DOI

2,5-dimethoxy-4-iodophenylisopropylamine, 2,5-Dimethoxy-4-iodoamphetamine

The Chemistry of DOI

DOI is a psychedelic drug that belongs to the amphetamine family of compounds.1 Its chemical skeleton consists of a phenyl ring that is attached to an alkyl chain which, in turn, is attached to an amine. DOI is amphetamine with an iodine molecule at position 4 and methoxy groups at positions 2 and 5.

DOI was first synthesized by Coutts and Malicky in 1973.2

The Pharmacology of DOI

In 1987, a research team including Dennis McKenna and Alexander Shulgin identified the DOI binding site in the rat brain using the radioactive form [125I]-DOI.3

Studies have shown that DOI is a potent agonist, and has a high affinity for, the serotonin 5-HT2 receptor subtypes (see table below).4–7

Alexander and Ann Shulgin explain the effects of ingesting various doses of DOI in their book PiHKAL (#67).8

The Applications and Potential of DOI

In 2008, Yu et al. observed that stimulating the serotonin 5-HT2A receptor with DOI rapidly inhibited several tumor necrosis factor (TNF) proinflammatory markers in vitro.9 The results also suggested that 5-HT2A has a role in the inflammatory process. Additional work done by Nau et al. in 2013 showed the anti-inflammatory effects of DOI in mice.10 These studies suggest that DOI-based therapies could be developed to prevent and treat inflammation.

A 2019 study found that DOI decreased voluntary ethanol consumption in mice.11 Regarding a possible mechanism, the authors hypothesized that the effects “may be related to modulation of the effects of ethanol in the reward circuitry of the brain, ethanol-induced neuroinflammation, or a combination of both.”

Receptor Binding Affinity Data

Receptor Ki (nM) Species Ref.
5-HT2A 0.65 Human 7
5-HT2B 20.2 Human 7
5-HT2C 2.36 Human 7
    References
  1. Canal CE, Morgan D. Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model. Drug Test Anal. 2012;4(0):556-576. doi:10.1002/dta.1333
  2. Coutts RT, Malicky JL. The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM). Canadian Journal of Chemistry. 1973;51(9):1402-1409. doi:10.1139/v73-210
  3. McKenna DJ, Mathis CA, Shulgin AT, Sargent T, Saavedra JM. Autoradiographic localization of binding sites for 125I-DOI, a new psychotomimetic radioligand, in the rat brain. Eur J Pharmacol. 1987;137(2-3):289-290. doi:10.1016/0014-2999(87)90239-1
  4. Sanders-Bush E, Breeding M. Choroid plexus epithelial cells in primary culture: a model of 5HT1C receptor activation by hallucinoginic drugs. Psychopharmacology. 1991;105(3):340-346. doi:10.1007/BF02244428
  5. Porter RHP, Benwell KR, Lamb H, et al. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. British Journal of Pharmacology. 1999;128(1):13-20. doi:10.1038/sj.bjp.0702751
  6. Nelson DL, Lucaites VL, Wainscott DB, Glennon RA. Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors. Naunyn-Schmiedeberg’s Arch Pharmacol. 1999;359(1):1-6. doi:10.1007/PL00005315
  7. Wainscott DB, Lucaites VL, Kursar JD, Baez M, Nelson DL. Pharmacologic characterization of the human 5-hydroxytryptamine2B receptor: evidence for species differences. J Pharmacol Exp Ther. 1996;276(2):720-727. Accessed May 11, 2020. http://jpet.aspetjournals.org/content/276/2/720
  8. Shulgin A, Shulgin A. PiHKAL- A Chemical Love Story. First Edition, Eighteenth Printing. Transform Press; 2018.
  9. Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD. Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factoralpha-induced inflammation with extraordinary potency. J Pharmacol Exp Ther. Published online 2008:316–323.
  10. Nau F, Yu B, Martin D, Nichols CD. Serotonin 5-HT2A Receptor Activation Blocks TNF-α Mediated Inflammation In Vivo. PLoS One. 2013;8(10). doi:10.1371/journal.pone.0075426
  11. Oppong-Damoah A, Curry KE, Blough BE, Rice KC, Murnane KS. Effects of the synthetic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on ethanol consumption and place conditioning in male mice. Psychopharmacology. 2019;236(12):3567-3578. doi:10.1007/s00213-019-05328-7