Diphenidine

Pre-existing hypertension or cardiovascular disease constitutes a relative contraindication. NMDA antagonists produce sympathomimetic cardiovascular effects; diphenidine's high rate of acute hypertension (76%) in the STRIDA case series indicates significant cardiovascular burden even in otherwise healthy individuals.

Pre-existing cardiac arrhythmia or structural heart disease increases risk of cardiovascular complications given the documented tachycardia and hypertension rates.

Personal or family history of psychotic disorders (schizophrenia, schizoaffective disorder) is an absolute contraindication. Diphenidine produces hallucinations, delusions, and paranoia as primary effects. NMDA hypofunction is a leading mechanistic model for schizophrenia; diphenidine directly induces this state.

Bipolar disorder, particularly with history of psychotic features, is a relative contraindication. Dissociative and psychotomimetic effects may destabilize mood cycling.

Hepatic impairment may reduce diphenidine clearance given its extensive CYP-mediated metabolism. The clinical significance is unquantified but constitutes a precautionary relative contraindication.

Pre-existing renal impairment is a relative contraindication given documented cases of rhabdomyolysis and acute kidney injury associated with diphenidine.

pregnancy, breastfeeding

Pregnancy and breastfeeding are absolute contraindications. NMDA receptors play essential roles in fetal neurodevelopment; antagonist exposure during critical developmental windows produces neurotoxicity in animal models of related compounds.