Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Adapting psychedelic medicine for headache and chronic pain disorders.

INTRODUCTION: While the majority of current research and development surrounds depression, demoralization, and substance use disorders, there are numerous reports of psychedelics having beneficial effects in other branches of medicine, including for headache disorders and chronic pain. AREAS COVERED: This perspective reviews conventional forms of treatment for headache and other chronic pain disorders and describes historical, recent, and ongoing investigations of the therapeutic effects of psychedelics in these disorders. The first two clinical trials of psilocybin in headache disorders and recent case reports of psilocybin mushroom self-administration in chronic pain patients are described. This perspective highlights several factors related to the application of psychedelics in chronic pain disorders, comparing this with the standard psychedelic-assisted psychotherapy model of treatment. EXPERT OPINION: When faced with a more constricted view of psychedelic medicine that features larger doses, underscores subjective effects in the mediation of therapeutic outcomes, and requires adjunctive psychotherapy to ensure safety and efficacy, the application of psychedelics in headache and chronic pain disorders may face challenges. It will be important to allow for flexibility and adaptation in protocols to evaluate different treatment paradigms, mechanisms of action, and the range of pharmacologic and extra-pharmacologic factors that affect psychedelic treatment outcomes.

The Potential of Psychedelics for the Treatment of Episodic Migraine.

PURPOSE OF REVIEW: This review presents the existing literature of and a framework for how psychedelic drugs might be applied as therapeutic agents in episodic migraine. RECENT FINDINGS: The therapeutic effects of psychedelics in headache disorders have been reported for decades and controlled investigations are now beginning. In the first and only clinical trial of a psychedelic drug in migraine, the single administration of low-dose psilocybin reduced weekly migraine days and pain intensity for the following 2 weeks in episodic subjects. These transitional effects, along with abortive effects in two subjects and additional findings in cluster headache, offer insight into the potential medicinal use of this and other psychedelic drugs in episodic migraine. The existing evidence supports the continued investigation of psilocybin and other psychedelics as transitional treatments in episodic migraine. Acute and preventive effects also exist, but the risks may outweigh benefits with these applications. Future research of psychedelics in episodic migraine should be tailored for this condition and not modeled after protocols used in other medical or psychiatric conditions.

Case report: Psychedelic-induced seizures captured by intracranial electrocorticography.

Classic psychedelics are currently re-emerging as therapeutic agents with unique clinical benefits; however, it is also important to recognize the adverse effects of this drug class. While the risk of seizures with this drug class is known, the literature is lacking in detail. We present a case of psychedelic mushroom-induced seizures in a person with refractory right temporal lobe epilepsy implanted with a responsive neurostimulation (RNS) system. A large increase in typical seizure frequency coincided with the ingestion of a large dose of the mushrooms. This is the first reported case of electrographically confirmed seizures associated with classic psychedelic drug use. With the surge of research and movements toward the clinical application of classic psychedelic compounds, the risk for drug-induced seizures should be considered, including factors such as a history of epilepsy and drug doses and regimens.

The therapeutic potential of psychedelics.

The development of psychedelics as medicines faces several challenges.

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.

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.

Psychedelics as preventive treatment in headache and chronic pain disorders.

The effects of psychedelic drugs in headache and chronic pain disorders have been reported for several decades, and now controlled studies are emerging. The existing evidence supports a lasting therapeutic benefit after limited dosing, a unique feature of the drug class that distinguishes it from conventional treatment. This commentary summarizes these reports of preventive effects of psychedelic drugs in headache and chronic pain disorders. The recently published controlled trial of psilocybin in migraine is reviewed, including its limitations. Several neurobiological targets of psychedelics that are related to headache and chronic pain are highlighted, though a clear separation of acute and lasting effects is key in uncovering the unique clinical effects of this drug class. Considerable investigation is required before the effects, safety, and mechanism of action of psychedelics in headache and chronic pain disorders can be known.

Psychedelics in the Treatment of Headache and Chronic Pain Disorders.

The therapeutic potential of psychedelics in headache and chronic pain disorders is documented over decades of anecdotal and early investigational reports, which have paved the way for the first controlled studies of psilocybin and lysergic acid diethylamide (LSD) in these disorders. The reported lasting clinical effects after limited dosing with psychedelics present a novel means for disease management, but considerable further study will be required to address disease-specific treatments, uncover mechanism(s) of action, and verify safety. In this chapter, these topics are reviewed with particular attention to the neurobiological systems that offer potential sources of psychedelics' unique clinical effects in headache and pain.

Recent advances in the diagnosis and management of cluster headache.

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).

