Natural supplementation to effectively treat cancer-induced fatigue: evidence of a meta-analysis on the use of guaraná

SUMMARY

BACKGROUND:

Cancer-related fatigue is a pervasive symptom, affecting up to 90% of cancer patients throughout their illness, and can persist well after treatment has ended. Despite its prevalence, no definitive evidence-based treatment exists, leading to an abundance of proposed alternatives, including natural supplements. To further explore the potential effects of guaraná on cancer-related fatigue, a systematic review with meta-analysis was conducted and registered on the International Prospective Register of Systematic Reviews (CRD42023484144).

METHODS:

A thorough search of PubMed/MEDLINE and Cochrane Library was conducted using MeSH terms and related keywords for cancer-related fatigue and guaraná. Eligible studies were selected according to predetermined criteria and assessed for quality in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Data extraction was independently performed by two reviewers, with any discrepancies resolved by a third researcher.

RESULTS:

In total, 4 full articles and 1 abstract, encompassing a total of 229 patients from 2009 to 2023, were included in the meta-analysis. Despite high heterogeneity between studies (I²=78%, ꭓ²=18.51, df=4, p=0.0010), the analysis revealed a significant benefit of using guaraná to alleviate cancer-related fatigue, with a standard mean difference of −0.77 (95%CI −1.34, −0.21) and a test for the overall effect of Z=2.68 (p=0.007).

CONCLUSION:

This meta-analysis provides support for the use of guaraná in the treatment of cancer-related fatigue. However, further investigation through larger prospective randomized controlled trials is necessary to validate these findings.

INTRODUCTION

Cancer-related fatigue (CRF) is a commonly reported symptom among cancer patients, with estimates suggesting that up to 90% may experience it during their illness, and some may experience it even after cancer treatment is completed ^1,2 . The causes of CRF are multifactorial, with systemic inflammation, endocrine, and even psychological factors playing a role ^3–7 .

Given the significant impact of CRF on patients’ overall well-being, the search for effective treatments remains an ongoing endeavor ^3–7 . While both non-pharmacological and pharmacological interventions have been explored, the latter often have limited evidential support, leading to much debate ⁵ . In light of this, a growing number of international groups have turned their attention toward natural supplements as a potential adjuvant therapy ⁸ . In fact, previous studies conducted by the Oncology Department at ABC Medical School examined the use of a purified extract of guaraná (Paullinia cupana), a plant indigenous to the Amazon region of Brazil, and reported promising results in clinical trials with cancer patients undergoing chemotherapy. However, due to the limited number of participants involved, the overall evidential significance of these findings remains low ^9–12 .

To address this limitation and consolidate the available evidence for the effects of guaraná on CRF, Araujo et al. conducted a meta-analysis ¹³ . However, upon review, certain discrepancies were identified, which could potentially be addressed through access to individual patient data. Furthermore, additional evidence regarding the effects of guaraná on CRF has emerged since the initial meta-analysis was conducted ¹⁴ , highlighting the need for a new meta-analysis to synthesize the findings from all randomized clinical trials conducted thus far.

METHODS

The present study followed the standards set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration code CRD42023484144. It involved a systematic review conducted between December 1, 2023, and February 1, 2024, with the goal of identifying relevant literature on the effects of guaraná supplementation on CRF. Articles written in English were retrieved from databases such as PUBMED, MEDLINE, LILACS, Embase, Web of Science, FSTA, clinicaltrials.gov, WHO-ICTRP, MedRxiv, and Cochrane Library. The search utilized Medical Subject Headings (MeSH) descriptors including: "Fatigue"[Mesh] OR Fatigue OR Lassitude AND "Paullinia"[Mesh] OR Paullinias OR Paullinia OR (Paullinia cupana) OR (Paullinia cupanas) OR (cupana, Paullinia) OR Guarana OR Guaranas OR (Paullinia pinnata) OR (Paullinia pinnatas) OR (pinnata, Paullinia) OR Barbasco OR Barbascos OR "guarana powder" [Supplementary Concept] OR (guarana powder) OR (guarana supplement). "Fatigue," "Paullinia," "Guarana," and "Guarana powder."

