Abstract
Background
Cluster headache is an excruciating condition for which standard treatments are usually insufficient. Evidence has accumulated that serotonergic psychedelic indoleamines including psilocybin and LSD can be effective in preventing attacks.
Methods
In this case series, nine patients with episodic and chronic cluster headache that didn’t respond to conventional treatments were treated at a clinic with psilocybin or LSD, under compassionate use provisions, and in most cases separately with ketamine.
Results
All patients responded positively to at least one of the treatments, and eight of nine responded positively to the treatment with the psychedelic indoleamines, in several cases with extended periods free of attacks.
Conclusion
These clinical data, though of an exploratory nature, add to the existing pool of evidence for the usefulness of these substances for treating cluster headache, and further support the lowering of legal and regulatory barriers to medical access to the psychedelic indoleamines.
This is a visual representation of the abstract.
Keywords
Introduction
Cluster headache is one of the most excruciating conditions known to medicine, commonly leading to suicidal ideation and sometimes suicide. 1 Standard medical treatments 2 are usually insufficient for preventing cycles from occurring or rapidly and consistently aborting attacks in progress. Among these treatments, high-flow oxygen is an effective abortive but typically takes about 15 min to work; subcutaneous sumatriptan is a rapid abortive but is widely reported by patients, though this has not been confirmed by studies, to become less effective over time and to lead to rebound attacks, and side effects limit its use; verapamil is only moderately effective as a preventative; and steroids are often effective at interrupting cycles, but have serious side effects if taken for prolonged periods, and attacks often resume once the treatment stops. Galcanezumab 3 and non-invasive vagus nerve stimulation 4 are two newer treatments that can be helpful for some patients, but the results are mixed.
A number of serotonergic indoleamines with psychedelic properties, in particular psilocybin and LSD, have been widely reported to be highly effective, more so than any standard pharmaceutical treatment, as preventatives. Most of the evidence comes from many patient self-reports based on self-administration, independent of medical supervision. 5 A few clinical trials have also been initiated, and the blinded extension phase of one small randomized controlled trial showed a statistically significant effect of psilocybin, 6 as did another small open-label trial. 7 Several factors complicate the completion of larger trials, including the difficulty of recruitment for this relatively rare condition and the lack of funding to test these non-proprietary compounds.
Switzerland is one of the few countries where psychedelics are legally allowed to be medically administered, under compassionate use provisions by several dozen authorised physicians, after approval by the Federal Office of Public Health on a case-by-case basis. While most such cases involve the use of psychedelics to treat mental health issues, accompanied by psychotherapy, one of the authors (LG) regularly treats cluster headache patients with psychedelics under these provisions. Canada has also granted approval for a single cluster headache patient to receive psilocybin treatment under Canada's Special Access Program, but to date, this remains an exception. 8
Because of the difficulty of carrying out clinical trials for this disease, patient reports and case studies play a potentially more important role in assessing the effectiveness of treatments and can provide insight into their therapeutic potential under the conditions of normal clinical use. Especially in the case of chronic patients, who typically have several attacks daily for many months or even years with little reprieve, effective interventions are more likely to be identified as such, as a sudden long reprieve coinciding with an intervention is statistically unlikely to occur by chance.
Patient information
This case series concerns nine cluster headache patients who were seen in the Zurich pain clinic of one of the authors (LG). All patients met the ICHD-3 diagnostic criteria for cluster headache. Patients with depression, which is common in cluster headache patients due to the condition, were not excluded. No other mental health issues were present that provided grounds for exclusion. One additional patient was excluded due to uncontrolled hypertension. Five patients were chronic and four were episodic according to the ICHD-3 criteria, with some heterogeneity within the episodic group, as three of the four (patients 4, 5 and 8 in Table 1) had attack patterns that neared but did not meet the definition of chronicity. All patients were experiencing two or more daily attacks at the time of first treatment at the clinic. All had previously been treated with conventional and other medical therapies without responding, which included verapamil, topiramate, lithium, galcanezumab, gammaCore vagus nerve stimulation and botulinum toxin.
Patient information, including treatments, responses and testimonials.
All patients were treated with psilocybin (tablet) or LSD (oral liquid) in a comfortable room at the clinic, with blood pressure monitored every 15–30 min, and patients remained at the clinic for 5–7 h (see Table 1 for dosages). selective serotonin reuptake inhibitors (SSRIs) (three patients) were stopped 2–3 days before the first treatment with psilocybin or LSD, and patients were allowed to resume after treatment. Sumatriptan (all patients) was only stopped from midnight on the day of treatment, and patients subsequently used it again if needed following treatment. Three of the patients also took part at one point in an ongoing clinical trial of LSD in Basel, Switzerland – one of these responded positively in the trial and was interested in continuing the treatment at the clinic. Most patients were first also treated at the clinic with ketamine (typically 0.5 mg/kg via an IV anesthesia pump over 40–60 min, with anti-nausea medication, and with blood pressure and oxygenation monitoring), and subsequently with psilocybin or LSD when they stopped responding or if they didn’t respond to the ketamine; in two cases, ketamine was administered after prior treatment with psilocybin or LSD. Ketamine, a psychoactive anaesthetic that is chemically distinct from the indoleamines and is not subject to the same legal restrictions as psilocybin and LSD, has also had documented success in treating cluster headache in a clinical setting, 9 though this treatment is less frequently mentioned in the literature and within cluster headache patient communities. In a few cases, ketamine treatment was accompanied by occipital nerve injection (ONI) and/or methadone administration. In addition to monitoring, patients were clinically assessed for side effects such as anxiety, panic or vomiting.
