high – by comparison, the best conventional preventive (verapamil) yields full effect in only ~12% of patients.
– Psilocybin was, in fact, rated the most effective of all substances tried for both aborting attacks and preventing cycles.
Implications:
Although self-report biases must be considered, the Swedish data solidify the earlier surveys’ message: a substantial proportion of CH patients obtain major relief or remission from psilocybin, even with low, intermittent dosing (so-called “busting” regimens. No serious adverse events were noted in these survey respondents; indeed, many described psilocybin’s side effects as far more tolerable than those of prescription drugs.
Citation: Smedfors, G., Jennysdotter Olofsgård, F., Steinberg, A., Waldenlind, E., Ran, C., & Belin, A. C. (2024). Use of prescribed and non-prescribed treatments for cluster headache in a Swedish cohort. Brain Sciences, 14(4), 348. https://doi.org/10.3390/brainsci14040348
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
Methodology: Double-blind, placebo-controlled RCT. Patients were randomized to receive either low-dose psilocybin or placebo, administered in three sessions approximately five days apart. Participants kept headache diaries for 2 weeks pre-treatment (baseline) and 8 weeks post-treatment to track attack frequency.
Sample: 16 CH patients (including both episodic and chronic cases).
Dosage: 0.143 mg/kg per session (about 10 mg for a 70 kg person), chosen to be a sub-hallucinogenic (micro) dose that CH patients believed could prevent attacks without a full psychedelic experience.
Key Findings:
– Over the 3 weeks following the dosing “pulse,” the placebo group saw essentially no change in attack frequency (+0.03 attacks/week), whereas the psilocybin group’s attack frequency decreased by 3.2 attacks per week relative to baseline.
– In chronic CH patients, psilocybin’s effect was especially pronounced (large effect size d = 1.25), often persisting through the 8-week follow-up.
– However, because the sample was small (14 completers) and individual responses varied, the psilocybin-vs-placebo difference did not reach statistical significance (p = 0.25).
– In other words, mean attack frequency dropped ~33% under psilocybin (from ~9.6 to 6.4 attacks/week) while remaining flat under placebo, but the trial was underpowered to declare a clear winner. Nonetheless, the moderate between-group effect size (d = 0.69) suggested a real preventive signal favoring psilocybin.
– Importantly, the investigators found no correlation between acute psychedelic intensity and headache improvements; patients who experienced only minimal psychoactive effects still often had substantial relief, consistent with the idea that therapeutic benefits may derive from psilocybin’s biological mechanism rather than the psychedelic experience itself.
Implications:
Psilocybin was well-tolerated in this RCT. There were no serious or unexpected adverse events reported. Some transient psychoactive effects occurred (as expected, even at low dose), but no participants required medical intervention. This safety profile aligns with other psilocybin studies in medical populations and with patient survey data indicating generally manageable side effects. Overall, authors concluded that while the trial’s efficacy outcome was technically negative (non-significant), the results were encouraging, especially for chronic CH, and warranted larger definitive trials.
Citation: Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Zhu, Y., Lindsey, H., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2022). 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. Headache, 62(10), 1383–1394. https://doi.org/10.1111/head.14420
Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial
Methodology: Blinded extension study (2024) to gather additional data. In this extension, participants who had completed the 2022 RCT were invited back after at least 6 months. All received an open-label psilocybin pulse in a blinded fashion (i.e. observers remained blinded to their original group).
Sample: 10 CH patients
Dosage: 0.143 mg/kg per session (about 10 mg for a 70 kg person), chosen to be a sub-hallucinogenic (micro) dose that CH patients believed could prevent attacks without a full psychedelic experience.
Key Findings:
– In the 3 weeks post-treatment, attack frequency dropped by ~50% on average (from a baseline of 18.4 attacks/week down to 9.8 attacks/week, p = 0.013).
– This ~50% reduction is a clinically meaningful improvement, achieved after just three low-dose exposures. Notably, even patients who had not responded in the first trial responded in the extension, and vice versa.
– Prior non-responders experienced significant benefits the second time, suggesting that lack of effect in a single pulse does not preclude benefit from a repeated pulse.
