Introduction: This study hypothesized that 3,4-methylenedioxymetamfetamine intoxication presents with distinct clinical features and outcomes when combined with other substances of misuse, compared to mono-3,4-methylenedioxymetamfetamine intoxication. This study investigated the clinical presentation of acute mono-3,4-methylenedioxymetamfetamine intoxication, 3,4-methylenedioxymetamfetamine intoxication with exclusive co-usage of ethanol, and 3,4-methylenedioxymetamfetamine-co-intoxication with co-usage of other substances with or without ethanol, with a focus on patient sex differences.

Methods: A retrospective analysis was conducted using the Euro-DEN Plus database (2013-2022), which collects data on emergency department presentations with acute drug intoxication from 28 sentinel centres in 18 European countries. Odds ratios for clinical features were calculated for the three study groups with mono-3,4-methylenedioxymetamfetamine intoxication as the reference group. A sub-analysis explored patient sex differences in clinical features.

Results: Among 4,102 presentations, 3,4-methylenedioxymetamfetamine-ethanol intoxication (n = 1,376) was associated with increased odds of agitation (OR: 1.34), drowsiness (OR: 2.30), and vomiting (OR: 1.85) compared to mono-3,4-methylenedioxymetamfetamine intoxication (n  = 359). 3,4-Methylenedioxymetamfetamine-co-intoxication (n  = 2,367) was associated with higher odds of bradycardia (OR: 3.14), psychosis (OR: 1.91), and coma (OR: 1.72). Mortality rates did not significantly differ across groups. Females reported a lower incidence of chest pain (OR 0.78) while reporting higher rates of vomiting (OR: 1.64), headache (OR: 1.61), and hypotension (OR: 1.89) compared to males.

Discussion: The variation in clinical manifestation of acute 3,4-methylenedioxymetamfetamine intoxication is associated with co-intoxication and patient sex. Co-intoxication with ethanol or other substances was associated with an increased incidence of more severe symptoms, such as agitation and psychosis, necessitating tailored management. These variations suggest the need for physicians to consider the type of co-intoxication and patient sex to optimize treatment strategies. Although co-intoxication affected the clinical trajectory, the mortality risk remains low.

Conclusions: Ethanol co-intoxication, co-intoxication with other substances of misuse, and patient sex were associated with varying clinical presentations in the emergency department, necessitating tailored treatment approaches.