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| Other names | BOL148; BOL; 2-Bromo-LSD; 2-Br-LSD; 2-bromolysergic acid diethylamide; Bromolysergide; Bromine-LSD; BETR-001; BTR001; TD-0148A; TD0148A; NYPRG-101; NYPRG101; 2-Bromo-N,N-diethyllysergamide; 2-Bromo-N,N-diethyl-6-methyl-9,10-didehydroergoline-8β-carboxamide |
| Routes of administration | Oral |
| Drug class | Serotonin receptor agonist; Non-hallucinogenicserotonin5-HT2A receptoragonist |
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| Formula | C20H24BrN3O |
| Molar mass | 402.336 g·mol−1 |
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BOL-148, also known as2-bromo-LSD or asbromolysergide, is a non-hallucinogenicserotonin receptor modulator of thelysergamide family related to thepsychedelic druglysergic acid diethylamide (LSD).[3][4][5][6] It is specifically the 2-bromoderivative of LSD.[4][5]
The drug is a non- or minimally-hallucinogenicserotonin5-HT2A receptorpartial agonist, as well as acting at othertargets such as otherserotonin receptors anddopamine receptors.[3][4] The lack of psychedelic effects with BOL-148 is thought to be due to lower-efficacy partial agonism at the serotonin 5-HT2A receptor compared to LSD that is insufficient to produce hallucinogenic effects.[4] The drug has been found to producepsychoplastogenic andantidepressant-like effects in animals.[3][4]
BOL-148 was initially developed byAlbert Hofmann in the 1950s, as part of the original research from which LSD was also derived.[4][3][7] It is now being reinvestigated and is under development for the potential treatment ofcluster headaches and other conditions.[8][9][6] This is under new developmental code names includingBETR-001,TD-0148A, andNYPRG-101.[8][9]
Clinical studies have found that unlikeLSD, BOL-148 lackshallucinogenic effects in humans at doses considered to be moderate to high.[10][11] In addition, some but not all clinical studies of BOL-148 in combination with LSD have found BOL-148 to block the psychedelic effects of LSD.[10]
However, some isolated incidents of hallucinogenic responses with BOL-148 have been reported.[10][11] There is onecase report of LSD-likedelirium with BOL-148, and very high doses of BOL-148 have been reported to produce mild mental changes as well as LSD-like subjective effects.[10][11] It may be that BOL-148, rather than being fully non-hallucinogenic, is actually mild psychedelic at sufficiently high doses.[10][11] In any case, as with other non-hallucinogenic LSD analogues such aslisuride, hallucinogenic effects with BOL-148 appears to be a rareside effect occurring only in individuals with an as yet unexplained susceptibility to this reaction.[citation needed]
BOL-148 was found to be inactive as apsychedelic and so was comparatively little researched for many years, although its similar behaviour in the body made it useful forradiolabelling studies. It was found to bind to many of the samereceptors as LSD, but acting as aneutral antagonist rather than an agonist.[12][13] BOL-148 reportedly attenuates the effects of LSD in humans.[14][15]
In 2023, BOL-148 was characterised as a non-hallucinogenicserotonin5-HT2A receptorbiasedpartial agonist and as a serotonin5-HT2B receptorantagonist.[3] It shows weaker partial agonism of the serotonin 5-HT2A receptor than LSD (Emax = 60% vs. 92%, respectively).[3] Unlike LSD, BOL-148 fails to produce thehead-twitch response, a behavioural proxy of psychedelic effects, in animals.[3][16] In addition, BOL-148 blocked the head-twitch response of the psychedelicDOI.[3]
BOL-148 shows weak recruitment ofβ-arrestin2 and has reduced potential to inducetolerance in the form of serotonin 5-HT2A receptordownregulation.[3] Similarly to LSD, the drug was also found to interact with numerous otherserotonin receptors andtargets.[3] However, BOL-148 reportedly shows lessoff-target activity compared to LSD.[3] In animals, BOL-148 showspsychoplastogenic (i.e.,neuroplasticity-enhancing) effects andantidepressant-like effects.[3][17]
Thecryo-EMstructures of the serotonin 5-HT2A receptor with BOL-148, as well as with various serotonergic psychedelics and other serotonin 5-HT2A receptor agonists, have been solved and published byBryan L. Roth and colleagues.[18][19]
Analogues of BOL-148 (2-bromo-LSD) include2-iodo-LSD (IOL,MBL-61 (MOB-61; 1-methyl-2-bromo-LSD),1-methyl-2-iodo-LSD (MIL),2-oxo-LSD, andbromocriptine, among others.1P-BOL-148 (1-propionyl-2-bromo-LSD; SYN-L-017) is anesterprodrug of BOL-148.
The generally similar behaviour of BOL-148 to LSD in some respects has shown to be very useful in potential the treatment ofcluster headaches.[20] These debilitating attacks have been known for some time to be amenable to treatment with certain hallucinogenic drugs such as LSD andpsilocybin, 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 BOL-148 can also produce this therapeutic effect, despite lacking the other effects of LSD. This has led to a resurgence of interest and research into BOL-148 and its possible medical uses.[citation needed]
BOL-148, under the developmental code name BETR-001 (previously TD-0148A), is under development by BetterLife Pharma for the treatment ofcluster headaches and other indications.[8][9] Aprodrug of BOL-148, under the developmental code nameSPT-348, is also under development by Seaport Therapeutics for the treatment ofdepression,anxiety, and otherneuropsychiatric disorders.[21][22][23][24]
Table 1 | Selected companies working on next-generation psychedelic therapeutics [...] Delix's Boston neighbor Seaport is also developing neuroplastogens, along with other compounds, to treat depression and anxiety disorders. "Our particular play is based on the notion that you don't need a psychedelic trip experience to gather the beneficial effects of these psychedelic agents," says founder and board chair Steve Paul. One of the company's preclinical antidepressants is a non-hallucinogenic LSD analog called SPT-348. LSD itself is a 5-HT2A agonist, but there is a lot of variation between patients in how quickly it is metabolized in the liver, making it challenging to determine the optimal dose. So Seaport has tethered its LSD analog to a novel drug delivery system called Glyph that helps the drug to circumvent the liver. The drug is attached via a linker to a triglyceride, which is absorbed through the gastrointestinal lymphatic system just like dietary fats and passes directly into the bloodstream before breaking down to release the drug. Classical psychedelic drugs are challenging to blind with a placebo in a clinical trial, but SPT348 should be able avoid that difficulty. "Since we don't have a psychedelic experience, the idea is you could do a real placebo-controlled trial, which I think is helpful," says Paul.
Patent Filings Provide First Look At Seaport Therapeutics' SPT-348 (2-Bromo-LSD) Program [...]
Seaport Therapeutics Inc. has divulged lipid prodrugs of bromolysergide reported to be useful for the treatment of cluster headache and mood disorder. [...] It hydrolyzed to active compound (release of 2-bromo-LSD>25%) in human plasma. [...]
