Chemistry:TCB-2

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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][2][3][4] 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.[2][1][4] 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][3][2]

The drug is a highly potent serotonin receptor agonist, including of the serotonin 5-HT2A receptor among others.[2][5][1][4] TCB-2 produces psychedelic-like effects in animals.[2][1][6][7][4] It may be among the most potent known serotonin 5-HT2A receptor agonists and psychedelic phenethylamines.[2][4] TCB-2 is often employed as its more potent and selective enantiomer (R)-TCB-2 in scientific research.[2][1][4]

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][4] It was encountered as a novel designer drug by 2018, though it appears to be very rare.[1][8][9] The drug is not an explicitly controlled substance in the United States and is fully legal for use in scientific research in this country.[3][1] TCB-2 was suggested as an alternative and replacement of the widely employed DOI for use in research in 2025.[3]

Use and effects

TCB-2 does not appear to have been formally tested in humans and its properties and effects are unknown.[1][3][2][10] 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 presumably oral).[2] No additional details were provided, including notably with regard to the nature of the effects.[2] 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

Pharmacology

Pharmacodynamics

(R)-TCB-2 activities
Target Affinity (Ki, nM)
5-HT1A 145 (Ki)
1.5–2,290 (EC50)
28–54% (Emax)
5-HT1B 49 (Ki)
1.9–13 (EC50)
87–100% (Emax)
5-HT1D 22 (Ki)
3.6–20 (EC50)
95–107% (Emax)
5-HT1E 62 (Ki)
4.7–98 (EC50)
100–112% (Emax)
5-HT1F ND (Ki)
25–331 (EC50)
96–110% (Emax)
5-HT2A 0.26–6.9 (Ki)
0.49–36 (EC50)
68–101% (Emax)
5-HT2B 2.2 (Ki)
4.3–8.7 (EC50)
82–90% (Emax)
5-HT2C 9.8 (Ki)
1.2–18 (EC50)
64–96% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000 (Ki)
28–135 (EC50)
38–40% (Emax)
5-HT6 40 (Ki)
30 (EC50)
80% (Emax)
5-HT7 42 (Ki)
1,740 (EC50)
79% (Emax)
α1A–α1D >10,000
α2A 661
α2B 1,550
α2C 447
β1–β3 >10,000
D1, D2 >10,000
D3 186
D4 2,290
D5 >10,000
H1 >10,000
H2 5,620
H3, H4 >10,000
M1–M5 >10,000
TAAR1 ND
I1 ND
σ1 603
σ2 >10,000
SERT >10,000 (Ki)
ND (IC50)
NET >10,000 (Ki)
ND (IC50)
DAT >10,000 (Ki)
ND (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [5][4][11]

TCB-2 acts as a potent agonist of the serotonin 5-HT2A and 5-HT2C receptors.[1][2][4] 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][2][4] 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][2][4] 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][2][4] Besides the serotonin 5-HT2 receptors, TCB-2 might importantly stimulate the serotonin 5-HT1A receptor.[1][12] The comprehensive receptor interactions of TCB-2 have been studied.[5] 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.[5]

(R)-TCB-2 has been found to substitute for LSD and DOI in rodent drug discrimination tests.[1][2][4] 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][2][4] In contrast to (R)-TCB-2, (S)-TCB-2 was inactive in the test even at a more than 10-fold higher dose.[2][4] TCB-2 also produces the head-twitch response, another behavioral proxy of psychedelic effects, in rodents.[1][6][7][12] 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][7][13] This might be related to TCB-2's biased serotonin 5-HT2A receptor agonism.[1][7] 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][6][7][14] The drug produces rapid antidepressant-, anti-anhedonic-, and anxiolytic-like effects in animals.[15] TCB-2 shows anti-inflammatory effects in preclinical research, albeit with lower potency and efficacy than non-cyclized analogues.[16][17] Unlike other psychedelic phenethylamines, TCB-2 produces some behavioral serotonin syndrome-like effects in rodents.[1][12] Other animal studies have also been done.[7][18][19][20]

Chemistry

Synthesis

The chemical synthesis of TCB-2 has been described.[4] 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.[21]

Analogues

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.[2] 2CBCB-NBOMe, the NBOMe derivative of TCB-2, shows 2.7-fold higher affinity for the serotonin 5-HT2A receptor than TCB-2 itself.[11]

History

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][4] 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.[4] However, subsequent studies using the head-twitch response found it to be much less potent.[1][6][7][12] TCB-2 was reported to have been encountered as a novel designer drug by 2018, although it appears to be very rare.[1][8][9] In late 2025, TCB-2 was suggested as an alternative and replacement of the widely employed DOI for use in research.[3] This was due to DOI being poised to become a restricted Schedule I controlled substance in the United States.[3][22][23]

Society and culture

Availability

TCB-2 is commercially available for use in scientific research.[21]

Canada

TCB-2 is not a controlled substance in Canada as of 2025.[24]

