2,5-Dimethoxy-4-iodoamphetamine

{{Short description|Chemical compound}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = verified | Watchedfields = verified | verifiedrevid = 477211688 | drug_name = DOI | image = DOI structure.svg | image_class = skin-invert-image | width = 200px | image2 = DOI ball-and-stick chemical structure.png | image_class2 = bg-transparent | width2 = 185px

<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = Oral<ref name="PiHKAL" /> | class = Serotonergic psychedelic; Hallucinogen; Serotonin 5-HT₂ receptor agonist; Anti-inflammatory agent | ATC_prefix = None | ATC_suffix =

<!-- Legal status --> | legal_BR = F2 | legal_BR_comment = <ref>{{Cite web | vauthors = Anvisa | title = RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial | date = 2023-07-24 | trans-title = Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control | url = https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 | url-status = live | archive-url = https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451 | archive-date = 2023-08-27 | access-date = 2023-08-27 | publisher = Diário Oficial da União | language = pt-BR | publication-date = 2023-07-25 }}</ref> | legal_CA = Schedule I | legal_status =

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = 16–30 hours<ref name="PiHKAL" /> | excretion =

<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|correct}} | CAS_number = 64584-34-5 | CAS_supplemental = <br />82864-06-0 ((''R'')-DOI)<br />99665-04-0 ((''S'')-DOI)<br />42203-78-1 (HCl) | PubChem = 1229 | PubChemSubstance = | IUPHAR_ligand = 147 | DrugBank = | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 1192 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = Q2E57V2WS3 | KEGG = | ChEBI = | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 6616 | NIAID_ChemDB = | PDB_ligand = | synonyms = DOI; 2,5-Dimethoxy-4-iodoamphetamine; 4-Iodo-2,5-dimethoxyamphetamine

<!-- Chemical data --> | IUPAC_name = 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine | C=11 | H=16 | I=1 | N=1 | O=2 | SMILES = IC(C=C1OC)=C(OC)C=C1CC(C)N | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C11H16INO2/c1-7(13)4-8-5-11(15-3)9(12)6-10(8)14-2/h5-7H,4,13H2,1-3H3 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = BGMZUEKZENQUJY-UHFFFAOYSA-N

<!-- Physical data --> | melting_point = 201.5 | melting_notes = (hydrochloride) | solubility = 10 | sol_units = {{nbsp}}mg/mL<ref name="titleD101 DOI hydrochloride ≥98% (HPLC), solid">{{cite web | title = D101 DOI hydrochloride ≥98% (HPLC), solid | url = http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/D101 | access-date = 13 April 2008 <!--DASHBot--> }}</ref> }}

'''2,5-Dimethoxy-4-iodoamphetamine''' ('''DOI''') is a psychedelic drug of the phenethylamine, amphetamine, and DOx families.<ref name="Cameron_2025">{{cite journal | vauthors = Cameron LP, Jaster AM, Ramos R, Ullman EZ | title = The Utility of DOI For the Study of Serotonin 2A and 2C Receptors | journal = Molecular Pharmacology | article-number = 100093 | date = 2025 | doi = 10.1016/j.molpha.2025.100093 }}</ref><ref name="PiHKAL">{{cite book | vauthors = Shulgin A, Shulgin A | chapter = #67 DOI | title = PiHKAL: A Chemical Love Story | date = 1990 | publisher = Transform Press | archive-url = https://web.archive.org/web/20141027003157/http://www.erowid.org/library/books_online/PiHKAL/PiHKAL067.shtml | archive-date = 2014-10-27 | chapter-url = https://www.erowid.org/library/books_online/PiHKAL/PiHKAL067.shtml | access-date = 2014-12-17 | url-status = live }}</ref><ref name="Glennon_2024">{{cite journal | vauthors = Glennon RA, Dukat M | title = 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 | journal = ACS Pharmacology & Translational Science | volume = 7 | issue = 6 | pages = 1722–1745 | date = June 2024 | pmid = 38898956 | pmc = 11184610 | doi = 10.1021/acsptsci.4c00157 | doi-access = free }}</ref><ref name="Canal_2012">{{cite journal | vauthors = Canal CE, Morgan D | title = 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 | journal = Drug Testing and Analysis | volume = 4 | issue = 7–8 | pages = 556–576 | date = 2012 | pmid = 22517680 | pmc = 3722587 | doi = 10.1002/dta.1333 }}</ref> It is little-used recreationally, but is widely used in scientific research in the study of psychedelics and serotonin receptors.<ref name="Cameron_2025" /><ref name="Glennon_2024" /><ref name="Canal_2012" /><ref name="Palamar_2025" /> The drug is taken orally.<ref name="PiHKAL" />

