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

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.

The study used a Phase I, single-blind, placebo-controlled, cross-over design. Fourteen healthy volunteers (9 male, 5 female) entered the trial and 12 completed all treatment conditions; the extracted text does not clearly report the sample age range. Each participant received single oral doses of 3-MMC at 25, 50 and 100 mg, and placebo, on separate days according to an escalating/Latin-square–like ordering (examples: 0-25-50-100 mg, 25-0-50-100 mg, 25-50-0-100 mg, 25-50-100-0 mg). Conditions were separated by a minimum 7-day washout. 3-MMC was dissolved in ~150 mL bitter lemon for oral administration; placebo was bitter lemon only. An independent safety group reviewed vital and behavioural data after the first cohort of six participants before the second cohort commenced. Sessions were medically supervised and conducted according to the Declaration of Helsinki. Pre-session requirements included abstinence from drugs for at least one week, no alcohol for 48 hours, no caffeine for 24 hours and no tobacco on test days. Participants provided negative breathalyser and urine toxicology screens on each test day (tested substances listed in the text) and female participants had pregnancy tests. During each session, heart rate, blood pressure and temperature were monitored at regular intervals; laboratory haematology, clinical chemistry and urinalysis were performed at screening, baseline and the end of test days. Adverse events were recorded during sessions and participants were asked to note events for 72 hours post-dose. Pharmacokinetic sampling involved serum collection at baseline and multiple post-dose time points; samples were frozen and 3-MMC concentrations quantified by LC–MS/MS with a lower limit of quantification of 1 ng/mL. The psychopharmacology assessment included a computerised neurocognitive battery: Digit Symbol Substitution Task (DSST) for processing speed and cognitive flexibility, Critical Tracking Task (CTT) for compensatory tracking and psychomotor control, Divided Attention Task (DAT) for dual-task tracking and target detection, Spatial Memory Task (SMT) with immediate and delayed relocation phases, Stop Signal Task (SST) for motor impulsivity, and the Matching Familiar Figures Test (MFFT) which was reported in results. Subjective measures comprised a 100 mm VAS for feeling "high", the Sensitivity to Drug Reinforcement Questionnaire (liking and wanting items), the Clinician-Administered Dissociative States Scale (CADSS), the Bowdle VAS composite scores (internal and external perception, feeling high, drowsiness) and appetite/hunger VAS ratings at specified time points. Statistical analysis used Linear Mixed Models estimated by restricted maximum likelihood (REML). Fixed effects included Dose, Time and Dose × Time with a random intercept; a first-order autoregressive residual covariance structure was applied. Main effects of Dose were followed by pairwise contrasts between each 3-MMC dose and placebo across time points. The significance threshold was p = 0.05 and analyses were performed in IBM SPSS v27.0.

