In a first‑in‑human, placebo‑controlled crossover study in 14 volunteers, escalating low–moderate doses (25–100 mg) of 3‑MMC produced dose‑dependent but clinically modest increases in heart rate and blood pressure, transient psychostimulant and mild psychotomimetic effects, and improved performance across processing speed, cognitive flexibility, attention, memory and psychomotor tasks without impairing impulse control. The authors conclude that these low–moderate doses were well tolerated and pharmacodynamically resemble amphetamine‑type stimulants, with potential health risks likely to arise only at high or excessive doses.
3-Methylmethcathinone (3-MMC) is a designer drug that belongs to the group of synthetic cathinones. The compound has been scheduled in many jurisdictions because of public health concerns associated with excessive use. To date, there are no clinical studies that have evaluated the risk profile of 3-MMC in the recreational range of low to moderate doses. The current, first-in-human study ( N = 14) assessed the impact of three escalating doses of 3-MMC (25, 50 and 100 mg) on vital signs, neurocognitive function, state of consciousness, appetite and drug desire, in a cross-over, placebo-controlled trial. A battery of neurocognitive tests and questionnaires as well as measures of vital signs were repeatedly administered up to 5 h after dosing. Overall, 3-MMC caused dose-dependent increases in heart rate and blood pressure, though not of clinical significance, and feelings of subjective high. Additionally, 3-MMC induced dose-related enhancement of task performance across several neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention and memory. Impulse control was not affected by 3-MMC. Participants also reported mild increases in dissociative and psychedelic effects, decreased appetite, and gave greater ratings of liking and wanting for 3-MMC that were transient over time. Overall, the cardiovascular, psychostimulant and psychotomimetic profile of 3-MMC appears consistent with that of compounds structurally related to amphetamine. It is concluded that low to moderate doses of 3-MMC were well tolerated and safe and that potential health risks might only occur at high or excessive doses of 3-MMC.
Papers cited by this study that are also in Blossom
Bowdle, A. T., Radant, A. D., Cowley, D. S. et al. · Anesthesiology (1998)
Van Heugten-Van Der Kloet, D., Giesbrecht, T., Van Wel, J. et al. · Psychiatry Research (2015)
Papers in Blossom that reference this study
Ramaekers, J. G., Kuypers, K. P. C., Vollenweider, F. X. · Molecular Psychiatry (2026)
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.
) is a synthetic analogue of the natural psychoactive substance cathinone, a psychostimulant present in the leaves of the khat shrub. Derivatives of cathinones such as 3,4-methylenedioxy-N-methylcathinone (methylone), 4-methylmethcathinone (4-MMC, mephedrone) or 3,4-methylenedioxypyrovalerone (MDPV) have come to prominence as designer drugs or 'legal highs' and have been the subject of critical review by public health organizations, resulting in restrictive legislation in several countries. Cathinones are structurally related to amphetamines, which is why there used to be an interest in the 1940s and 50's to synthesize cathinones as medicinal products to suppress appetite, reduce symptoms of depression or stimulate brain activity. Likewise, the capacity of synthetic cathinones such as 3-MMC to increase alertness, wakefulness, euphoria and to suppress appetite has been a main driver of recreational use. 3-MMC is a monoamine transporter substrate that potently inhibits noradrenaline, dopamine and serotonin reuptake, but in addition also displays strong binding affinities for adrenergic receptors, which are known to modulate stimulant-induced behavior. Moreover, 3-MMC also shows binding affinities for 5HT1A and 5HT2A receptors, but the role of these receptors to the psychoactive effects of 3-MMC, either through stimulation or antagonism, is currently unknown. Users describe the effects of 3-MMC as similar to, but less potent and less intense than those of 3,4methylenedioxymethamphetamine (MDMA) and 4-MMC. Besides psychostimulant effects, 3-MMC may also increase feelings of empathy and affection and cause sensory enhancement. Synthetic cathinones are administered recreationally by nasal insufflation (snorting), orally, and by intravenous injection. For 3-MMC, oral doses range from 25-75 mg (light), 75-150 (common) and 150-300 mg (high), although the use of even higher doses has been reported as well]. 