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.