2,5-Dimethoxy-4-iodoamphetamine

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2,5-Dimethoxy-4-iodoamphetamine (DOI) is a psychedelic drug of the amphetamine and 4-substituted-2,5-dimethoxyamphetamine (DOx) families.<ref name="GlennonDukat2024">Template:Cite journal</ref><ref name="CanalMorgan2012">Template:Cite journal</ref> It is relatively little-used as a recreational drug but is frequently used in scientific research in the study of psychedelics and serotonin receptors.<ref name="GlennonDukat2024" /><ref name="CanalMorgan2012" />

DOI acts as a potent serotonin 5-HT₂ receptor agonist, including of the serotonin 5-HT_2A and 5-HT_2C receptors.<ref name="GlennonDukat2024" /><ref name="CanalMorgan2012" /> The compound has a stereocenter, and R-(−)-DOI is the more active stereoisomer. [¹²⁵I]-R-(−)-DOI is used as a radioligand and indicator of the presence of serotonin 5-HT_2A receptors in studies.<ref name="GlennonDukat2024" />

DOI's effects have been compared to LSD, although there are differences that experienced users can distinguish.Template:Citation needed Besides the longer duration of DOI compared to LSD, the trip tends to be more energetic than an LSD trip, with more body load and a different subjective visual experience.Template:Citation needed The after effects include residual stimulation and difficulty sleeping, which, depending on the dose, may persist for days.<ref name="pihkal">Template:Cite book</ref> While rare, DOI has sometimes been sold as a substitute for LSD, or even sold falsely as LSD, which may be dangerous because DOI does not have the same established safety profile as LSD.<ref name="dea micro">Template:Cite magazine</ref>

DOI was first synthesized in 1973, by Coutts and Malicky.<ref name="GlennonDukat2024" /> Unlike many other psychedelic drugs, DOI is not an explicitly controlled substance in the United States.<ref name="USDOJ" /> However, it could be considered a controlled substance under the Federal Analog Act. In any case, its non-controlled status has made DOI usefully accessible for use in scientific research, which has contributed to its popularity for such uses.<ref name="GlennonDukat2024" /> In December 2023, the Drug Enforcement Agency (DEA) proposed making DOI a schedule I controlled substance.<ref name="Federal Register 2023" /> This proposal has been opposed by psychedelic researchers and the DEA has consequently delayed its June 2024 hearing on the proposal.<ref name="Jane2024" />

Pharmacology

Pharmacodynamics

Actions

Template:Nowrap

Target	Affinity (Ki, nM)
5-HT1A	2,219–4,177
5-HT1B	>10,000
5-HT1D	458
5-HT1E	1,013–2,970
5-HT1F	1,739–2,511
5-HT2A	0.46–165 (Ki) 0.42–57 (Template:Abbrlink) 46–111% (Template:Abbrlink)
5-HT2B	1.4–336 (Ki) 1.4–39 (Template:Abbr) 71–103% (Template:Abbr)
5-HT2C	1.8–48 (Ki) 0.14–178 (Template:Abbr) 90–114% (Template:Abbr)
5-HT3	>10,000
5-HT4	Template:Abbr
5-HT5A	>10,000
5-HT5B	1,000 (rat)
5-HT6	2,113
5-HT7	5,769
α1A	>10,000
α1B	>10,000
α1D	Template:Abbr
α2A	74
α2B	340
α2C	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
Template:Abbrlink	685 (Ki)
Template:Abbrlink	>10,000 (Ki)
Template:Abbrlink	>10,000 (Ki)
Template:Abbrlink	37,000 (Template:Abbr)
Template:Abbrlink	>200,000 (Template:Abbr)
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">{{#invoke:citation/CS1|citation		CitationClass=web }}</ref><ref name="BindingDB">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref><ref name="Ray2010" /><ref name="CanalMorgan2012" /><ref name="vanWijngaardenSoudijn1997">Template:Cite book</ref><ref name="Reyes-ParadaIturriaga-VasquezCassels2019">Template:Cite journal</ref><ref name="MatsumotoMaenoKato2014">Template:Cite journal</ref><ref name="RudinLuethiHoener2022">Template:Cite journal</ref><ref name="Acuña-CastilloVillalobosMoya2002">Template:Cite journal</ref><ref name="HemanthNistalaNguyen2023">Template:Cite journal</ref><ref name="WallachCaoCalkins2023">Template:Cite journal</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="Ray2010">Template:Cite journal</ref><ref name="CanalMorgan2012" /> 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="PoulieJensenHalberstadt2020">Template:Cite journal</ref>

The drug is not a monoamine releasing agent of serotonin or dopamine.<ref name="MatsumotoMaenoKato2014">Template:Cite journal</ref>

DOI is an agonist of the rat trace amine-associated receptor 1 (TAAR1).<ref name="BunzowSondersArttamangkul2001">Template:Cite journal</ref>

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="pmid9928254">Template:Cite journal</ref><ref name="pmid18708586">Template:Cite journal</ref><ref name="pmid20048135">Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> These findings could make DOI and other serotonin 5-HT_2A agonists novel treatments for inflammatory conditions.<ref>Template:Cite journal</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>Template:Cite journal</ref>

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. It is structurally related to the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). Other closely related DOx drugs include DOM, DOB, DOC, and DOF, among many others.

History

DOI was first synthesized by Alexander Shulgin.<ref name="pihkal" /> The radioactive iodine-125 form of DOI for PET imaging was first developed in the lab of David E. Nichols.

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. This would appear to be the first indication that DOI has found more widespread use as a recreational drug in the UK.<ref>Template:Cite 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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Society and culture

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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Canada

Listed as a Schedule 1<ref name="CDSA Schedule I: Amphetamines">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> as it is an analogue of amphetamine.<ref name="Definitions and Interpretations">{{#invoke:citation/CS1|citation |CitationClass=web }}</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Denmark

Illegal since 8 April 2007.<ref name="Erowid DOC Vault : Legal status">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Finland

DOI is classified as a psychoactive substance banned from the consumer market in Finland.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

United States

As of 2023, DOI is not scheduled in the United States,<ref name="USDOJ">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> but it is likely that DOI would be considered an analog (of DOB), in which case, sales or possession could be prosecuted under the Federal Analogue Act. In December 2023, the US Drug Enforcement Administration (DEA) issued a notice of proposed rulemaking that would classify both DOI and 2,5-dimethoxy-4-chloroamphetamine (DOC) as schedule I controlled substances.<ref name="Federal Register 2023">{{#invoke:citation/CS1|citation |CitationClass=web }}</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="Jane2024">Template:Citation</ref><ref name="Law3602024">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This followed opposition to the proposal by psychedelic researchers.<ref name="Jane2024" /> DOI is frequently used in scientific research due in considerable part to its non-scheduled status,<ref name="GlennonDukat2024" /><ref name="CanalMorgan2012" /> and DOI becoming a controlled substance would cause problems for scientists.<ref name="Federal Register 2023" /><ref name="Jane2024" />

DOI is a Schedule I controlled substance in the state of Florida.<ref name="Florida Statutes - Chapter 893 - DRUG ABUSE PREVENTION AND CONTROL">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

See also

• 5-HT_2A receptor § Anti-inflammatory effects

External links

• DOI - Isomer Design
• DOI - PsychonautWiki
• DOI - Erowid
• DOI - Lycaeum
• DOI - PiHKAL - Erowid
• DOI - PiHKAL - Isomer Design
• DOI (2,5-Dimethoxy-4-iodoamphetamine): A Potent & Unique Psychedelic Compound - Tripsitter

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