Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia, with increasing prevalence among older adults (Mian et al., 2024). Research indicates that approximately 10%–20% of elderly individuals aged 65 and older experience MCI (Petersen et al., 2009), with 10%–15% of these patients progressing to dementia each year (Eshkoor et al., 2015). MCI typically affects one or more cognitive domains, which not only disrupts daily life (Winblad et al., 2004) but also frequently leads to significant psychological distress, including symptoms of depression and a decline in overall quality of life (Dietlin et al., 2019). Therefore, timely intervention is crucial to mitigate the onset and progression of dementia, ultimately improving patients’ quality of life.

Currently, treatment options for MCI remain limited and often fail to prevent progression to dementia, highlighting the need for alternative therapies (Anderson and Malone, 2022). Therefore, plant-derived metabolites have been proposed as neuroprotective agents due to their antioxidant and anti-inflammatory properties. Plant extracts are rich in bioactive metabolites, including flavonoids, polyphenols, and alkaloids. These metabolites have been shown to improve nerve cell function and protect neurons from damage (Liu et al., 2023; Rajaram et al., 2019). Clinical research indicates that plant extracts enhance memory, cognitive abilities, and improve symptoms of neurodegenerative diseases, as demonstrated by the active metabolites found in plants such as Ginkgo biloba leaves, ginseng, and kudzu root. Significant progress has been made in mitigating or delaying the progression of cognitive decline (Kandiah et al., 2021; Lee et al., 2024; Wang et al., 2022). Previous research suggests that its mechanisms of action include promoting cognitive function through antioxidative and anti-inflammatory pathways, modulating neurotransmitters, and enhancing neuronal growth and connectivity (Ren and Qu, 2023; Yao et al., 2021; Zhao et al., 2021). Thus, plant extracts show promising potential in the management of mild cognitive impairment. However, their relative efficacy remains uncertain. This study aimed to synthesize evidence from randomized controlled trials through a network meta-analysis (NMA) to rank the relative effects of plant extracts in improving cognitive and functional outcomes in patients with MCI. The term ‘effects’ is deliberately used here to accurately reflect the synthesis of outcomes from multiple, heterogeneous trials, whereas “efficacy” typically implies performance under ideal, controlled conditions.

This systematic review and network meta-analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. The completed PRISMA checklist is available in Supplementary Table S7.

MCI most commonly presents with memory impairment symptoms that differ from normal aging, including frequent forgetfulness of daily events, difficulty recalling newly learned information, challenges in maintaining prolonged attention, reduced language expression, and a noticeable impact on daily life (Anand and Schoo, 2024). Although numerous drugs have been studied for MCI, no specific medication has been conclusively proven effective in its treatment.

Cognitive function screening tools, such as the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), effectively differentiate between normal cognition and MCI by assessing memory, attention, language, and executive function (Zhuang et al., 2021). Notably, MMSE and MoCA scores increase with better cognitive function, so a positive mean difference (MD) reflects improvement, whereas for ADAS-cog, which increases with greater impairment, a negative MD indicates improvement.

In recent years, several studies have explored the potential therapeutic effects of plant extracts on MCI, yet no research has evaluated which specific intervention is most effective. Thus, this study employed a Bayesian network meta-analysis to rank the effectiveness of 18 plant extract interventions, providing evidence-based guidance for selecting natural remedies for MCI patients.

This network meta-analysis, which synthesized data from 19 trials and 4,956 patients, provides a comprehensive synthesis of the currently available evidence on 18 plant extracts for MCI management. However, the findings must be interpreted with considerable caution in light of the methodological limitations identified across many of the primary studies, as will be discussed further. Our analysis identified Pycnogenol as the most effective intervention for improving both cognitive function, showing a large positive effect size (SMD = 0.85), and activities of daily living (ADL). This key finding warrants further discussion regarding the underlying mechanisms and clinical implications of Pycnogenol. A standardized extract from French maritime pine bark, Pycnogenol has been shown to significantly enhance working and spatial memory and positively affect psychomotor function (Belcaro et al., 2014). Animal studies confirm its neuroprotective effects via reducing oxidative stress, inflammatory factors, and regulating apoptosis (Xia et al., 2017). Since age-related oxidative stress impairs memory encoding pathways, antioxidants like Pycnogenol may counteract cognitive decline (Bastianetto and Quirion, 2004; Joseph et al., 2009).

