2-Bromo-LSD

Last updated
BOL-148
2-bromo-LSD structure.svg
Clinical data
Other namesBOL148; 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-hallucinogenic serotonin 5-HT2A receptor agonist
Legal status
Legal status
  • Not scheduled (United States, Canada, Germany, EU precursors) [1] [2]
Identifiers
  • (6aR,9R)-5-bromo-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H24BrN3O
Molar mass 402.336 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3=C(NC4=CC=CC(=C34)C2=C1)Br)C
  • InChI=1S/C20H24BrN3O/c1-4-24(5-2)20(25)12-9-14-13-7-6-8-16-18(13)15(19(21)22-16)10-17(14)23(3)11-12/h6-9,12,17,22H,4-5,10-11H2,1-3H3/t12-,17-/m1/s1 Yes check.svgY
  • Key:VKRAXSZEDRWLAG-SJKOYZFVSA-N Yes check.svgY
   (verify)

BOL-148, also known as 2-bromo-LSD or as bromolysergide, is a non-hallucinogenic serotonin receptor modulator of the lysergamide family related to the psychedelic drug lysergic acid diethylamide (LSD). [3] [4] [5] [6] It is specifically the 2-bromo derivative of LSD. [4] [5]

Contents

The drug is a non- or minimally-hallucinogenic serotonin 5-HT2A receptor partial agonist, as well as acting at other targets such as other serotonin receptors and dopamine 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 produce psychoplastogenic and antidepressant-like effects in animals. [3] [4]

BOL-148 was initially developed by Albert 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 of cluster headaches and other conditions. [8] [9] [6] This is under new developmental code names including BETR-001, TD-0148A, and NYPRG-101. [8] [9]

Use and effects

Clinical studies have found that unlike LSD, BOL-148 lacks hallucinogenic 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 one case report of LSD-like delirium 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 as lisuride, hallucinogenic effects with BOL-148 appears to be a rare side effect occurring only in individuals with an as yet unexplained susceptibility to this reaction.[ citation needed ]

Interactions

Pharmacology

Pharmacodynamics

BOL-148 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. [12] [13] BOL-148 reportedly attenuates the effects of LSD in humans. [14] [15]

In 2023, BOL-148 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, BOL-148 fails to produce the head-twitch response, a behavioural proxy of psychedelic effects, in animals. [3] [16] In addition, BOL-148 blocked the head-twitch response of the psychedelic DOI. [3]

BOL-148 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, BOL-148 reportedly shows less off-target activity compared to LSD. [3] In animals, BOL-148 shows psychoplastogenic (i.e., neuroplasticity-enhancing) effects and antidepressant-like effects. [3] [17]

The cryo-EM structures 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 by Bryan L. Roth and colleagues. [18] [19]

Chemistry

Analogues

Analogues of BOL-148 (2-bromo-LSD) include 2-iodo-LSD (IOL, MBL-61 (MOB-61; 1-methyl-2-bromo-LSD), 1-methyl-2-iodo-LSD (MIL), 2-oxo-LSD, and bromocriptine, among others. 1P-BOL-148 (1-propionyl-2-bromo-LSD; SYN-L-017) is an ester prodrug of BOL-148.

Development

The generally similar behaviour of BOL-148 to LSD in some respects has shown to be very useful in potential the treatment of cluster headaches. [20] 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 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 of cluster headaches and other indications. [8] [9] A prodrug of BOL-148, under the developmental code name SPT-348, is also under development by Seaport Therapeutics for the treatment of depression, anxiety, and other neuropsychiatric disorders. [21] [22] [23] [24]