It acts as a potent serotonin 5-HT₂ receptor agonist, including of the serotonin 5-HT_2A and 5-HT_2C receptors.<ref name="Glennon_2024" /><ref name="Canal_2012" /> Analogues of DOI include 2C-I, DOB, DOC, DOM, and 25I-NBOMe, among others.<ref name="PiHKAL" />

DOI was first described in the scientific literature by Ronald Coutts and Jerry Malicky in 1973.<ref name="Glennon_2024" /><ref name="Coutts_1973">{{cite journal | vauthors = Coutts RT, Malicky JL | title = The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM) | journal = Canadian Journal of Chemistry | volume = 51 | issue = 9 | pages = 1402–1409 | date = 1 May 1973 | doi = 10.1139/v73-210 | issn = 0008-4042 | url = https://cdnsciencepub.com/doi/10.1139/v73-210 | access-date = 27 November 2025 }}</ref> Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book ''PiHKAL'' (''Phenethylamines I Have Known and Loved'').<ref name="PiHKAL" /> DOI has been encountered as a novel designer drug.<ref name="Cameron_2025" /><ref name="Palamar_2025" /><ref name="dea micro">{{cite magazine | title = LSD Blotter Acid Mimics (Actually containing 4-IODO-2,5-DIMETHOXYAMPHETAMINE (DOI) and 4-CHLORO-2,5-DIMETHOXYAMPHETAMINE (DOC)) in Lantana, Florida | location = Washington, DC | date = June 2008 | magazine = DEA Microgram Bulletin | publisher = Office of Forensic Sciences, Drug Enforcement Administration | url = http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0608/mg0608.html | access-date = 12 February 2009 | archive-url = https://web.archive.org/web/20090204025435/http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0608/mg0608.html | archive-date = 2009-02-04 }}</ref> Owing to their very long and disagreeable durations however, DOI and other DOx drugs have seen very little recreational availability and use.<ref name="Cameron_2025" /><ref name="Palamar_2025" /><ref name="Glennon_2024" /><ref name="Nichols_2016">{{cite journal | vauthors = Nichols DE | title = Psychedelics | journal = Pharmacological Reviews | volume = 68 | issue = 2 | pages = 264–355 | date = April 2016 | pmid = 26841800 | pmc = 4813425 | doi = 10.1124/pr.115.011478 | quote = Although studies have appeared that employed psilocybin or LSD or a select few other agents, probably the majority of animal experiments have used the "psychedelic" 5-HT2A agonist DOI. That is another unfortunate consequence of the current drug laws. DOI has never been popular as a recreational drug, nor has any clinical study been carried out to compare its effects with classic drugs such as LSD, mescaline, or psilocybin, and only anecdotal reports of its human psychopharmacology exist (e.g., Shulgin and Shulgin, 1991). Although DOI is quite potent, it likely never became popular as a street drug because of its very prolonged duration of action, so it had never been placed into Schedule I of the Controlled Substances Act (although as of November 2015, there are congressional moves afoot to change that). Therefore, DOI has been commercially available to qualified investigators and did not require a U.S. Drug Enforcement Administration license to work with it. }}</ref><ref name="Today_2025">{{cite web | vauthors = Today P | title = Is the DEA Sabotaging Psychedelic Research? Inside the Push to Schedule DOI and DOC | date = 21 January 2025 | website = Psychedelics Today | url = https://psychedelicstoday.com/2025/01/21/is-the-dea-sabotaging-psychedelic-research-inside-the-push-to-schedule-doi-and-doc/ | access-date = 6 June 2025 }}</ref><ref name="Baggott_2023">{{cite journal | vauthors = Baggott MJ | title = Learning about STP: A Forgotten Psychedelic from the Summer of Love | journal = History of Pharmacy and Pharmaceuticals | volume = 65 | issue = 1 | pages = 93–116 | date = 1 October 2023 | doi = 10.3368/hopp.65.1.93 | issn = 2694-3034 | doi-access = free | url = https://hopp.uwpress.org/content/wphopp/65/1/93.full.pdf | access-date = 27 January 2025 }}</ref><ref name="Trout_2024">{{cite journal | vauthors = Trout K, Daley PF | title = The origin of 2,5-dimethoxy-4-methylamphetamine (DOM, STP) | journal = Drug Testing and Analysis | volume = 16 | issue = 12 | pages = 1496–1508 | date = December 2024 | pmid = 38419183 | doi = 10.1002/dta.3667 }}</ref> Unlike many other psychedelic drugs, DOI is not an explicitly controlled substance in the United States.<ref name="USDOJ" /> However, in 2023, the Drug Enforcement Administration (DEA) began taking steps to make DOI a controlled substance.<ref name="Federal Register 2023" /><ref name="Hu_2024" /><ref name="Palamar_2025" /> As of late 2025, DOI is poised to become a Schedule I controlled substance in the United States.<ref name="Cameron_2025" /><ref name="Palamar_2025" />