Beyond Pycnogenol, our analysis also highlighted the significant cognitive-enhancing effects of other extracts, notably medium-to-large effect sizes were observed. These included CCSupplement (SMD = 0.26, 95% CI = [-0.52, 1.04]), Ferguar (SMD = 0.25, 95% CI = [-0.05, 0.55]), and Ashwagandha (SMD = 0.45, 95% CI = [0.14, 0.89]), all of which exhibited some effects, such as Memophenol (SMD = 0.23, 95% CI = [-0.05, 0.51]). Among the seven highly effective interventions, medium-to-large effect sizes were observed. This suggests the existence of several highly effective interventions. In contrast, some extracts showed no significant difference from placebo, highlighting the variability in efficacy across different plant-derived products.

Declines in cognitive function adversely impact patients’ quality of life, including self-care ability and independence in basic ADL, increasing the need for assistance and risk of injury (Hussenoeder et al., 2020). Consistent with its effects on cognition, our findings also highlighted Pycnogenol’s superiority in improving ADL compared to placebo, a result that aligns with prior research Pycnogenol’s antioxidant and anti-inflammatory properties reduce pro-inflammatory cytokines and β-amyloid plaques, contributing to therapeutic benefits in neurodegenerative diseases (Nattagh-Eshtivani et al., 2022; Paarmann et al., 2019). Enhanced memory and attention likely underlie the observed quality of life improvements.

Mental health is also a concern in MCI, with anxiety and depression commonly observed due to cognitive decline and social withdrawal (Orgeta et al., 2022). Tools like the Neuropsychiatric Inventory (NPI) and Geriatric Depression Scale (GDS) assess psychological symptoms comprehensively (Ginsberg et al., 2019). A key finding of our systematic review analysis was the superior performance of Cosmos caudatus Supplement (CCSupplement; Cosmos caudatus; commonly known as Ulam Raja or King’s Salad) in its beneficial role as a natural health supplement, attributable to its strong antioxidant and anti-inflammatory properties. Its potent effects on mental and oxidative stress are metabolites such as quercetin, and other flavonoids and phenolic acids. Chronic neuroinflammation and oxidative stress are well-established contributors not only to cognitive decline but also to mood disorders like depression and anxiety, which are highly prevalent in MCI patients. By mitigating these pathological processes in the brain, CCSupplement may help alleviate depressive symptoms and improve overall emotional stability. Furthermore, findings from the trial by study (You et al., 2021; You et al., 2020), which contributed data to our analysis, align with this hypothesis, demonstrating that supplementation led to significant improvements in mood and quality of life scores in the MCI population.

This meta-analysis observed heterogeneity, particularly in study regions and participant gender distributions, which may affect generalizability. Cultural, genetic, and environmental differences, including dietary patterns and baseline health—could influence botanical intervention efficacy. Gender imbalances may bias outcomes; thus, future research should target more homogeneous populations or perform pre-specified subgroup analyses to clarify these effects.

Furthermore, MCI itself is a heterogeneous clinical syndrome with various underlying etiologies (e.g., Alzheimer’s disease, vascular pathology). The therapeutic effects of plant extracts could vary significantly across these subtypes. Unfortunately, the primary studies included in our analysis generally did not stratify their participants or report outcomes based on MCI subtypes (e.g., amnestic vs. non-amnestic), which precluded any subgroup analysis to investigate this potential variation. This lack of detailed patient characterization in the source literature is a significant limitation of the current evidence base and highlights a critical direction for future research.

Additionally, the included studies used various cognitive, functional, and psychological scales with differing sensitivity and specificity, potentially impacting pooled SMD precision. Standardization of validated outcome measures in future MCI trials is crucial for reliable meta-analytic conclusions.

Not all studies assessed all three primary outcomes (cognition, daily living, psychological wellbeing) comprehensively, limiting full efficacy profiling for each botanical intervention. For example, the psychological effects of Pycnogenol remain unclear, underscoring the need for comprehensive outcome assessment in future research.