United States

TCB-2 is not a controlled substance in the United States.[3][1][25] However, it could be considered an analogue of 2C-B under the Federal Analogue Act.[3] In any case, as it is not an explicitly controlled substance, there are no restrictions on use of TCB-2 for scientific research purposes.[3][1]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 "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. November 2018. doi:10.1016/j.neuropharm.2017.10.004. PMID 28987938. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 (in de) Phenethylamine: von der Struktur zur Funktion. Nachtschatten-Science (1 ed.). Solothurn: Nachtschatten-Verlag. 2013. pp. 819, 848–850, 858–859, 861. ISBN 978-3-03788-700-4. OCLC 858805226. https://books.google.com/books?id=-Us1kgEACAAJ. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 "The Utility of DOI For the Study of Serotonin 2A and 2C Receptors". Molecular Pharmacology. 2025. doi:10.1016/j.molpha.2025.100093. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 "1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists". Journal of Medicinal Chemistry 49 (19): 5794–5803. September 2006. doi:10.1021/jm060656o. PMID 16970404. 
  5. ↑ 5.0 5.1 5.2 5.3 "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron 113 (19): 3129–3142.e9. October 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf. 
  6. ↑ 6.0 6.1 6.2 6.3 "Effect of Hallucinogens on Unconditioned Behavior". Current Topics in Behavioral Neurosciences 36: 159–199. 2018. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMID 28224459. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "The serotonin 5-HT(2A) receptor agonist TCB-2: a behavioral and neurophysiological analysis". Psychopharmacology 212 (1): 13–23. September 2010. doi:10.1007/s00213-009-1694-1. PMID 19823806. 
  8. ↑ 8.0 8.1 "Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine, Tryptamine, and Lysergamide Psychedelics". Front Psychiatry 10: 896. 2019. doi:10.3389/fpsyt.2019.00896. PMID 32116806. 
  9. ↑ 9.0 9.1 "The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides". Psychopharmacology (Berl) 239 (6): 1783–1796. June 2022. doi:10.1007/s00213-022-06142-4. PMID 35487983. PMC 9166850. https://isomerdesign.com/bitnest/external/10.1007/s00213-022-06142-4. "TCB-2 was not included in subsequent reporting due to a lack of observations (0.1%).". 
  10. ↑ The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. 1. Berkeley: Transform Press. 2011. ISBN 978-0-9630096-3-0. 
  11. ↑ 11.0 11.1 Braden MR (2007). Towards a biophysical understanding of hallucinogen action (Ph.D. thesis). Purdue University. ProQuest 304838368.
  12. ↑ 12.0 12.1 12.2 12.3 "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. 2014. doi:10.1016/j.vascn.2014.07.003. PMID 25087754. 
  13. ↑ "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology 167. May 2020. doi:10.1016/j.neuropharm.2019.107933. PMID 31917152. 
  14. ↑ "Role of the 5-HT₂A receptor in the locomotor hyperactivity produced by phenylalkylamine hallucinogens in mice". Neuropharmacology 70: 218–227. July 2013. doi:10.1016/j.neuropharm.2013.01.014. PMID 23376711. 
  15. ↑ "ACNP 61st Annual Meeting: Poster Abstracts P271-P540". Neuropsychopharmacology 47 (Suppl 1): 220–370. December 2022. doi:10.1038/s41386-022-01485-0. PMID 36456694. 
  16. ↑ "Psychedelics and Anti-inflammatory Activity in Animal Models". Current Topics in Behavioral Neurosciences 56: 229–245. 2022. doi:10.1007/7854_2022_367. ISBN 978-3-031-12183-8. PMID 35546383. 
  17. ↑ "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. April 2021. doi:10.1021/acsptsci.0c00063. PMID 33860179. 
  18. ↑ "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. July 2010. doi:10.1016/j.neuroscience.2010.04.032. PMID 20412834. 
  19. ↑ "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. February 2011. doi:10.1007/s00213-010-1887-7. PMID 20577718. 
  20. ↑ "Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice". Neuropharmacology 64 (1): 403–413. January 2013. doi:10.1016/j.neuropharm.2012.06.007. PMID 22722027. 
  21. ↑ 21.0 21.1 "Emerging Designer Drugs". The Effects of Drug Abuse on the Human Nervous System. Elsevier. 2014. pp. 575–596. doi:10.1016/b978-0-12-418679-8.00019-8. ISBN 978-0-12-418679-8. https://linkinghub.elsevier.com/retrieve/pii/B9780124186798000198. 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." 
  22. ↑ "The Epidemiology of Recreational Use and Availability of DOC and DOI in the United States". Journal of Psychoactive Drugs: 1–10. October 2025. doi:10.1080/02791072.2025.2570937. PMID 41065346. 
  23. ↑ "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. June 2024. doi:10.1021/acsptsci.4c00157. PMID 38898956. 
  24. ↑ "Controlled Drugs and Substances Act". https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 
  25. ↑ Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026), United States: U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division, January 2026, https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf 



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