Amitriptyline × Methylthioninium chloride (methylene blue)

IV methylene blue inhibits MAO-A. Amitriptyline (TCA) raises serotonin and norepinephrine through reuptake blockade. Co-administration sharply increases monoaminergic transmission.

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: profuse sweating, tachycardia, hypertension, fever above 38.5 °C. Severe cases progress to seizures, rhabdomyolysis, disseminated intravascular coagulation, and death. First signs appear within hours of concurrent dosing.

Avoid the combination. Methylene blue is reserved for emergencies with amitriptyline withdrawn 5 days in advance. If unavoidable on a TCA, monitor temperature, pulse, and reflexes in ICU with cyproheptadine available.