2,5-Dimethoxy-4-iodoamphetamine

2,5-Dimethoxy-4-iodoamphetamine (DOI) is a psychedelic drug of the phenethylamine, amphetamine, and DOx families. It is little-used recreationally, but is widely used in scientific research in the study of psychedelics and serotonin receptors. Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved). Owing to their very long and disagreeable durations however, DOI and other DOx drugs have seen very little recreational availability and use. Unlike many other psychedelic drugs, DOI is not an explicitly controlled substance in the United States.

Pharmacology

Pharmacodynamics

Actions

{| class="wikitable floatleft" style="font-size:small;"

|+

|-

! 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 ()<br />46–111% ()

|-

| 5-HT_2B || 1.4–336 (K_i)<br />1.4–39 ()<br />71–103% ()

|-

| 5-HT_2C || 1.8–48 (K_i)<br />0.14–178 ()<br />90–114% ()

|-

| 5-HT₃ || >10,000

|-

| 5-HT₄ ||

|-

| 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 ||

|-

| 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

|-

| || 685 (K_i)

|-

| || >10,000 (K_i)

|-

| || >10,000 (K_i)

|-

| || 37,000 ()

|-

| || >200,000 ()

|- 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: <br />

|}

DOI is a serotonin 5-HT_2A, 5-HT_2B and 5-HT_2C receptor agonist. The drug shows biased agonism at the serotonin 5-HT_2C receptor.

The drug is not a monoamine releasing agent of serotonin or dopamine.

The compound has a stereocenter, and R-(−)-DOI is the more active stereoisomer. (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.

DOI, along with other psychedelics, has been reported to produce serotonergic neurotoxicity in vitro and in rodents in vivo at high doses given repeatedly. Serotonin 5-HT_2A receptor antagonism or knockdown could partially but greatly block this neurotoxicity in vitro. Subsequently, it was described in greater detail by Alexander Shulgin in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved).

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.

As of late 2025, DOI is expected to become a Schedule I controlled substance in the United States.

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. 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. 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 a Schedule I controlled substance in the state of Florida.

See also

• DOx (psychedelics)
• 5-HT_2A receptor § Anti-inflammatory effects

References

External links

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