Recent studies suggest that CCSupplement may exert psychological benefits by activating Nrf2-mediated antioxidant pathways and inhibiting neuroinflammation, stabilizing mood and enhancing neuroprotection. CCSupplement and similar supplements synergistically improve mental health by modulating antioxidant, anti-inflammatory, and neuroprotective mechanisms, including NF-κB and JAK-STAT pathway inhibition and neurotrophic factor upregulation (Wu et al., 2025; Liao et al., 2020; Godos et al., 2020). Although direct human evidence is limited, these mechanisms are well-supported in the literature.

It is also valuable to consider conceptual subgroups based on the primary mechanisms of the most effective botanical drugs. Our findings suggest that successful interventions may fall into distinct mechanistic classes. For instance, Pycnogenol and GSPE represent a class of potent antioxidant and vasodilatory agents, whose benefits likely stem from reducing oxidative stress and improving cerebral blood flow. In contrast, Ashwagandha represents an “adaptogen” class, which is thought to enhance cognitive resilience by modulating the body’s stress response (e.g., regulating cortisol levels) in addition to its antioxidant effects. Meanwhile, extracts like LI1370 (Bacopa monnieri) are considered “nootropics” that may directly influence neurotransmitter systems involved in memory and learning. While the current evidence base is too sparse to conduct a formal statistical subgroup analysis by these categories, recognizing these distinct pharmacological profiles is essential for generating new hypotheses and designing future trials that could compare these different approaches.

An essential consideration for any therapeutic option is its safety and tolerability. Our review found that the botanical drugs included were generally reported as safe and well-tolerated, with most adverse events being mild and comparable in frequency to placebo. This favorable safety profile is a significant advantage, particularly for the MCI population, which is often elderly and may have multiple comorbidities. However, this finding must be interpreted with caution. The quality and comprehensiveness of safety reporting were inconsistent across the included trials. Many studies lacked systematic and active monitoring for adverse events. Therefore, while the current evidence is reassuring, a definitive conclusion on the long-term safety and potential for drug interactions for these botanical interventions cannot be drawn. Future trials must incorporate rigorous and standardized safety monitoring protocols.

Overall, our study has important clinical implications. Pycnogenol and CCSupplement significantly enhance cognitive function, activities of daily living, and psychosocial health in MCI patients. Physicians might consider incorporating these plant extracts as therapeutic options in clinical practice.

The primary strength of this study lies in its comprehensive scope, synthesizing data from 19 trials and providing the first network meta-analysis to systematically compare a wide array of botanical extracts for Mild Cognitive Impairment (MCI). However, the conclusions are subject to several important limitations, primarily inherited from the included studies.

First, and most critically, the methodological quality of the primary evidence base is a major concern. As our risk of bias assessment revealed, a large proportion of studies presented an “unclear” risk of bias, particularly in the fundamental domains of allocation concealment and the blinding of participants and personnel. This poor or non-reporting is highly problematic, as it introduces a substantial potential for selection, performance, and detection biases. This uncertainty significantly tempers any strong conclusions about the “efficacy” of these preparations. While our analysis reflects the best available evidence, it is crucial to acknowledge that these methodological weaknesses mean the true effect sizes could be overestimated. The findings should therefore be viewed as preliminary and hypothesis-generating rather than definitive.

Second, the evidence base is characterized by significant heterogeneity. This includes not only variations in study regions and participant gender distributions but also the clinical heterogeneity within the MCI population itself (e.g., different underlying pathologies), which could influence treatment effects. A key limitation stemming from the source data is our inability to perform subgroup analyses by sex or population, as none of the included trials reported outcomes stratified in this manner. This lack of granular data in the primary literature prevents a deeper exploration of heterogeneity and underscores a critical gap in the current research landscape. We strongly urge future RCTs in this field to prespecify and report outcomes for these important subgroups.

Finally, other limitations include the variations in the sensitivity and specificity of the scales used for outcome assessment and the fact that not all studies assessed all three primary outcomes (cognition, daily living, and psychological wellbeing). These factors underscore the need for further, higher-quality research with standardized, comprehensive outcome assessments to address these limitations.

Based on our systematic review and network meta-analysis, we recommend Pycnogenol for improving cognitive function, where it demonstrated the largest and most consistent beneficial effect (SMD = 0.85), and for enhancing quality of daily life, and CCSupplement for enhancing mental psychology. Overall, although the studies on Pycnogenol did not include psychological assessments, it demonstrated more substantial effects in enhancing cognitive function and quality of daily life in patients with mild cognitive impairment, making it the most recommended plant extract.