==Use and effects== In his book ''PiHKAL'' (''Phenethylamines I Have Known and Loved''), Alexander Shulgin lists DOI's dose as 1.5 to 3{{nbsp}}mg orally and its duration as 16 to 30{{nbsp}}hours.<ref name="PiHKAL" /> The effects of DOI have been reported to include feelings of unreality, strangeness, closed-eye imagery, time dilation, having none of LSD's sparkle, depression and sadness, enhanced eroticism, lightheadedness, and spaciness, among others.<ref name="PiHKAL" /> It was said to have little or no body load.<ref name="PiHKAL" /> The (''R'')-enantiomer, (''R'')-DOI, was active at doses of 1.0 to 2.3{{nbsp}}mg orally, whereas the (''S'')-enantiomer, (''S'')-DOI, was active at a dose of 6.3{{nbsp}}mg orally.<ref name="PiHKAL" />

== Interactions == {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

It is unclear whether DOI may interact with monoamine oxidase inhibitors (MAOIs).<ref name="RachedCampanaFiani2026">{{cite journal | vauthors = Rached G, Campana A, Fiani D, Nguyen C, Van den Eynde V, Gillman PK, Barnett BS | title = Safety and Efficacy of Monoamine Oxidase Inhibitors in Patients Who Use Psychoactive Substances: Potential Drug Interactions and Substance Use Disorder Treatment Data | journal = CNS Drugs | volume = | issue = | pages = | date = January 2026 | pmid = 41546846 | doi = 10.1007/s40263-025-01256-7 | url = }}</ref>

==Pharmacology== ===Pharmacodynamics=== ====Actions==== {| class="wikitable floatleft" style="font-size:small;" |+ {{Nowrap|DOI activities}} |- ! Target !! Affinity (K_i, nM) |- | 5-HT_1A || 2,219–4,177 |- | 5-HT_1B || >10,000 |- | 5-HT_1D || 458 |- | 5-HT_1E || 1,013–2,970 |- | 5-HT_1F || 1,739–2,511 |- | 5-HT_2A || 0.46–165 (K_i)<br />0.42–57 ({{Abbrlink|EC₅₀|half-maximal effective concentration}})<br />46–111% ({{Abbrlink|E_max|maximal efficacy}}) |- | 5-HT_2B || 1.4–336 (K_i)<br />1.4–39 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />71–103% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_2C || 1.8–48 (K_i)<br />0.14–178 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />90–114% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT₃ || >10,000 |- | 5-HT₄ || {{Abbr|ND|No data}} |- | 5-HT_5A || >10,000 |- | 5-HT_5B || 1,000 (rat) |- | 5-HT₆ || 2,113 |- | 5-HT₇ || 5,769 |- | α_1A || >10,000 |- | α_1B || >10,000 |- | α_1D || {{Abbr|ND|No data}} |- | α_2A || 74 |- | α_2B || 340 |- | α_2C || 601 |- | β₁ || 591 |- | β₂ || 139 |- | D₁ || 9,688 |- | D₂–D₅ || >10,000 |- | H₁ || 1,757 |- | H₂–H₄ || >10,000 |- | M₁ || 2,720 |- | M₂ || 1,989 |- | M₃ || 1,428 |- | M₄ || 578 |- | M₅ || 2,208 |- | TAAR₁ || >1,000 |- | I₁ || >10,000 |- | σ₁ || 8,565 |- | σ₂ || 9,172 |- | {{Abbrlink|SERT|Serotonin transporter}} || 685 (K_i) |- | {{Abbrlink|NET|Norepinephrine transporter}} || >10,000 (K_i) |- | {{Abbrlink|DAT|Dopamine transporter}} || >10,000 (K_i) |- | {{Abbrlink|MAO-A|Monoamine oxidase A}} || 37,000 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- | {{Abbrlink|MAO-B|Monoamine oxidase B}} || >200,000 ({{Abbr|IC₅₀|half-maximal inhibitory concentration}}) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title = PDSP Database | website = UNC | url = https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=doi&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | language = zu | access-date = 4 February 2025 }}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title = BindingDB BDBM28582 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine::CHEMBL6616::DOI::DOI,(+)::DOI,(-)::US20240166618, Compound DOI::[125I]2,5-dimethoxy-4-iodoamphetamine::[125I]4-iodo-2,5-dimethoxyphenylisopropylamine::[125I]DOI | website = BindingDB | url = https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=28582 | access-date = 4 February 2025 }}</ref><ref name="Ray_2010" /><ref name="Canal_2012" /><ref name="van_Wijngaarden_1997">{{cite book | vauthors = van Wijngaarden I, Soudijn W | chapter = 5-HT2A, 5-HT2B and 5-HT2C receptor ligands | title = Pharmacochemistry Library | volume = 27 | pages = 161–197 | date = 1997 | doi = 10.1016/s0165-7208(97)80013-x | publisher = Elsevier | isbn = 978-0-444-82041-9 }}</ref><ref name="ReyesParada_2019">{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Frontiers in Pharmacology | volume = 10 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | article-number = 1590 }}</ref><br /><ref name="Matsumoto_2014">{{cite journal | vauthors = Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, Nagao M, Aoki Y | title = 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis | journal = European Neuropsychopharmacology | volume = 24 | issue = 8 | pages = 1362–1370 | date = August 2014 | pmid = 24862256 | doi = 10.1016/j.euroneuro.2014.04.009 }}</ref><ref name="Rudin_2022">{{cite journal | vauthors = Rudin D, Luethi D, Hoener MC, Liechti ME | title = Structure-activity Relation of Halogenated 2,5-Dimethoxyamphetamines Compared to their α‑Desmethyl (2C) Analogues | journal = The FASEB Journal | volume = 36 | issue = S1 | date = 2022 | doi = 10.1096/fasebj.2022.36.S1.R2121 | article-number = fasebj.2022.36.S1.R2121 | issn = 0892-6638 | doi-access = free | url = https://www.researchgate.net/publication/360423277 }}</ref><ref name="AcunaCastillo_2002">{{cite journal | vauthors = Acuña-Castillo C, Villalobos C, Moya PR, Sáez P, Cassels BK, Huidobro-Toro JP | title = Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors | journal = British Journal of Pharmacology | volume = 136 | issue = 4 | pages = 510–519 | date = June 2002 | pmid = 12055129 | pmc = 1573376 | doi = 10.1038/sj.bjp.0704747 }}</ref><ref name="Hemanth_2023">{{cite journal | vauthors = Hemanth P, Nistala P, Nguyen VT, Eltit JM, Glennon RA, Dukat M | title = Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT_2A and 5-HT_2B serotonin receptors | journal = Frontiers in Pharmacology | volume = 14 | date = 2023 | pmid = 36762110 | pmc = 9902381 | doi = 10.3389/fphar.2023.1101290 | doi-access = free | article-number = 1101290 }}</ref><ref name="Wallach_2023">{{cite journal | vauthors = Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD | title = Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential | journal = Nature Communications | volume = 14 | issue = 1 | date = December 2023 | pmid = 38102107 | pmc = 10724237 | doi = 10.1038/s41467-023-44016-1 | bibcode = 2023NatCo..14.8221W | article-number = 8221 }}</ref> |}

