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TCB-2

From Wikipedia, the free encyclopedia

TCB-2
(R)-TCB-2, the (R)-enantiomer of TCB-2
Clinical data
Other names2CBCB; 2C-BCB; 6,β-Methylene-2C-B
Routes of
administration		Unknown[1][2][3][4]
Drug classSerotonin receptor agonist; Serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Legal status
Legal status
  • In general unscheduled
Pharmacokinetic data
Duration of actionUnknown[1][2][3][4]
Identifiers
  • (3-bromo-2,5-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl)methanamine
PubChem CID
ChemSpider
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC11H14BrNO2
Molar mass272.142 g·mol−1
3D model (JSmol)
  • COC1=CC(=C(C2=C1C(C2)CN)OC)Br
  • InChI=1S/C11H14BrNO2/c1-14-9-4-8(12)11(15-2)7-3-6(5-13)10(7)9/h4,6H,3,5,13H2,1-2H3
  • Key:MPBCKKVERDTCEL-UHFFFAOYSA-N
  (verify)

TCB-2, also known as 2CBCB or 2C-BCB, is a putative psychedelic drug of the phenethylamine, 2C, and benzocyclobutene families related to 2C-B.[1][3][2][5] It is a cyclized phenethylamine and is the derivative of 2C-B in which the β position has been connected to the 6 position by a methylene bridge to form a benzocyclobutene ring system.[3][1][5] It is unclear whether TCB-2 produces hallucinogenic effects in humans and its route of administration and properties such as dose and duration are unknown.[1][2][3]

The drug is a highly potent serotonin receptor agonist, including of the serotonin 5-HT2A receptor among others.[3][6][1][5] TCB-2 produces psychedelic-like effects in animals.[3][1][7][8][5] It may be among the most potent known serotonin 5-HT2A receptor agonists and psychedelic phenethylamines.[3][5] TCB-2 is often employed as its more potent and selective enantiomer (R)-TCB-2 in scientific research.[3][1][5]

TCB-2 was first described in the scientific literature by Thomas McLean and colleagues of the lab of David E. Nichols at Purdue University in 2006.[1][5] It is not an explicitly controlled substance in the United States and is fully legal for use in scientific research in this country.[2][1] In 2025, TCB-2 was suggested as an alternative and replacement of the widely employed DOI for use in research.[2]

Use and effects

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TCB-2 does not appear to have been formally tested in humans and its properties and effects are unknown.[1][2][3][4] However, Daniel Trachsel has reported based on anonymous personal communication in 2009 that TCB-2 is psychoactive in the low-milligram range (route unspecified but presmably oral).[3] No additional details were provided, including notably with regard to the nature of the effects.[3] There are also a number of trip reports of TCB-2 on online forums, but such reports are unconfirmed and may not be reliable.[1] In relation to the preceding, it has been said that there are no valid data on TCB-2 in humans.[1]

Interactions

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See also: Psychedelic drug § Interactions, and Trip killer § Serotonergic psychedelic antidotes

Pharmacology

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Pharmacodynamics

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TCB-2 acts as a potent agonist of the serotonin 5-HT2A and 5-HT2C receptors.[1][3][5] Its affinity (Ki) for the serotonin 5-HT2A receptor has been reported to be 0.75 nM and to be similar to that of 2C-B (Ki = 0.88 nM).[1][3][5] The (R)-enantiomer shows 3-fold higher affinity for the serotonin 5-HT2A receptor as well as 2-fold higher activational potency at this receptor.[1][3][5] TCB-2 is a biased agonist of the serotonin 5-HT2A receptor, showing 65-fold higher potency in stimulating phosphoinositide turnover than in activating arachidonic acid release.[1][3][5] Besides the serotonin 5-HT2 receptors, TCB-2 might importantly stimulate the serotonin 5-HT1A receptor.[1][9] The comprehensive receptor interactions of TCB-2 have been studied.[6] It is a potent agonist of the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, and 5-HT2C receptors, with the highest activity at the serotonin 5-HT2A receptor.[6]

