Lysergic Acid Diethylamide (LSD) as Treatment for Cluster Headache

Phase 2RecruitingNCT03781128

University Hospital, Basel, Switzerland30 enrolled

Overview

Background: After no official research in humans in the last 40 years, research and therapeutic uses of the serotonergic psychedelic lysergic acid diethylamide (LSD) are now re-recognized and include its use in brain research, alcoholism, anxiety associated with terminal illness, and treatment of headache disorders. Specifically, LSD has been reported to abort attacks, to decrease frequency and intensity of attacks, and to induce remission in patients suffering from cluster headache (CH). Objective: To investigate the effects of an oral LSD pulse regimen (3 x 100 µg LSD in three weeks) in patients suffering from CH compared with placebo. Design: Double-blind, randomized, placebo-controlled two-phase cross-over study design. Participants: 30 patients aged ≥ 25 and ≤ 75 years with chronic or episodic CH with predictable periods lasting approximately 2 months and attacks responding to oxygen. Main outcome measures: Changes in frequency and intensity of CH attacks assessed with a standardized headache diary Significance: CH is often rated as the most painful of all primary headaches, which not only causes significant disability, but is also associated with enormous personal, economic, and psychiatric burden. At the moment, there is no specific treatment available for CH, but serotonergic compounds represent an important drug class, especially in the abortive management of cluster attacks. However, there is a need for new treatment approaches, as CH is also often insufficiently managed with available medication. This study will evaluate the potential benefit and safety of a treatment with LSD for patients with CH.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Eligibility

Sex: ALLMin age: 25 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Age ≥ 25 and ≤ 75 years * Chronic cluster headache (according to the International Headache Society (IHS) criteria) OR * Episodic cluster headache (according to the IHS criteria) with recurrent predictable episodes lasting approximately 2 months and expected ongoing cluster period for at least one month beyond the inclusion * Attacks respond to oxygen * Sufficient understanding of the study procedures and risks associated with the study * Participants must be willing to adhere to the study procedures and sign the consent form * Participants are willing to abstain from taking preventive and abortive medication (except from oxygen) long enough before and after the LSD/placebo treatment session to avoid the possibility of a drug-drug interaction * Participants are willing to refrain from taking any psychiatric medications during the experimental session period. If they are being treated with antidepressants, lithium or are taking anxiolytic medications on a fixed daily regimen, such drugs must be discontinued long enough before the LSD/placebo treatment session to avoid the possibility of a drug-drug interaction. * Participants must also refrain from the use of any psychoactive drugs and caffeine within 24 hours of each LSD/placebo treatment session. They must agree not to use nicotine for at least 2 hours before and 6 hours after each dose of LSD. They must agree to not ingest alcohol-containing beverages for at least 1 day before each LSD treatment session. Non-routine medications for treating breakthrough pain taken in the 24 hours before the LSD treatment session may result in rescheduling the treatment session to another date, with the decision at the discretion of the investigators after discussion with the participant. * Participants must be willing not to drive a traffic vehicle or to operate machines within 24 hours after LSD/placebo administration. Exclusion Criteria: * Other forms of headache attacks (migraine, paroxysmal hemicranias, shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating and rhinorrhea (SUNCT) or with cranial autonomic symptoms (SUNA)) * Women who are pregnant, nursing or of child-bearing potential and are not practicing an effective means of birth control (double-barrier method, i.e. pill/intrauterine device and preservative/diaphragm) * Past or present diagnosis of a primary psychotic disorder. Subjects with a first degree relative with psychotic disorders are also excluded. * Past or present bipolar disorder (DSM-IV). * Current substance use disorder (within the last 2 months, DSM-V, except nicotine). * Somatic disorders including severe cardiovascular disease, untreated hypertension (systolic blood pressure \> 160mmHg without treatment, systolic blood pressure \> 140 mmHg with treatment), severe liver disease (liver enzymes increase by more than 5 times the upper limit of normal) or severely impaired renal function (estimated creatinine clearance \<30 ml/min), or other that in the judgement of the investigators pose too great potential for side effects. * Weight \< 45kg * Participation in another clinical trial (currently or within the last 30 days) * Participants taking higher steroid doses (\>10mg/d) over a longer time period (\>2 weeks), as this would require tapering * Use of immunomodulatory agents (i.e. azathioprine) in the past 2 weeks * Use of serotonergic antiemetics (i.e. ondansetron) in the past 2 weeks