DOI is a serotonin 5-HT_2A, 5-HT_2B and 5-HT_2C receptor agonist.<ref name="PDSPKiDatabase" /><ref name="BindingDB" /><ref name="Ray_2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | bibcode = 2010PLoSO...5.9019R | doi-access = free | article-number = e9019 }}</ref><ref name="Canal_2012" /> It is said to be approximately 5- to 12-fold selective for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor.<ref name="Poulie_2020">{{cite journal | vauthors = Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL | title = DARK Classics in Chemical Neuroscience: NBOMes | journal = ACS Chemical Neuroscience | volume = 11 | issue = 23 | pages = 3860–3869 | date = December 2020 | pmid = 31657895 | pmc = 9191638 | doi = 10.1021/acschemneuro.9b00528 | quote = The psychedelic phenethylamines typically exhibit less than 5–10-fold selectivity for 5-HT2A over 5-HT2C receptors.53,54 [...] The reported selectivity of 25CN-NBOH for 5-HT2A over 5-HT2C varies depending on the experimental conditions,49,59,60 but 25CN-NBOH is clearly more selective than DOI, which is only ~5-fold and 12-fold selective for 5-HT2A over 5-HT2C at the human and murine receptors, respectively.93–95 [...] }}</ref> The drug shows biased agonism at the serotonin 5-HT_2C receptor.<ref name="Bonniwell_2025">{{cite journal | vauthors = Bonniwell EM, Alabdali R, Hennessey JJ, McKee JL, Cavalco NG, Lammers JC, Moore EJ, Franchini L, Orlandi C, McCorvy JD | title = Serotonin 5-HT_2C Receptor Signaling Analysis Reveals Psychedelic Biased Agonism | journal = ACS Chemical Neuroscience | volume = 16 | issue = 19 | pages = 3899–3914 | date = October 2025 | pmid = 40944639 | doi = 10.1021/acschemneuro.5c00647 | pmc = 12629614 }}</ref>

The drug is not a monoamine releasing agent of serotonin or dopamine.<ref name="Matsumoto_2014" />

DOI is an agonist of the rat trace amine-associated receptor 1 (TAAR1).<ref name="Bunzow_2001">{{cite journal | vauthors = Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK | title = Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor | journal = Molecular Pharmacology | volume = 60 | issue = 6 | pages = 1181–1188 | date = December 2001 | pmid = 11723224 | doi = 10.1124/mol.60.6.1181 }}</ref>

