Alpha-methyltryptamine (AMT) is an analogue of endogenous tryptamine with psychotropic effects and is available on the web as designer drug or new psychoactive substance (NPS). A clinical case of a severe serotoninergic syndrome after ingestion of this substance is reported. The patient (male, 33 years), known as autist and poly-addict with a substitution treatment by methadone, was admitted at hospital (H0) for agitation. Tablets found in a bag at home should be methoxphenidine (MXP). Clinical symptoms suggested serotoninergic syndrome with Glasgow Score 10/15, diaphoresis, mydriasis, hyperthermia and tachycardia (140 beats/min). The major hyperthermia (42 °C) needed to transfer the patient in an intensive care unit (H4). The biological constants showed metabolic and respiratory acidosis with pH at 7.28, PaCO 2 6.5 kPa and lactates at 3.7 mmol/L. Creatinine was 156 μmol/L (325 on day D2), creatine phosphokinase (CPK) was 1973 U/L (26,895 on D2), ASAT and ALAT enzymes were at 75 N on D2 with prothrombin time < 10%, bilirubin level at 187 μmol/L and thrombopenia < 10 G/L. This serotoninergic syndrome with multiple organ failure was treated by mechanical ventilation, sedation, endovascular targeted temperature management, large hydration, noradrenaline infusion, renal replacement therapy and blood transfusions. The patient recovered progressively and was discharged of the intensive care unit on D16. Methadone (0.3 mg/L), lormetazepam (0.2 mg/L) and its metabolite lorazepam (0.05 mg/L) were detected in the initial plasma sample (H2) using HPLC/UV-DAD and GC/MS screening approaches following liquid–liquid extraction. Another unknown compound was detected in plasma, urine samples and in the tablet. UV and MS spectra suggested an indole structure more especially a methyltryptamine derivative. The identification of AMT was further confirmed by comparison to pure reference substance. Quantitative analyses were realized by UHPLC/MS/MS after single protein-precipitation purification. AMT plasma levels were measured to 440 and 180 μg/L at H2 and H16, respectively. The urinary levels were 78.3 and 58.2 mg/L at H2 and H16, respectively. Suspected methoxphenidine was detected only in the tablet at a very low level while it was not detected in biological samples (< 10 μg/L). This clinical case needed a very high and sophisticated survey due to the patient's critical state illness related to a severe serotoninergic syndrome complicated by multiple organ failure.