3-MMC administrations are sometimes repeated to prolong their desired effects resulting in total doses as large as 2 grams during a single session. Estimates of 'typical' doses are however based on self-reports, and should be interpreted with caution, as the users are not always aware of the actual substance or amount used. Besides their desired psychostimulant effects, synthetic cathinones may also cause serious adverse events, including acute sympathomimetic (e.g., blurred vision, dry mouth, hyperthermia, and mydriasis) and cardiovascular (e.g., increase in blood pressure and heart rate) changes. Additionally, there is a risk of psychological dependence, abuse potential, and withdrawal symptoms.. Most knowledge on adverse events with synthetic cathinones comes from case-studies, often involving the use of high doses combined with alcohol or other drugs. In the case of acute 3-MMC intoxication, case reports on adverse eventshave included fatigue, a reduced level of consciousness, aggression, agitation, psychomotor impairment and tachycardia. Less frequently reported adverse events included concentration difficulties, tingling in the arms and legs, diaphoresis, seizures, hyperthermia, and rhabdomyolysis. A small number of fatal intoxications have been associated with the use of 3-MMC, although in the majority of these cases other drugs were present as well. To date, no clinical studies have been conducted with synthetic cathinones that could serve as a scientific base for risk evaluations, particularly at the low and moderate dose ranges that are most common among users. The current placebo-controlled, first-in-human study therefore aimed to determine the safety profile of low to moderate doses (25, 50, and100mg) of 3-MMC and monitored vital signs, psychomotor and cognitive function, state of consciousness, appetite and desire for 3-MMC for up to 5 hours after acute administration.
Fourteen participants (9 males, 5 females) entered the study, of whom 12 completed all treatment conditions. Two participants dropped out without completing all treatment conditions for reasons unrelated to the study. Participants' age ranged between
This study was conducted according to a phase 1, single-blind, placebo-controlled, cross-over design. Participants received single doses of 3-MMC (25, 50 and 100) or placebo on separate days. 3-MMC was dissolved in approximately 150 mL of a bittering agent (bitter lemon) and administered orally. Placebo drinks consisted solely of bitter lemon. An escalating dosing scheme was used. Participants received one of the following treatment orders: 0-25-50-100mg, 25-0-50-100, 25-50-0-100mg or 25-50-100-0mg. Conditions were separated by a minimum washout period of 7 days to avoid carry-over effects. During each 3-MMC administration day, participants were closely monitored and under medical supervision. An independent Safety Group (SSG) was installed to evaluate vital and behavioral data collected after each dose during the first batch of 6 participants. The 2nd batch of participants only started after a positive SSG evaluation of all adverse events experienced during the 1st batch. The study was conducted according to the code of ethics on human experimentation established by the declaration of Helsinki
Participants were asked to refrain from drug use at least one week prior to the start of the study, and to refrain from drug use throughout the entire study. Participants were not allowed to consume alcohol (48h), caffeine-containing beverages (24h) or tobacco before and during experimental sessions and were requested to arrive well rested. An alcohol breathalyzer and urine drug screen were conducted on test days after arrival of the participants. Urine drug screens checked for the presence of amphetamine, barbiturates, benzodiazepines, cocaine, methamphetamine, morphine, methadone, phencyclidine and tetrahydrocannabinol (THC) Treatments were administered only after verifying negative results for drug and alcohol screens, and, in the case of female participants, after confirming negative pregnancy tests. Throughout the 5 hours following treatment, subjective drug effects, vital signs and neurocognitive function were repeatedly assessed under medical supervision. Tableprovides a schedule of safety and pharmacodynamic measures collected on treatment days. Participants underwent a training session before the experimental sessions to become acquainted with the neurocognitive tests and reduce practice effects.