The compound has a stereocenter, and ''R''-(−)-DOI is the more active stereoisomer.<ref name="PiHKAL" /><ref name="Glennon_2024" /> [[125I|[¹²⁵I]]]-''R''-(−)-DOI is used as a radioligand and indicator of the presence of serotonin 5-HT_2A receptors in studies.<ref name="Glennon_2024" />

====Effects==== (''R'')-DOI and several other serotonergic psychedelics, including TCB-2, LSD, and LA-SS-Az, have been found to show potent inhibition of tumor necrosis factor alpha (TNFα)-induced inflammation.<ref name="Miller_1998">{{cite journal | vauthors = Miller KJ, Gonzalez HA | title = Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells | journal = Annals of the New York Academy of Sciences | volume = 861 | issue = 1 | pages = 169–173 | date = December 1998 | pmid = 9928254 | doi = 10.1111/j.1749-6632.1998.tb10188.x | s2cid = 23264746 | bibcode = 1998NYASA.861..169M }}</ref><ref name="Yu_2008">{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 | s2cid = 25374241 }}</ref><ref name="Pelletier_2009">{{cite journal | vauthors = Pelletier M, Siegel RM | title = Wishing away inflammation? New links between serotonin and TNF signaling | journal = Molecular Interventions | volume = 9 | issue = 6 | pages = 299–301 | date = December 2009 | pmid = 20048135 | pmc = 2861806 | doi = 10.1124/mi.9.6.5 }}</ref> (''R'')-DOI was the most active of the assessed drugs and showed extremely high potency that was in the picomolar range and was an order of magnitude more potent than its action as a hallucinogen. TNFα may play a mediating role in the pathophysiology of degenerative inflammatory conditions like rheumatoid arthritis and Alzheimer's disease. (''R'')-DOI has also been found to block pulmonary inflammation, mucus hyperproduction, airway hyperresponsiveness, and to turn off key genes in pulmonary immune response, effects which block the development of allergic asthma in animal models.<ref>{{cite web | title = LSU Health New Orleans research finds psychedelic drug prevents asthma development in mice | url = http://www.eurekalert.org/pub_releases/2015-02/lsuh-lhn020915.php | website = EurekAlert! }}</ref> These findings could make DOI and other serotonin 5-HT_2A agonists novel treatments for inflammatory conditions.<ref>{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 | s2cid = 25374241 }}</ref>

DOI has been shown to induce rapid growth and reorganization of dendritic spines and synaptic connections with other neurons, processes known to underlie neuroplasticity, and hence to be a psychoplastogen.<ref>{{cite journal | vauthors = Jones KA, Srivastava DP, Allen JA, Strachan RT, Roth BL, Penzes P | title = Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 46 | pages = 19575–19580 | date = November 2009 | pmid = 19889983 | pmc = 2780750 | doi = 10.1073/pnas.0905884106 | doi-access = free | bibcode = 2009PNAS..10619575J }}</ref>

DOI, along with other psychedelics, has been reported to produce serotonergic neurotoxicity ''in vitro'' and in rodents ''in vivo'' at high doses given repeatedly.<ref name="RudinLiechtiLuethi2021">{{cite journal | vauthors = Rudin D, Liechti ME, Luethi D | title = Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics | journal = Exp Neurol | volume = 343 | issue = | article-number = 113778 | date = September 2021 | pmid = 34090893 | doi = 10.1016/j.expneurol.2021.113778 | url = | doi-access = free }}</ref><ref name="CapelaCarmoRemião2009">{{cite journal | vauthors = Capela JP, Carmo H, Remião F, Bastos ML, Meisel A, Carvalho F | title = Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview | journal = Mol Neurobiol | volume = 39 | issue = 3 | pages = 210–271 | date = June 2009 | pmid = 19373443 | doi = 10.1007/s12035-009-8064-1 | url = | quote = To further corroborate the fact that MDMA agonistic properties at the 5-HT2A receptor could produce neuronal death, DOI, a prototypical agonist of that receptor was added to cortical neurons [289]. DOI (10 to 100 μM for 24 or 48 h) also induced a dose- and time-dependent apoptotic cortical neuronal apoptosis, which was attenuated by ketanserin and R-96544 [289]. Ketanserin and R-96544 are competitive selective 5-HT2A receptor antagonists and only attenuated MDMA-induced cortical neurodegeneration. However, an antibody raised against the 5-HT2A-receptor, an "irreversible" non-competitive 5-HT2A receptor blocker, prevented almost completely MDMA- and DOI-induced cortical neurotoxicity [289, 290]. Neuronal apoptosis mediated by MDMA is accompanied by activation of caspase 3, which could be blocked by the antibody raised against the 5-HT2A receptor [290]. Therefore, it is likely that DOI- and MDMA-induced neuronal apoptosis arises from direct stimulation of the 5-HT2A receptor [289, 290].}}</ref><ref name="CapelaRuscherLautenschlager2006">{{cite journal | vauthors = Capela JP, Ruscher K, Lautenschlager M, Freyer D, Dirnagl U, Gaio AR, Bastos ML, Meisel A, Carvalho F | title = Ecstasy-induced cell death in cortical neuronal cultures is serotonin 2A-receptor-dependent and potentiated under hyperthermia | journal = Neuroscience | volume = 139 | issue = 3 | pages = 1069–1081 | date = 2006 | pmid = 16504407 | doi = 10.1016/j.neuroscience.2006.01.007 | url = }}</ref><ref name="CustodioOrtizLee2025">{{cite journal | vauthors = Custodio RJ, Ortiz DM, Lee HJ, Sayson LV, Kim M, Lee YS, Kim KM, Cheong JH, Kim HJ | title = Serotonin 2C receptors are also important in head-twitch responses in male mice | journal = Psychopharmacology (Berl) | volume = 242 | issue = 7 | pages = 1585–1605 | date = July 2025 | pmid = 37882810 | doi = 10.1007/s00213-023-06482-9 | url = }}</ref><ref name="CapeladaCostaAraujoCosta2013">{{cite journal | vauthors = Capela JP, da Costa Araújo S, Costa VM, Ruscher K, Fernandes E, Bastos Mde L, Dirnagl U, Meisel A, Carvalho F | title = The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons | journal = Neurotoxicology | volume = 34 | issue = | pages = 254–263 | date = January 2013 | pmid = 22983118 | doi = 10.1016/j.neuro.2012.09.005 | url = }}</ref> Serotonin 5-HT_2A receptor antagonism or knockdown could partially but greatly block this neurotoxicity ''in vitro''.<ref name="RudinLiechtiLuethi2021" /><ref name="CapelaCarmoRemião2009" /><ref name="CapelaRuscherLautenschlager2006" /><ref name="CapeladaCostaAraujoCosta2013" />

