Effectiveness and Safety of Liuwei Dihuang as an Adjunctive Therapy for Cognitive Impairment: A Systematic Review,...

Background/Objectives: Liuwei Dihuang (LWDH) is a classical plant-derived herbal formula widely used for cognitive decline. This study aimed to evaluate its efficacy and safety in cognitive disorders and to explore its potential pharmacological mechanisms using network pharmacology. Methods: We searched 11 databases through November 2024 for randomized controlled trials comparing LWDH plus conventional therapy with conventional therapy alone in cognitive disorders. Meta-analysis was performed for clinical outcomes, and herb-compound-target and disease-target datasets were integrated to identify core molecular modules. Results: Twelve randomized controlled trials involving 1137 participants were included. Adjunctive LWDH was associated with improvements in Mini-Mental State Examination scores (MD = 2.34, 95% CI 0.88-3.79), activities of daily living, and quality of life. However, substantial heterogeneity and methodological limitations, including unclear randomization and blinding, were observed across studies, indicating a potential risk of bias. Fewer adverse events were reported in the LWDH plus conventional treatment group, although reporting quality was limited. The overall risk of bias was judged as "some concerns". Network pharmacology analysis identified a broad set of overlapping genes between LWDH-associated targets and cognitive disorder-related genes, which were further refined through filtering procedures. Subsequent analyses suggested associations with pathways related to neurodegeneration, apoptosis, and central nervous system function; however, these findings are exploratory and based on in silico predictions. Conclusions: LWDH may be associated with potential adjunctive benefits in cognitive disorders. However, given the methodological limitations and clinical heterogeneity of the included studies, the findings should be interpreted with caution. The proposed pharmacological mechanisms are exploratory and require further validation. Well-designed randomized controlled trials are needed to establish more robust evidence.