The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: An open, non-randomized case series

Cluster headache (CH) is a primary headache disorder marked by strictly unilateral severe orbital or periorbital pain and occurs as either episodic or chronic illness, with a population prevalence around 0.1%. Acute attacks are typically treated with oxygen or subcutaneous sumatriptan, while preventive options include verapamil, lithium, corticosteroids and other neuromodulators; nevertheless, many patients remain refractory and some undergo invasive neurosurgical procedures that carry significant risks. Anecdotal reports and an Internet survey have suggested that classical serotonergic psychedelics (LSD, psilocybin) can both abort attacks and extend remission periods, but their hallucinogenic properties, tight legal control and safety concerns limit clinical research and potential therapeutic use. To explore whether the anti‑cluster effects attributed to LSD and psilocybin depend on their hallucinogenic properties, the investigators examined a structurally related but reportedly non‑hallucinogenic LSD analogue, 2‑bromo‑LSD (BOL‑148). Prior volunteer and vascular‑headache studies had characterised BOL‑148 as non‑toxic and non‑hallucinogenic at doses up to those used historically. This paper reports an open, non‑randomized case series testing whether a short course of orally administered BOL‑148 could reduce attack frequency or intensity or induce remission in patients with refractory CH.

The study enrolled patients referred to the Hannover Medical School Pain Clinic who met International Classification of Headache Disorders criteria for CH and who were severely affected and non‑responders to verapamil (or intolerant of higher doses). Not all other prophylactic options or invasive procedures had necessarily been tried for every patient. Participation was on a compassionate‑use basis; all patients provided informed consent and the protocol had local ethics committee approval under German law. Baseline symptom monitoring used a standardised daily diary completed for at least two weeks before BOL‑148 administration. BOL‑148 was manufactured by THC pharm GmbH and assessed for purity (>99.2%) by HPLC and other analyses. The dosing regimen was three oral administrations of BOL‑148 (reported in the text as 30 mg/kg/body weight) given once every five days over a ten‑day period. Drug administration occurred in the presence of two of the investigators (identified in the paper by initials MK and TP), and patients were observed for three to four hours after dosing, with measurements of alterations in consciousness, thought disturbances and vital signs (blood pressure, heart rate), consistent with the drug’s expected two to three hour activity window. After dosing, patients continued daily diary recording for at least one month or until they experienced three consecutive days of attacks signaling a new cluster period. As this is a descriptive case series, no formal comparator group or statistical hypothesis testing is described; outcomes reported include changes in attack frequency, pain intensity, remission duration and acute treatment use, together with observed vital signs and subjective side effects.

Five patients entered the series (labelled S1–S5). One patient (S2) had episodic CH and was in an active cluster period at treatment; the remaining four had chronic CH. All but S1 had endured symptoms for more than ten years. Following the three doses of BOL‑148 over ten days, outcomes varied across individuals but included sustained remissions and marked clinical improvement for several patients. Patient S2’s cluster period terminated after treatment and entered a sustained remission reported as lasting at least six months at last follow‑up. Patients S3 and S5 experienced pronounced reductions in attack frequency, including complete remission for more than one month; S5’s remission lasted two months before attacks resumed. Nine months after treatment S3 reported continued remission of cluster periods with only a few sporadic attacks. Patient S4 had a profound reduction in attack frequency but did not meet the study’s one‑month remission threshold; attack frequency increased again about six months after treatment. Both S3 and S4 described remaining attacks as substantially less painful, to the extent that they no longer required their prior acute interventions. Patient S1 did not achieve a marked reduction in attack frequency but reported approximately a 30% reduction in pain intensity during the first four months; the authors note that S1 continued to consume alcohol, a common trigger, contrary to advice. No clinically meaningful changes in heart rate or blood pressure were observed during treatment sessions. Subjective adverse effects were generally mild and short‑lived: most patients reported feelings described as “flabby” or “light drunk” lasting about one to two hours. Patient S2 reported a “funny” feeling, muscle tension and sweaty palms. Importantly, no visual hallucinations, perceptual distortions, delusional thinking or overt psychosis were observed in any subject.

Karst and colleagues interpret these observations as indicating that three single oral doses of BOL‑148 within ten days can break an active CH cycle or substantially reduce attack frequency and intensity, in some cases apparently converting a chronic presentation to episodic disease with remissions extending for months. They acknowledge that for some patients (notably S1 and the episodic S2) spontaneous fluctuation in the natural history of CH might account for part of the observed change, but emphasise that the pattern and durability of response in several subjects make a treatment effect plausible. Side effects were mild and transient in this small series. The authors discuss historical and anecdotal literature on LSD, psilocybin and other ergot derivatives in headache disorders, noting that prior studies of BOL‑148 did not appear to target active CH and were poorly documented for follow‑up. They highlight that single or few doses of classical psychedelics have been reported to produce long‑lasting remission in some sufferers, a phenomenon mirrored here with BOL‑148. On mechanistic grounds they suggest that the long‑range extension of remission is unlikely to be explained purely by receptor‑level acute effects and propose a speculative hypothesis that these agents may influence gene expression (epigenetic mechanisms) related to the organism’s biological clock. The authors further note that BOL‑148 reportedly does not induce cross‑tolerance to LSD, which argues that its anti‑CH action may be unrelated to the 5‑HT1A and 5‑HT2A receptor systems usually implicated in hallucinogenicity; by extension, they propose that LSD and psilocybin’s therapeutic effects in CH might also be independent of their hallucinogenic properties. Comparisons are made with other ergot derivatives: methysergide and dihydroergotamine can have preventive effects but generally require chronic or repetitive dosing and have recognised risks (including fibrotic complications with prolonged use); the limited, non‑chronic dosing here makes such risks less likely, although the risk profile of BOL‑148 remains essentially unknown. The authors state that no approved ergot‑based CH treatment appears to produce the kind of durable response after just three oral doses reported in this series. They emphasise important limitations: the uncontrolled, unblinded design and very small sample mean findings are preliminary. The investigators acknowledge incomplete prior trialling of all prophylactic alternatives in some patients, and they discuss placebo response literature, noting variable placebo rates in acute trials and generally modest placebo response in chronic CH—arguing this reduces the likelihood that long durable remissions reported here are solely placebo artifacts. Finally, the paper calls for rigorous follow‑up, recommending randomised controlled trials with clearer inclusion criteria (for example, documented failure of verapamil at 500 mg/day and separate evaluation of episodic versus chronic CH). The authors also disclose a potential conflict: Dr Halpern co‑holds a patent on BOL‑148 for CH with Dr Passie, which to date has not been licensed or produced royalties; Drs Bernateck and Karst report no conflicts of interest.