Chemistry:2C-I

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2C-I, also known as 2,5-dimethoxy-4-iodophenethylamine, is a phenethylamine of the 2C family with psychedelic effects.[1] It was first synthesized by Alexander Shulgin, and is described in Shulgin's book PiHKAL (1991).

The substance is consumed as a recreational drug, and is circulated in the drug market in a powder form. 2C-I is sometimes confused with other related chemical substances such as 25I-NBOMe (2C-I-NBOMe), nicknamed "Smiles" and "N-bomb" in the media.[2][3][4]

Use

In the early 2000s, 2C-I was sold in Dutch smart shops as a recreational drug after the drug 2C-B was banned.[5]

According to the US Drug Enforcement Administration, 2C-I is taken orally or snorted in a powder form.[6]

Interactions

2C-I is metabolized by the monoamine oxidase (MAO) enzymes MAO-A and MAO-B.[7][8] Monoamine oxidase inhibitors (MAOIs) such as phenelzine, tranylcypromine, moclobemide, and selegiline may potentiate the effects of 2C-I.[7][8][9] This may result in overdose and serious toxicity.[9][7]

Pharmacology

Pharmacodynamics

2C-I activities
Target Affinity (Ki, nM)
5-HT1A 107–970 (Ki)
4,900 (EC50)
102% (Emax)
5-HT1B 56
5-HT1D 40
5-HT1E 131
5-HT1F ND
5-HT2A 3.5–9.3 (Ki)
1.48–513 (EC50)
17–93% (Emax)
5-HT2B 9.3 (Ki)
19.1–150 (EC50)
70–101% (Emax)
5-HT2C 9.3–40 (Ki)
0.46–537 (EC50)
44–107% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 ND
5-HT7 1,316
α1A 5,100–>10,000
α1B >10,000
α1D >10,000
α2A 70–305
α2B 608
α2C 315
β1 4,512
β2 >10,000
β3 ND
D1 13,000
D2 1,013–2,700
D3 989–5,000
D4 2,788
D5 >10,000
H1 6,100
H2 >10,000
H3 >10,000
M1 >10,000
M2 1,429
M3 950
M4 1,129
M5 2,151
I1 ND
σ1 >10,000
σ2 5,470
MOR 2,522
DOR ND
KOR >10,000
TAAR1 3,300 (Ki) (mouse)
120 (Ki) (rat)
2,400 (EC50) (mouse)
190 (EC50) (rat)
>10,000 (EC50) (human)
51% (Emax) (mouse)
50% (Emax) (rat)
SERT 950–4,900 (Ki)
5,600–13,000 (IC50)
IA (EC50)
NET 15,000 (Ki)
22,000 (IC50)
IA (EC50)
DAT >30,000 (Ki)
126,000 (IC50)
IA (EC50)
MAO-A 125,000 (IC50)
MAO-B 55,000 (IC50)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [10][11][12][13][14][15]
[16][17][18][19][20][21]

2C-I acts as a serotonin receptor agonist. It produces psychedelic effects via serotonin 5-HT2A receptor activation.

It is inactive as a monoamine releasing agent and shows negligible activity as a monoamine reuptake inhibitor.[12][11]

2C-I is a highly potent anti-inflammatory drug similarly to various other serotonergic psychedelics.[19] However, 2C-I showed the highest anti-inflammatory potency of any other assessed drug in a large series in one study.[19] It was more potent than (R)-DOI in terms of anti-inflammatory activity.[19]

Chemistry

Analogues and derivatives

Analogues and derivatives of 2C-I:

25I-NB*:

Society and culture

2C-I in powder form.

Australia

2C-I is a schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015).[22] A schedule 9 drug is outlined in the Poisons Act 1964 as "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of the CEO".[23]

Canada

As of October 31, 2016, 2C-I is a controlled substance (Schedule III) in Canada.[24]

European Union

In December 2003, the European Council issued a binding order compelling all European Union member states to ban 2C-I within three months.[25]

Finland

Illegal: scheduled in the "government decree on substances, preparations and plants considered to be narcotic drugs".[26]

Sweden

Sveriges riksdag added 2C-I to schedule I ("substances, plant materials and fungi which normally do not have medical use") as a narcotic on March 16, 2004, published by the Medical Products Agency in their regulation LVFS 2004:3.[27]

United Kingdom

In the United Kingdom, 2C-I is controlled as a Class A substance.[25]

United States

As of July 9, 2012, in the United States 2C-I is a Schedule I substance under the Synthetic Drug Abuse Prevention Act of 2012, making possession, distribution and manufacture illegal.[25] A previous bill, introduced in March 2011, that would have done the same passed the House of Representatives, but was not passed by the Senate.[28]

