Cranberry Polyphenols and Stress Resilience During Multitasking in Healthy Adults

Cranberry Polyphenols and Human Stress Resilience: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Integrating Cognitive, Physiological, and Microbiome Adaptations Underlying Nutritional Neuroprotection and Multitasking Performance in Healthy Adults.

This randomized, double-blind, placebo-controlled clinical trial evaluates whether 70 days of daily cranberry juice consumption improves cognitive performance and motor accuracy and reduces psychological and physiological stress responses during a motor-cognitive dual-task multitasking challenge in healthy adults aged 30-55 (Aim 1). It is hypothesized that chronic cranberry juice intake will enhance dual-task performance and attenuate stress reactivity (Hypothesis 1). It is further hypothesized that cranberry juice will mitigate multitasking-related fatigue, mood fluctuations, and cognitive impairment, accompanied by favorable changes in circulating stress biomarkers and stress-regulatory neurochemical pathways (Aim 2/Hypothesis 2). Finally, the study incorporates gut analysis to determine whether cranberry juice induces beneficial shifts in the gut microbiota and microbial metabolites (e.g., SCFAs) and whether these changes are associated with improved cognitive and stress-related outcomes, consistent with a microbiome-gut-brain axis mechanism (Aim 3/Hypothesis 3).

Recruitment and Screening

Individuals who express interest will complete an initial study interest form. If preliminarily qualified, individuals will proceed to a screening process conducted via Qualtrics. Study staff will review responses to confirm eligibility and identify exclusions based on predefined criteria.

Study Design, Visits, and Timeline

This randomized, double-blind, placebo-controlled, parallel-design trial spans 13 weeks and includes three in-person visits: the consent visit (V1), the baseline visit (V2), and the final visit (V3).

Consent Visit (V1)

At V1, participants complete the informed consent process and undergo eligibility checks. These include measurement of height and weight to confirm BMI eligibility, pregnancy testing for female participants to ensure non-pregnant status, and a brief multitasking task capability check to confirm participants can comfortably perform the protocol tasks. Study staff will answer any questions, and V2 and V3 will be scheduled. Upon providing consent, participants enter the run-in phase.

Run-In Phase (Pre-Baseline)

Following V1, participants begin the run-in phase, adhering to the study's dietary restrictions. This includes avoiding cranberry products and specific polyphenol- or supplement-rich foods, as well as limiting caffeine and alcohol near visit days.

Baseline Visit (V2) and Final Visit (V3) Procedures

V2 (baseline) and V3 (final) follow the same structure, with the key difference being the assigned beverage at breakfast during V3.

Pre-Visit Requirements and Intake

Participants arrive after a 10-hour overnight fast. Upon arrival, participants submit a self-collected fecal sample for gut microbiome analysis. Compliance with dietary restrictions is confirmed, after which a phlebotomist draws a fasting blood sample (20 mL). Height and weight are measured.

Core Assessments (V2 and V3)

Multitasking (Dual-Task) Challenge and Stress Reactivity Participants perform a dual-task multitasking paradigm with continuous physiological monitoring. The cognitive task involves counting backward aloud from a random number between 800 and 999, subtracting by 3, 7, and 17 across three series. Each series lasts 4 minutes, with 90-second breaks in between, totaling 15 minutes. Scoring is based on the total correct/incorrect subtractions; if errors occur, participants continue from the new number. The motor task involves clicking rapidly shrinking dots on a screen, scored for target efficiency and accuracy. The multitasking session is video-recorded. Mood and stress are assessed using the State-Trait Anxiety Inventory (STAI-State) and Visual Analog Mood Scales (VAMS) immediately before and after the task. Saliva samples are collected immediately before, immediately after, and 60 minutes after the task to measure cortisol and alpha-amylase.

Standardized Meal (V2 vs. V3)

At V2, participants are served a standardized meal with water. At V3 (Day 70), the standardized meal remains the same, but water is replaced with 8 oz of the assigned beverage (either cranberry juice or placebo).

Cognitive Testing

Following the multitasking challenge and standardized meal, participants complete NIH Toolbox cognition and memory assessments.

Questionnaires and Symptom Monitoring

Participants complete measures assessing mental fatigue, perceived stress, and trait anxiety via Qualtrics.

Post-Visit and Follow-Up

After V2, participants leave with assigned beverages (8 oz per bottle; two bottles per day). V3, the final visit, mirrors V2, except the standardized meal includes 8 oz of the assigned beverage and an additional compliance questionnaire is administered. Participation ends after all final assessments are completed at V3.

Inclusion Criteria:

• At least 110 pounds
• Between 30 and 55 years
• BMI between 18.9 and 29.9 kg/m²
• A minimum education level of high school or above

Exclusion Criteria:

• Heavy caffeine users (consuming more than 300 mg/day or more than two cups of coffee per day)
• Alcohol consumption exceeding three drinks per week
• A smoking history of 10 years or more, or current use of cannabis products
• Uncontrolled hypertension
• Clinically diagnosed illnesses such as diabetes, cardiovascular disease, neurological disorders, or mental health conditions
• Participants currently taking prescribed anti-inflammatory medications, antibiotics, or antidepressants that may affect study outcomes, particularly those related to blood and fecal sample analysis
• Individuals who regularly take vitamin or mineral supplements and are unwilling to discontinue them for the duration of the study will not qualify.
• Participants must be willing to maintain their current daily routine and lifestyle, undergo body weight and height measurements, and notify study coordinators of any illnesses or significant adverse life events during the study period
• Those with specific dietary restrictions that prevent them from consuming the standardized breakfast sandwich required in the study protocol
• Participants must successfully complete the on-site multitasking task as a screening measure prior to signing consent.
• Beck's Depression Inventory score of 21 or higher
• Beck's Anxiety Inventory score of 21 or higher
• A history of severe suicidal tendencies, or seasonal depression
• Pregnancy and breastfeeding (Female participants must complete four pregnancy tests throughout the study and track their menstrual cycle. Those unwilling to comply with these requirements will not be eligible.)
• Potential participants must not have taken any anti-inflammatory medications, antibiotics, or antidepressants within the past three months prior to the start of the study
• Individuals who were previously enrolled in IRB#202300950 will be excluded due to the learning effect of cognitive tests, ensuring accurate data collection for this study