Nuts4Brain-RCT: Protocol for a Three-Arm Randomized Controlled Trial Examining the Dose-Response Effects of Nut...

Introduction: Mental disorders, particularly depression and anxiety, represent a leading source of morbidity and disability in young adults, a group increasingly exposed to cumulative psychological processes and environmental stressors. Although evidence links healthy dietary patterns with improved mental health symptoms, the specific contribution of nut consumption (rich in anti-inflammatory, antioxidant, and neuroprotective compounds) remains insufficiently examined in this population. Current evidence also lacks robust data on the dose-response effects of nut consumption and mechanistic pathways involving biomarkers relevant to brain function and mental health. The Nuts4Brain-RCT will investigate the impact of a 6-month mixed-nut consumption intervention on mental health symptoms, cognitive functioning, sleep quality, overall well-being, health-related quality of life, and biochemical brain function mediators in young adults. Methods and analysis: A 6-month, randomized, single-blinded, three-arm, dose-response, parallel-group clinical trial will be conducted with 135 university students aged 18-24 years from the University of Castilla-La Mancha, Cuenca, Spain. The participants will be randomly assigned in a 1:1:1 ratio to one of three groups: (1) a control group maintaining their habitual diet while avoiding nut consumption; (2) a 30 g/day mixed-nut consumption group; or (3) a 60 g/day mixed-nut consumption group. The nut consumption intervention will include unsalted, unroasted walnuts, almonds, hazelnuts, and pistachios. The primary outcomes will include depressive (BDI-II) and anxiety (GAD-7) symptoms, perceived stress (PSS-10), cognitive performance (NIH Toolbox), and plasma brain-derived neurotrophic factor (BDNF). Assessments will take place at baseline and at 3 (intermediate), 6 (end of intervention) and 12 months (follow-up). Repeated-measures mixed-effects models will be applied to estimate the effects of nut consumption and dosage on mental health outcomes. Ethics and dissemination: The study adheres to the principles of the Declaration of Helsinki and the Singapore Statement on Research Integrity and obtained approval from the Clinical Research Ethics Committee of the Virgen de la Luz Hospital, Cuenca, Spain (REG: 2025/E0125). The findings will be disseminated through high-impact open-access peer-reviewed publications, presentations at scientific conferences, and social media platforms. Trial registration: ClinicalTrials.gov. Identifier: NCT07292610.