==Chemistry== DOI, also known as 2,5-dimethoxy-4-iodoamphetamine or as 2,5-dimethoxy-4-iodo-α-methylphenethylamine, is a substituted phenethylamine and amphetamine derivative and a member of the DOx family of drugs.<ref name="PiHKAL" /> It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine).<ref name="PiHKAL" />

===Synthesis=== The chemical synthesis of DOI has been described.<ref name="PiHKAL" />

===Analogues=== Analogues of DOI include 2C-I, 4C-I, DOB, DOC, DOF, and DOM, among many others.<ref name="PiHKAL" /> Other analogues include ''N''-methyl-DOI, IDNNA (''N'',''N''-dimethyl-DOI), DOI-NBOMe, and 25I-NBOMe, among others.<ref name="PiHKAL" />

==History== DOI was first described in the scientific literature by Ronald Coutts and Jerry Malicky in 1973.<ref name="Glennon_2024" /><ref name="Coutts_1973">{{cite journal | vauthors = Coutts RT, Malicky JL | title = The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM) | journal = Canadian Journal of Chemistry | volume = 51 | issue = 9 | pages = 1402–1409 | date = 1 May 1973 | doi = 10.1139/v73-210 | issn = 0008-4042 | url = https://cdnsciencepub.com/doi/10.1139/v73-210 | access-date = 27 November 2025 }}</ref> Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book ''PiHKAL'' (''Phenethylamines I Have Known and Loved'').<ref name="PiHKAL" /> The radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of David E. Nichols.{{Citation needed|date=November 2025}}

In January 2007, British police reported that three young men had fallen ill, reportedly, after taking DOI at a rave in Biggleswade, near Milton Keynes, and warned others who had taken it to seek medical attention.<ref name="BBC2007" /> This would appear to be the first indication that DOI has found more widespread use as a recreational drug in the United Kingdom.<ref name="BBC2007">{{Cite news | title = New drug alert as three taken ill | date = 29 January 2007 | url = https://news.bbc.co.uk/2/hi/uk_news/england/beds/bucks/herts/6308895.stm | work = BBC News }}</ref>

South Australian man Cody Edwards who brutally murdered Synamin Bell controversially plead guilty to the lesser sentence of manslaughter after attesting that the drug DOI had induced paranoia, and that he had subsequently acted in 'self-defence' when he had beaten the mother-of-three to death with a dumbbell, resulting in over fifty wounds.<ref>{{Cite web | title = Man sentenced to prison for manslaughter of partner, as government moves to close 'defence loophole' - ABC News | date = 6 September 2024 | url = https://www.abc.net.au/news/2024-09-06/cody-edwards-11-years-prison-manslaughter-synamin-bell/104319886 | access-date = 2024-09-06 | website = amp.abc.net.au }}</ref>

As of late 2025, DOI is expected to become a Schedule I controlled substance in the United States.<ref name="Cameron_2025" /><ref name="Palamar_2025" />