Heart rate, blood pressure and temperature were monitored at regular intervals (Table). A lab safety blood and urine sample were taken at screening, baseline, and at the end of a test day for hematology, clinical chemistry and urinalysis. Blood samples to quantify 3-MMC concentrations were collected at baseline and at regular intervals after drug administration (see Table). Blood samples were centrifuged immediately and the serum was subsequently frozen at -30°C until analyses for pharmacokinetic assessment. 3-MMC serum concentrations were quantified by a forensic routine analysis method (liquidliquid extraction of 0.2 ml serum, analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 1 ng/ml lower limit of quantification). Adverse events were documented at the end of treatment days. Participants were also asked to note any adverse events for 72 hours following dosing.
A battery of tasks was included to assess psychomotor function, attention, decision-making, impulsivity and memory. The Digit Symbol Substitution Task (DSST)is a computerized version of the original paper and pencil test taken from the Wechsler Adult Intelligence Scale that measures processing speed, attention, and cognitive flexibility. In this task, participants are presented with an encoding scheme displayed as a row of squares at the top of the screen, where nine digits are randomly paired with specific symbols. The participant's objective is to match each digit with its corresponding symbol from the encoding list and click the appropriate response button. The performance measure is the number of digits correctly encoded within a 3-minute time frame. The Critical Tracking Task (CTT)assesses a participant's ability to manage a displayed error signal in a first-order compensatory tracking task. In this task, participants must make compensatory movements that increase in frequency over time. Eventually, the participant's response frequency falls behind the error signal by 180°, causing their response to amplify the error rather than correct it, leading to a loss of control. The frequency at which this loss of control happens is known as the 'critical frequency,' or 'lambda-c.' The Divided Attention Task (DAT) evaluates a person's ability to simultaneously manage two tasks. The primary task involves using a joystick to continuously keep a cursor centered on a display by counteracting its horizontal movement. The tracking error is quantified as the absolute distance (in millimeters) between the cursor's position and the center. For the secondary task, participants must monitor 24 single digits located at the corners of the computer screen and respond as quickly as possible by lifting their foot from a pedal whenever the target number '2' appears. The dependent variables in this task are the mean tracking error and the mean reaction time to the targets. The Spatial Memory Task (SMT) includes two phases: an immediate relocation phase and a delayed relocation phase. In the immediate relocation phase, participants complete six trials where they are shown a series of ten black-and-white pictures (totaling 60 pictures) at different locations on a computer screen. They must remember and indicate the locatio of each picture. After a 30-minute interval, the delayed relocation phase begins, during which the pictures reappear in random order at the center of the screen, and participants must again indicate the correct locations. The dependent variables measured in this task are the number of correct immediate relocations and the delayed relocation score. The Stop Signal Task (SST) assesses motor impulsivity, defined as the inability to inhibit a pre-cued response, leading to errors of commission. Participants are required to respond quickly to visual go-signals and inhibit their response if a subsequent visual stop-signal, represented by an asterisk ("*"), appears in one of the four corners of the screen. The total duration of the task is approximately 8 minutes. The main dependent variables include the number of commission errors (failure to inhibit a response on no-go trials) and omission errors (failing to respond on go trials).
Subjective drug experience ("high") was measured using a 100 mm visual analogue scale with "not influenced by 3-MMC at all" at one end and "very influenced by 3-MMC" at the other end of the line. The Sensitivity to Drug Reinforcement Questionnaire (SDRQ) asked two questions: How pleasant is using 3-MMC right now; How much do you want to use 3-MMC right now. Subjective valence of liking and wanting was scored on a 5-point scale: 1=somewhat; 2=slightly; 3=moderately; 4=very and 5=extremely. The Clinician-Administered Dissociative States Scale (CADSS)is a standardized measure of dissociative symptomatology. It comprises 19 subjective items, ranging from 0 'not at all' to 4 'extremely. It is divided into 3 components: 1) depersonalization, 2) derealization and 3) amnesia. Summed together, these subscales form a total dissociative score. The Bowdle Visual Analogue Scales (B-VAS) measures psychedelic effects using a 13-item visual analogue scale. From these, log-transformed composite scores of 'internal perception' (i.e perception of the inner world) and 'external perception' (i.e. perception of the external world), as well as composite scores of 'feeling high' and 'drowsiness' are calculated. Feelings of hunger and appetite were also rated by participants by means of 10 cm visual analogue scales after breakfast, lunch,and 10 hours after treatment (at home).