See also

  • Recreational drug use

References

  1. ↑ "Recurrent seizures and serotonin syndrome following "2C-I" ingestion". Journal of Medical Toxicology 9 (2): 196–198. June 2013. doi:10.1007/s13181-013-0287-x. PMID 23378129. 
  2. ↑ "25I-NBOMe (2C-I-NBOMe): Fatalities / Deaths". http://www.erowid.org/chemicals/2ci_nbome/2ci_nbome_death.shtml. 
  3. ↑ Weiss, Piper (September 20, 2012). 2C-I or 'Smiles': The New Killer Drug Every Parent Should Know About. Yahoo! News
  4. ↑ "Dangerous synthetic drug making its way across the country.". October 9, 2012. http://www.wishtv.com/dpp/news/indiana/dangerous-synthetic-drug-smiles-making-its-way-across-the-country.  WISH-TV
  5. ↑ "More data about the new psychoactive drug 2C-B". Journal of Analytical Toxicology 23 (3): 227–228. May–June 1999. doi:10.1093/jat/23.3.227. PMID 10369336. 
  6. ↑ Reuters (March 20, 2011). Synthetic drug, subject of proposed bans, kill teen.
  7. ↑ 7.0 7.1 7.2 "2C or not 2C: phenethylamine designer drug review". J Med Toxicol 9 (2): 172–178. June 2013. doi:10.1007/s13181-013-0295-x. PMID 23494844. 
  8. ↑ 8.0 8.1 "Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series)". Biochem Pharmacol 73 (2): 287–297. January 2007. doi:10.1016/j.bcp.2006.09.022. PMID 17067556. 
  9. ↑ 9.0 9.1 "Drug-drug interactions involving classic psychedelics: A systematic review". J Psychopharmacol 38 (1): 3–18. January 2024. doi:10.1177/02698811231211219. PMID 37982394. 
  10. ↑ "Kᵢ Database". 16 March 2025. https://pdsp.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=12953&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=14673&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D=. 
  11. ↑ 11.0 11.1 "Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)". Neuropharmacology 99: 546–553. December 2015. doi:10.1016/j.neuropharm.2015.08.034. PMID 26318099. https://psilosybiini.info/paperit/Receptor%20interaction%20profiles%20of%20novel%20N-2-methoxybenzyl%20(NBOMe)%20derivatives%20of%202,5-dimethoxy-substituted%20phenethylamines%20(2C%20drugs)%20(Rickli%20et%20al.,%202015).pdf. 
  12. ↑ 12.0 12.1 "Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function". Psychopharmacology (Berl) 231 (5): 875–888. March 2014. doi:10.1007/s00213-013-3303-6. PMID 24142203. PMC 3945162. https://www.researchgate.net/publication/258061356. 
  13. ↑ "Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers". Eur J Nucl Med Mol Imaging 38 (4): 681–693. April 2011. doi:10.1007/s00259-010-1686-8. PMID 21174090. 
  14. ↑ "Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues". The FASEB Journal 36 (S1). 2022. doi:10.1096/fasebj.2022.36.S1.R2121. ISSN 0892-6638. https://www.researchgate.net/publication/360423277. 
  15. ↑ "In vitro structure-activity relationship determination of 30 psychedelic new psychoactive substances by means of β-arrestin 2 recruitment to the serotonin 2A receptor". Arch Toxicol 94 (10): 3449–3460. October 2020. doi:10.1007/s00204-020-02836-w. PMID 32627074. Bibcode: 2020ArTox..94.3449P. 
  16. ↑ "Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential". Nat Commun 14 (1). December 2023. doi:10.1038/s41467-023-44016-1. PMID 38102107. Bibcode: 2023NatCo..14.8221W. 
  17. ↑ "Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors". Br J Pharmacol 136 (4): 510–519. June 2002. doi:10.1038/sj.bjp.0704747. PMID 12055129. 
  18. ↑ "Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors". J Pharmacol Exp Ther 321 (3): 1054–1061. June 2007. doi:10.1124/jpet.106.117507. PMID 17337633. https://repositorio.uchile.cl/bitstream/handle/2250/119461/Moya_Pablo_R.pdf. 
  19. ↑ 19.0 19.1 19.2 19.3 "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci 4 (2): 488–502. April 2021. doi:10.1021/acsptsci.0c00063. PMID 33860179. PMC 8033619. https://www.researchgate.net/publication/360537036. 
  20. ↑ "Interactions of phenethylamine-derived psychoactive substances of the 2C-series with human monoamine oxidases". Drug Test Anal 11 (2): 318–324. February 2019. doi:10.1002/dta.2494. PMID 30188017. 
  21. ↑ "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA. 
  22. ↑ Poisons Standard October 2015
  23. ↑ "Poisons Act 1964". http://www.slp.wa.gov.au/pco/prod/FileStore.nsf/Documents/MRDocument:26063P/$FILE/Poisons%20Act%201964%20-%20%5B09-f0-04%5D.pdf?OpenElement. 
  24. ↑ Regulations Amending the Food and Drug Regulations (Part J — 2C-phenethylamines)
  25. ↑ 25.0 25.1 25.2 "Erowid 2C-I Vault : Legal Status". http://www.erowid.org/chemicals/2ci/2ci_law.shtml. 
  26. ↑ "Valtioneuvoston asetus huumausaineina pidettävistä aineista, valmisteista ja kasveista | 543/2008 | Lainsäädäntö | Finlex". https://finlex.fi/fi/lainsaadanto/2008/543. 
  27. ↑ "Läkemedelsverkets författningssamling" (in sv). http://www.lakemedelsverket.se/upload/lvfs/LVFS_2004-3.pdf. 
  28. ↑ "H.R. 1254 (112th): Synthetic Drug Control Act of 2011". https://www.govtrack.us/congress/bills/112/hr1254. 

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