Recently abstinent methamphetamine users showed Trail Making Test deficits consistent with Parkinsonian cognitive inflexibility, with intravenous use in women linked to greater errors.

The work highlights a clinically relevant PD-like phenotype in methamphetamine users that could inform risk stratification and tailored interventions, but offers limited mechanistic or biomarker insight for direct therapeutic discovery.

INTRODUCTION: Methamphetamine misuse is associated with elevated rates of Parkinson's disease (PD), and both conditions degrade fronto-striatal circuitry, primarily demonstrated in animal and post-mortem human studies. Despite this, few clinical studies have examined overlapping presentation, or whether long-term methamphetamine users exhibit a Parkinsonian-like phenotype. To examine whether recently abstinent individuals with methamphetamine use disorder (MUD) show Parkinsonian-like cognitive inflexibility, and whether these deficits vary by sex or patterns of use. METHODS: Forty-nine individuals with MUD (26 males, 23 females) were recruited from a 30-day residential treatment program and compared with thirty controls (16 males, 14 females). Cognitive flexibility was assessed using the Trail Making Task (TMT), a task sensitive to fronto-striatal deficits in PD. Between-group differences were tested with a two-way between-groups MANCOVA, within-group sex effects with a two-way within-group MANCOVA, and linear regression evaluated the influence of sex and drug intake patterns on PD-like presentation. RESULTS: Both sexes in the methamphetamine group showed significant TMT deficits relative to controls, consistent with PD populations. Age of first use, duration, and amount of methamphetamine used did not impact performance. Intravenous use, however, was linked to more TMT errors in females but not males. DISCUSSION: These findings support literature suggesting methamphetamine use resembles aspects of an early Parkinsonian-like phenotype. To our knowledge, this is among the first studies to show PD-like presentation in individuals with MUD, highlighting that women who inject methamphetamine may face disproportionate PD risk. As cognitive inflexibility can hinder treatment engagement, comprehensive interventions for MUD may need to address these deficits.