The effects of 3-MMC on all dependent measures were analyzed using a Linear Mixed Model with a restricted maximum likelihood method (REML). Model parameters included Dose, Time (after dosing) and Dose × Time as fixed effects, and a random intercept. The main effect of Dose was further segregated by pairwise comparisons between each 3-MMC dose and placebo (across time points). A first-order autoregressive residual covariance structure was used. The alpha criterion significance level was set at p = 0.05. All statistical tests were conducted with IBM SPSS version 27.0.
Laboratory safety analyses, including hematology, clinical chemistry, and urinalysis, did not reveal clinically relevant deviations from normal ranges. Figurein the MFFT (F3, 22.884=13.724, p<.001). There were no effects of Dose on measures of the SST. Dose by Time interactions did not reach significance for any of the neurocognitive measures. Drug-placebo contrasts revealed that 3-MMC increased the number of correct substitutions at 50mg (p=.005) and 100mg (p<.001), improved tracking performance (lamda-c) at 50mg (p<.001) and 100mg (p<.001), and reduced tracking error at 25mg (p<.001), 50mg (p<.001) and 100mg (p<.001), and increased the number of delayed relocations at 25mg (p=.007) and 50mg (p=.006). A dose of 50mg 3-MMC also increased efficiency in the MFFT as compared to placebo (p=.016). perception. Dose by Time interactions were found for ratings of high (F3,67.398=8.316, p<.001) and external perception (F3,69.695=2.840, p=.044). Drug-placebo contrasts revealed increments in derealization at 25mg (p=.022), 50 mg (p<001) and 100mg (p<.001), increments in depersonalization at 100mg (p=.035) and increments in CADSS total score at 50mg (p=.003) and 100mg (p<.001). Drug-placebo contrasts also revealed increments in ratings of high at 25mg (p=.018), 50mg (p<.001) and 100mg (p<.001), increments in internal perception at 100mg (p<.001), and increments in external perception at 25mg (p=.006), 50mg (p=.005) and 100mg (p=.001).
Figureshows subjective ratings of hunger and appetite, as well as ratings of 3-MMC wanting and liking in every treatment condition. LMM analyses showed main effects of Dose and Dose by Time on 3-MMC liking (F3,59.813=4.391, p=.007; F 6, 106.446=2.786, p=.015) and wanting (F3,65.114=5.030, p=.003, F6,106.630=3.569, p=.003). Dose effects on hunger (F3,55.753=2.450, p=.073) and appetite (F3, 75.681=2.582, p=.060) failed to reach significance. Drug-placebo contrasts revealed that a dose of 100mg 3-MMC decreased appetite (p=.011), and increased ratings of drug liking (p=.007) and wanting (p=.010).
During treatment with 25mg 3-MMC there were reports of ringing in ears (1x), fatigue (1x), forgetfulness (1x) and headache (1x). Following treatment with 50mg 3-MMC reports of headache (1x) and visual flicker (1x) were noted. After treatment with 100mg 3-MMC fatigue (1x) and bruxism (1x) were reported. All adverse events were transient and mild in severity. No adverse events were reported during placebo.