Cluster Headache: Clinical Characteristics and Opportunities to Enhance Quality of Life.

PURPOSE OF REVIEW: Cluster headache is a highly disabling primary headache disorder characterized by severe pain and autonomic features. We present the existing body of literature on psychological factors associated with cluster headache and recommendations to address gaps in current clinical care with regards to psychological treatments for cluster headache. RECENT FINDINGS: People with cluster headache often endorse depressive symptoms, are more likely than the general population to report suicidal ideation and behaviors, and experience significantly decreased quality of life. Psychological treatments such as Acceptance and Commitment Therapy may be particularly valuable for patients with cluster headache given that they are transdiagnostic in nature and can therefore simultaneously address the disease burden and common psychiatric comorbidities that present. Greater understanding of the debilitating nature of cluster headache and behavioral interventions that seek to reduce the burden of the disease and improve the quality of life of people with cluster headache is paramount.

Demoralization predicts suicidality in patients with cluster headache.

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.

"You will eat shoe polish if you think it would help"-Familiar and lesser-known themes identified from mixed-methods analysis of a cluster headache survey.

OBJECTIVE: To characterize patient-reported ideas and concerns about cluster headache, treatment options, and management strategies. BACKGROUND: Cluster headache patients experience severe pain and often suffer additional consequences from their disease. Patients have identified methods to cope with and combat cluster headache that are not widely known. METHODS: Secondary analysis was performed using deidentified data from the online Clusterbusters Medication Use survey, wherein 10 questions allowed for freely written comments. Using mixed-methods techniques, neurologists with expertise in headache medicine identified themes from these comments. Subgroup analysis sought to identify variables associated with specific themes. RESULTS: Among 2274 free-text responses from 493 adult participants, 23 themes were identified. Themes commonly discussed in the literature included such topics as "nothing worked" (24.7%, 122/493), "side effects" (12.8%, 63/493), and difficulties with "access/cost" (2.4%, 12/493). Less widely recognized themes included the use of "illicit substances" (35.5%, 175/493) and "vitamins/supplements" (12.2%, 60/493) in disease management. Lesser-known themes included "coffee" (5.3%, 26/493) and "exercise/physical activity" (4.7%, 23/493). Using strict significance criteria, no subgroup was associated with any theme. Several poignant quotes highlighted patient thoughts and experiences. CONCLUSIONS: This mixed-methods analysis identified challenges endured by cluster headache patients, as well as a variety of patient-directed disease management approaches. The volunteered information spotlights pharmacological, physiological, and psychological aspects of cluster headache that warrant further exploratory and interventional investigation.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) 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-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

In an exploratory randomized, double-blind, placebo-controlled, cross-over study, psychoactive doses of intravenous delta-9-tetrahydrocannabinol fail to produce antinociceptive effects in healthy human volunteers.

RATIONALE: Animal studies and anecdotal human reports suggest that cannabinoids have antinociceptive effects. Controlled human studies have produced mixed results. OBJECTIVES: We sought to reduce existing variability by investigating the effects of intravenous delta-9-tetrahydrocannabinol (THC) in several pain paradigms within the same human subjects, addressing some of the limitations to the published literature. METHODS: In this exploratory randomized, double-blind, placebo-controlled, cross-over study, healthy human subjects received 0.01 mg/kg or 0.03 mg/kg intravenous THC or placebo (ethanol vehicle) infused over 10 min on three test days, each separated by at least 72 h. Capsaicin (250 µg) was injected intradermally to induce chemical pain and hyperalgesia. Four other forms of acute pain were induced: mechanical (von Frey filament), hot and cold (thermode), and electrical (pulse generator). Pain ratings were obtained before drug administration, at peak drug effects, and 2 h after drug administration and included both objective and subjective measures. THC drug effects and vital signs were also collected during experimental sessions. Nonparametric analysis with repeated measures was performed. RESULTS: THC induced euphoria, perceptual and cognitive alterations, and tachycardia in a dose-related manner, but failed to have significant effects in experimentally induced acute chemical, mechanical, thermal, or electrical pain and capsaicin-induced hyperalgesia. CONCLUSIONS: In this exploratory controlled study, intravenous THC lacked significant antinociceptive properties in experimental models of acute pain and capsaicin-induced hyperalgesia in healthy human subjects. Continued study of THC and other cannabinoids through high-quality, controlled studies in both healthy volunteers and patients with pain conditions is warranted to inform the growing demand for the clinical application of cannabinoids in pain management.

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

OBJECTIVE: In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. BACKGROUND: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. METHODS: A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. RESULTS: The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. CONCLUSION: 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.

Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics.

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.

Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey.

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.