Written by Keely Puchalski, ND. Results from this study suggest that broad-spectrum polyphenols may enhance memory and attention in healthy young adults, alongside favorable increases in peripheral BDNF and CREB – two brain proteins involved in neuroplasticity, learning, and cognitive performance.

Cognitive decline, even in its early stages, can affect memory, concentration, and quality of life¹. Cognitive decline can progress over decades, and early efforts to preserve cognitive function are critical as late stage interventions are often ineffective^1,2. Oxidative stress and inflammation are key contributors to neurodegeneration, and polyphenols—naturally occurring compounds in fruits, vegetables, tea, and cocoa—have shown potential to protect brain health by reducing inflammation and neutralizing harmful free radicals^3-5 Polyphenols have also been shown to modulate critical neuroprotective brain proteins involved in many cognitive functions and synaptic plasticity, including cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF)^6-8. CREB is a transcription factor that, when activated, binds to DNA and turns on the expression of genes involved in neuronal development and survival and a gene that encodes BDNF, among others⁹.  Activation of CREB often leads to increased BDNF, which is associated with neuronal growth, connections, adaptation, and resilience^9,10.

To evaluate the relationships between polyphenol intake, cognitive performance, and CREB and BDNF levels, Carrillo et al. (2025) conducted a randomized, crossover, double-blind, placebo-controlled clinical trial of 92 healthy young adults in Spain. Participants were 51.09% male and 48.91% female, with a mean age of 34 years, and were not following any specific type of special diet or eating more than two servings of fruits or vegetables per day prior to the study. Participants were randomly assigned to receive either the tested product or placebo capsules of indistinguishable appearance and dosage. The six polyphenol capsules contained 600mg of a unique homogenized blend of fruits, vegetables, and berries (56%), as well as cocoa powder, green tea extract, grape seed extract, and several other ingredients. A total of 119 distinct polyphenolic compounds from various phenolic families were identified in the product by UHPLC-QqQ-MS in a previous 2017 study¹¹. The product was consumed orally – 3 caps twice daily for two 16-week periods – and there was a 4-week washout period before the crossover.

The Stroop Test, The Trail Making Test (TMT), and The Reynolds Intellectual Screening Test (RIST) were all used to evaluate different changes in cognitive abilities amongst baseline, product, and placebo groups. Plasma levels of CREB and BDNF were tested using commercially available enzyme-linked immunosorbent assay (ELISA) kits for human samples. Mean and standard deviation were reported for baseline and follow-up values. Normality was tested using the Kolmogorov–Smirnov test. Baseline comparisons between groups used Student’s t-tests. To assess treatment effects over time, repeated measures ANOVA was performed with time (baseline vs. final) and treatment (polyphenol vs. placebo) as factors. Post hoc Bonferroni tests identified specific differences. A p-value of less than 0.05 was considered statistically significant. Based on this threshold, the study found several significant results, including:

• Stroop Test scores (PT Stroop), PT RIST scores, and TMT-B scores all significantly improved in the product group compared to both baseline and placebo groups.
• The most significant improvements were observed in the Stroop PC task scores: group vs. placebo (p < 0.001) and RIST scores (group vs. baseline and placebo, p < 0.01).
• CREB and BDNF plasma concentrations significantly improved in the product group compared to both baseline and placebo groups.
• Improvements in Stroop Test and RIST scores were correlated with increases in both CREB and BDNF levels, and the TMT-B test scores showed positive correlations with CREB levels in the product group.
  • RIST product group: BDNF (r = 0.63; p < 0.001) and CREB (r = 0.55; p < 0.01)
  • TMT-B product group: CREB levels (r = 0.42; p = 0.02)

The results of this study demonstrated that repeated daily intake of the polyphenol-rich supplement led to statistically significant improvements in several domains of cognitive function in healthy adults, including working memory, attention, and processing accuracy compared to baseline and placebo and that these observed improvements were correlated with measurable increases in CREB and BDNF levels.

The study provides compelling evidence that polyphenol-rich supplements can enhance cognitive performance and support brain health, even in healthy individuals. These findings are particularly meaningful given the global increase in cognitive disorders and the general aging of the population.

Further research is needed to explore the long-term impact of such supplements, their efficacy in older or cognitively impaired individuals, and the mechanisms behind the observed effects. Larger trials and those comparing different types of polyphenols may also help refine dosing strategies and identify optimal formulations.

Source: Carrillo, Juan Ángel, Raúl Arcusa, Raquel Xandri-Martínez, Begoña Cerdá, Pilar Zafrilla, and Javier Marhuenda. “Impact of Polyphenol-Rich Nutraceuticals on Cognitive Function and Neuroprotective Biomarkers: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” Nutrients 17, no. 4 (2025): 601.

© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/
licenses/by/4.0/).

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Posted June 16, 2025.

Keely Puchalski, ND, is a naturopathic physician and natural products expert specializing in integrative psychiatry, gut health, and chronic illness. She earned her ND from Sonoran University of Health Sciences (formerly Southwest College of Naturopathic Medicine) in 2020. She co-founded Restored Counseling & Wellness Center in Gilbert, AZ where she practices with a team of therapists and naturopathic doctors:  https://restoredcw.com

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