Severe Serotonin Syndrome in an Autistic New Psychoactive Substance User After Consumption of Pills Containing Methoxphenidine and α-Methyltryptamine

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To the Editors
Methoxphenidine (MXP) emerged as a new psychoactive substance (NPS) since the banning of a related compound methoxetamine in 2013.1 Methoxphenidine is structurally related to ketamine, with a greater intensity of effects and a longer half-life.2 Methoxphenidine is an N-methyl-D-aspartate (NMDA) antagonist and is also a moderate inhibitor of dopamine and norepinephrine reuptake but does not seem to be a serotonin reuptake inhibitor.3 Methoxphenidine is used as a recreational psychoactive substance with dissociative effects and might be highly addictive because of its ability to produce intense psychedelic effects.4 We report here the case of a polydrug user who developed a serotonin syndrome after he took MXP pills he bought on the internet. Analysis revealed α-methyltryptamine (AMT), a synthetic tryptamine and an indole analog of amphetamine5,6 with a serotonin receptor agonist and an inhibitor of the reuptake of serotonin properties that interacted with pharmacological properties of his medical treatment.
A 33-year-old man, known as an autistic patient and whose usual treatments were methadone, loxapine, and lorazepam, was admitted in an emergency unit after his mother found him in a state of great agitation. A small bag containing yellow pills said to be MXP according to his mother, was found in his room. The patient presented profuse sudation, hyperthermia, tachycardia (140 bpm), and mydriasis. Glasgow score was 10/15. A serotonin syndrome was suspected. Hyperthermia worsened within minutes with a body temperature at 42°C, and so he was transferred to a resuscitation department. He presented a hypercapnic acidosis with increased catabolism despite the hyperventilation (15 L/min) (PaCO2, 6.53 kPa [N = 4.8–5.6]; pH, 7.28 [N = 7.38–7.42]; lactates, 3.7 mmol/L [N = 0.5–1.2]). He also had a renal dysfunction (creatinine, 156 μmol/L [N = 50–110] increasing to 325 μmol/L 2 days later) due to rhabdomyolysis (creatine phosphokinase, 1,973 U/L [N = 20–171] increasing to 26,895 U/L 2 days later). At this moment, alanine aminotranferase and aspartate aminotransferase were 75-fold above normal values, prothrombin time was below 10% (N = 70–100), and bilirubin was 187 μmol/L (N = 1–17). The hepatic biopsy objectified a focal lobular necrosis compatible with a toxic origin.
Supportive care was performed including mechanical ventilation with sedation, endovascular targeted temperature management, large hydration, hemodialysis, and blood transfusions. Dantrolene (100 mg) was administered at 24 hours after hospital admission (H + 24) to prevent a possible neuroleptic syndrome related to the recent treatment with loxapine. The patient was discharged from the resuscitation department after 16 days with good recovery. Two samples of blood and urine were obtained respectively at H + 2 and H + 16 for toxicological explorations.
In the H + 2 blood sample, methadone was found at 192 μg/L (N = 400–500), lormetazepam at 0.2 mg/L, and lorazepam at 0.05 mg/L, and AMT was identified, corresponding to the usual treatment, except for AMT. In H + 16 urine sample, MXP, AMT, methadone and its metabolite 2-ethylidiene-1,5-dimethyl-3,3-diphenylpyrrolidine, amantadine, nortriptyline, mirtazapine, fentanyl, midazolam (and the metabolite α-hydroxymidazolam), ephedrine, fentanyl, midazolam, and ephedrine were drugs given at the admission.
The pills (yellow, weighing 150 mg, with a diameter of 6 mm, thickness from 3.3 to 4.5 mm and scored on 1 face) were also analyzed using a gas chromatography-mass spesctrometry method highlighting the presence of MXP and AMT.
Among the drugs and pharmaceuticals found by the different analyses, only MXP, AMT, amantadine, nortriptyline, and mirtazapine were not declared as a usual treatment of the patient and were not given in the emergencies.
α-Methyltryptamine is a drug synthesized in the early 20th century and which is a potent hallucinogen at doses above 30 mg.
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