==Society and culture== ===Scientific research=== DOI is widely used in scientific research to study serotonergic psychedelics and the serotonin 5-HT₂ receptors.<ref name="Cameron_2025" /><ref name="Glennon_2024" /><ref name="Canal_2012" /><ref name="Palamar_2025" /> This is in part due to the fact that it is not a controlled substance in the United States.<ref name="Cameron_2025" /><ref name="Glennon_2024" /><ref name="Palamar_2025" /> However, DOI is poised to become a Schedule I controlled substance in this country in the near future, which will greatly restrict access to the drug.<ref name="Cameron_2025" /><ref name="Palamar_2025" /> A number of alternatives to DOI have been suggested for use in research, including the non-selective serotonin 5-HT_2A receptor agonist TCB-2 and the selective serotonin 5-HT_2A receptor agonists 25CN-NBOH and LPH-5.<ref name="Cameron_2025" /> Another notable but much more recent compound is TGF-8027, which is a highly selective serotonin 5-HT_2A receptor agonist and among the most selective such drugs currently known.<ref name="FenskeMcKeeCavalco2025">{{cite journal | vauthors = Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, Shacham N, Cuccurazzu B, Halberstadt AL, McCorvy JD | title = Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design | journal = J Med Chem | date = September 2025 | article-number = acs.jmedchem.5c01855 | pmid = 40997862 | doi = 10.1021/acs.jmedchem.5c01855 }}</ref>

===Legal status=== ====Australia==== The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) of Australia does not list DOI as a prohibited substance.<ref>{{cite web | vauthors = Gill A | title = POISONS STANDARD 2013 | date = 22 July 2013 | department = Therapeutic Goods Administration | publisher = Australian Government Department of Health and Ageing | access-date = 4 March 2014 | url = http://www.comlaw.gov.au/Details/F2013L01607/229bdf2e-7014-4379-b751-0b584f55d699 | format = PDF }}</ref>

====Canada==== Listed as a Schedule 1<ref name="CDSA Schedule I: Amphetamines">{{Cite web | title = Controlled Drugs and Substances Act: Legislative history · Schedule I · Section 19: Tramadol [Proposed]; Amphetamines | url = http://isomerdesign.com/Cdsa/schedule.php?schedule=1&section=18.5&structure=C | website = isomerdesign.com | access-date = 2012-11-27 | archive-date = 2022-03-31 | archive-url = https://archive.today/20220331223632/http://isomerdesign.com/Cdsa/schedule.php?schedule=1&section=18.5&structure=C }}</ref> as it is an analogue of amphetamine.<ref name="Definitions and Interpretations">{{Cite web | title = Controlled Drugs and Substances Act: Definitions and Interpretations | url = http://isomerdesign.com/Cdsa/definitions.php?structure=C | website = isomerdesign.com | access-date = 2012-11-27 | archive-date = 2013-11-10 | archive-url = https://web.archive.org/web/20131110213450/http://isomerdesign.com/Cdsa/definitions.php?structure=C }}</ref> The CDSA was updated as a result of the ''Safe Streets and Communities Act,'' changing amphetamines from Schedule 3 to Schedule 1.<ref name="Safe Streets Act">{{cite web | title = Backgrounder: The Safe Streets and Communities Act Four Components Coming Into Force | url = http://www.justice.gc.ca/eng/news-nouv/nr-cp/2012/doc_32759.html | work = Department of Justice | publisher = Government of Canada | archive-url = https://web.archive.org/web/20121018122345/http://www.justice.gc.ca/eng/news-nouv/nr-cp/2012/doc_32759.html | archive-date = 18 October 2012 }}</ref>

====Denmark==== Illegal since 8 April 2007.<ref name="Erowid DOC Vault : Legal status">{{Cite web | title = Erowid DOC Vault: Legal Status | url = https://www.erowid.org/chemicals/doc/doc_law.shtml | website = www.erowid.org }}</ref>

====Finland==== DOI is classified as a psychoactive substance banned from the consumer market in Finland.<ref>{{cite web | title = FINLEX ® - Ajantasainen lainsäädäntö: Valtioneuvoston asetus kuluttajamarkkinoilta… 1130/2014 | url = https://www.finlex.fi/fi/lainsaadanto/2014/1130 }}</ref>

====Sweden==== ''Sveriges riksdag'' added DOI to schedule I (''"substances, plant materials and fungi which normally do not have medical use"'') as narcotics in Sweden as of August 30, 2007, published by ''Medical Products Agency'' in their regulation LVFS 2007:10 listed as DOI, 4-jod-2,5-dimetoxi-amfetamin.<ref>{{Cite web | title = Läkemedelsverkets föreskrifter - LVFS och HSLF-FS &#124; Läkemedelsverket | url = https://badzsoba.com.pl/b/lvfs_2007-10.pdf }}</ref>

