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2-Bromo-LSD
Chemical compound From Wikipedia, the free encyclopedia
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2-Bromo-LSD, also known as BOL-148 or as bromolysergide, is a derivative of lysergic acid invented by Albert Hofmann, as part of the original research from which the closely related compound LSD was also derived.[3][4] It is a non-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets, with psychoplastogenic and antidepressant-like effects in animals.[3]
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Pharmacology
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2-Bromo-LSD was found to be inactive as a psychedelic and so was comparatively little researched for many years, although its similar behaviour in the body made it useful for radiolabelling studies. It was found to bind to many of the same receptors as LSD, but acting as a neutral antagonist rather than an agonist.[5][6] 2-Bromo-LSD reportedly attenuates the effects of LSD in humans.[7][8]
In 2023, 2-bromo-LSD was characterised as a non-hallucinogenic serotonin 5-HT2A receptor biased partial agonist and as a serotonin 5-HT2B receptor antagonist.[3] It shows weaker partial agonism of the serotonin 5-HT2A receptor than LSD (Emax = 60% vs. 92%, respectively).[3] Unlike LSD, 2-bromo-LSD fails to produce the head-twitch response, a behavioural proxy of psychedelic effects, in animals.[3][9] In addition, 2-bromo-LSD blocked the head-twitch response of the psychedelic DOI.[3] Clinical studies have found that 2-bromo-LSD lacks hallucinogenic effects in humans at doses considered to be moderate to high.[10][11] In addition, some but not all clinical studies of 2-bromo-LSD in combination with LSD have found 2-bromo-LSD to block the psychedelic effects of LSD.[10] However, there is one case report of LSD-like delirium with 2-bromo-LSD, and very high doses of 2-bromo-LSD have been reported to produce mild mental changes as well as LSD-like subjective effects.[10][11] It may be that 2-bromo-LSD, rather than being fully non-hallucinogenic, is actually mild psychedelic at sufficiently high doses.[10][11]
2-Bromo-LSD shows weak recruitment of β-arrestin2 and has reduced potential to induce tolerance in the form of serotonin 5-HT2A receptor downregulation.[3] Similarly to LSD, the drug was also found to interact with numerous other serotonin receptors and targets.[3] However, 2-bromo-LSD reportedly shows less off-target activity compared to LSD.[3] In animals, 2-bromo-LSD shows psychoplastogenic (i.e., neuroplasticity-enhancing) effects and antidepressant-like effects.[3][12]
The cryo-EM structures of the serotonin 5-HT2A receptor with 2-bromo-LSD, as well as with various serotonergic psychedelics and other serotonin 5-HT2A receptor agonists, have been solved and published by Bryan L. Roth and colleagues.[13][14]
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Clinical development
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The generally similar behaviour of 2-bromo-LSD to LSD in some respects has shown to be very useful in potential the treatment of cluster headaches.[15] These debilitating attacks have been known for some time to be amenable to treatment with certain hallucinogenic drugs such as LSD and psilocybin, but because of the illegal status of these drugs and the kind of mental changes they induce, research into their medical use has been slow and therapeutic application limited to very specific circumstances under strict supervision. It had been thought that this specific therapeutic action against cluster headaches was limited to hallucinogenic drugs of this type, and would always present a major barrier to their clinical use. However, a serendipitous discovery found that 2-bromo-LSD can also produce this therapeutic effect, despite lacking the other effects of LSD. This has led to a resurgence of interest and research into 2-bromo-LSD and its possible medical uses. Some isolated incidents of hallucinogenic responses with 2-bromo-LSD have been reported, but as with other non-hallucinogenic LSD analogs such as lisuride, this appears to be a rare side effect occurring only in individuals with an as yet unexplained susceptibility to this reaction.
2-Bromo-LSD, under the developmental code name BETR-001 (previously TD-0148A), is under development by BetterLife Pharma for the treatment of cluster headaches and other indications.[16][17]
A prodrug of 2-bromo-LSD, under the developmental code name SPT-348, is also under development by Seaport Therapeutics for the treatment of depression, anxiety, and other neuropsychiatric disorders.[18][19][20][21]
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