Table 1 provides information about each of the patients, including treatments and responses, while Figure 1 provides a visual timeline of treatments and responses for each patient, aligned at the moment of their first treatment at the pain clinic.
Timeline of treatments and responses for each patient, aligned at moment of first treatment at pain clinic.
Clinical findings
All patients showed improvement following at least one of the treatments at the clinic, and all substances were well tolerated, with no blood pressure issues and without any significant side effects, including any unpleasant hallucinogenic experiences. Some patients (2, 3, 4 and 9) reported psychological responses such as feeling emotional, laughing or gaining personal insights. Of the seven patients who were initially treated at the clinic with ketamine (in three cases also with methadone and/or ONI), five responded with a cessation of attacks, in one case after a period of milder attacks; one patient had a reduction in frequency of attacks from up to 12 attacks/day to 4 attacks/day, and later, after a successful psilocybin treatment, when again experiencing 2 attacks/day, responded to a new treatment with ketamine with a cessation of attacks; and one patient did not respond. Responsiveness lasted for varying periods of time. We note that one additional patient had previously been treated with ketamine without responding, before their first visit to the clinic.
Of all nine patients who were treated with psilocybin or LSD, six responded with a cessation of attacks; one responded after the first round of treatment with a drop in frequency from 2 to 3 attacks/day to one milder attack per day, and after the second round with a reduction in and then cessation of attacks; one responded with a drop in frequency from up to 16 attacks/day to six milder attacks/day; and one patient had not responded after one single session and declined further such treatment. This last patient was then treated with ketamine, ONI and methadone and responded with a drop in frequency from up to 16 attacks/day to 3 milder attacks/day. We also note that one of the patients who responded to psilocybin declined further treatment for financial reasons when the cluster headaches recurred a year later – these treatments were not free of charge and are not covered by Swiss health insurance.
Patient perspectives
Patient testimonials showed that, except for the one non-responder, they were all pleased with their treatments with the psychedelic indoleamines, for their effect on their cluster attacks and in some cases for the experience itself. We have included them in Table 1, translated from German, with slight editing.
Discussion
These clinical results, though of an exploratory nature, add to the growing pool of evidence that indoleamine psychedelics including psilocybin, LSD, DMT and 5-MeO-DALT, as well as ketamine, are effective in reducing the burden of cluster headache. In particular, we found that psilocybin, LSD and ketamine are all useful tools for the cessation of cycles in progress or a reduction in the frequency or severity of attacks. While we cannot draw precise conclusions as to the relative effectiveness of LSD and psilocybin compared to ketamine, in a few cases one led to responsiveness when the other did not, consistent with their different pharmacological actions. In the case of the one patient who did not respond to psilocybin, prior overuse of triptans (ca. 10 times a day for many months) is a possible reason for the lack of response; this patient also stopped psilocybin therapy after just one session, although he had not responded either in a prior LSD study.
The study also provided insights into treatment protocols that may be effective. For example, patients only had a brief pause in the use of serotonergic abortives prior to treatment with psychedelics, and some treatments were closely spaced (e.g., 1–2 days between treatments), which differs from protocols widely used within some patient communities with non-pharmaceutical grade substances.
Limitations of this study include the heterogeneity in the patients’ pre-treatment attack frequency and in the treatments provided. It is not possible to definitively rule out that an attack cycle might have spontaneously ended even without treatment. Nonetheless, positive responses to treatments were rapid, including in chronic patients, strongly suggesting a causal relationship.
Another limitation is that it was not possible to rule out placebo effects, for which there is some evidence in the preventative treatment of cluster headaches. 10 Patient expectations regarding treatments with ketamine and psychedelics could, in principle, contribute to such an effect. The treatments were not blinded, which is in any case not possible for psychedelics at perceptible doses. Relatedly, we cannot formally rule out a contribution of the psychological effects of the treatments with psychedelics in some patients, rather than a direct physiological mechanism. Nonetheless, we consider any placebo effects highly unlikely to account for most of the positive responses seen, and psychological effects of the treatments with psychedelics similarly unlikely to be a primary mechanism of action in the reduction in attack frequencies and intensities or the cessation of cycles.
We believe the evidence supports an expanded role for indoleamine psychedelics and ketamine in the treatment of cluster headache, and the funding of more research to compare their effectiveness with standard treatments. 11 In order to allow adequate medical access, legal and/or regulatory obstacles to the medical use of psychedelics need to be lowered, through the introduction of or easier access to compassionate use provisions and the potential regulatory approval of these substances as standard treatments for cluster headache. 12 Patients and headache medicine providers should be involved in discussions regarding expanded access and regulatory approval.
Clinical implications
Both ketamine and the serotonergic psychedelic indoleamines psilocybin and LSD can be effective tools in the management of cluster headache, including for the cessation of cycles in progress or a reduction in their severity.
Regulatory changes to facilitate medical access to psilocybin and LSD for the treatment of cluster headache, through unbureaucratic compassionate use provisions and eventual approval as standard treatments, would greatly benefit patients and help reduce the severe burden of pain from this disease. Patients and headache medicine providers should be involved in discussions on this issue.
Supplemental Material
sj-xlsx-1-rep-10.1177_25158163251345472 - Supplemental material for Clinical treatment of cluster headache with the serotonergic indoleamine psychedelics psilocybin and LSD and with ketamine: A case series
Supplemental material, sj-xlsx-1-rep-10.1177_25158163251345472 for Clinical treatment of cluster headache with the serotonergic indoleamine psychedelics psilocybin and LSD and with ketamine: A case series by Jonathan Leighton, Carmen Lau, Aisha Savdo and Livia Granata in Cephalalgia Reports
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval
Written informed consent was obtained from all patients.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
