2-Bromo-LSD

2-Bromo-lysergic acid diethylamide (2-Br-LSD; BOL-148; CAS 478-84-2), the 2-bromo derivative of lysergic acid diethylamide (LSD), is a non-hallucinogenic lysergamide serotonin receptor modulator first synthesized by Franz Troxler and Albert Hofmann at Sandoz in 1957 as part of a systematic structure-activity exploration of ergoline pharmacology. The compound binds with high affinity to the same serotonin, dopamine, and adrenergic receptor targets as LSD but exhibits a fundamentally different functional profile: at the serotonin 5-HT2A receptor, 2-Br-LSD acts as a biased partial agonist with an Emax of approximately 60 percent of the serotonin reference response (compared to approximately 92 percent for LSD), weak beta-arrestin recruitment (Emax approximately 37 percent), and no induction of the head-twitch response in mice across a 100-fold dose range, the accepted rodent behavioral proxy for human hallucinogenic activity. At the serotonin 5-HT2B receptor, 2-Br-LSD acts as an antagonist, eliminating the cardiac valvulopathy liability that constrains chronic dosing of LSD and other ergoline agonists at this target. Across the 5-HT1 receptor family (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F), the compound demonstrates potent pan-agonism, engaging the established anti-migraine drug targets 5-HT1B, 5-HT1D, and 5-HT1F at sub-nanomolar to low-nanomolar functional concentrations.

The therapeutic interest in 2-Br-LSD spans two principal domains. The first is cluster headache prophylaxis, supported by a 2010 open-label case series (Karst, Halpern, Bernateck, Passie) in which five patients with chronic or episodic cluster headache received three oral doses of 2-Br-LSD (approximately 30 micrograms per kilogram) over 10 days and experienced pronounced reductions in attack frequency, including sustained remissions of one to nine months. The second is rapid-acting antidepressant activity, supported by the Lewis et al. (2023) characterization in Cell Reports demonstrating that 2-Br-LSD promotes dendritogenesis and spinogenesis in primary rat cortical neurons at 1 to 10 micromolar concentrations (comparable to ketamine), reverses chronic variable stress-induced behavioral deficits in mice with effects persisting at least 28 days after a four-dose regimen, and does so through a 5-HT2A-dependent mechanism confirmed by volinanserin blockade both in vitro and in vivo. The compound does not produce tolerance on seven-day repeated dosing, in contrast to classical psychedelics that produce rapid tachyphylaxis.

Multiple pharmaceutical development programs are active. BetterLife Pharma is advancing BETR-001 (2-Br-LSD) through IND-enabling studies for major depressive disorder and cluster headache, with FDA pre-IND feedback received in January 2022 confirming suitability of the development program for IND filing. Seaport Therapeutics is developing SPT-348 (Glyph2BLSD), an oral prodrug of 2-Br-LSD, for treatment-resistant depression and post-traumatic stress disorder, with first-in-human-enabling studies underway. Cryo-electron microscopy structures of the 5-HT2A receptor bound to 2-Br-LSD in complex with mini-Gq protein (PDB 9AS0; Gumpper, Fay, Roth) have elucidated the structural basis of its biased partial agonism and provide a molecular template for next-generation non-hallucinogenic psychoplastogen design.

Pharmacokinetics in mice demonstrate rapid absorption (Tmax 0.2 hours in plasma, 0.17 hours in brain), brain penetrance (brain-to-plasma ratio 0.27 to 0.75), and short central nervous system residence (brain half-life 0.7 to 1.3 hours, below detection at 4 hours). Human pharmacokinetic data are limited to the Karst et al. (2010) cluster headache case series, in which oral doses of approximately 2 to 3 milligrams produced mild, transient subjective effects lasting 1 to 2 hours without hallucinogenic phenomena. The compound is not scheduled in the United States, Canada, Germany, or the European Union. This monograph reviews the chemistry and synthesis; the comprehensive multi-receptor pharmacology across 33 aminergic GPCRs; the preclinical neuroplasticity, behavioral, and cardiovascular safety data; the clinical evidence in cluster headache; the active pharmaceutical development programs; sourcing, reconstitution, and handling considerations; stack interactions; adverse-event signal; and a comparative assessment of five lysergamide and serotonergic compounds against 2-Br-LSD on five competency standards.