Higher Semaglutide Dose Linked to Fewer Neuropsychiatric Diagnoses

Higher recorded doses of semaglutide were associated with lower subsequent rates of several broad neuropsychiatric diagnosis categories among patients with preexisting neurologic or neuropsychiatric conditions, according to a retrospective observational study.

Investigators analyzed federated electronic health record data from 63,215 semaglutide-treated patients and evaluated 24 incident neurologic or neuropsychiatric outcomes. Separate propensity-matched analyses compared semaglutide with metformin, sodium-glucose cotransporter 2 inhibitors, and dipeptidyl peptidase 4 inhibitors. Over approximately 2 years, semaglutide was generally associated with lower recorded rates of several outcomes than the comparator medications.

A landmark analysis examined maximum recorded semaglutide dose during the first 2 years after treatment initiation and outcomes during the subsequent 2 years. Patients with a maximum recorded dose of at least 1.7 mg had lower subsequent rates of substance-related neuropsychiatric disorders, mood or affective disorders, anxiety-, trauma-, obsessive-compulsive disorder–, or somatoform-related disorders, hereditary or systemic central nervous system atrophies, neuromuscular junction or muscle disease, eating, sleep, or behavioral syndromes, and personality or impulse-control disorders than patients whose maximum recorded dose was 0.25 to 1.0 mg.

The relative risk was 0.71 (95% CI, 0.62-0.81) for substance-related neuropsychiatric disorders and 0.82 (95% CI, 0.75-0.89) for mood or affective disorders. Dementia or degenerative central nervous system disease did not differ significantly between the high- and low-dose groups. Cognitive and speech or language symptoms were more closely associated with weight-loss strata than with dose. Recorded cognitive-symptom rates were higher in some groups with greater weight loss, but the investigators cautioned that this pattern could reflect frailty, illness-related weight loss, surveillance differences, reverse causation, or other biases rather than cognitive harm from semaglutide.

The findings do not establish that semaglutide or a higher dose caused the observed differences. Maximum recorded dose may also reflect tolerability, treatment persistence, adherence, access to care, and healthy-adherer bias. The analysis included all semaglutide formulations, although its dose categories reflected injectable dosing increments. The authors said the results should not be interpreted as a benefit-risk assessment or as support for off-label semaglutide prescribing and called for prospective validation.

Source: Murugadoss K, Venkatakrishnan AJ, Soundararajan V. Higher semaglutide dose is associated with lower neuropsychiatric event incidence independent of weight loss. npj Metab Health Dis. 2026;4:36. doi:10.1038/s44324-026-00131-3