Twelve participants completed all conditions; safety laboratory tests (haematology, clinical chemistry, urinalysis) showed no clinically relevant deviations. Cardiovascular monitoring revealed dose-related increases in heart rate and blood pressure, which the authors report largely remained within normal ranges and did not indicate acute cardiovascular events in this sample. Effects were minimal at 25 and 50 mg and became more pronounced at 100 mg. Pharmacokinetic data indicated peak subjective and perceptual effects around 1.5 hours after ingestion and a reported elimination half-life of approximately 3 hours. Mean serum 3-MMC concentrations observed after low and moderate doses reached up to about 200 ng/mL, overlapping the lower range of concentrations reported in clinical intoxication cases (case series reported 2–1490 ng/mL, median 91 ng/mL), although the authors note clinical samples were often collected late and commonly involved other substances. On neurocognitive measures, 3-MMC produced dose-related improvements across multiple domains. Compared with placebo, 50 mg and 100 mg increased the number of correct substitutions on the DSST (50 mg p = .005; 100 mg p < .001). Critical tracking performance (CTT lambda-c) improved at 50 mg and 100 mg (both p < .001). Divided Attention Task tracking error was reduced at 25 mg, 50 mg and 100 mg (all p < .001). The Spatial Memory Task showed increased delayed relocations at 25 mg (p = .007) and 50 mg (p = .006). Performance efficiency on the MFFT was higher after 50 mg (p = .016). There were no significant effects of Dose on SST measures of motor impulsivity, and Dose × Time interactions did not reach significance for neurocognitive outcomes. Subjective effects showed dose-dependent increases in feeling "high" and in measures of altered perception. Linear mixed models identified Dose × Time interactions for ratings of high and external perception. Drug–placebo contrasts indicated increases in CADSS derealization at 25 mg (p = .022), 50 mg (p < .001) and 100 mg (p < .001); depersonalization increased at 100 mg (p = .035); and total CADSS scores rose at 50 mg (p = .003) and 100 mg (p < .001). Bowdle composite scores showed increases in internal perception at 100 mg (p < .001) and in external perception at 25 mg (p = .006), 50 mg (p = .005) and 100 mg (p = .001). Feeling "high" increased at 25 mg (p = .018), 50 mg (p < .001) and 100 mg (p < .001). Measures of reward and appetite revealed increased drug liking and wanting under 3-MMC. There were main effects of Dose and Dose × Time on liking and wanting; contrasts showed 100 mg decreased appetite (p = .011) and increased liking (p = .007) and wanting (p = .010). These subjective drug-reinforcement ratings peaked around peak concentrations and returned to baseline by 5 hours post-dose. Adverse events were infrequent, mild and transient: 25 mg—tinnitus (1), fatigue (1), forgetfulness (1), headache (1); 50 mg—headache (1), visual flicker (1); 100 mg—fatigue (1), bruxism (1). No adverse events were reported during placebo.

Jg and colleagues interpret their findings as showing that single low-to-moderate oral doses of 3-MMC (25–100 mg) produce dose-dependent sympathomimetic effects and transient subjective stimulation, together with enhancements in several neurocognitive domains. The authors attribute cardiovascular changes to autonomic stimulation via increased noradrenaline and dopamine availability, but note that in this controlled sample increases in heart rate and blood pressure largely remained within normal clinical limits, becoming more prominent only at the highest tested dose. They caution that the dose-related nature of these effects implies a risk of clinically relevant adverse cardiovascular events at higher or excessive doses. With respect to cognition, the study found improvements in processing speed, attention, tracking, cognitive flexibility and spatial memory, a profile consistent with other stimulant drugs such as amphetamine, methylphenidate, cocaine, MDMA and certain designer stimulants. The authors highlight that cognitive enhancement is typically observed at low stimulant doses and that high or repeated dosing can lead to overstimulation and adverse neuropsychiatric outcomes. Importantly, motor impulsivity as measured by the SST was not increased in this study; the investigators note that it remains unclear whether impulsive behaviour would emerge at higher doses. Subjective dissociative and perceptual changes (CADSS and Bowdle scales) were dose-related but of low intensity, substantially smaller than those produced by potent dissociatives such as ketamine. The authors acknowledge that intense dissociative or psychotic states have been reported in clinical cases of amphetamine-type drug abuse and 3-MMC intoxication, but argue that their findings suggest single low-to-moderate doses are unlikely to produce strong psychedelic or dissociative experiences in otherwise healthy individuals. Ratings of liking and wanting increased transiently at peak concentrations and returned to baseline within hours, and appetite suppression after 100 mg was short-lived. From these patterns the authors infer that single low-to-moderate doses may pose limited sustained abuse liability, while recognising that short-lived effects could nonetheless prompt repeated ingestion during a session and that abuse potential may rise with higher or repeated dosing. The discussion positions this controlled human data as a complement to case reports and forensic findings, noting that many clinical intoxication samples involve polysubstance use and delayed sampling, which complicates interpretation. The authors emphasise the value of controlled studies for informing public health assessments of designer drugs and conclude that, in their sample, low-to-moderate single doses of 3-MMC were well tolerated. The extracted text does not present additional formal limitations explicitly (for example, on sample size or the single-blind design), nor does it report generalisability bounds beyond those discussed above; the age range of participants was not clearly reported in the extracted material.