ESSIAC tea is a traditional herbal blend widely used by cancer patients as a complementary therapy [1,2,3]. Originally employed in traditional Ojibwa medicine, it was later reformulated by Canadian nurse René Caisse in the 1920s. The classic ESSIAC decoction contains four main botanicals: burdock root (Arctium lappa), Turkish rhubarb root (Rheum palmatum), sheep sorrel (Rumex acetosella), and slippery elm bark (Ulmus rubra). Commercial variations (e.g., FlorEssence^®) expand this list to include blessed thistle (Cnicus benedictus), kelp (edible Laminaria seaweeds), red clover (Trifolium pratense), and watercress (Nasturtium officinale) [3,4]. In vitro and preclinical studies have demonstrated ESSIAC’s capacity to scavenge free radicals, reduce DNA strand breaks, and modulate enzyme systems such as CYP3A4 [5]. Leonard et al. reported potent antioxidant activity of ESSIAC in neutralizing superoxide and hydroxyl radicals and preventing hydroxyl-induced DNA strand breaks [5].

Martinez Marignac et al. observed reduced X-ray-induced genotoxicity in mice consuming ESSIAC [4]. However, systematic reviews and observational data have raised concerns about inconsistent formulation and lack of robust human clinical trials [1,2,3,4,5,6].

A North American, retrospective phase 1 trial by Richardson et al. [3], designed as a pattern-of-use survey of 5051 Flor-Essence™ consumers (response rate 6.4%), demonstrates that most were long-term users (mean 15.8 ± 17.4 months) treating medical conditions, particularly cancer [3]. Among 1560 cancer patients, 88.6% adhered to the recommended ≤4 oz/day dose, while 11.4% reported exceeding it [3]. This study reported that adverse events were uncommon (6.6%), the most frequent being diarrhea (1.9%), constipation (1.2%), nausea (1.1%), and fatigue (0.9%) [3].

Although 64.5% discussed tonic use with physicians and 50.6% perceived symptom improvement, the remarkably low incidence of adverse events observed in retrospective analyses underscores the need for rigorous prospective, controlled trials to definitively establish the safety and tolerability profile of ESSIAC. Moreover, extensive phytochemical investigations of each botanical component within the ESSIAC formulation have identified a spectrum of bioactive compounds such as flavonoids, phenolic acids, polysaccharides, and anthraquinones, which exert antioxidant, anti-inflammatory, and glycomodulatory effects in preclinical models. Arctium lappa (burdock) is rich in polyphenolic antioxidants (e.g., caffeoylquinic acids) and flavonoids; its extracts have demonstrated anti-oxidative and lipid-lowering actions in animal and in vitro models [7,8,9,10]. Rheum palmatum (Turkish rhubarb) provides anthraquinones such as emodin, aloe-emodin, and rhein, which exhibit anti-proliferative and pro-apoptotic effects on cancer cells through multiple signaling pathways [11,12]. The component Rumex acetosella (sheep sorrel) similarly contains antioxidant anthraquinones, though high doses can cause mild laxation and electrolyte loss [13]. Ulmus rubra (slippery elm) contributes mucilaginous polysaccharides thought to soothe mucosal tissues, and has a history of use for gastrointestinal inflammation, but scientific data on its antioxidant effects are limited [14,15]. Other ESSIAC ingredients like Trifolium pratense (red clover) and Cnicus benedictus (blessed thistle) contain isoflavones and flavonoids that modulate metabolism and inflammation [16,17,18].

The other two compounds, kelp and watercress, affect glycemic and lipid metabolism [19,20,21,22]. Overall, ESSIAC is a concentrated source of polyphenols and related compounds that, in principle, could scavenge reactive oxygen species (ROS) and ameliorate oxidative stress [4,5].

Oxidative stress and resultant DNA damage are hallmarks of cancer and aging-related pathologies [4]. Many dietary phytochemicals exert chemopreventive effects by bolstering antioxidant defenses or enhancing DNA repair; however, they may present interactions with different treatments [5,23,24].

