Cholinesterase inhibitors and sexual disinhibition in dementia: a FAERS disproportionality study

Sexual disinhibition under cholinesterase inhibitors (CHEIs; donepezil, rivastigmine, galantamine) appears only as scattered case reports and is largely absent from product labels. We examined whether it is disproportionately reported for CHEIs relative to memantine, a same-indication dementia drug of distinct mechanism, using the publicly available US FDA Adverse Event Reporting System (FAERS). We analysed 47 quarters (2014Q3-2026Q1; 15,901,334 de-duplicated reports) in a within-class active-comparator design, computing reporting odds ratios (ROR, 95% CI) with Benjamini-Hochberg FDR control (family m = 60). Reporting followed READUS-PV; the analysis is hypothesis-generating and does not address incidence, risk, or causation. Each CHEI versus memantine showed a concordant sexual disinhibition signal: donepezil ROR 5.16 (95% CI 2.23-11.90, q = 0.00036), rivastigmine 5.07 (2.02-14.98, q = 0.002), galantamine 6.18 (2.24-17.05, q = 0.0011); pooled CHEI class 5.58 (2.24-17.89, q = 0.0017). Excluding cases co-reporting memantine left all estimates at or above these values with lower bounds > 1. The reward/impulse cluster reached significance only when pooled (ROR 1.74, 1.06-2.85, q = 0.042). Negative controls were unremarkable (event controls ROR ≤ 1; drug controls < 1). The sexual disinhibition signal was reproducible and consistent across all three CHEIs relative to memantine, stronger than for other impulse/reward behaviours and largely absent from current labels. Disproportional reporting reflects relative frequency in the database, not actual harm, and is subject to channelling and detection bias; this exploratory signal warrants prospective study with individual-level temporality and dechallenge/rechallenge data.