Chemical cousins with contrasting behavioural profiles: MDMA users and methamphetamine users differ in social-cognitive functions and aggression

Methamphetamine (METH) and 3,4-methylenedioxy-methamphetamine (MDMA) are chemically related substituted amphetamines whose patterns of use and neurochemical actions differ markedly. Previous research has documented shared cognitive alterations among regular users of both substances, such as impaired impulse control and memory, but has also noted divergent effects on social cognition: chronic METH use has been linked to disturbances in emotion processing and increased hostility, whereas acute MDMA is reliably pro-social and some studies of recreational MDMA users have reported enhanced cognitive empathy. Much of the prior work, however, relied on self-report measures of substance use and has not directly compared chronic METH and chronic MDMA users within the same study. Zacher and colleagues set out to fill this gap by directly comparing chronic METH users, chronic MDMA users, and stimulant-naïve controls on objective and behavioural measures of social cognition and aggressive behaviour. The study combined laboratory tasks assessing cognitive and emotional empathy (Multifaceted Empathy Task, MET), sensitivity to changing facial emotions (Face Morphing Task, FMT), and punitive behaviour under provocation (Competitive Reaction Time Task, CRTT) with both subjective history and quantitative hair toxicology to examine dose-related and polysubstance-use effects. The investigators hypothesised that chronic METH users would show impaired cognitive and emotional empathy and elevated aggression, while regular MDMA users would show higher cognitive empathy, particularly for positive emotions, with little change in emotion sensitivity or aggression.

This was a cross-sectional case-control investigation conducted within a multicentre project (Dresden, Germany and Zurich, Switzerland). The analysed sample comprised 40 chronic METH users, 39 chronic MDMA users, and 86 pooled stimulant-naïve controls (controls were frequency-matched on age and sex across sites). Participants were aged 18–45 years. Substance-user inclusion required a minimum of 25 lifetime occasions of METH or MDMA use and recent use within the past 12 months, confirmed by hair analysis. Controls were stimulant-naïve by set criteria and excluded if they reported more than 15 lifetime illicit substance occasions (except cannabis). General exclusions included pregnancy, major neurological or severe psychiatric disorders likely to affect task performance, current psychotropic medication (not applicable to the METH group), and daily cannabis use (not applicable to the METH group). Participants abstained from illicit substances for at least 48 hours and alcohol for 24 hours before testing; abstinence was verified with urine screening. Procedurally, testing took place over two days. Day one included consent, clinical and substance-use assessments, and collection of hair and urine samples; day two included clinical questionnaires, urine screening and completion of an electroencephalogram in the larger protocol. Three behavioural tasks were administered in fixed order on day two: the Face Morphing Task (FMT), the Multifaceted Empathy Task (MET), and the Competitive Reaction Time Task (CRTT). The MET assessed cognitive empathy (emotion labelling) and emotional empathy (implicit arousal and explicit empathic concern) separately for positive and negative stimuli. The FMT measured sensitivity to graded morphs between angry and happy expressions and neutral perception. The CRTT operationalised punitive/aggressive behaviour by letting participants set noise intensity (1–8) as punishment across 25 trials, with analyses separating retaliatory from non-retaliatory responses. Substance use was characterised both subjectively via structured interviews and objectively via proximal hair samples (4 cm) analysed by LC-MS/MS; body hair was used when scalp hair was insufficient (n = 9). Additional measures included screening for DSM-IV/DSM-5 disorders, the CESD for depression, ADHD-SR, Barratt Impulsiveness Scale (BIS), STAXI-2 for state/trait anger, Need for Recovery Scale for fatigue, and a vocabulary test for premorbid verbal IQ. Statistical analyses were carried out in R 4.1.2. Group differences used chi-square tests and ANOVAs with FDR-corrected pairwise comparisons. Main outcome comparisons used multiple linear regressions with controls for sex, age and years of education; effect sizes reported as Cohen's f 2. Additional models incorporated BIS, CESD and SKB scores, and models controlling for recent and lifetime alcohol, cannabis and nicotine use were run. Hair concentrations and usage variables were log10-transformed with a constant of 1 for skewed distributions. Subgroup sensitivity analyses examined polystimulant MDMA users (n = 13 above forensic cut-offs) versus relatively pure MDMA users (n = 26), and MDMA users with any amphetamine (n = 21) or cocaine residuals (n = 25) were analysed separately. The authors stated that analysis code and data would be shared on request.

