Xanthohumol Microbiome and Signature in Healthy Adults (the XMaS Trial): Safety and Tolerability Results of a Phase I Triple‐Masked, Placebo‐Controlled Clinical Trial

Abstract

Scope: Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. Methods and Results: Thirty healthy volunteers were randomized to 24 mg day −1 xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in the placebo and xanthohumol groups, respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs are documented in both the placebo (n = 42) and xanthohumol (n = 58) groups. Conclusion: Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults.

Bioavailability and Cardiometabolic Effects of Xanthohumol: Evidence from Animal and Human Studies

“…• Half-lives exceeded 20 h. Bradley et al [57] and Langley et al [58] RCT total xanthohumol (after enzyme hydrolysis of conjugates) with maximum concentrations (C max ) of 4.4 ng mL −1 reached after 3.8 h, 22.2 ng mL −1 reached after 3.6 h, and 27.6 ng mL −1 reached after 1.8 h, respectively. [45] The low bioavailability of xanthohumol in animals and humans may be a result of very limited uptake in the small intestine and rapid metabolization by microorganisms in the colon [11] as well as rapid and almost complete biotransformation in the small intestine and liver (see next paragraph).…”

“…[44,45] A recently published placebo-controlled clinical trial (the XMaS Trial) confirmed the safety of xanthohumol given at daily doses of 24 mg for 8 weeks with all clinical biomarkers and anthropometrics being unaffected and/or staying within the clinically normal reference ranges. [57,58] Toxicological studies in mice indicate that even higher dosages and longer intakes of xanthohumol do not cause harm. Neither ad libitum intake of drinking water with 0.5 mmol L −1 xanthohumol for 4 weeks, nor daily feeding of about 1000 mg xanthohumol kg −1 body weight for 3 weeks impaired major organ functions.…”

“…A placebo-controlled clinical trial on the safety and tolerability of xanthohumol showed that a daily intake of 24 mg xanthohumol over 8 weeks is safe and well tolerated (Table 1). [57,58] Anthropometric parameters were measured, but neither body weight, nor BMI was affected by xanthohumol supplementation. [57,58] Two placebo-controlled intervention trials demonstrated that the daily consumption of a xanthohumol-containing drink (12 mg xanthohumol) over 2 weeks protected against oxidative DNA damage (Table 3) [77,78] ; however, there was no effect of xanthohumol on body weight, BMI, blood pressure, or pulse.…”

“…Only two placebo-controlled studies measured blood glucose concentrations, neither of which found an effect of xanthohumol at daily intakes of 12 and 24 mg over 2 and 8 weeks, respectively (Tables 5 and 6). [57,58,77]…”

“…[78] Both studies showed protective effects of xanthohumol on DNA stability. [77,78] In a safety study, Langley et al [57,58] investigated the effects of xanthohumol consumption on complete blood count, including different immunocompetent cells (e.g., neutrophils, monocytes). No effect was reported, suggesting that xanthohumol consumption is safe and well tolerated.…”