The present study aimed to evaluate safety and cognitive pharmacodynamics of healthy volunteers after receiving single doses of 25, 50 and 100mg 3-MMC. Overall, 3-MMC produced significant, dose-related elevations in heart rate, blood pressure and subjective high. In addition, 3-MMC induced dose-related performance improvements in a range of neurocognitive domains, including processing speed, cognitive flexibility, psychomotor function, attention and memory. Subjectively, 3-MMC induced mild increments in dissociative and psychedelic effects, reduced appetite and increased ratings of 3-MMC liking and wanting. Increments in blood pressure and heart rate are very common with stimulant drugs and usually arise from stimulation of the autonomic nervous system through the release of noradrenaline and dopamine. In the present study, 3-MMC induced variations in blood pressure and heart rate fell largely within the normal range and did not signal any acute, adverse cardiovascular event. Cardiovascular effects were absent or mild after 25 and 50mg doses of 3-MMC and became more prominent at 100mg. The dose-relatedness of cardiovascular effects of 3-MMC suggests that their intensity might increase and potentially develop into (serious) adverse events at higher doses. Sympathomimetic effects such as agitation, tachycardia, hypertension, and hyperthermia have previously been reported for designer drugs that are structurally related to amphetamine such as mephedrone, MDMA, MDPV, methoxetamine, 6-ABP, and 4-FA, sometimes resulting in fatalities. 3-MMC has also been associated with a series of intoxications in individuals who presented to hospitals with clinical manifestations of tachycardia, agitation, and hyperthermia. Serum 3-MMC concentrations in these cases ranged between 2 to 1490 ng/mL (median of 91 ng/mL). Mean 3-MMC concentrations (up to 200ng/mL) as observed in the present study after low and moderate doses overlap with the lower part of this wide, clinical range. Yet, blood samples of clinical cases were not taken acutely but after treatment in the hospital or during the following day, suggesting that their residual 3-MMC concentrations resulted from the use of (very) high doses of 3-MMC at a much earlier stage. Moreover, the co-occurrence of other substances was very common, and "mono intoxication" of 3-MMC was found in 4 out of 50 cases only. A high level of 3-MMC (800 ng/mL) was also detected in a suicidal death case, from blood taken 2 days after the body was found, again suggesting the use of an extremely high dose. Overall, the present study confirms the clinical notion that 3-MMC can produce cardiovascular effects, but also indicates that such effects are dose-dependent and may only become adverse and of clinical relevance at high doses. In addition, only a few adverse events were recorded after treatment with 3-MMC doses in the present study, and those that were recorded were mild and transient by nature, and of no clinical relevance. Together these findings indicate that low and moderate doses of 3-MMC were well tolerated in the present study and produced cardiovascular effects that were well within the normal range. 3-MMC enhanced task performance in a range of neurocognitive domains. Dose-related increments were observed in tracking performance and attention in the CTT and DAT, processing speed and cognitive flexibility in the DSST, spatial memory in the SMT, and performance efficiency in the MFFT. Similar improvements in neurocognitive function have been documented for various stimulant drugs, including cocaine, MDMA, amphetamine, modafinil, methylphenidateand designer drugs such as 4-FA. Psychostimulant properties of amphetamine-like compounds have long been recognized and utilized in medical applications to treat attention deficit disorders, and in military applications to maintain and sustain vigilance during operations. It should be noted that enhancement of neurocognitive function is usually observed after low doses of psychostimulants and that the use of high doses can produce effects of overstimulation that are well outside the range of cognitive enhancement such as agitation, confusion, disturbed thinking, and even psychosis. Psychostimulant properties of 3-MMC are likely caused by an increase in availability of dopamine and noradrenaline through blockage of the dopamine and noradrenaline transportersas also observed with other stimulants such as amphetamine, methylphenidate, mephedrone and bupropion that share the same pharmacological mechanism. It is noteworthy in this context that presumed increments in dopamine and noradrenaline after 3-MMC did not (negatively) affect cognitive and motor impulsivity in the present study, a finding that was previously also noted with other stimulants such as amphetamine, MDMA, methylphenidate, bupropion and 4-FA. is unclear at this point whether increments in impulsive behaviors would become prominent with higher doses of 3-MMC. Overall, the present study indicates that low to moderate doses of 3-MMC produce a profile of performance enhancement similar to other stimulants. 