Safety and cognitive pharmacodynamics following dose escalations with 3-methylmethcathinone (3-MMC): a first in human, designer drug study

Introduction

Synthetic cathinones are stimulant compounds related to amphetamines that have emerged as designer drugs, with 3-methylmethcathinone (3-MMC) increasingly implicated in recreational use and clinical intoxications. Earlier literature and case reports link synthetic cathinones to sympathomimetic and neuropsychiatric adverse events, but most published information derives from high-dose or polysubstance exposures and from forensic/clinical case series rather than controlled human trials. Pharmacologically, 3-MMC is a monoamine transporter substrate that inhibits noradrenaline, dopamine and serotonin reuptake and shows affinity for adrenergic and certain serotonin receptors; however, the contribution of these interactions to human subjective and cognitive effects has been uncertain. Typical user-reported oral dose ranges are roughly 25–300 mg, with repeated dosing sometimes producing very large cumulative intakes, but these self-reports are imprecise and leave risk at low-to-moderate doses largely uncharacterised. This first-in-human, placebo-controlled study led by Jg and colleagues sought to characterise the safety and cognitive pharmacodynamics of single ascending oral doses of 3-MMC in healthy volunteers. The investigators tested three doses commonly reported by users (25, 50 and 100 mg) against placebo in a Phase I single-blind, cross-over design, with repeated assessments of vital signs, serum concentrations, a battery of neurocognitive tests, subjective state measures (including dissociation and psychedelic-like effects), appetite and indices of drug liking and wanting over a 5-hour post-dose period. The aim was to determine dose-related cardiovascular, cognitive and subjective effects within the low-to-moderate recreational range and to provide a human data point to complement the case-report literature.