The control selected was mate cocido or yerba-mate (Ilex paraguariensis A.St.-Hil.), it was selected as it has a similar taste to Genuine ESSIAC™ tea blend, and it is popular and part of the breakfast in Argentina. Yerba mate is a native plant from South America, highly consumed in this region in different traditional presentations, such as yerba mate, mate tea, mate cocido, and tereré, obtained from the yerba-mate leaves and consumed as an herbal infusion [25,26]. Yerba mate is a rich source of bioactive phenolic compounds, mainly caffeoylquinic acids. The richness of different mono- and dicaffeoylquinic acids is a peculiarity of yerba mate-derived products. However, in contrast to other plant-based beverages rich in polyphenols like tea or coffee, the research and the industry have yet to explore the potential interest of yerba mate products to promote human health despite its daily consumption [25,26].

Given its widespread use among oncology patients and its potential DNA-protective effects, rigorous clinical assessment of ESSIAC tea’s safety and efficacy by a formal, prospective clinical evaluation is justified [3,4,5]. We therefore conducted a fixed-dose, exploratory Phase I study designed to assess short-term tolerability, safety, and preliminary biological signals rather than dose-response relationships or efficacy throughout the 6-week intervention. Because the study objective was to evaluate safety under closely monitored conditions, dose escalation was not part of the design. We conducted a prospective randomized exploratory trial to assess whether daily ingestion of ESSIAC tea is safe and to explore its effects on blood biochemistry and genomic integrity (via the alkaline comet assay) in healthy volunteers. The use of a single standardized dose allowed us to focus on adherence, adverse events, and within-range biochemical and comet-assay outcomes. Therefore, the findings should be interpreted as more hypothesis-generating, safety-exploration, rather than as confirmatory evidence of efficacy. Therefore, we hypothesized that an eight-herb ESSIAC decoction would be well tolerated, reduce leukocyte DNA strand breaks compared to our control choice, and have beneficial effects in the short term.

A tea of 4 to 8 herbs, marketed as ESSIAC and Flor-essence, is widely used by North American cancer patients during chemotherapy and radiation therapy. Although ESSIAC is currently unavailable for sale in Canada, the Canadian government allows its sale to patients on compassionate grounds [2,3,30,31]. By 2009, ESSIAC was graded C under the Natural Standard Grades in Canada, which reflects the level of scientific evidence supporting the efficacy of a given therapy for a specific indication, in this case, cancer [2].

Regarding ESSIAC safety, Richardson et al. [3] have reported a 6.6% overall adverse event rate among 5051 Flor-essence users, with the most common symptoms being diarrhea (1.9%), constipation (1.2%), nausea (1.1%), and fatigue (0.9%). These low rates of primarily mild gastrointestinal effects underscore the favorable tolerability profile and support further prospective, placebo-controlled evaluation of ESSIAC’s safety.

There was a lack of prospective, randomized, controlled trials evaluating its safety. Our first-in-human prospective study demonstrates that daily consumption of an 8-herb ESSIAC tea is safe and well-tolerated in healthy adults. Over six weeks, no serious adverse events or laboratory toxicities were observed. Mild gastrointestinal complaints (nausea, vomiting, diarrhea) occurred in only 12% of participants and were self-limited. Moreover, extensive phytochemical investigations of each botanical component in the ESSIAC formulation have identified a diverse array of bioactive compounds as flavonoids, phenolic acids, polysaccharides, and anthraquinones, which exert antioxidant, anti-inflammatory, and glycomodulatory effects in preclinical models [31,32,33,34,35,36]. These mechanistic insights not only rationalize the composite therapeutic potential of the ESSIAC blend but also provide a scientific foundation for interpreting our clinical outcomes and optimizing dosage strategies in future trials [37].