(R)-TCB-2 has been found to substitute for LSD and DOI in rodent drug discrimination tests.[1][3][5] It showed similar potency in this regard as LSD and 11- to 13-fold greater potency than DOI, making it one of the most potent known psychedelic drugs in this assay.[1][3][5] In contrast to (R)-TCB-2, (S)-TCB-2 was inactive in the test even at a more than 10-fold higher dose.[3][5] TCB-2 also produces the head-twitch response, another behavioral proxy of psychedelic effects, in rodents.[1][7][8][9] However, in contrast to drug discrimination, the drug required surprisingly high doses to produce the head-twitch response, showing similar potency to that of DOI in this assay.[1][8][10] This might be related to TCB-2's biased serotonin 5-HT2A receptor agonism.[1][8] In addition to its psychedelic-like effects, TCB-2 has been found to produce hyperlocomotion at lower doses and hypolocomotion at higher doses in rodents.[1][7][8][11] The drug produces rapid antidepressant-, anti-anhedonic-, and anxiolytic-like effects in animals.[12] TCB-2 shows anti-inflammatory effects in preclinical research, albeit with lower potency and efficacy than non-cyclized analogues.[13][14] Unlike other psychedelic phenethylamines, TCB-2 produces some behavioral serotonin syndrome-like effects in rodents.[1][9] Other animal studies have also been done.[8][15][16][17]

Chemistry

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Synthesis

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The chemical synthesis of TCB-2 has been described.[5] The synthesis of TCB-2 has been described as tedious, such that its manufacture has been prevented from being economical, although it is still available commercially for use in scientific research.[18]

Analogues

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See also: Cyclized phenethylamine

Analogues of TCB-2 include 2C-B, DOB, β-methyl-2C-B (BMB), tomscaline, 2CB-Ind, jimscaline, LPH-5, 2CBCB-NBOMe (NBOMe-TCB-2), and ZC-B, among others.[3] 2CBCB-NBOMe, the NBOMe derivative of TCB-2, shows 2.7-fold higher affinity for the serotonin 5-HT2A receptor than TCB-2 itself.[19]

History

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TCB-2 was first described in the scientific literature by Thomas McLean and colleagues of the lab of David E. Nichols at Purdue University in 2006.[1][5] At the time of its discovery, it was the most potent known phenethylamine psychedelic, with (R)-TCB-2 having similar potency as the better-known LSD, at least on the basis of rodent drug discrimination assays.[5] However, subsequent studies using the head-twitch response found it to be much less potent.[1][7][8][9] In late 2025, TCB-2 was suggested as an alternative and replacement of the widely employed DOI for use in research.[2] This was due to DOI being poised to become a restricted Schedule I controlled substance in the United States.[2][20][21]

Society and culture

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Availability

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TCB-2 is commercially available for use in scientific research.[18]

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United States

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TCB-2 is not a controlled substance in the United States.[2][1] However, it could be considered an analogue of 2C-B under the Federal Analogue Act.[2] In any case, as it is not an explicitly controlled substance, there are no restrictions on use of TCB-2 for scientific research purposes.[2][1]

