The State of the Art of Psilacetin (4-AcO-DMT)

A research team including chemists Albert Hofmann and Franz Troxler performed the first synthesis of psilacetin while working at Sandoz Laboratories in Switzerland.¹ They patented their discovery in 1963 along with other indole esters they had synthesized.² 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.³

The Chemistry of Psilacetin

Psilacetin is a structural analog of the magic mushroom compound psilocybin (Figure 1). It is known by other names including 4-AcO-DMT, O-Acetylpsilocin, 4-Acetoxy-DMT, and 4-Acetoxy-N,N-dimethyltryptamine. 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.

Figure 1: The chemical structures of psilacetin, psilocybin, psilocin, and serotonin.

The Pharmacology of Psilacetin

In their 1963 patent, Hofmann and Troxler described indole acetate esters like 4-AcO-DMT as serotonin receptor antagonists.² However, over the years, scientists have come to classify them as prodrugs that are inactive on their own by way of analogy to psilocybin.

The way psilacetin is metabolized in the human body is unknown. However, based on the chemistry and metabolism of similar tryptamine compounds,⁴ 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-HT_2A receptor, causing a psychedelic effect.⁵

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-HT_2A, 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.⁶

A 2017 substance abuse study using rodents suggests a single administration of 4-AcO-DMT prevents and reverses heroin and nicotine addictions.⁷ 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.⁸ In their 1999 work, Dr. Nichols and Dr. Stewart Frescas synthesized the fumarate salt of psilacetin. In the paper, they also explain the economic advantages of psilacetin:

 This O-acetyl prodrug of psilocin is much more easily prepared than psilocybin, and may offer an economical alternative for clinicians wishing to study the psychopharmacology of psilocin.

 

This material [psilacetin] is readily crystallized as the fumarate salt, and is considerably more stable than psilocin itself. It would seem to be an ideal prodrug to replace psilocybin in future clinical studies, since psilocin is the principal metabolite of psilocybin.

Because no scientific studies have been conducted, the only information on the effects of psilacetin are the anecdotal reports captured in online discussion boards and experience reports. Some psilacetin users find its effects similar to psilocybin mushrooms (aka psychedelic mushrooms or “magic mushrooms”) whereas others have distinctly different experiences. Therefore, framing discussions about the effects of psilacetin are frequently in comparison to magic mushrooms. Comparing reports for those who noticed a difference between psilacetin and magic mushrooms could provide insight into the unique clinical attributes of psilacetin. Based on these comparisons, psilacetin appears to give a more colorful experience and imparts more feelings of warmth, relaxation, and euphoria than psilocybin mushrooms.⁹ Also, anecdotal reports suggest that the psilacetin experience has a faster onset and shorter duration than magic mushrooms. This information was summarized by Geiger et al. in a 2018 review article.¹⁰

The clinical differences between magic mushrooms and psilacetin can be ascribed to (1) the chemical differences between psilacetin and psilocybin and (2) the fact that magic mushrooms include multiple active ingredients, which synergistically produce the user’s experience. In the world of cannabis research, this phenomenon is called the entourage effect. Because of the lack of scientific data about psilacetin, its mechanism of action remains a mystery. Conceivably, psilacetin’s clinical properties arise from binding to serotonin receptor active sites, binding elsewhere on receptors and causing allosteric modulation, or both.

Recent Scientific Studies on Psilacetin

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 2019.¹¹ 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 (Figure 2). Despite its use as a research chemical in the illicit drug market, this work was the first conclusive structural characterization of the molecule.

Figure 2: The crystal structure of 4-AcO-DMT fumarate.

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.¹² The crystal structure consists of two protonated psilacetin molecules that are charge-balanced by one fumarate dianion (Figure 3). This new solvate form of psilacetin is an important discovery because it opens the door to more options for drug development.

Figure 3: The crystal structure of bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate.

The Future of Psilacetin in Psychedelic Drug Research

After 20 years without any studies, the scientific community appears to have renewed its interest in psilacetin. As an easier to synthesize and less expensive alternative prodrug to psilocin, psilacetin could change the landscape of psychedelic drug therapy. This work is also important because of the increasing numbers of recreational drug users who are consuming the chemical despite virtually no information about its chemical or biological properties.

Any therapeutic uses of psilacetin are only speculative at this time, based solely on experience reports. There are many uncontrolled variables woven into these reports, including set, setting, dosage, and purity of the compounds. Further study of the pharmacology of pure psilacetin will lead to a better understanding of how formulating specific combinations of molecules can lead to formulations.

Barbara E. Bauer, MS

Barb is the former Editor and one of the founders of Psychedelic Science Review. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.

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