Our tolerability results align with expectations for polyphenol-rich herbal beverages: transient GI discomfort (nausea, bloating) is commonly reported with green tea extracts and similar infusions [24,25,26,31,32,33,34,35,36]. Importantly, no hepatotoxicity or hematologic adverse events emerged, and fasting glucose remained stable. The ACA results mirrored preclinical animal data; for example, Martinez Marignac et al. reported that 7-week ESSIAC tea ingestion in mice did not cause weight loss, glucose changes, or changes in blood counts [4]. Our data confirm that clinically significant organ toxicity is unlikely at usual consumption levels. Our biochemical analyses showed that liver enzymes (AST) increased significantly with ESSIAC. Mechanistically, such a modest AST rise can reflect transient hepatocyte adaptive responses to bioactive botanical constituents, extra-hepatic release (e.g., minor skeletal muscle turnover or recent exertion), or short-lived alterations in mitochondrial/redox signaling, rather than a toxic effect [31,32].

All individual values in both cohorts remained within conventional clinical reference ranges, and there were no concurrent clinical signs of hepatic dysfunction. In fact, we observed modest improvements in lipid profiles and stable (or slightly reduced) liver enzyme levels in both the ESSIAC and mate cocido arms. Biochemically, a reproducible rise of this magnitude in HDL is consistent with favorable modulation of reverse cholesterol transport and HDL metabolism rather than an adverse change. Dietary polyphenols and multi-herb infusions have been shown to improve HDL or HDL function by up-regulating apolipoprotein A-I expression, enhancing LCAT activity, reducing CETP-mediated HDL remodeling, and lowering systemic inflammation that otherwise remodels and depletes HDL particles [31,32,33,34]. In practical terms, because all individual HDL values remained within conventional clinical reference ranges, the observed mean increase should be interpreted as a beneficial metabolic shift (improved HDL quantity and plausibly function) rather than a safety concern. To strengthen mechanistic inference and clinical relevance, follow-up measures are recommended in future works: quantify ApoA-1, assess cholesterol-efflux capacity (functional HDL assay), and measure CETP/LCAT activity and inflammatory markers; also replicate in a larger, prespecified trial that includes adjustment for multiplicity and stratification by baseline lipid status [30,31,32,33,34,35,36].

In our present study, the control employed, mate cocido, was selected because it has a similar taste to ESSIAC tea and is popular and part of breakfast in Argentina. However, in contrast to other plant-based beverages rich in polyphenols like tea or coffee, the research and the industry have yet to explore the potential of brewed yerba mate products to promote human health despite their widespread daily consumption in South America and Argentina [26].

Overall, the data may support a new hypothesis that the herbal infusion exerts favorable lipid-modifying effects consistent with prior trials of tea and polyherbal beverages [30,31,32,33,34,35,36]. Crucially, neither infusion impaired liver or renal function during the 6-week trial; this disagrees with some reports indicating that moderate tea polyphenol intake seldom causes organ toxicity [10,17,18,25,30,31,32,33,34,35,36].

In summary, no hepatotoxicity, nephrotoxicity, or hematologic toxicity was observed with daily ESSIAC or yerba mate consumption. These findings align with clinical analyses showing that regular consumption of tea polyphenols typically has neutral or modest beneficial effects on liver enzymes [9,10,18,19,20,33,34,35].

Our genotoxicity data, through ACA, suggest a protective trend for both infusions, rather than only safety; these results warrant a new hypothesis-testing trial. The inclusion of healthcare personnel employed in institutions with radiology or other X-ray-associated services was intentional, as such environments may involve chronic low-dose occupational exposure to ionizing radiation. Previous human biomonitoring studies, including comet assay-based evaluations such as Martínez et al. [38] and Zabarmawi et al. [39], have reported increased DNA damage in occupationally exposed healthcare workers. Accordingly, this cohort was considered relevant for an exploratory genomic safety assessment, indicating that occupational exposure may have contributed to baseline/week 0 variability and to DNA damage more severe than that of the normal population in comet assay outcomes.

