Cluster headache is one of the most debilitating pain syndromes. A significant number of patients are refractory to conventional therapies. The Clusterbusters.org medication use survey sought to characterize the effects of both conventional and alternative medications used in cluster headache. Participants were recruited from cluster headache websites and headache clinics. The final analysis included responses from 496 participants. The survey was modeled after previously published surveys and was available online. Most responses were chosen from a list, though others were free-texted. Conventional abortive and preventative medications were identified and their efficacies agreed with those previously published. The indoleamine hallucinogens, psilocybin, lysergic acid diethylamide, and lysergic acid amide, were comparable to or more efficacious than most conventional medications. These agents were also perceived to shorten/abort a cluster period and bring chronic cluster headache into remission more so than conventional medications. Furthermore, infrequent and non-hallucinogenic doses were reported to be efficacious. Findings provide additional evidence that several indoleamine hallucinogens are rated as effective in treating cluster headache. These data reinforce the need for further investigation of the effects of these and related compounds in cluster headache under experimentally controlled settings.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT 2A ) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, − 1.65 (95% CI: − 2.53 to − 0.77) days/week) than after placebo (− 0.15 (− 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT 2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov: NCT03341689

LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.

Objective To determine the frequency of suicidal ideation and assess suicide risk in cluster headache (CH) patients compared to matched controls without CH in this observational case-control study. Background CH is characterized by recurrent intolerable attacks of unilateral retro-orbital pain, which can cause disability, depression, and desperation. CH has been linked to suicide since its early descriptions by B.T. Horton; however, there is relatively little empiric data showing the association between suicidality and CH, especially in the context of other psychological phenomena, such as depression and demoralization. Methods CH and control participants were recruited through community and CH patient group advertisements. CH diagnosis was confirmed using the International Classification of Headache Disorders, 3rd edition diagnostic criteria for CH. Lifetime suicidal ideation and suicide risk were assessed using the Suicidal Behavior Questionnaire-revised and the Columbia Suicide Severity Rating Scale. The Brief Lifetime Depression Scale evaluated lifetime depression. Demoralization was assessed using the Diagnostic Criteria for use in Psychosomatic Research – Demoralization and the Kissane Demoralization Scale. Forward stepwise logistic regression determined the odds of suicidal ideation. Results One hundred CH and 135 control participants were comparable for age, sex, race, income, and marital status. Significantly more CH than control participants had lifetime active suicidal ideation (47.0% vs. 26.7%; p = 0.001), high suicide risk (38.0% vs. 18.5%; p = 0.0009), lifetime depression history (67.0%% vs. 32.6%; p < 0.00001), and demoralization (28.0% vs. 15.6%; p = 0.02). The odds of lifetime suicidal ideation were higher in those with CH (odds [95% confidence interval]; 2.04 [1.08,3.85]), even after accounting for depression and demoralization. In CH, suicidal ideation was associated with demoralization (6.66 [1.56,28.49]) but not depression (1.89 [0.66,5.46]). Conclusions Lifetime suicidal ideation and high suicide risk are prevalent in CH sufferers, and its likelihood is dependent on the presence of demoralization.

Cluster headache, a primary headache disorder, consists of short (15-180 minutes), frequent (up to eight a day), unilateral attacks of facial pain with associated ipsilateral autonomic features and restlessness. The attacks are suspected to be one of the most painful human experiences, and the disorder is associated with a high rate of suicidal ideation. Proper diagnosis is key, as some of the most effective treatments, such as high flow oxygen gas, are rarely used in other headache disorders. Yet diagnostic delay is typically years for this disorder, as it is often confused with migraine and trigeminal neuralgia, and secondary causes may be overlooked. This review covers the clinical, pathophysiologic, and therapeutic features of cluster headache. Recent updates in diagnosis include the redefinition of chronic cluster headache (remission periods lasting less than three months instead of the previous one month), and recent advances in management include new treatments for episodic cluster headache (galcanezumab and non-invasive vagus nerve stimulation).

Objective Using a patient‐informed regimen, we conducted an exploratory randomized, double‐blind, placebo‐controlled study to systematically investigate the effects of psilocybin in cluster headache. Background Sustained reductions in cluster headache burden after limited quantities of psilocybin‐containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. Methods Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. Results In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] −2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and −3.2 (95% CI −8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8‐week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well‐tolerated without any unexpected or serious adverse events. Conclusions Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

Recent reports on the effects of psychedelic-assisted therapies for mood disorders and addiction, as well as the effects of psychedelics in the treatment of cluster headache, have demonstrated promising therapeutic results. In addition, the beneficial effects appear to persist well after limited exposure to the drugs, making them particularly appealing as treatments for chronic neuropsychiatric and headache disorders. Understanding the basis of the long-lasting effects, however, will be critical for the continued use and development of this drug class. Several mechanisms, including biological and psychological ones, have been suggested to explain the long-lasting effects of psychedelics. Actions on the neuroendocrine system are some such mechanisms that warrant further investigation in the study of persisting psychedelic effects. In this report, we review certain structural and functional neuroendocrinological pathologies associated with neuropsychiatric disorders and cluster headache. We then review the effects that psychedelic drugs have on those systems and provide preliminary support for potential long-term effects. The circadian biology of cluster headache is of particular relevance in this area. We also discuss methodologic considerations for future investigations of neuroendocrine system involvement in the therapeutic benefits of psychedelic drugs.