4-HO-MET

4-Hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET), also designated metocin and methylcybin, is a synthetic substituted tryptamine and close structural analog of psilocin (4-hydroxy-N,N-dimethyltryptamine; 4-HO-DMT) in which one of the two N-methyl groups on the ethylamine side chain is replaced by an N-ethyl substituent. The compound was first synthesized by Alexander Shulgin in the 1970s and first described in the peer-reviewed literature by Repke and colleagues in 1981 as part of a systematic exploration of psilocin homologs; Shulgin subsequently reported dosimetry and qualitative effects in TiHKAL (1997) at oral doses of 10 to 20 milligrams with a duration of 4 to 6 hours. 4-HO-MET acts as a non-selective serotonin receptor agonist with primary pharmacological activity at the 5-hydroxytryptamine type 2A receptor (5-HT2A), where it functions as a full agonist with nanomolar potency (EC50 approximately 4 nM at human 5-HT2A, Emax approximately 97 percent relative to serotonin) and demonstrates binding affinity (Ki) values ranging from approximately 46 to 177 nM depending on assay conditions and radioligand. The compound also exhibits meaningful binding at 5-HT2B (Ki approximately 12 nM), 5-HT2C (Ki approximately 153 to 164 nM), 5-HT7 (Ki approximately 60 nM), 5-HT6 (Ki approximately 70 nM), 5-HT1A (Ki approximately 135 to 950 nM), and the serotonin transporter (Ki approximately 1,830 to 2,310 nM), with weak activity at the norepinephrine transporter. In the mouse head-twitch response assay, a validated 5-HT2A-dependent behavioral model that correlates strongly with human psychedelic potency, 4-HO-MET produces the response with an ED50 of approximately 0.65 micromol/kg, comparable to or slightly more potent than psilocin. Metabolism in humans proceeds through multiple Phase I biotransformation pathways including mono- and dihydroxylation of the indole ring, N-demethylation, N-deethylation, oxidative deamination, and N-oxide formation, with subsequent Phase II glucuronidation of the 4-hydroxy group constituting a major elimination pathway by analogy to psilocin. Bruni and colleagues (2018) identified 12 in vitro metabolites using pooled human liver microsomes and confirmed 4 metabolites in vivo (N-demethyl-4-HO-MET, oxo-4-HO-MET, hydroxy-4-HO-MET, and the N-oxide). The clinical and forensic literature on 4-HO-MET is limited but growing: a phenomenological study of 25 recreational experience reports in Sweden (Kjellgren and Soussan, 2011) documented effects closely resembling those of psilocybin and psilocin; a case report documented acute psychosis in an adolescent first-time user (Taljemark and Johansson, 2012); a fatality report described postmortem detection of 4-HO-MET in a polydrug context with 4-methoxyphencyclidine (Johansson et al., 2017); and a clinical toxicology case established a plasma concentration of 193 ng/mL in a hospitalized individual (Wagmann et al., 2021). The compound is not approved by any regulatory authority for therapeutic use. It is classified as a new psychoactive substance in forensic and regulatory frameworks, is scheduled in Sweden and Germany, falls under Class A tryptamine provisions in the United Kingdom, and is unscheduled at the federal level in the United States though potentially prosecutable under the Federal Analogue Act. This monograph reviews the chemistry, synthesis, and structural pharmacology of 4-HO-MET; the receptor interaction profile across serotonin receptor subtypes, monoamine transporters, and non-serotonergic targets; the available pharmacokinetic and metabolic data; the preclinical behavioral pharmacology; the limited clinical and forensic evidence base; sourcing and quality verification considerations; reconstitution and handling; stack-interaction implications; adverse-event signals; and a comparative assessment of five structurally related 4-hydroxytryptamine and tryptamine psychedelics (psilocin, 4-AcO-DMT, 4-HO-MiPT, 4-HO-DET, and 5-MeO-DMT) against 4-HO-MET on five competency standards.