Effects of ADHD Medications on Male Reproductive Function: A Systematic Review of In Vivo Mammalian Evidence

Abstract

Long-term treatment with attention-deficit/hyperactivity disorder (ADHD) medications may begin before reproductive maturity, but their effects on male reproductive health remain uncertain. We systematically evaluated controlled in vivo mammalian evidence on male reproductive effects of medications used for ADHD, including the consistency, timing, reversibility, and certainty of reported associations. PubMed/MEDLINE, Embase, and Scopus were searched from inception to 8 August 2026. Eligible studies were English-language, controlled in vivo mammalian experiments evaluating a prespecified ADHD medication and at least one male reproductive outcome. Human, in-vitro-only, uncontrolled, conference-abstract, and preprint reports were excluded. Risk of bias was independently assessed by two reviewers using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool, and certainty was evaluated using an adapted preclinical Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results were grouped by drug and nine prespecified outcome domains and synthesized narratively. Meta-analysis was not performed because of substantial methodological and outcome heterogeneity. Twenty-two studies were included: 19 evaluated methylphenidate (MPH), two clonidine, and one lisdexamfetamine (LDX); 17 were conducted in rats, four in mice, and one in rhesus macaques. During active MPH exposure, adverse changes predominated in spermatogenesis, sperm quantity or quality, testicular or epididymal microstructure, testosterone, and apoptotic or inflammatory markers. Findings after drug-free follow-up were more often neutral, mixed, or partially reversible. Possible persistent sperm DNA fragmentation and adverse paternal embryonic outcomes were reported but were based on few studies with clustering concerns. Clonidine studies indicated altered epididymal contractility and transport, whereas the single high-dose LDX study reported adverse sperm, testicular, endocrine, DNA-fragmentation, and inflammatory findings. Risk-of-bias assessments were dominated by unclear judgments. None of the 18 drug-by-outcome-domain bodies of evidence reached high or moderate certainty; all were rated as very low certainty. Evidence was limited by small samples, heterogeneous species, developmental stages, doses, routes, exposure durations and assays, incomplete numerical reporting, serious indirectness to therapeutic use in men, and sparse replication outside MPH. ADHD medications, particularly MPH during active exposure, show a possible male reproductive toxicity signal in animal models, but the evidence does not permit quantitative risk estimation or class-wide or clinical conclusions. Better-controlled, exposure-validated animal studies and prospective human cohorts are needed.