2,5-Dimethoxy-4-iodoamphetamine (DOI) is a

psychedelic drug Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluc ...

of the

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and

4-substituted-2,5-dimethoxyamphetamine 4-Substituted-2,5-dimethoxyamphetamines (DO''x'') is a chemical class of Substitution reaction, substituted amphetamine derivative (chemistry), derivatives featuring methoxy functional group, groups at the 2- and 5- positions of the phenyl simp ...

(DOx) families. It is relatively little-used as a

recreational drug Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

but is frequently used in

scientific research The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...

in the study of psychedelics and

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s. DOI acts as a potent

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT₂ receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

, including of the serotonin 5-HT_2A and 5-HT_2C receptors. The compound has a

stereocenter In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

, and ''R''-(−)-DOI is the more active

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

. sup>125I''R''-(−)-DOI is used as a radioligand and indicator of the presence of

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 Stimulation is the encouragement of development or the cause of activity in general. For example, "The press provides stimulation of political discourse." An interesting or fun activity can be described as "stimulating", regardless of its physic ...

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 Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

profile as LSD. Owing to their very long durations, which users tend to find disagreeable however, DOI and other DOx psychedelics have seen very little recreational use. 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 The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

. 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.

Interactions

Pharmacology

Pharmacodynamics

Actions

DOI is a

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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. DOI is an agonist of the rat

trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1).

Effects

(''R'')-DOI and several other

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

s, including TCB-2, LSD, and LA-SS-Az, have been found to show potent inhibition of tumor necrosis factor alpha (TNFα)-induced

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. (''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 Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

. TNFα may play a mediating role in the

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

of degenerative inflammatory conditions like

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. (''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 Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s. 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 A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

, processes known to underlie

neuroplasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...

, and hence to be a

psychoplastogen Psychoplastogens, also known as neuroplastogens, are a group of Small molecule#Drugs, small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single admin ...

Chemistry

DOI, also known as 2,5-dimethoxy-4-iodoamphetamine or as 2,5-dimethoxy-4-iodo-α-methylphenethylamine, is a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and a member of the DOx family of drugs. It is structurally related to the

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

phenethylamine psychedelic

mescaline Mescaline, also known as mescalin or mezcalin, and in chemical terms 3,4,5-trimethoxyphenethylamine, is a natural product, naturally occurring psychedelic drug, psychedelic alkaloid, protoalkaloid of the substituted phenethylamine class, found ...

(3,4,5-trimethoxyphenethylamine). Other closely related DOx drugs include DOM,

DOB DOB or Dob often refers to date of birth. DOB or Dob may also refer to: Biochemistry * 2,5-dimethoxy-4-bromoamphetamine, Bromo-DMA, a psychedelic drug ** Meta-DOB, related substance ** Methyl-DOB, related substance * HLA-DOB, human gene Organiz ...

, DOC, and DOF, among many others.

History

DOI was first synthesized by

Alexander Shulgin Alexander Theodore "Sasha" Shulgin (June 17, 1925 – June 2, 2014) was an American biochemist, broad researcher of synthetic psychoactive compounds, and author of works regarding these, who independently explored the organic chemistry and ph ...

. The

radioactive Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...

iodine-125 Iodine-125 (125I) is a radioisotope of iodine which has uses in biological assays, nuclear medicine imaging and in radiation therapy as brachytherapy to treat a number of conditions, including prostate cancer, uveal melanomas, and brain tumor ...

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 Biggleswade ( ) is a market town and civil parish in Central Bedfordshire in Bedfordshire, England. It lies on the River Ivel, 11 miles (18 km) south-east of Bedford. Its population was 16,551 in the 2011 United Kingdom census, This figur ...

, near

Milton Keynes Milton Keynes ( ) is a city status in the United Kingdom, city in Buckinghamshire, England, about north-west of London. At the 2021 Census, the population of Milton Keynes urban area, its urban area was 264,349. The River Great Ouse forms t ...

, 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

in the UK. South Australian man Cody Edwards who brutally murdered Synamin Bell controversially plead guilty to the lesser sentence of

manslaughter Manslaughter is a common law legal term for homicide considered by law as less culpable than murder. The distinction between murder and manslaughter is sometimes said to have first been made by the ancient Athenian lawmaker Draco in the 7th ce ...

after attesting that the drug DOI had induced

paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...

, and that he had subsequently acted in ‘

self-defence Self-defense (self-defence primarily in Commonwealth English) is a countermeasure that involves defending the health and well-being of oneself from harm. The use of the right of self-defense as a legal justification for the use of force in tim ...

’ 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

), in which case, sales or possession could be prosecuted under the

Federal Analogue Act The Federal Analogue Act, , is a section of the United States Controlled Substances Act passed in 1986 which allows any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were listed ...

. In December 2023, the US

Drug Enforcement Administration The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...

(DEA) issued a

notice of proposed rulemaking A notice of proposed rulemaking (NPRM) is a public notice that is issued by law when a U.S. federal agency wishes to add, remove, or change a rule or regulation as part of the rulemaking process. The notice is an important part of US administrat ...

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

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.

References

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
{{DEFAULTSORT:Dimethoxy-4-iodoamphetamine, 2,5- 5-HT2A agonists 5-HT2B agonists 5-HT2C agonists Designer drugs DOx (psychedelics) Iodobenzene derivatives PET radiotracers Psychedelic phenethylamines TAAR1 agonists TNF inhibitors