====United States==== As of 2023, DOI is not scheduled in the United States.<ref name="USDOJ">{{cite web | title = PART 1308 - Section 1308.11 Schedule I | url = http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm | website = www.deadiversion.usdoj.gov | access-date = 2014-12-17 | archive-date = 2009-08-27 | archive-url = https://web.archive.org/web/20090827043725/http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm }}</ref> However, DOI may be considered an analog of other controlled DOx drugs like DOB, in which case, sales or possession could be prosecuted under the Federal Analogue Act. The drug's non-controlled status has made it usefully accessible for use in scientific research, which has contributed to its popularity for such uses.<ref name="Glennon_2024" />

In December 2023, the United States Drug Enforcement Administration (DEA) issued a notice of proposed rulemaking that would classify both DOI and DOC as schedule I controlled substances.<ref name="Federal Register 2023">{{cite web | title = Schedules of Controlled Substances: Placement of 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-chloroamphetamine (DOC) in Schedule I | url = https://www.regulations.gov/document/DEA-2022-0026-0001/comment | website = www.regulations.gov }}</ref> However, in May 2024, it was reported that the DEA's June 10, 2024 hearing on scheduling of DOI and DOC had been postponed.<ref name="Hu_2024">{{citation | last=Hu | first=Jane C. | title=Revisions made to report critical of Lykos's research on MDMA-assisted therapy; Lawsuit postpones hearing for contentious DEA proposal; and former MAPS employees make troubling allegations | work=The Microdose | publisher=U.C. Berkeley Center for the Science of Psychedelics | date=17 May 2024 | url=https://themicrodose.substack.com/p/revisions-made-to-report-critical | access-date=6 February 2025 | page=}}</ref><ref name="Law3602024">{{cite web | title = Judge Halts DEA's Hearing On Proposed Psychedelics Ban | date = 9 May 2024 | website = Law360 | url = https://www.law360.com/cannabis/articles/1835534/judge-halts-dea-s-hearing-on-proposed-psychedelics-ban | access-date = 6 February 2025 }}</ref> This followed opposition to the proposal by psychedelic researchers.<ref name="Hu_2024" /> DOI is frequently used in scientific research due in considerable part to its non-scheduled status,<ref name="Glennon_2024" /><ref name="Canal_2012" /> and DOI becoming a controlled substance would cause problems for scientists.<ref name="Federal Register 2023" /><ref name="Hu_2024" /> In any case, an administrative judge recommended placement of DOI into Schedule I in June 2025, and it is likely that the drug will be scheduled.<ref name="Cameron_2025" /><ref name="Palamar_2025">{{cite journal | vauthors = Palamar JJ, Fitzgerald ND | title = The Epidemiology of Recreational Use and Availability of DOC and DOI in the United States | journal = Journal of Psychoactive Drugs | pages = 1–10 | date = October 2025 | pmid = 41065346 | doi = 10.1080/02791072.2025.2570937 | pmc = 12645445 }}</ref>

DOI is a Schedule I controlled substance in the state of Florida.<ref name="Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL">{{cite web | title = Statutes & Constitution :View Statutes: Online Sunshine | url = http://leg.state.fl.us/statutes/index.cfm?App_mode=Display_Statute&URL=0800-0899/0893/0893.html | website = leg.state.fl.us }}</ref>

== See also == * DOx (psychedelics) * 5-HT_2A receptor § Anti-inflammatory effects

== References == {{Reflist}}

== External links == {{Sister project links|auto=y}} * [https://isomerdesign.com/pihkal/explore/67 DOI - Isomer Design] * [https://psychonautwiki.org/wiki/DOI DOI - PsychonautWiki] * [http://www.erowid.org/chemicals/doi/ DOI - Erowid] * [https://web.archive.org/web/20090802035910/http://leda.lycaeum.org/?ID=180 DOI - Lycaeum] * [http://www.erowid.org/library/books_online/PiHKAL/PiHKAL067.shtml DOI - PiHKAL - Erowid] * [http://PiHKAL.info/read.php?domain=pk&id=67 DOI - PiHKAL - Isomer Design] * [https://www.bluelight.org/xf/threads/224091 The Big & Dandy DOI Thread - Bluelight] * [https://tripsitter.com/doi/ DOI (2,5-Dimethoxy-4-iodoamphetamine): A Potent & Unique Psychedelic Compound - Tripsitter]

{{Psychedelics}} {{Serotonin receptor modulators}} {{TAAR modulators}} {{Phenethylamines}}

{{DEFAULTSORT:Dimethoxy-4-iodoamphetamine, 2,5-}}

Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:Anti-inflammatory agents Category:Biased ligands Category:Designer drugs Category:DOx (psychedelics) Category:Iodobenzene derivatives Category:PET radiotracers Category:PiHKAL Category:Psychoplastogens Category:Psychedelic drug research Category:Psychedelic phenethylamines Category:TAAR1 agonists Category:TNF inhibitors