3-MMC produced small but consistent changes in the subjective experience of consciousness as assessed with the CADSS and Bowdle scale. Symptoms of derealization, depersonalization, subjective high, internal and external perception increased in a dose-dependent manner at the time that 3-MMC reached peak concentrations (1.5 hours after ingestion, c.f. Figure). The intensity of these experiences however was very low and comparable to those reported with moderate doses of other stimulants such MDMA, cocaine and 4-FA, negligible in comparison to effects observed after a potent dissociative like ketamine, which were 4-5 times as high. This is not to say that intense dissociative or psychedelic effects may never occur with 3-MMC, as amphetamine abuse of high doses has been associated with disturbed thinking and symptoms of psychosis in clinical cases. Hallucinations and states of confusion have indeed been reported in cases of 3-MMC abuse. However, the present study suggests that single administrations of low and moderate doses of 3-MMC do not seem to hold a propensity to induce strong dissociative or psychedelic effects. Self-ratings of drug liking and wanting, considered sensitive indicators of the potential for drug abuse, were elevated under 3-MMC as compared to placebo. Ratings of drug liking and wanting were most prominent during peak concentrations of 100 mg 3-MMC, but returned to baseline at 5 hours after administration. This appears consistent in view of the rather short elimination half-life of about 3 hours. Likewise, ratings of appetite after lunch decreased after 100mg of 3-MMC as compared to placebo, but these also returned to baseline at 10 hours after administration. These findings suggest that low to moderate doses of 3-MMC are unlikely to lead to sustained feelings of drug liking and wanting or sustained appetite suppression that may lead to repeated or compulsive use, however, it cannot be excluded that the short-lived effects may trigger repeated ingestion during short periods. Yet again, abuse liability of 3-MMC, as with any amphetamine, may increase with the use of higher doses. Abuse liability after (repeated) use of high doses of 3-MMC has not been systematically studied in humans but preclinical evidence has suggested addictive properties of 3-MMCand clinical cases of 3-MMC dependence have been reported. The present study is the first to assess the safety profile of the designer drug 3-MMC. Where new pharmaceutical drugs must undergo rigorous rounds of safety checks in extensive clinical trials before they can be approved for human use, this is typically not the case for designer drugs that come from clandestine chemistry labs. Hence, potential harms caused by designer drugs that enter the consumer market are basically unknown. The general lack of safety data on designer drugs also hampers accurate risk evaluations by public health organizations that are mostly limited to basic pharmacology, anecdotal clinical case reports and expert opinion. Full-scale evaluations of health risks associated with designer drugs are virtually missing because there is a general lack of controlled studies with these compounds, often due to ethical and legal constraints. The present evaluation of the risk profile of low and moderate doses of 3-MMC therefore complements and nuances existing risk evaluationthat are solely based on extreme cases of fatal and non-fatal poisonings in which 3-MMC, mostly in combination with other drugs, was implicated. Though important, extreme cases of 3-MMC abuse are not representative of risks that may be endured among the majority of 3-MMC users who consume the drug recreationally and avoid excessive use. The current study suggests that in this type of user, the safety risks of 3-MMC at single doses up to 100 mg are very low to negligible. This is relevant as also public health committees have noted the importance of collecting additional and accurate knowledge on 3-MMC that can be disseminated to people who use 3-MMC, as well as to practitioners, policymakers and decision-makers. In summary, low to moderate doses of 3-MMC produced cardiovascular effects that remained within the normal range and improved performance across a range of neurocognitive domains in a doserelated manner. 3-MMC induced mild dissociative and psychedelic effects and transiently increased ratings of 3-MMC liking and wanting. Overall, the cardiovascular, psychostimulant and psychotomimetic profile of 3-MMC appears in line with that of compounds that are structurally related to amphetamine. It is concluded that low to moderate doses of 3-MMC were well tolerated and safe, and that potential health risks might only occur at high or excessive doses of 3-MMC.
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