Notably, subjects with higher initial DNA damage responded strongly to Essiac, and both groups showed reductions in DNA damage, likely because the control was not inert. Moreover, randomization allocated more “high-damage” individuals to the ESSIAC arm (though medians were similar), creating a potential regression-to-the-mean effect, where inter-individual comparisons were needed. Furthermore, it could mean the between-group difference underestimates any true effect of ESSIAC. A neutral placebo (e.g., water) and/or stratified randomization in future trials might better isolate ESSIAC’s unique impact. The reduced DNA strand breaks in the ESSIAC group by week 6 were consistent with preclinical antioxidant effects [4,5]. Leonard et al. demonstrated that ESSIAC scavenges superoxide and hydroxyl radicals and prevents free-radical–induced DNA damage in cultured cells [5]. Likewise, Martinez Marignac et al. reported that mice given ESSIAC had significantly lower X-ray–induced DNA lesions compared to controls [4].

However, the DNA protection results must be interpreted cautiously, as mentioned above. The brewed yerba mate is rich in antioxidants and has been shown to protect DNA in vitro as well [26]. Biologically, the observed DNA trends are plausible. Dietary antioxidants have been linked to upregulation of DNA repair pathways and prevention of mutagenesis in preclinical models [4,40].

Our study has limitations: The small sample size and exploratory design preclude definitive efficacy conclusions; the use of yerba mate as an “active” control, while preserving blinding, introduced confounding antioxidant effects biases; Another limitation is that, although participants completed a structured interview, where they were asked to maintain their usual lifestyle, and to avoid additional herbal interventions, dietary, lifestyle-related and occupational factors affecting oxidative stress were not fully controlled. As observed in similar exploratory human studies, such factors may influence oxidative stress-related endpoints and contribute to biological variability. Nonetheless, this proof-of-concept exploratory study achieved its primary aim of safety evaluation. The absence of clinically significant toxicity over 6 weeks is reassuring and aligns with the general safety profile of polyphenolic herbal infusions [25,26,34,35,36,37].

Daily ingestion of Genuine ESSIAC™ tea for 6 weeks was safe and well-tolerated in healthy adults, with no significant adverse laboratory findings. Mild gastrointestinal symptoms were infrequent and comparable to the known effects of the two herbal brews. Laboratory trends toward improved lipids, bilirubin, and ALP changes are mechanistically coherent with antioxidant, anti-inflammatory, and transporter-modulating actions of polyphenolic botanical constituents of both infusion and decoction. These measured variables, as well as others used in the present work, were grouped and interpreted according to distinct physiological domains, including genomic integrity, hepatic biochemistry, and lipid metabolism, rather than as a single unified efficacy endpoint. Within this framework, each outcome was treated as exploratory and intended to inform short-term safety and biological behavior under controlled exposure conditions, not to provide confirmatory evidence of efficacy. Practically, these data allowed the generation of a new hypothesis: that these infusions and decoctions may exert modest hepatoprotective and lipid-modulating effects, in addition to their genoprotective and ROS-scavenging effects; confirmation will require larger, longer-term, placebo-controlled trials with larger cohorts to assess the magnitude, durability, and therapeutic relevance of these effects.

Concluding, this study was intentionally designed as a fixed-dose, exploratory Phase I safety trial rather than a dose-escalation study. As we reported, 24 participants completed the protocol (12 per arm), which is appropriate for a closely monitored first-in-human safety assessment [28,37]. FDA guidance describes Phase I studies as the initial introduction of an investigational product into humans, usually in healthy volunteers, and FDA guidelines note that total enrollment is generally in the range of 20 to 80 participants; broader clinical-trial guidance likewise characterizes Phase I studies as small trials focused on safety, pharmacology, and dose selection rather than confirmatory efficacy [28]. Yerba mate was selected as an active comparator to preserve blinding and cultural acceptability, but it is not an inert placebo: human randomized data show antioxidant-related effects and an association with higher HDL-c, and experimental work has demonstrated free-radical scavenging and DNA-protective activity [25,26].