Objective: Extrapyramidal side-effects (EPSE) are frequent in patients treated with antipsychotics and comorbid substance use disorders (SUDs). Methamphetamine has been shown to act as a dopaminergic neurotoxin. We aimed to determine whether EPSE occur more often in patients with psychotic disorders and co-occurring methamphetamine (MA) use disorders, and we examined the relationship between MA use, antipsychotic type, dose and EPSE. Methods: This study was a secondary analysis of data from three separate primary studies. Across all studies, psychiatric and SUD diagnoses were determined using the SCID-I for DSM-IV. EPSE were determined using the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating scale (BARS), and the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia. Participants were classified as having any EPSE if they scored above the cutoff on any of the EPSE scales (SAS, BARS, AIMS). We analyzed data using multivariable logistic regression analysis. Results: The sample included 102 patients with non-affective or affective psychotic disorders. Of the total sample, 65.7% were male, 54.9% had schizophrenia spectrum disorders, 20.5% bipolar type I disorder with psychotic features, 11.7% schizoaffective disorder and 12.7% had substance-induced psychosis. A diagnosis of a methamphetamine use disorder (abuse or dependence) was present in 25.5% of participants. EPSE occurred in 38.2% of patients and were significantly associated with MA use in the unadjusted and adjusted analysis, OR_adj = 4.01, 95% CI [1.07, 14.98], p = .039. Patients with MA dependence and MA use >3 years were significantly more likely to have EPSE. We found a significant interaction effect between MA use disorders and standardized antipsychotic dose on the occurrence of EPSE, OR_adj = 1.01, 95% CI [1.00, 1.01], p = .042, with MA users having a disproportionally higher likelihood of having EPSE compared to MA non-users as antipsychotic dosage increased. There were no significant associations of EPSE with comorbid alcohol, cannabis, or methaqualone use disorders. Conclusions: Patients with a MA use disorder were significantly more likely to have EPSE with evidence for a dose-response effect. Clinicians should carefully titrate antipsychotic dosage from lower to higher doses to avoid EPSE in patients with MA use disorders.

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