Lysergic Acid Diethylamide (LSD) as Treatment for Cluster Headache

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 predictableepisodes lasting approximately 2 months and expected ongoing cluster period for atleast 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 consentform

• Participants are willing to abstain from taking preventive and abortive medication (except from oxygen) long enough before and after the LSD/placebo treatment sessionto avoid the possibility of a drug-drug interaction

• Participants are willing to refrain from taking any psychiatric medications duringthe experimental session period. If they are being treated with antidepressants,lithium or are taking anxiolytic medications on a fixed daily regimen, such drugsmust be discontinued long enough before the LSD/placebo treatment session to avoidthe possibility of a drug-drug interaction.

• Participants must also refrain from the use of any psychoactive drugs and caffeinewithin 24 hours of each LSD/placebo treatment session. They must agree not to usenicotine for at least 2 hours before and 6 hours after each dose of LSD. They mustagree to not ingest alcohol-containing beverages for at least 1 day before each LSDtreatment session. Non-routine medications for treating breakthrough pain taken inthe 24 hours before the LSD treatment session may result in rescheduling thetreatment session to another date, with the decision at the discretion of theinvestigators after discussion with the participant.

• Participants must be willing not to drive a traffic vehicle or to operate machineswithin 24 hours after LSD/placebo administration.

Exclusion Criteria:

• Other forms of headache attacks (migraine, paroxysmal hemicranias, shortlastingunilateral 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 practicingan effective means of birth control (double-barrier method, i.e. pill/intrauterinedevice and preservative/diaphragm)

• Past or present diagnosis of a primary psychotic disorder. Subjects with a firstdegree 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 > 140mmHg with treatment), severe liver disease (liver enzymes increase by more than 5times the upper limit of normal) or severely impaired renal function (estimatedcreatinine clearance <30 ml/min), or other that in the judgement of theinvestigators 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 (>2weeks), 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