Implications:
Psilocybin remained well-tolerated with no serious adverse events in the extension as well. These findings bolster the case that repeated low-dose psilocybin can effectively cut cluster headache frequency, and they justify larger trials to confirm long-term efficacy.
Citation: Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H., Flynn, L. T., Zhu, Y., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2024). Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial. Journal of the neurological sciences, 460, 122993. https://doi.org/10.1016/j.jns.2024.122993
CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity
Methodology: Open-label trial (Phase 1b) with neuroimaging endpoints. Prolonged observation: patients recorded daily attacks for 4 weeks (baseline), then received three oral doses of psilocybin once weekly for 3 weeks (weeks 5, 6, 7), and were followed for another 4 weeks. Thus, each patient served as their own control (baseline vs. post-treatment). Additionally, functional MRI scans were done the week before the first dose and one week after the final dose to probe brain connectivity changes.
Sample: 10 patients with chronic CH
Dosage: 0.14 mg/kg of psilocybin.
Key Findings:
– Psilocybin showed clear benefits even in this open trial. Mean attack frequency decreased by 31% in the 4 weeks after treatment compared to baseline (a drop of roughly 3 fewer attacks per week).
– Despite the small sample, this reduction was statistically significant (p<0.01).
– One chronic patient had an especially dramatic response – a complete remission lasting 21 weeks (5+ months) with no attacks.
– While an isolated case, it exemplifies the possible long-term remission that some CH patients report after psilocybin. The fMRI data provided a fascinating mechanistic clue: changes in functional connectivity between the hypothalamus and other diencephalic regions correlated inversely with attack frequency changes (r = –0.81).
– In other words, patients whose hypothalamic connectivity normalized the most also had the greatest reduction in attacks.
– The hypothalamus is known to be a key generator in cluster headache; this finding suggests psilocybin may therapeutically modulate hypothalamic activity or related networks.
– Safety-wise, the treatment was again well tolerated, no serious adverse effects were observed, and patients handled the moderate doses without issues.
Implications:
This Danish pilot concluded that psilocybin shows promise as a CH prophylactic and merited larger controlled studies (the positive result here aligns with the trend seen in the extension study, although this was open-label).
Citation: Madsen, M. K., Petersen, A. S., Stenbaek, D. S., Sørensen, I. M., Schiønning, H., Fjeld, T., Nykjaer, C. H., Larsen, S. M. U., Grzywacz, M., Mathiesen, T., Klausen, I. L., Overgaard-Hansen, O., Brendstrup-Brix, K., Linnet, K., Johansen, S. S., Fisher, P. M., Jensen, R. H., & Knudsen, G. M. (2024). CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity. Headache, 64(1), 55–67. https://doi.org/10.1111/head.14656
Clinical treatment of cluster headache with the serotonergic indoleamine psychedelics psilocybin and LSD and with ketamine: A case series
Methodology: Case series (compassionate use). Treatment was individualized: some received psilocybin and others received LSD, and in most cases patients also underwent separate ketamine infusions as an adjunct (ketamine has anecdotally helped some CH patients)
Sample: 9 patients with refractory CH (both episodic and chronic)
Dosage: Doses not specified, likely full psychedelic doses
Key Findings:
– All 9 patients responded to at least one of the treatments, and 8 of 9 had a positive response specifically to the psychedelic (psilocybin/LSD) therapy.
– Several patients achieved extended periods with no attacks following one or a few doses of psilocybin or LSD.
– For example, one chronic CH patient experienced a multi-month remission after psilocybin administration (consistent with other case reports in the literature).
– The authors noted that the psychedelic treatments often provided more sustained relief than ketamine, although ketamine helped some individuals.
– No severe adverse events occurred under the clinic’s monitoring.
Implications:
This case series, while small, adds real-world clinical evidence that full-dose psychedelic therapy can induce remission or marked improvement in otherwise intractable cluster headache. It underscores the need to lower regulatory barriers so that larger cohorts of CH patients can access these potentially life-altering treatments in safe medical settings.
Citation: Leighton, J., Lau, C., Savdo, A., & Granata, L. (2025). Clinical treatment of cluster headache with the serotonergic indoleamine psychedelics psilocybin and LSD and with ketamine: A case series. Cephalalgia Reports, 8. https://doi.org/10.1177/25158163251345472