This study aims to investigate the efficacy and safety of LSD 25μg every 3 days for 3 weeks versus placebo in the treatment of chronic cluster headache (cCH).

It is a 3-week double-blind placebo-controlled intervention study, preceded by a 4-week baseline observation period and followed by a 5-week post-treatment observation period.

Primary objective: to evaluate the efficacy of LSD 25μg every 3 days for 3 weeks in cCH.

Additional objectives:

• To evaluate the safety of LSD 25μg every 3 days for 3 weeks in cCH.
• To explore the exposure-response relationship of 25μg LSD in cCH.
• To explore cost-effectiveness of treatment with LSD in cCH.
• To evaluate the efficacy of LSD on health-related quality of life.

Treatment of cluster headache consists of acute remedies for attacks (mainly 100% O2, sumatriptan), transitional treatment for temporary frequency reduction (subcutaneous steroid injection at the greater occipital nerve (GON block), oral steroids or frovatriptan) and prolonged prophylaxis (e.g. verapamil, lithium, topiramate). Although the latter compounds have shown some efficacy in reducing the attack frequency, the evidence for their effect is weak. All current prophylactics are prescribed off-label and are limited in their utility due to associated side effects. Despite treatment, many (notably chronic) cluster headache patients continue suffering headache attacks.

Invasive, expensive treatments like hypothalamic deep brain stimulation, occipital nerve stimulation and sphenopalatine ganglion stimulation are last resort options. Recently, a monoclonal antibody targeting calcitonin gene related peptide (CGRP) received FDA approval for episodic cluster headache, but was shown to be ineffective in cCH. Thus, there is a considerable unmet need for effective treatments that are better tolerated, safe and affordable.

In this study, the investigators will assess the efficacy of prophylactic treatment with LSD in cCH. The evidence for the efficacy of LSD is limited, with the majority of data originating from case reports or uncontrolled and retrospective (internet) surveys. Nevertheless, these studies do provide indications that LSD may hold potential as a cluster headache prophylaxis.

The primary objective of this randomized double-blind placebo-controlled trial is to compare the efficacy of LSD 25μg every 3 days for 3 weeks versus placebo in cCH. The investigators aim to show that, at the end of treatment, verum is more efficacious than placebo with comparable tolerability in an ambulatory setting. To explore the sustainability of benefit the investigators will also assess the (sustained) response at 5 weeks post-treatment (8 weeks postrandomization).

If the study findings are positive, LSD should be further studied before use in routine clinical practice. Non-hallucinogenic low-dosed LSD may provide an alternative or adjunctive option for patients who do not respond to or cannot tolerate currently available treatments.

Inclusion Criteria:

• CCH according to the International Classification of Headache Disorders version 3 (ICHD-3)
• At screening: stable weekly attack frequency in the 4 weeks prior to screening (assessed retrospectively), averaging at least 8 per week and each week within a 40% window around the average
• At randomization: average of at least 8 attacks per week and no absence of attacks on more than two consecutive days during baseline

Exclusion Criteria:

• Use of excluded concomitant treatment at screening (lithium; other prophylactics if not on a stable dose for less than one month; steroids/GON block within 2 months before screening; sphenopalatinum block, neurostimulation (changed setting within 3 months before screening) or botulinum toxin within 3 months before screening) and during the double-blind phase
• Use of LSD(-derivatives) (other than investigational drug), psilocybin, ketamine or cannabis within 3 months prior to screening and throughout the study
• Lifetime and/or family history (first degree relatives) of psychotic or bipolar disorder, suicidal intention or attempt
• A score of 6 or more on the 'Ervaringenlijst' (PQ-16) to exclude subclinical susceptibility to psychosis
• Actual abuse of alcohol and/or recreational drugs
• Lifetime history of cardiac valvular disease
• History or evidence of cognitive disorder at screening
• Positive urine drug screen at screening
• Females: Pregnancy, lactation, no acceptable contraceptive use

Individual patient data underlying publication, after deidentification, will be shared upon request to the corresponding author

9-36 months after article publication

For purpose of meta-analysis and approved by an independent review board

Study drug or placebo are similar in appearance, taste and smell