4-AcO-DMT

psilacetin, O-acetylpsilocin, psilocetin

In 1963, German chemists Albert Hofmann and Franz Troxler patented their discovery of 4-AcO-DMT along with other indole esters they had synthesized.1 Just as Hofmann put LSD aside for five years after synthesizing it in 1938, unaware of its psychedelic properties, psilacetin was patented but shelved. According to the United Nations Office on Drugs and Crime, synthetic tryptamines like psilacetin began appearing in illicit drug markets throughout the 1990s.2

The Chemistry of 4-AcO-DMT

Psilacetin is a structural analog of the psychedelic mushroom (aka psilocybin mushroom or magic mushroom) compound psilocybin. Psilocybin is a prodrug of psilocin, and psilocin is an analog of the neurotransmitter of serotonin. Chemically, psilacetin is O-acetylated psilocin, whereas psilocybin is O-phosphorylated.

The Pharmacology of 4-AcO-DMT

The way psilacetin is metabolized in the human body is unknown. However, based on the chemistry and metabolism of similar tryptamine compounds,3 it is reasonable to assume that psilacetin undergoes deacetylation to form psilocin. From that point, psilocin would follow the accepted theory of binding to the serotonin 5-HT2A receptor, causing a psychedelic effect.4

There are no published scientific studies specifically addressing whether psilacetin is metabolically active on its own. The possibility exists that when ingested, psilacetin may bind to serotonin receptors, including 5-HT2A, and elicit a psychedelic effect, perhaps one that is unique from psilocin. According to anecdotal reports, the psychoactivity of psilacetin is immediate when in injected, bypassing the first-pass metabolism in the stomach and liver.5

A 2017 substance abuse study using rodents suggests a single administration of 4-AcO-DMT prevents and reverses heroin and nicotine addictions.6 The authors of the study theorize the mechanism involves preventing the up-regulation of brain-derived neurotrophic factor via serotonin 5-HT2A receptor signaling.

The renowned psychedelic researcher Dr. David Nichols has suggested that psilacetin, like psilocybin, is a prodrug of psilocin.7 In their 1999 work, Dr. Nichols and Dr. Stewart Frescas synthesized the fumarate salt of psilacetin.

Recent Scientific Studies on 4-AcO-DMT

Following 20 years of inactivity, the chemical community recently published new data about psilacetin. Building on the work Nichols and Frescas did in 1999 scientists solved the crystal structure of 4-AcO-DMT fumarate in March 2019.8 Chadeayne, et al. demonstrated that the solid-state structure is an asymmetric unit containing one 4-acetoxy-N,N-dimethyltryptammonium cation, and one 3-carboxyacrylate anion. Despite its use as a research chemical in the illicit drug market, this work was the first conclusive structural characterization of the molecule.

In a follow-up to this study, the same research team defined the crystal structure of a new solvate form of 4-AcO-DMT fumarate, bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate.9 The crystal structure consists of two protonated psilacetin molecules that are charge-balanced by one fumarate dianion. This new solvate form of psilacetin is an important discovery because it opens the door to more options for drug development.

    References
  1. Hofmann A, Troxler F. Esters of indoles. US3075992A. January 1963. https://patents.google.com/patent/US3075992A/en?oq=US3075992.
  2. UNODC. The Challenges of New Psychoactive Substances. Vienna, Austria: United Nations Office on Drugs and Crime; 2013. https://www.unodc.org/documents/scientific/NPS_Report.pdf
  3. Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metabolism Reviews. 2017;49(1):84-91. doi:10.1080/03602532.2016.1278228
  4. Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport. 1998;9(17):3897.
  5. 4-AcO-DMT vs. Psilocin. Bluelight.org. https://www.bluelight.org/xf/threads/4-aco-dmt-vs-psilocin.365088/
  6. Vargas-Perez H, Grieder TE, Ting-A-Kee R, Maal-Bared G, Chwalek M, van der Kooy D. A single administration of the hallucinogen, 4-acetoxy-dimethyltryptamine, prevents the shift to a drug-dependent state and the expression of withdrawal aversions in rodents. Eur J Neurosci. 2017;45(11):1410-1417. doi:10.1111/ejn.13572
  7. Nichols DE, Frescas S. Improvements to the Synthesis of Psilocybin and a Facile Method for Preparing the O-Acetyl Prodrug of Psilocin. Synthesis. 1999;(06):935-938. doi:10.1055/s-1999-3490
  8. Chadeayne AR, Golen JA, Manke DR. The Crystal Structure of 4-AcO-DMT Fumarate. 2019. https://psychedelicreview.com/wp-content/uploads/2019/03/The-Crystal-Structure-of-4-AcO-DMT-Fumarate.pdf
  9. Chadeayne AR, Golen JA, Manke DR. Bis(4-acetoxy-N,N -dimethyltryptammonium) fumarate: a new crystalline form of psilacetin, an alternative to psilocybin as a psilocin prodrug. Acta Crystallographica Section E Crystallographic Communications. 2019;75(6):900-902. doi:10.1107/S2056989019007370