Sample characteristics showed group differences in sex distribution, years of education, verbal IQ, and questionnaire measures including ADHD-SR, CESD and BIS; METH users also had higher trait anger (STAXI). Hair toxicology confirmed methamphetamine as the primary recent substance in METH users. Although MDMA was the most reported substance among MDMA users, 54% and 62% of that group reported recreational amphetamine and cocaine use respectively, supported by hair residuals; pooling and sensitivity analyses addressed polystimulant use. Controls had no appreciable METH or MDMA hair residues. On the Multifaceted Empathy Task, regression models controlling for sex, age and education indicated that METH users performed worse than controls on both cognitive and emotional empathy for positive stimuli. No group contrasts reached significance for negative stimuli. MDMA users did not differ from controls on cognitive or emotional empathy. When impulsivity (BIS), depressive symptoms (CESD) and fatigue (SKB) were added as covariates, the contrasts between METH users and controls in empathy for positive stimuli lost statistical significance (adjusted p = .051 for cognitive empathy and p = .200 for emotional empathy). Performance in the Face Morphing Task showed no significant group differences for the angry, happy or neutral conditions in models controlling for demographics; adding BIS, CESD and SKB did not change this result. In the Competitive Reaction Time Task, METH users selected higher punishment levels than controls in non-retaliatory trials and also differed from controls in retaliatory trials. MDMA users did not differ from controls in baseline punishment levels, but paired t-tests showed all groups increased punishment from non-retaliatory to retaliatory trials (METH t = 3.318, p < .01; MDMA t = 5.274, p < .001; controls t = 4.560, p < .001). An ANOVA with Tukey HSD post-hoc tests indicated MDMA users exhibited a significantly larger increase in punishment from non-retaliatory to retaliatory trials compared with controls (mean difference = 0.549, adjusted p < .05). Adding BIS, CESD and SKB to the CRTT models attenuated some group contrasts (the MDMA vs METH difference in non-retaliatory punishment became adjusted p = .072). Doubts about the opponent's legitimacy were infrequent and did not alter results when controlled for. Sensitivity analyses that included recent or lifetime alcohol, cannabis and nicotine use altered some findings: several contrasts (including differences between MDMA and METH users and between METH users and controls in positive emotional empathy and non-retaliatory punishment) lost significance when other substance use was accounted for. Dose–response analyses yielded some uncorrected associations that did not survive FDR correction: in METH users higher hair methamphetamine concentration was associated with lower cognitive empathy for positive stimuli (f 2 = 0.213, β = -0.420, uncorrected p < .05). Among MDMA users, higher MDMA hair concentrations were associated with lower cognitive empathy for positive stimuli (f 2 = 0.138, β = -0.368, uncorrected p < .05) and with higher scores in the angry condition of the FMT (f 2 = 0.127, β = 0.358, uncorrected p < .05). Cumulative lifetime MDMA dose positively predicted retaliatory punishment in the CRTT (f 2 = 0.131, β = 0.375, uncorrected p < .05). METH craving predicted positive cognitive empathy in models controlling for positive urine (f 2 = 0.151, β = 0.348, uncorrected p < .05). Comparison of relatively pure versus polystimulant MDMA users did not show significant group differences. Among MDMA users, greater amphetamine residuals correlated with higher neutral FMT scores and higher cognitive empathy for negative stimuli (β = 0.538 and β = 0.422 respectively, uncorrected p < .05). The authors note some missing hair samples for METH users and emphasise that dose-related p-values did not survive FDR correction.

Zacher and colleagues interpret their findings as evidence that chronic METH and MDMA use are associated with distinct social-cognitive and social-behavioural profiles. Chronic METH users exhibited reduced cognitive and emotional empathy for positive stimuli and elevated punitive behaviour irrespective of provocation, along with higher self-reported trait anger. The investigators suggest these effects may relate to chronic METH-induced alterations in dopaminergic function, reward processing and attendant mood symptoms, which could selectively impair processing of positive emotions and thereby contribute to aggressive tendencies and social difficulties. In contrast, chronic MDMA users did not show the previously reported enhancement in cognitive empathy; instead, they displayed a larger behavioural increase in punishment in response to provocation compared with controls. The authors propose that this pattern reflects task-specific impulsivity and possibly cumulative serotonergic changes with heavier MDMA exposure. They also consider alternative explanations for the divergence from prior reports of enhanced empathy in MDMA users, including differences in dosage or a U-shaped dose–response relationship in which light use associates with higher empathy but heavier or longer-term use does not. The dose–response correlations observed in hair analyses—associating higher recent concentrations of either substance with reduced cognitive empathy and higher cumulative MDMA use with more retaliatory punishment—are presented cautiously because they did not survive correction for multiple comparisons. Several limitations acknowledged by the investigators temper causal interpretation. The cross-sectional design precludes firm inference about causality and the role of predisposition versus substance-induced change. Group differences were partly attenuated when controlling for impulsivity, depression, fatigue and other substance use (alcohol, cannabis, nicotine), indicating those factors may confound or mediate observed effects. Sex distribution was unbalanced across user groups, psychiatric comorbidity burden was higher in METH users, some hair samples were missing, recruitment occurred at two sites, and sample sizes—particularly within user subgroups—were moderate, which may have limited power to detect dose-dependent effects. The authors call for longitudinal studies that track social-cognitive change over time, consider chronicity and abstinence, and better disentangle predispositional factors from substance-induced alterations to inform tailored interventions and support for chronic stimulant users.