See also

References

  1. ↑ "BOL-148 hydrochloride". THC Pharm GmbH. Archived from the original on 2012-12-17. Retrieved 2019-04-23.
  2. ↑ "BetterLife Confirms Non-Controlled Status of 2-bromo-LSD with Health Canada - Psilocybin Alpha". Psychedelic Alpha. 19 January 2021.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Lewis V, Bonniwell EM, Lanham JK, Ghaffari A, Sheshbaradaran H, Cao AB, Calkins MM, Bautista-Carro MA, Arsenault E, Telfer A, Taghavi-Abkuh FF, Malcolm NJ, El Sayegh F, Abizaid A, Schmid Y, Morton K, Halberstadt AL, Aguilar-Valles A, McCorvy JD (March 2023). "A non-hallucinogenic LSD analog with therapeutic potential for mood disorders". Cell Rep. 42 (3) 112203. doi:10.1016/j.celrep.2023.112203. PMC   10112881 . PMID   36884348.
  4. 1 2 3 4 5 6 Cameron LP, Benetatos J, Lewis V, Bonniwell EM, Jaster AM, Moliner R, Castrén E, McCorvy JD, Palner M, Aguilar-Valles A (November 2023). "Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action". J Neurosci. 43 (45): 7472–7482. doi:10.1523/JNEUROSCI.1384-23.2023. PMC   10634557 . PMID   37940583.
  5. 1 2 Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". Br J Pharmacol. doi:10.1111/bph.17361. PMID   39354889.
  6. 1 2 Schindler EA (September 2022). "Psychedelics as preventive treatment in headache and chronic pain disorders". Neuropharmacology. 215 109166. doi:10.1016/j.neuropharm.2022.109166. PMID   35718005.
  7. ↑ Troxler F, Hofmann A (1957). "Substitutionen am Ringsystem der Lysergsäure. III. Halogenierung. 45. Mitteilung über Mutterkornalkaloide". Helvetica Chimica Acta. 40 (7): 2160–2170. Bibcode:1957HChAc..40.2160T. doi:10.1002/hlca.19570400716.
  8. 1 2 3 "BETR 001". AdisInsight. 29 August 2024. Retrieved 24 October 2024.
  9. 1 2 3 "Delving into the Latest Updates on Bromolysergide with Synapse". Synapse. 14 October 2024. Retrieved 24 October 2024.
  10. 1 2 3 4 5 Kehler J, Lindskov MS (May 2025). "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology. 39 (9): 889–895. doi:10.1177/02698811251330741. PMID   40322975.
  11. 1 2 3 4 Fanchamps, A. (1978). "Some Compounds With Hallucinogenic Activity". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 567–614. doi:10.1007/978-3-642-66775-6_8. ISBN   978-3-642-66777-0 . Retrieved 30 June 2025.
  12. ↑ Ginzel KH, Mayer-Gross W (July 1956). "Prevention of psychological effects of d-lysergic acid diethylamide (LSD 25) by its 2-brom derivative (BOL 148)". Nature. 178 (4526): 210. Bibcode:1956Natur.178..210G. doi: 10.1038/178210a0 . PMID   13348662. S2CID   4169373.
  13. ↑ Isbell H, Miner EJ, Logan CR (November 1959). "Cross tolerance between D-2-brom-lysergic acid diethylamide (BOL-148) and the D-diethylamide of lysergic acid (LSD-25)". Psychopharmacologia. 1 (2): 109–116. doi:10.1007/bf00409110. PMID   14405871. S2CID   1915318.
  14. ↑ Mehta MA, Tricklebank MD (2019). "Serotonin and the psychedelics". The Serotonin System. pp. 193–202. doi:10.1016/B978-0-12-813323-1.00011-6. ISBN   978-0-12-813323-1. S2CID   196510587.
  15. ↑ Tfelt-Hansen P (April 2011). "Is BOL-148 hallucinogenic?". Cephalalgia. 31 (5): 634, author reply 635-634, author reply 636. doi:10.1177/0333102410392069. PMID   21163816. S2CID   12412491.
  16. ↑ Corne SJ, Pickering RW (1967). "A possible correlation between drug-induced hallucinations in man and a behavioural response in mice". Psychopharmacologia. 11 (1): 65–78. doi:10.1007/BF00401509. PMID   5302272.
  17. ↑ Aguilar Valles A, Lewis V, Telfer A, Arsenault E, Taghavi-Abkuh FF, El Sayegh F, Abizaid A (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P271-P540: P358. A Non-Hallucinogenic LSD Analog With Therapeutic Potential for Mood Disorders". Neuropsychopharmacology. 47 (Suppl 1): 220–370 (269–270). doi:10.1038/s41386-022-01485-0. PMC   9714399 . PMID   36456694.
  18. ↑ Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL (March 2025). "The structural diversity of psychedelic drug actions revealed". Nature Communications. 16 (1) 2734. Bibcode:2025NatCo..16.2734G. doi:10.1038/s41467-025-57956-7. PMC   11923220 . PMID   40108183.
  19. ↑ Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL (September 2022). Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias (PDF). University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center.
  20. ↑ Karst M, Halpern JH, Bernateck M, Passie T (September 2010). "The non-hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-randomized case series". Cephalalgia. 30 (9): 1140–1144. doi:10.1177/0333102410363490. PMID   20713566. S2CID   33199115.
  21. ↑ "Delving into the Latest Updates on SPT-348 with Synapse". Synapse. 8 May 2025. Retrieved 12 May 2025.
  22. ↑ Peplow M (June 2024). "Next-generation psychedelics: should new agents skip the trip?". Nat Biotechnol. 42 (6): 827–830. doi:10.1038/s41587-024-02285-1. PMID   38831049. 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.
  23. ↑ Psychedelic Alpha (1 May 2025). "March & April 2025 Psychedelic Patent Update: Lykos' Patent Woes Continue; Filings Provide First Look at Seaport's 2-Bromo-LSD Program; Delix's Ergoline Analogues; CaaMTech's Spinout". Psychedelic Alpha. Retrieved 12 May 2025. Patent Filings Provide First Look At Seaport Therapeutics' SPT-348 (2-Bromo-LSD) Program [...]
  24. ↑ "New lipid prodrugs of bromolysergide disclosed in Seaport Therapeutics patent". BioWorld. 11 May 2025. Retrieved 12 May 2025. 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. [...]
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