P.O. Box 144345 Austin, TX 78714-4345 . 512.926.4900 . Fax: 512.926.2345 . www.herbalgram.org HerbClip™ Mariann Garner-Wizard Shari Henson Heather S Oliff, PhD Samaara Robbins Gavin Van De Walle, MS, RD, LN Executive Editor – Mark Blumenthal Managing Editor – Lori Glenn Consulting Editors –Thomas Brendler, Meghan Henshaw, Allison McCutcheon, PhD, Kristen McPhee, MSciTH, Beth Quintana, ND, Carrie Waterman, PhD File: ■ Guayusa (Ilex guayusa, Aquifoliaceae) ■ Composition and Safety ■ Stimulant and Antioxidant Activities HC 091948-640 Date: May 15, 2020 RE: A Review of the Composition and Safe Use of Guayusa Wise G, Negrin A. A critical review of the composition and history of safe use of guayusa: a stimulant and antioxidant novel food. [published online August 1, 2019]. Crit Rev Food Sci Nutr. doi: 10.1080/10408398.2019.1643286. The world market for herbal teas is likely to grow by 4.5% compounded annually between 2018 and 2024. A total of 412 plants or plant parts were listed as herbal tea ingredients in 2016 by the European Union (EU). Guayusa (Ilex guayusa, Aquifoliaceae) leaf is one of many traditional herbs with growing accessibility to other parts of the world through international trade. Since guayusa is a traditional herbal drink to the western Amazon and was not consumed in Europe before 1997, it is currently considered a novel, yet unapproved food in the EU. A new EU Regulation on Novel Foods took effect in 2018, requiring that the composition and safety of novel foods with a traditional use as foods be examined. This review is a contribution to a pre-market risk assessment of guayusa. An electronic database search on guayusa in English or Spanish including peer-reviewed articles, reviews, books, book chapters, historical monographs, conference proceedings, and opinions of food safety authorities or advisory committees yielded 37 documents. The initial screen was followed by a review of the references cited in the retrieved documents as well as additional sources provided by experts in the field, resulting in 103 articles. The genus, Ilex, is the sole member of the Aquifoliaceae family. Guayusa is one of over 500 species of holly belonging to the Ilex genus. Guayusa has many names among Amazonian ethnic groups but has no recognized subspecies, cultivars, or varieties, despite one nomenclatural synonym. A tropical evergreen growing up to 30 m tall, it is found in Ecuador, Peru, and Colombia, and associated with archaeological remains in Bolivia. It has lost the capacity for sexual reproduction after generations of vegetative propagation in indigenous agroforestry systems. Leaves are harvested manually twice a year from three-year-old trees from these low-yield, organic polyculture systems. Processing guayusa leaves into tea involves the following steps: (1) cleaning to remove contaminants, (2) a short resting period to wither and ferment the leaves, (3) oven drying to dehydrate the leaves, and (4) mechanical maceration to produce a granular material. Sun-drying guayusa may prove inadequate for mainstream commercial production but the method is safer than the intense heat used to roast yerba maté (I. paraguariensis), which may produce polycyclic aromatic hydrocarbons and cause negative health effects. Ecuador’s biggest exporters of guayusa are mainly sourced from indigenous collectives. As demand grows, more efficient farming methods may be needed and if not done correctly, could negatively impact biodiversity. Early ethnobotanical reports describe guayusa’s use in the Amazon for stomach pain, dysentery, respiratory congestion, venereal disease, fever, hyperglycemia, and female sterility. Modern studies report its use in Ecuador and Peru as a blood purifier, with potential hypoglycemic effects; as a mouthwash, perhaps with anti-microbial effects, for body aches, especially headache, due to its caffeine, and in fertility, possibly due to its estrogenic effects. Additional modern studies note its use in gastritis, skin care, asthma, lactation, weight control, poor libido, prostate and kidney function, and repelling insects as well as for good luck with snake bites, hunting, and fishing. Claims about guayusa's emetic effects are often associated with its ritualistic morning use in Ecuador; however, no emetic compounds have been scientifically validated. Rather, behavioral emesis has been proposed as a mechanism to regulate caffeine intake. Among the Kichwa people, guayusa is cited, planted, and harvested more than any other medicinal plant. Its use as a stimulant has had the most scientific attention. Guayusa is one of the few known caffeine-bearing hollies. Yerba maté is another. Guayusa's chemical and nutritional content is fairly well known, but questions remain about the wide range of levels of caffeine reported (17.3±0.4 ‒ 75.7±1.2 mg/g) in fresh leaves in a 1991 study. Later reports found smaller but still varying ranges. The broad range may be due to variances in analytical methods, trees, locations, or leaf growth. Regardless, further research is needed to determine the intraspecies variation of caffeine. Producers, sellers, and some published reports claim that L-theanine is found in guayusa, attributing to a "mellowing" of the stimulatory effect produced by caffeine; however, L -theanine has been scientifically reported only in some Camellia spp. (Theaceae) and the bay bolete (Boletus badius syn. Xerocomus badius, Boletaceae) mushroom. Dry leaves consist mostly of carbohydrates (64.1±1.5 g/100 g) and crude fiber (37.0±1.7 g/100 g), with some protein (14.8±0.3 g/100 g). Low moisture (5.4±0.7 g/100 g) reduces risks of microbial contamination, reflected in negative screens of dry leaves compared to a variety of food microbes. With a dietary profile otherwise similar to that reported for tea, guayusa has nearly twice the crude fiber. New cultivation and processing practices might reduce crude fiber in guayusa to conform with perceived tea quality and good production practices. One analysis found identified four macro- and 12 microelements in guayusa, again broadly like those in tea and yerba maté. More research is needed on heavy metal accumulation, especially aluminum, since it is an agricultural-related challenge in Amazonia. However, reported levels of aluminum are lower than in tea and yerba maté. Two studies found 17 amino acids in guayusa, again similar to tea and yerba maté, with relatively high levels of asparagine, aspartic acid, glutamic acid, and arginine. Guayusa has more alanine, glutamine, and tryptophan and less glutamic and aspartic acids. Phenolic content in gallic acid equivalents is variously reported from 33.44±0.48 ‒ 106.62±4.41 mg/g (dry weight of extract). Phenolics include hydroxycinnamoylquinic isomers and flavonoids. Caffeoyl derivatives include chlorogenic, neochlorogenic, and isochlorogenic acids. Terpenoids include triterpenoids, carotenoids, xanthophylls, and carotenes. Its antioxidant capacity is similar to other medicinal plants of Ecuador but lower than in tea. In vitro and in vivo toxicological studies report no evidence of guayusa genotoxicity. One double-blind crossover randomized clinical trial found no differences between guayusa and synthetic caffeine intake in terms of heart rate, blood pressure, and epinephrine. Along with anecdotal reports, an epidemiological study of guayusa use in Ecuador over three years found no evidence of adverse effects. Notably, new guayusa fortified foods have no such record of safe, historical and continuing use. —Mariann Garner-Wizard The American Botanical Council has chosen not to reprint the original article. The American Botanical Council provides this review as an educational service. By providing this service, ABC does not warrant that the data are accurate and correct, nor does distribution of the article constitute any endorsement of the information contained or of the views of the authors. ABC does not authorize the copying or use of the original articles. Reproduction of the reviews is allowed on a limited basis for students, colleagues, employees and/or members. Other uses and distribution require prior approval from ABC. .