Systematic review of animal studies on the use of herbal medicine for attention-deficit/hyperactivity disorder.

Background: Attention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition, often requires treatment with stimulants such as methylphenidate and nonstimulants such as atomoxetine. Despite their effectiveness, medication-related side effects, adherence and symptom control issues have increased the interest in alternative therapies, especially herbal medicine. However, existing preclinical studies vary in quality and relevance. This systematic review evaluates animal studies investigating herbal medicines for ADHD; identifies limitations in experimental models, behavioral assessments, safety evaluation, and methodological rigor; and proposes a framework to guide future research. Methods: Following PRISMA 2020 guidelines, PubMed and Web of Science were systematically searched for eligible studies published between 1995 and March 2025 that used animal models to interventions for the treatment of ADHD-like symptoms. Results: Analysis of 25 studies revealed a strong reliance on a limited range of animal models, particularly the spontaneously hypertensive rat (48%), with 88% of studies using male animals exclusively. Behavioral assessments predominantly focused on hyperactivity (72%), whereas evaluations of inattention and impulsivity were comparatively limited. Herbal interventions were associated with improvements in ADHD-like behaviors and modulation of catecholaminergic neurotransmission, including increased dopamine and norepinephrine levels in the prefrontal cortex. Additional mechanisms included activation of neurotrophic signaling pathways (brain-derived neurotrophic factor/TrkB) and suppression of proinflammatory mediators such as TNF-α and IL-1β. However, 80% of the studies did not report safety outcomes, and no study clearly described randomization or blinding procedures, limiting the translational relevance of the findings. Despite these limitations, several formulations, including the Long Mu Qing Xin mixture, An Shen Ding Zhi Ling demonstrated promising multitarget effects. Conclusion: Although herbal medicines demonstrate promising multipathway effects for ADHD, progress remains constrained by the limited diversity of animal models and narrow scope of behavioral assessments. Future research should prioritize the use of diverse models, more comprehensive assessments, and the implementation of rigorous methodological standards.