Don’t Block Psychedelic Research

In the late 1960s and early 1970s, chemist Alexander “Sasha” Shulgin pioneered a new era of psychedelic research through the systematic modification of chemical compounds related to the naturally occurring psychedelic mescaline. Through these compounds, known as substituted phenethylamines, Shulgin and his peers explored how subtle chemical substitutions at specific positions on the aromatic ring dramatically altered psychoactive properties.

Of the 179 compounds detailed in his opus Phenethylamines I Have Known and Loved (PiHKAL), one such chemical, 2,5-dimethoxy-4-methylamphetamine (DOM) (which Shulgin called his “hair shirt” and, à la Albert Hofmann, his “problem child”), became the starting material for a pair of Canadian chemists in 1973, which culminated in the synthesis of two important chemicals: 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-chloroamphetamine (DOC).

In the fifty years since Coutts and Malicky first synthesized DOI and DOC, DOI in particular has been pivotal in understanding serotonin receptor pharmacology and function. Due to its high selectivity for the 5-HT2A receptor subtype, DOI is distinguished from earlier psychedelics like LSD, which, although potent, interact promiscuously with multiple serotonin, dopamine, and adrenergic receptors. For this reason DOI became one of the most widely used synthetic psychedelics in neuroscience research for studying 5-HT2A receptor function.

1979 represented a groundbreaking year in serotonin research, when the 5-HT1 and 5-HT2 were isolated in the mammalian brain by Snyder and Peroutka. Soon after, it was found that most serotonin antagonists (molecules that bind to a receptor and block the activity of an agonist) at that time would bind with higher affinity to the 5-HT2 receptor than the 5-HT1 receptor. For this reason, researchers speculated that antagonists exerted their effects by binding to the 5-HT2 while 5-HT1 was the site of action of agonists.

DOI’s useful pharmacological properties and legal status made it ubiquitous in biomedical research for decades and has resulted in close to 1,000 scholarly publications mentioning DOI.

In addition to its pivotal role in serotonin receptor research, DOI has shown great therapeutic potential in a number of neuropsychiatric disorders, such as Major Depressive Disorder, PTSD, and addiction, based on preclinical research.

With the breakthrough success of recent psychedelic clinical trials, the use of DOI and DOC in preclinical models of psychiatric disease has only increased, leading to many unexpected and interesting findings.

In particular, the R-enantiomer of DOI has shown incredible anti-inflammatory properties and is active at concentrations in the picomolar range (one trillionth of mole of solute per liter of solvent), making it about 500x more potent than the most potent anti-inflammatory agents currently available (corticosteroids), at their respective targets.

DOI’s use revolutionized psychiatric drug discovery since it was used to map the distribution of serotonin receptor in the brain, which are critical in learning, memory and psychiatric disease. For this reason, over 80% of the antidepressant drugs on the market affect the serotonin system.

The placement of DOI and DOC in Schedule I of the CSA is not commensurate with its abuse potential and is further complicated by its extensive utility in scientific research. The low abuse potential of psychedelics combined with mounting preclinical and clinical study of their efficacy provides evidence against their placement in Schedule I

SSDP opposes the placement of DOI and DOC in Schedule 1 of the Controlled Substances Act.

*For a more comprehensive scientific history of DOI, DOC, and other DOX compounds, see 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 by Glennon and Dukat.

Placing DOI and DOC in Schedule I would jeopardize vital scientific progress and potentially life-saving research, and yet SSDP is the only drug policy organization currently fighting to keep DOI and DOC off the Controlled Substances Act.

Click through the graphics below to read a portion of court transcripts from SSDP’s legal battle against the DEA. To read the full transcript, simply click the graphic you would like to view.

The Controlled Substances Act (CSA) in the United States (U.S.) and the United Nations (U.N.) Single Convention on Narcotics set out a system for classifying controlled substances and regulating their manufacture, importation, possession, use, and distribution. US drug policy is further complicated by obligations to follow scheduling recommendations made by the UN. as in the case of DOC. As such, SSDP’s efforts extend to global drug policy reform.

For instance: SSDP presented on research harm at the United Nations Commission on Narcotic Drugs (CND) in Vienna, Austria (February 2025) and at the United Nations High-Level Political Forum (July 2025), highlighting how Schedule I classification obstructs critical scientific research worldwide. Additionally, SSDP Science Policy Committee Co-Chair and M.D./PhD Candidate Joseph Hennessey was selected as one of just 17 speakers at the Intersessional Meeting of the Commission on Narcotic Drugs (October 2025).

He addressed how burdensome requirements for researchers studying controlled substances have slowed scientific development and emphasized the recent passage of the HALT Fentanyl Act in the United States, which streamlines the licensing process for scientists working with Schedule I substances. He proposed that member nations adopt similar reforms, and, at the same time, argued that the measure does not go far enough, as substantial barriers to research still remain.

Enacting these reforms would significantly lower barriers for researchers, making it easier to conduct research with controlled substances and accelerating scientific discovery. This combined domestic and international strategy positions SSDP as a leading voice for sensible drug policy and accessible research.

On March 12, 2025, SSDP Science Policy Committee Co-founder Dr. Elijah Ullman, PhD traveled to Vienna, Austria to represent SSDP at the 68th Session of the UN Commission on Narcotic Drugs (CND), where he strongly urged international lawmakers to prevent poorly planned drug scheduling regulations from halting vital scientific research, and made the following recommendations:

Recommendations for the U.S. and U.N.

1) The DEA asks the following question in the 8 Factor Analysis as Factor 6, “What, if any, Risk there is to the Public Health?” This question should be amended to include or require consideration of, “What, if any, harms would the scheduling of a drug pose to public health? And how do these harms compare; is the drug’s harm to the public health significantly greater than the harm to research?”

2) In line with the Biden-Harris Administration’s previous goals and recommendation by the U.K. ACMD, Schedule I drugs, for scientific research, should only be subject to the registration requirements of Schedule II drugs. OR;

3) Drug class-wide registration be established such that a researcher who wishes to study e.g. hallucinogenic compounds can purchase any compound within a specific class without requiring that an amendment to the Schedule I registration be submitted if a researcher wishes to study any one of the compounds in a class. This action will promote greater flexibility in researchers’ experimental design.

4) Increase funding for unexpected lines of research from Schedule I drugs. Ibogaine, a Schedule I drug, has demonstrated some efficacy in the treatment of addiction broadly but is a Schedule I narcotic due to alleged abuse potential. Recent work has established that non-psychoactive analogs of Ibogaine can be created with notable pre-clinical efficacy in the reduction of alcohol and heroin-seeking behavior. By funding novel, unexpected lines of research such as this, there may be a reduction in trafficking and the use of ibogaine for self-experimentation.

5) Change “…drugs with no currently accepted medical use…” to insert “or scientific” between medical and use to the definition of Schedule I drugs.