Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of foodstuffs
such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms
of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the
past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-
based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of
these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed
using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns
(adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations,
etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and
mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid
an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a
conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It
is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile,
glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high
RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on
humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that
is evolving from a minor dietary compound to a possible multi-target therapeutic drug.
Resveratrol, clinical trials, cardiovascular, cancer, nutraceutical, polyphenol.
Research Group of Quality, Safety and Bioactivity of Plant Foods, CEBAS-CSIC, 30100 Campus de Espinardo, Murcia, Spain.