A PICO strategy was implemented to identify relevant studies, with the following criteria:

1. clinical trial,

2. adult population (age ≥18 years),

3. evaluation of the association between guaraná supplementation and CRF, and (4) well-established primary outcome measures such as the use of standard fatigue assessment scales as the BFI.

Additionally, the references to selected articles were screened for eligibility, as well as abstracts from relevant conferences. Two reviewers independently assessed all articles for inclusion, with a third reviewer resolving any discrepancies. Studies were deemed eligible if they met the aforementioned criteria. Studies not reporting outcomes such as the hazard ratio for reduction of fatigue with guaraná compared to placebo were excluded. Data were extracted from eligible studies, including title, authors, publication year and journal, sample size, formulation and active ingredient, medication regimen, and outcomes evaluated. For studies with data available for analysis, a meta-analysis was performed using Review Manager version 5.3.16, with standard deviations (SD) calculated using the RevMan calculator ¹⁵ . The risk of bias and assumptions for analysis were assessed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, employing the GRADE approach ^16,17 . The random effects model was utilized, with a significance level of 5%.

RESULTS

The present review identified a total of 117 articles with MeSH terms related to guaraná and CRF in six different databases. Upon removing duplicates, the remaining 43 articles underwent further screening, of which 11 were deemed relevant based on the established inclusion criteria. After a full abstract review, seven studies met all criteria and were included in the final analysis, consisting of five articles, one abstract, and one PhD thesis ^{9-11,14,18-20} . Ultimately, a total of 371 patients with cancer diagnoses were included in the review, with the majority of cases being breast cancer. The intervention phase ranged from 90 days or less, with only one study investigating a dose greater than 100 mg of guaraná per day. The Brief Fatigue Inventory (BFI) was the most commonly utilized instrument to measure and analyze fatigue, with a relatively even distribution of positive and negative findings across the included studies. Of note, two articles did not provide outcome data and were therefore excluded from the subsequent meta-analysis. Notably, we excluded two studies by Sette et al. published together in a single paper and the paper by dos Santos Martins et al. also due to insufficient outcome data availability (Table 1) ^11,18 .

Table 1. Summary of characteristics of studies included in the systematic review.

Author's name and year of publication	Cancer	N*	Intervention	Crossover	Duration of intervention	Instruments for analysis	Outcome
Costa Miranda et al., 200920	Breast	36	Guaraná extract (75 mg) daily	Yes	14 radiotherapy sessions	Chalder Fatigue Scale	Negative
						BFIa
						Beck Inventory Depression
Oliveira Campos et al., 201110	Breast	60	Guaraná extract (50 mg) 2x a day	Yes	21 days	BFIa	Positive
						FACIT-Fb
						Chalder Fatigue Scale
						FACT-ESc
						HADSd
						Pittsburgh Sleep Quality Index
Giglio et al., 20139	Multiple	33	Guaraná dried extract (PC-18) 37.5 mg 2x a day	Yes	21 days	BFIa	Positive
						FACIT-Fb
						Chalder
						HADSd
						PSQIe
Martins et al., 201618	Head and neck	60	Guaraná extract (50 mg) 2x a day	No	42 days	General Questionnaire	Negative
						Guaraná Toxicity Assessment
						FACT-Fb
						FACIT-HNf
						EORTC QLQ-30g
						QLQ H&N35h
Sette et al., 201711	Breast	32	Guaraná dried extract (PC-18) 37.5 mg 2x a day	Yes	21 days	BFIa	Negative
						Chalder
	Breast	72	Guaraná dried extract (PC-18) 7.5 mg or 12.5 mg 2x a day	No	21 days	BFIa	Negative
						Chalder
Albarnaz et al., 201719	Breast	42	Guaraná extract (50 mg) 2x a day	No	90 days	Piper Fatigue Scale	Positive
Inglis et al., 202314	Not informed	36	Guaraná powder (Energy bar) 280 mg or 560 mg per day	No	42 days	BFIa	Positive

^*Number of patients analyzed in the study.

^aAnderson Brief Fatigue Inventory.