See also

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References

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  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Di Giovanni G, De Deurwaerdère P (November 2018). "TCB-2 [(7R)-3-bromo-2, 5-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine]: A hallucinogenic drug, a selective 5-HT2A receptor pharmacological tool, or none of the above?". Neuropharmacology. 142: 20–29. doi:10.1016/j.neuropharm.2017.10.004. PMID 28987938.
  2. ^ a b c d e f g h i j k l Cameron LP, Jaster AM, Ramos R, Ullman EZ (2025). "The Utility of DOI For the Study of Serotonin 2A and 2C Receptors". Molecular Pharmacology 100093. doi:10.1016/j.molpha.2025.100093.
  3. ^ a b c d e f g h i j k l m n o p q r s t Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 819, 848–850, 858–859, 861. ISBN 978-3-03788-700-4. OCLC 858805226. Archived from the original on 21 August 2025.
  4. ^ a b c Shulgin A, Manning T, Daley P (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
  5. ^ a b c d e f g h i j k l m n o p q McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE (September 2006). "1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists". Journal of Medicinal Chemistry. 49 (19): 5794–5803. CiteSeerX 10.1.1.688.9849. doi:10.1021/jm060656o. PMID 16970404.
  6. ^ a b c Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, et al. (October 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics" (PDF). Neuron. 113 (19): 3129–3142.e9. doi:10.1016/j.neuron.2025.06.012. PMID 40683247.
  7. ^ a b c d Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". Current Topics in Behavioral Neurosciences. 36: 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459.
  8. ^ a b c d e f g Fox MA, French HT, LaPorte JL, Blackler AR, Murphy DL (September 2010). "The serotonin 5-HT(2A) receptor agonist TCB-2: a behavioral and neurophysiological analysis". Psychopharmacology. 212 (1): 13–23. doi:10.1007/s00213-009-1694-1. PMID 19823806.
  9. ^ a b c d Haberzettl R, Fink H, Bert B (2014). "Role of 5-HT(1A)- and 5-HT(2A) receptors for the murine model of the serotonin syndrome". Journal of Pharmacological and Toxicological Methods. 70 (2): 129–133. doi:10.1016/j.vascn.2014.07.003. PMID 25087754.
  10. ^ Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167 107933. doi:10.1016/j.neuropharm.2019.107933. PMC 9191653. PMID 31917152.
  11. ^ Halberstadt AL, Powell SB, Geyer MA (July 2013). "Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice". Neuropharmacology. 70: 218–227. doi:10.1016/j.neuropharm.2013.01.014. PMC 3934507. PMID 23376711.
  12. ^ "ACNP 61st Annual Meeting: Poster Abstracts P271-P540". Neuropsychopharmacology. 47 (Suppl 1): 220–370. December 2022. doi:10.1038/s41386-022-01485-0. PMC 9714399. PMID 36456694.
  13. ^ Flanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models". Current Topics in Behavioral Neurosciences. 56: 229–245. doi:10.1007/7854_2022_367. ISBN 978-3-031-12183-8. PMID 35546383.
  14. ^ Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacology & Translational Science. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC 8033619. PMID 33860179.
  15. ^ Aira Z, Buesa I, Salgueiro M, Bilbao J, Aguilera L, Zimmermann M, et al. (July 2010). "Subtype-specific changes in 5-HT receptor-mediated modulation of C fibre-evoked spinal field potentials are triggered by peripheral nerve injury". Neuroscience. 168 (3): 831–841. doi:10.1016/j.neuroscience.2010.04.032. PMID 20412834. S2CID 207248287.
  16. ^ Katsidoni V, Apazoglou K, Panagis G (February 2011). "Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine". Psychopharmacology. 213 (2–3): 337–354. doi:10.1007/s00213-010-1887-7. PMID 20577718. S2CID 1580337.
  17. ^ Zhang G, Ásgeirsdóttir HN, Cohen SJ, Munchow AH, Barrera MP, Stackman RW (January 2013). "Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice". Neuropharmacology. 64 (1): 403–413. doi:10.1016/j.neuropharm.2012.06.007. PMC 3477617. PMID 22722027.
  18. ^ a b Nichols DE, Fantegrossi WE (2014). "Emerging Designer Drugs". The Effects of Drug Abuse on the Human Nervous System. Elsevier. pp. 575–596. doi:10.1016/b978-0-12-418679-8.00019-8. ISBN 978-0-12-418679-8. Retrieved 1 December 2025. A potent molecule that was developed by constraint of the side chain is TCB-2 (McLean et al., 2006), now commercially available as a 5-HT2A/2C agonist for experimental laboratory studies. Although its synthesis is tedious enough to prevent its manufacture from being economical, it does exemplify the fact that relatively modest structural changes can lead to active compounds.
  19. ^ Braden MR (2007). Towards a biophysical understanding of hallucinogen action (Ph.D. thesis). Purdue University. ProQuest 304838368.
  20. ^ Palamar JJ, Fitzgerald ND (October 2025). "The Epidemiology of Recreational Use and Availability of DOC and DOI in the United States". Journal of Psychoactive Drugs: 1–10. doi:10.1080/02791072.2025.2570937. PMC 12645445. PMID 41065346.
  21. ^ Glennon RA, Dukat M (June 2024). "1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review". ACS Pharmacology & Translational Science. 7 (6): 1722–1745. doi:10.1021/acsptsci.4c00157. PMC 11184610. PMID 38898956.
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