# 2,5-Dimethoxy-4-iodoamphetamine

2,5-Dimethoxy-4-iodoamphetamine (DOI) is a psychedelic drug of the amphetamine and 4-substituted-2,5-dimethoxyamphetamine (DOx) families. It is relatively little-used as a recreational drug but is frequently used in scientific research in the study of psychedelics and serotonin receptors.
DOI acts as a potent serotonin 5-HT$_2$ receptor agonist, including of the serotonin 5-HT$_{2A}$ and 5-HT$_{2C}$ receptors. The compound has a stereocenter, and R-(−)-DOI is the more active stereoisomer. [$^{125}$I]-R-(−)-DOI is used as a radioligand and indicator of the presence of serotonin 5-HT$_{2A}$ receptors in studies.
DOI's effects have been compared to LSD, although there are differences that experienced users can distinguish. 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. The after effects include residual stimulation and difficulty sleeping, which, depending on the dose, may persist for days. 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.
DOI was first synthesized in 1973, by Coutts and Malicky. Unlike many other psychedelic drugs, DOI is not an explicitly controlled substance in the United States. 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. In December 2023, the Drug Enforcement Agency (DEA) proposed making DOI a schedule I controlled substance. This proposal has been opposed by psychedelic researchers and the DEA has consequently delayed its June 2024 hearing on the proposal.

## Pharmacology
### Pharmacodynamics
#### Actions

DOI activities :
| Target | Affinity (K$_i$, nM) |
| 5-HT$_{1A}$ | 2,219 |
| 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$_i$) 0.42–57 (EC$_{50}$Tooltip half-maximal effective concentration) 46–111% (E$_{max}$Tooltip maximal efficacy) |
| 5-HT$_{2B}$ | 1.4–336 (K$_i$) 1.4 (EC$_{50}$) |
| 5-HT$_{2C}$ | 1.8–46 (K$_i$) 0.14–178 (EC$_{50}$) 90–110% (E$_{max}$) |
| 5-HT$_3$ | >10,000 |
| 5-HT$_4$ | ND |
| 5-HT$_{5A}$ | >10,000 |
| 5-HT$_{5B}$ | 1,000 (rat) |
| 5-HT$_6$ | 2,113 |
| 5-HT$_7$ | 5,769 |
| α$_{1A}$ | >10,000 |
| α$_{1B}$ | >10,000 |
| α$_{1D}$ | ND |
| α$_{2A}$ | 74 |
| α$_{2B}$ | 340 |
| α$_{2C}$ | 601 |
| β$_1$ | 591 |
| β$_2$ | 139 |
| D$_1$ | 9,688 |
| D$_2$–D$_5$ | >10,000 |
| H$_1$ | 1,757 |
| H$_2$–H$_4$ | >10,000 |
| M$_1$ | 2,720 |
| M$_2$ | 1,989 |
| M$_3$ | 1,428 |
| M$_4$ | 578 |
| M$_5$ | 2,208 |
| TAAR$_1$ | >1,000 |
| I$_1$ | >10,000 |
| σ$_1$ | 8,565 |
| σ$_2$ | 9,172 |
| SERTTooltip Serotonin transporter | 685 (K$_i$) |
| NETTooltip Norepinephrine transporter | >10,000 (K$_i$) |
| DATTooltip Dopamine transporter | >10,000 (K$_i$) |
| MAO-ATooltip Monoamine oxidase A | 37,000 (IC$_{50}$) |
| MAO-BTooltip Monoamine oxidase B | >200,000 (IC$_{50}$) |
| Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: ||
DOI is a serotonin 5-HT$_{2A}$, 5-HT$_{2B}$ and 5-HT$_{2C}$ receptor agonist. 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.
The drug is not a monoamine releasing agent of serotonin or dopamine.
DOI is an agonist of the rat trace amine-associated receptor 1 (TAAR1).

#### 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. (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. These findings could make DOI and other serotonin 5-HT$_{2A}$ agonists novel treatments for inflammatory conditions.
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.

## 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. 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.
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.

## 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.

#### Canada

Listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets and Communities Act, changing amphetamines from Schedule 3 to Schedule 1.

#### Denmark

Illegal since 8 April 2007.

#### Finland

DOI is classified as a psychoactive substance banned from the consumer market in Finland.

#### 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.

#### United States

As of 2023, DOI is not scheduled in the United States, 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. However, in May 2024, it was reported that the DEA's June 10, 2024 hearing on scheduling of DOI and DOC had been postponed. This followed opposition to the proposal by psychedelic researchers. DOI is frequently used in scientific research due in considerable part to its non-scheduled status, and DOI becoming a controlled substance would cause problems for scientists.
DOI is a Schedule I controlled substance in the state of Florida.