^bFunctional Assessment of Chronic Illness Therapy–Fatigue.

^cFunctional Assessment of Chronic Illness Therapy–Endocrine Symptoms.

^dHospital Anxiety and Depression Scale.

^ePittsburgh Sleep Quality Index.

^fFunctional Assessment of Chronic Illness Therapy–Head and Neck Cancer.

^gEuropean Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30.

^hEuropean Organization for Research and Treatment of Cancer Quality of Life Questionnaire-H&N35.

Of the five studies selected for meta-analysis, four were published as full manuscripts and one was an abstract containing sufficient data for statistical analysis. Thus, 269 patients were included in the meta-analysis, with some overlap in cases due to crossover study designs. A Cochran's Q test and Higgin and Thompson's I ² statistic revealed significant heterogeneity among the included studies, with a Tau ² value of 0.32, Chi² value of 18.51 with 4 degrees of freedom (p=0.0010), and an I² value of 78%. The results indicated a statistically significant difference in favor of guaraná for the treatment of CRF, with a mean of −0.77 (95%CI −1.34, −0.21) and a p-value of 0.007 (Figure 1). However, it should be noted that the overall quality of evidence according to the GRADE framework for all studies included was low (Chart 1).

Figure 1. Forest plot of all studies included in the meta-analysis.

Chart 1. Quality of evidence according to GRADE.

Guaraná for fatigue compared to placebo for fatigue
Patient or population: Fatigue Setting: Intervention: Guaraná for fatigue Comparison: Placebo
Outcomes	Anticipated absolute effects* (95%CI)		Relative effect (95%CI)	N° of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with guaraná for fatigue
Fatigue	–	SMD 0.77 lower (1.34 lower to 0.21 lower)	–	269 (5 RCTs)	⨁⨁◯◯ Low
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI). CI: confidence interval; SMD: standardized mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

DISCUSSION

In this systematic review with meta-analysis, it was determined that the utilization of guaraná may hold promise as a potential intervention for the treatment of CRF. This finding is particularly significant given the current landscape, in which effective treatments for this condition are lacking, and there is a growing interest among both patients and researchers in natural and complementary therapies ^21–23 .

It is important to note, however, that our results differ from a previous meta-analysis by Araujo et al. ¹³ . Upon careful examination, it becomes apparent that this previous meta-analysis contains certain inconsistencies. For instance, the authors have misinterpreted the results when utilizing data from Sette et al., as hazard ratios and SD for the BFI scores comparing placebo with guaraná dry extract PC-18 were unable to be derived from the publication ¹¹ . Furthermore, even when individual patient data were accessible, the researchers were unable to obtain these outcome data. As such, these two studies were excluded from our meta-analysis, and given their negative results, it is possible that their inclusion in the analysis by Araujo et al. may have impacted the overall findings. In addition, when utilizing the dataset of Oliveira Campos et al., the authors specifically opted to present functional assessment of chronic illness therapy–fatigue (FACIT-F) data, as opposed to BFI results, which may have resulted in increased study heterogeneity ¹⁰ . It should also be noted that our more recent meta-analysis had access to the data of Ingris et al., provided in abstract form by the University of Rochester team, which had not yet been presented at the time of the de Araujo et al.'s study ^11,14 .

From a practical standpoint, our findings hold significant implications, suggesting that physicians managing cancer patients experiencing fatigue may consider incorporating guaraná supplementation as a viable therapeutic option, particularly for patients who are seeking alternative natural treatment modalities or who have found conventional therapies to be ineffective. In this regard, it should be recognized that other non-pharmacological approaches may also have utility, such as exercise and yoga ^24,25 .

It must also be acknowledged that no consensus currently exists regarding the appropriate dosage of guaraná for the improvement of CRF. It should also be acknowledged that our study comes with certain limitations, including its reliance on preexisting research data, the small sample sizes of the included studies, and the limitation that most of the participants were from a single country, which may restrict the generalizability of our findings.

In conclusion, our meta-analysis provides promising evidence for the use of guaraná supplementation as an adjunctive strategy for addressing CRF. However, larger-scale prospective randomized controlled trials are warranted to validate our findings.