What is Psilacetin?

You may have never heard of psilacetin. In fact, when you first saw it, it may have confused you.

“Is this a misspelling of psilocybin? Is it a variation? Is it a mushroom? I need more information!”

Well, that’s what we hope to do with this piece. But let’s start at the beginning – all the way back in 1963.

A research team, including legendary chemists Albert Hofmann and Franz Troxler, performed the first synthesis of psilacetin while working at Sandoz Laboratories in Switzerland. Their discovery was patented in 1963 along with other indole esters they had synthesized. Psilacetin was then shelved. No different from how LSD was set aside for five years after being synthesized in 1938. According to the United Nations Office on Drugs and Crime, synthetic versions of psilacetin began surfacing again in illicit drug markets in the 1990s.

Psilacetin is a structural analogue of the mushroom compound psilocybin. It is known by other names including, but not limited to: 

Psilocybin is a prodrug of psilocin. Psilocybin is an analogue of the neurotransmitter of serotonin. This means that psilacetin is O-acetylated psilocin, whereas psilocybin is O-phosphorylated.

Does that make sense? We hope so.

In1999, the psychedelic researchers Dr. David Nichols and Dr. Stewart Frescas synthesized the fumarate salt of psilacetin. In a published paper that same year, they explain the potential economic advantages of leveraging psilacetin.They were quoted as saying the following:

Despite similarities, there remain clinical differences between magic mushrooms and psilacetin. Magic mushrooms contain multiple active ingredients while psilacetin continues to be mostly a mystery.

The following information was published by CaaMTech in an excerpt titled “Psilacetin is More Potent than Psilocybin.”

A new study comparing the pharmacology of naturally occurring and synthetic psilocybin analogues led by scientists at the Designer Drug Research Unit in the Intramural Research Program of the National Institute on Drug Abuse (part of the National Institutes of Health), Ghent University, the Usona Institute, the University of Wyoming, and the Manke Lab at UMass Dartmouth in collaboration with CaaMTech, was recently published. “Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice” was published in the American Chemical Society’s journal, ACS Pharmacology & Translational Science. The study was the first comprehensive receptor binding screen comparing the effects of psilocybin, baeocystin, aeruginascin, their active metabolites, and synthetic analogues in radioligand binding assays and functional assays. The team also conducted in vivo studies comparing the properties of these tryptamines across head twitch response (HTR), locomotor, and temperature depression assays. These results led to multiple key findings, advancing the scientific community’s understanding of how “minor” tryptamines in psychedelic magic mushrooms may contribute to psychedelic effects or therapeutic potential. The work also highlights why psilacetin (4-acetoxy-N, N-dimethyltryptamine or 4-AcO-DMT), a popular gray-market recreational drug, is being studied as an improved alternative to psilocybin as a psilocin prodrug. Psilocybin, which is metabolized into psilocin in the body, is being investigated in clinical trials as a therapeutic for the treatment of substance use disorders, depression, cluster headaches, and various other psychiatric disorders. For treating severe depression, psilocybin in conjunction with psychotherapy has received the “Breakthrough Therapy” designation from the FDA, but has not been approved by the FDA for the treatment of any medical condition and remains a DEA Schedule I controlled substance.

While psilocybin has garnered the overwhelming majority of attention as “the active ingredient” in magic mushrooms, other structurally similar tryptamine compounds – which are naturally present in these mushrooms – have largely been ignored as “minor” and unimportant. Characterizing these compounds and comparing them to psilocybin is critical to understanding their role in the psychedelic effects of magic mushrooms and their potential as therapeutics.  The authors of the study collaborated to perform comprehensive in vitro screens to identify potential biological targets, asses functional activity at several receptors, and conduct in vivo HTR assays directly comparing naturally occurring tryptamines, active metabolites, and their synthetic analogs.

The research produced several interesting results pertaining to the structure-activity relationships (SARs) of the studied compounds, the potential roles of the “minor” alkaloids in the psychedelic experience occasioned by magic mushrooms, and the potential for psilacetin (a synthetic psilocin prodrug) to be studied as an improved pharmacological alternative to psilocybin.  The SAR findings reported in the paper show that “the degree of N-methylation and 4-position ring substitution can powerfully influence pharmacological effects of psilocybin analogues.”  The ability of compounds to induce robust HTR in rodents has been used as a preclinical predictor of potential psychedelic-like activity.  Data from the HTR studies indicated that baeocystin and aeruginascin, two naturally occurring magic mushroom tryptamines, do not produce an HTR in mice, indicating that they may not induce psychedelic-like effects in humans on their own.  

Notably, psilacetin, a synthetic psilocybin analog, was found to be more potent than psilocybinin mouse studies. While this result highlights psilacetin’s potential for use as a psilocybin alternative, the authors were careful to qualify their findings by noting that psilacetin “displays its own serotonergic receptor activities” in cellular assays.  The authors concluded that “future studies should directly test the hypothesis that psilacetin is hydrolyzed to psilocin in vivo.” 

With the psychedelic renaissance taking hold over the last few years, it will be interesting to see how psilacetin may play an inevitable role as a studied and pursued compound. I’m sure we’ll see more published studies and observations that will lead to a lot more data and understanding of this mysterious compound.