LSD to Improve Cluster Headache Impact Trial

NCT ID: NCT05477459

Last Updated: 2025-04-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-16
• Study Completion Date: 2027-04-30

Brief Summary

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.

Detailed Description

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.

Conditions

Chronic Cluster Headache

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Verum

Lysergic diethylamide tartrate (equivalent to 25 microgram LSD base), one dose every 3 days for 3 weeks (totalling 7 vials)

Group Type: EXPERIMENTAL

LSD tartrate

Intervention Type: DRUG

LSD tartrate equivalent to 25 microgram LSD base

Placebo

Placebo vial looking like verum vial, one vial every 3 days for 3 weeks (totalling 7 vials)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo with equal appearance

Interventions

LSD tartrate

LSD tartrate equivalent to 25 microgram LSD base

Intervention Type: DRUG

Placebo

Placebo with equal appearance

Intervention Type: DRUG

Other Intervention Names

Lysergic acid diethylamide

Eligibility Criteria

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

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Canisius-Wilhelmina Hospital

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kees Kramers, Prof.

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

Leiden University Medical Center (LUMC)

Leiden, , Netherlands

Site Status: RECRUITING

Canisius-Wilhelmina Ziekenhuis (CWZ)

Nijmegen, , Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Julia Jansen, MD

Role: CONTACT

julia.jansen@cwz.nl

+31 24 3658765

Facility Contacts

Martien van Liefland

Role: primary

LICIT@LUMC.nl

071 526 21 11

Julia Jansen

Role: primary

LICIT@cwz.nl

024 365 82 10

References

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Reference Type: BACKGROUND

PMID: 29174963 (View on PubMed)

Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012 Jan;52(1):99-113. doi: 10.1111/j.1526-4610.2011.02028.x. Epub 2011 Nov 11.

Reference Type: BACKGROUND

PMID: 22077141 (View on PubMed)

Tepper SJ, Stillman MJ. Cluster headache: potential options for medically refractory patients (when all else fails). Headache. 2013 Jul-Aug;53(7):1183-90. doi: 10.1111/head.12148. Epub 2013 Jun 28.

Reference Type: BACKGROUND

PMID: 23808603 (View on PubMed)

McGeeney BE. Cannabinoids and hallucinogens for headache. Headache. 2013 Mar;53(3):447-58. doi: 10.1111/head.12025. Epub 2012 Dec 20.

Reference Type: BACKGROUND

PMID: 23278122 (View on PubMed)

Andersson M, Persson M, Kjellgren A. Psychoactive substances as a last resort-a qualitative study of self-treatment of migraine and cluster headaches. Harm Reduct J. 2017 Sep 5;14(1):60. doi: 10.1186/s12954-017-0186-6.

Reference Type: BACKGROUND

PMID: 28870224 (View on PubMed)

Sewell RA, Halpern JH, Pope HG Jr. Response of cluster headache to psilocybin and LSD. Neurology. 2006 Jun 27;66(12):1920-2. doi: 10.1212/01.wnl.0000219761.05466.43.

Reference Type: BACKGROUND

PMID: 16801660 (View on PubMed)

Schindler EA, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell RA. Indoleamine Hallucinogens in Cluster Headache: Results of the Clusterbusters Medication Use Survey. J Psychoactive Drugs. 2015 Nov-Dec;47(5):372-81. doi: 10.1080/02791072.2015.1107664. Epub 2015 Nov 23.

Reference Type: BACKGROUND

PMID: 26595349 (View on PubMed)

de Coo IF, Naber WC, Wilbrink LA, Haan J, Ferrari MD, Fronczek R. Increased use of illicit drugs in a Dutch cluster headache population. Cephalalgia. 2019 Apr;39(5):626-634. doi: 10.1177/0333102418804160. Epub 2018 Oct 5.

Reference Type: BACKGROUND

PMID: 30290701 (View on PubMed)

Other Identifiers

131-2022

Identifier Type: -

Identifier Source: org_study_id