4-AcO-MET

4-AcO-MET (4-acetoxy-N-methyl-N-ethyltryptamine; metacetin) is a synthetic tryptamine of the 4-substituted indole class, structurally characterized by an O-acetyl ester at the 4-position of the indole ring and an asymmetric N-methyl-N-ethyl substitution on the terminal amine. The compound is the O-acetylated ester of 4-HO-MET (metocin, methylcybin), a psilocin analog first synthesized by Alexander Shulgin in the 1970s and first formally described in the scientific literature by Repke, Ferguson, and Bates in 1981. By analogy with the well-characterized 4-AcO-DMT (psilacetin) to psilocin (4-HO-DMT) prodrug relationship, 4-AcO-MET is hypothesized to undergo rapid O-deacetylation by serum and hepatic esterases to yield the pharmacologically active 4-HO-MET in vivo, although direct human pharmacokinetic confirmation of this metabolic conversion remains absent.

The molecular pharmacology of 4-AcO-MET has been characterized in two principal receptor-binding studies. Kozell et al. (2023) reported binding affinity at the human 5-HT2A receptor (Ki approximately 86 nM), with partial agonist efficacy (Emax 40 percent of serotonin maximum) and functional activity at the 5-HT2C receptor (Ki approximately 460 nM, Emax 90 percent) and the 5-HT1A receptor (Ki approximately 1210 nM, Emax 83 percent). Glatfelter et al. (2023) independently confirmed submicromolar 5-HT2A affinity (Ki 514 nM) and identified high-affinity binding at the 5-HT2B receptor (Ki 17 nM), a finding with implications for cardiac safety assessment under chronic exposure paradigms. The putative active metabolite 4-HO-MET demonstrates approximately two-fold higher 5-HT2A affinity (Ki 46 nM, Kozell et al.) and greater functional efficacy (Emax 54 percent), consistent with the prodrug model in which the acetylated precursor is less potent at the primary psychedelic target than its deacetylated product.

Behaviorally, 4-HO-MET is among the most potent 4-substituted tryptamines in the mouse head-twitch response assay (ED50 0.65 micromol/kg; Klein et al. 2021), exceeding psilocin (ED50 0.81 micromol/kg) and all other tested N,N-dialkyl-4-hydroxytryptamine analogs. In rat drug-discrimination studies, 4-hydroxytryptamines fully substitute for the discriminative stimulus effects of the 5-HT2A/2C agonist DOM, with 4-OH-MET demonstrating an ED50 of 0.38 mg/kg (Gatch et al. 2021). O-Acetylated tryptamines are consistently less potent than their 4-hydroxy counterparts in these paradigms, supporting the prodrug hypothesis.

4-AcO-MET was first identified as a novel psychoactive substance in European forensic seizures in 2009. The compound has no approved therapeutic indication in any jurisdiction, has not been evaluated in controlled clinical trials, and is not registered as a pharmaceutical product. The toxicological profile is incompletely characterized; a 2020 study by Yoon et al. demonstrated that the structurally related compounds 4-AcO-DET and 4-HO-MET prolong the QT interval in rat electrocardiography and inhibit hERG potassium channels, raising a signal for potential cardiovascular liability across the class. The metabolism of 4-HO-MET has been characterized by Bruni et al. (2018) using pooled human liver microsomes, identifying twelve phase I metabolites including hydroxylated, demethylated, deethylated, and N-oxide products. This monograph reviews the chemistry, structural pharmacology, prodrug metabolism, receptor binding, preclinical pharmacology, sourcing, handling, adverse-event signal, and comparative positioning of 4-AcO-MET within the 4-substituted tryptamine research landscape.