Guaraná Supplementation for Cancer-Related Fatigue

Evaluation of the Effectiveness of Guaraná (Paullinia Cupana) Supplementation in Reducing Cancer-Related Chronic Fatigue

Cancer-related fatigue is one of the most common and distressing symptoms experienced by patients during and after cancer treatment, and current options to manage it are limited. Guaraná (Paullinia cupana), an Amazonian plant rich in caffeine and other methylxanthines with anti-inflammatory and central-nervous-system-stimulating properties, has shown preliminary benefit for fatigue in small studies but lacks robust evidence. This pragmatic, prospective, single-arm study will evaluate whether guaraná supplementation reduces chronic cancer-related fatigue and improves quality of life in 60 patients with breast, lung, colorectal, or gastric cancer receiving active systemic treatment. Participants will take a 50 mg guaraná capsule by mouth every 12 hours for up to six 21-day cycles. The main outcome is the change in fatigue (baseline vs. post-intervention) measured with the FACIT-F and the Brief Fatigue Inventory (BFI). Secondary outcomes include quality of life (EORTC QLQ-C30) and adverse events. The study aims to support guaraná as a safe, accessible complementary option in supportive cancer care.

Background and rationale: Cancer-related fatigue affects 50-90% of patients across the disease trajectory and may persist for years after treatment. Its pathophysiology involves systemic inflammation, mitochondrial and skeletal-muscle dysfunction, oxidative stress, immune activation, and central-nervous-system involvement, with proinflammatory cytokines (IL-1, IL-6, TNF-α) contributing to symptom perpetuation. Available pharmacologic options (methylphenidate, modafinil, megestrol acetate) carry meaningful toxicity. Guaraná seeds contain 6-8% caffeine plus theophylline, theobromine, tannins, flavonoids and saponins, conferring stimulant, antioxidant and anti-inflammatory activity; prior trials and meta-analyses suggest benefit on fatigue with minimal toxicity, but results are inconsistent and ASCO/SIO have called for more rigorous trials.

Design: Pragmatic, prospective, single-arm study conducted in real-world clinical practice at a single center. Intervention: guaraná 50 mg capsule orally every 12 hours, 21 days per cycle, up to 6 cycles (total 126 days). Assessments at baseline, week 3, and end of treatment. Primary outcome: change in fatigue (FACIT-F and BFI). Secondary outcomes: quality of life (EORTC QLQ-C30), adverse events (CTCAE v5.0), and caregiver-perceived quality of life (proxy survey). Exploratory: adherence (capsule count, diary) and change in serum proinflammatory cytokines (IL-1, IL-6, TNF-α by ELISA) in a randomly selected subset of 30 participants (5 mL fasting venous blood at baseline, after 6-8 weeks, and at end of treatment; serum stored at -80 °C). Statistics: paired t-test or Wilcoxon for the pre-post change; multivariable regression adjusting for prespecified covariates; ITT with multiple imputation and per-protocol sensitivity analyses; α = 0.05 (two-sided), 80% power. Data captured in REDCap.

Inclusion Criteria:

• Histologic diagnosis of breast, lung, colorectal, cervical or gastric cancer
• Receiving active cancer treatment
• Has completed at least three cycles of chemotherapy

Exclusion Criteria:

• Intolerance to the oral route
• Contraindications to guaraná intake
• Uncontrolled cardiovascular disease (uncontrolled atrial fibrillation, symptomatic tachyarrhythmias, prolonged QT)
• History of intolerance to caffeine, methylxanthines, or flavonoids
• Use of CNS stimulants
• Recent history of bleeding
• Use of warfarin or any other vitamin K antagonist
• Use of theophylline