Outcomes

Primary Outcomes

Change in frequency of the cluster headache attacks

assessed with a standardized headache diary, within-subjects analysis

Time frame: 8 weeks before and after pulse regimen

Change in intensity of the cluster headache attacks

assessed with a standardized headache diary, within-subjects analysis

Time frame: 8 weeks before and after pulse regimen

Secondary Outcomes

Episode abortion

assessed with a standardized headache diary

Time frame: through study completion, an average of 1 year

Change in duration of attacks

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Time to first attack after completion of pulse regimen

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Cumulative time with headache

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Change in cluster period duration and interval between cluster periods

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Number of attacks requiring abortive medication

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Number of Attack-associated autonomic symptoms

assessed with a standardized headache diary

Time frame: 8 weeks after pulse regimen

Quality of life assessed by questionnaires: 36-item short-form health survey (SF-36)

assessment with the validated 36-item short-form health survey (SF-36), which measures health-related quality of life

Time frame: through study completion, an average of 1 year

Quality of life assessed by questionnaires: 5-level EuroQoL-5D (EQ-5D-5L)

assessment with the 5-level EuroQoL-5D (EQ-5D-5L), which is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life

Time frame: through study completion, an average of 1 year

Quality of life assessed by questionnaires: Headache Impact Test (HIT-6)

assessment with the Headache Impact Test (HIT-6), which measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning and psychological distress.

Time frame: through study completion, an average of 1 year

Effects on depressive /anxious symptoms assessed by questionnaires: State-trait anxiety inventory (STAI)

assessment with the State-trait anxiety inventory (STAI), which measures anxiety

Time frame: through study completion, an average of 1 year

Effects on depressive /anxious symptoms assessed by questionnaires: Generalized anxiety disorder-7 (GAD-7)

assessment with the Generalized anxiety disorder (GAD-7), which measures anxiety

Time frame: through study completion, an average of 1 year

Effects on depressive /anxious symptoms assessed by questionnaires: Hospital Anxiety and Depression Scale (HADS)

assessment with the Hospital Anxiety and Depression Scale (HADS), which measures anxiety and depression severity

Time frame: through study completion, an average of 1 year

Effects on depressive /anxious symptoms assessed by questionnaires: Beck Depression Inventory (BDI)

assessment with the Beck Depression Inventory (BDI), which measures depression

Time frame: through study completion, an average of 1 year

Effects on depressive /anxious symptoms assessed by questionnaires: Patient health questionnaire-9 (PHQ-9)

assessment with the Patient health questionnaire-9 (PHQ-9), which measures depression

Time frame: through study completion, an average of 1 year

Acute autonomic effects assessed by blood pressure

systolic and diastolic blood pressure in mmHg

Time frame: 10 hours after drug administration

Acute autonomic effects assessed by heart rate

heart rate in beats per minute

Time frame: 10 hours after drug administration

Acute autonomic effects assessed by body temperature

body temperature in °Celsius

Time frame: 10 hours after drug administration

Adverse Events

adverse events will be recorded

Time frame: through study completion, an average of 1 year

Acute psychological effects assessed by questionnaire Visual analogue scales (VAS)

assessment of subjective effects using visual analogue scales

Time frame: 10 hours after drug administration

Acute psychological effects assessed by SCQ

assessed with the states of consciousness questionnaire (SCQ)

Time frame: 10 hours after drug administration

Acute psychological effects assessed by questionnaire 5-dimensions of altered states of consciousness

assessed with the 5-dimensions of altered states of consciousness questionnaire (5D-ASC)

Time frame: 10 hours after drug administration

Persisting effects attributed to the LSD experience

assessment of persisting effects with the persisting effects questionnaire (PEQ) which assesses changes in attitude, mood, behavior and spiritual experience. The questionnaire will be completed at the beginning, after pulse regimens, and at the end of the study.

Time frame: through study completion, an average of 1 year

Change of attack frequency at the end of the study compared with baseline

pre-post study comparison in all subjects, assessed with a standardized headache diary

Time frame: through study completion, an average of 1 year

Change of attack intensity at the end of the study compared with baseline

pre-post study comparison in all subjects, assessed with a standardized headache diary

Time frame: through study completion, an average of 1 year

Change in attack frequency before and after pulse regimen

between-subjects analysis before cross-over, assessed with a standardized headache diary

Time frame: 8 weeks after first pulse regimen

Change in attack intensity before and after pulse regimen

between-subjects analysis before cross-over, assessed with a standardized headache diary

Time frame: 8 weeks after first pulse regimen

Blinding

patients and investigators will be asked at the end of a study day and and the end of the study visit to guess the drug treatment

Time frame: after study days and at the end of study visit

Expectancy

a modified 2-item version of the Credibility / Expectancy Questionnaire (CEQ) will be used

Time frame: at screening

Lysergic Acid Diethylamide (LSD) as Treatment for Cluster Headache

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts