therefore receive strong attention from the general population, the scientific community and companies invested in food additives, cosmetics and ‘‘natural medicine.’’ A number of long-term clinical studies in humans have recently been initiated or is under planning and ideally in 2–5 years, we will know much more about the biological effects of Resv in humans. But before these data are available, the prediction of biological effects of Resv in humans have to rely primarily on data obtained in experimental animals and from in vitro screening in combination with elucidation of its mechanism of action. All reliable Resv data should be included to convert knowledge generated in animals into a clinically safe Resv treatment approach in humans. Therefore, a critical evaluation of the present scientific state-of-the-art knowl- edge is needed. The aim of the recent conference, Resveratrol2010, 1st International Conference on Resveratrol and Health (www.resveratrol2010. com), was to present the state-of-art of knowledge in the Resv field. After the conference invited speakers and the scientific committee formed a working group which formulated the recommendations described herein. The task of the working group discussion was to formulate a number of scientifically based recommendations for 1the human use of resveratrol and 2research on resveratrol for the coming years based on scientific literature and data made available during the previous 2K days of the conference. As Resv has been suggested to promote health in relation to various diseases or sufferings, the participating scientists covered a broad range of research on the biological effects of Resv, which included the following subjects, 1resveratrol and cancer; 2resveratrol and heart disease; 3neuroprotective activity of resveratrol; 4effect of resveratrol on longevity; 5effect of resveratrol on inflammation; 6effect of resveratrol on obesity and diabetes; 7metabolism and stability of resveratrol and 8production and commercial use of resveratrol. The final recommendations to the use of resveratrol are given in Tables 1, 2, 3, 4, 5, 6, whereas Table 7 describes recommenda- tions for research goals for the coming years in this field. The recommendations to the use of resveratrol do not differentiate between Resv used as a drug (for disease treatment), as part of food or as food supplement (maintenance of good health). On the other hand, Resv consumption as a food item or food supplement is considered as the primary area. Methods To generate a scientifically valid foundation for the formulation of these recommendations, a systematic search was performed in MEDLINE (http://www.ncbi.nlm.nih.gov/pubmed/) and ISI Web of Science (http://apps.isiknowledge.com/) to indentify studies in humans or experimental animals on Resv in relation to cancer, coronary heart disease, diabetes/metabolic syndrome, Table 1. Recommendations for the use of resveratrol – part 1. Can resveratrol be recommended in the prevention or treatment of human diseases? N There are not yet unequivocal scientific data for the effect of resveratrol as a disease preventative substance in humans nor for human life extension. N There is not yet sufficient evidence for a therapeutic effect of resveratrol in humans, either alone or in combination with other natural compounds or formulations. Recommendations on the Use of Resveratrol Table 2. Recommendations for the use of resveratrol – part 2. Are there observed ‘‘side effects’’ caused by the intake of resveratrol in humans? N There are no valid data on the toxicity of chronic intake of resveratrol in humans. N A short term human study (29 days) indicated frequent gastrointestinal discomfort/diarrhea only at high doses (2.5 g or 5 g per day). Only minor and inconsistent side effects have been observed in other short-term or acute studies. doi:10.1371/journal.pone.0019881.t002 neurodegenerative diseases and inflammation up to September 2010. The search terms ‘‘resveratrol’’ was used in combination with ‘‘cancer’’, ‘‘carcinogenesis’’, ‘‘chemoprevention’’, ‘‘hyperten- sion’’, ‘‘heart failure’’, ‘‘myocardial infarct’’, ‘‘cardiac arrest’’, ‘‘ischemia heart disease’’, ‘‘stroke’’, ‘‘serum lipids’’, ‘‘metabolic syndrome’’, ‘‘obesity’’, ‘‘diabetes’’, ‘‘insulin sensitivity’’, ‘‘plasma glucose’’, ‘‘visceral fat’’, ‘‘neuroprotection’’, ‘‘neuroprotective’’, ‘‘inflammation’’ or ‘‘inflammatory’’, were used to search for words in titles, abstracts, or Medical Subject Headings. The search was limited to English language but include both human data and experimental animals. Beside the database searches a manual search was performed using reference lists of original articles and previous reviews. For all studies, only the original publication was included in the present evaluation. Only studies investigating Resv and Resv metabolites are evaluated whereas various derivatives of resveratrol were not included. The identified publications were used to answer the following five questions: 1Can resveratrol be recommended in the prevention or treatment of human diseases?; 2Are there observed side effects caused by intake of resveratrol in humans?; 3What is the relevant dose of resveratrol?; 4What valid data are available regarding an effect in various species of experimental animals?; 5Which relevant (overall) mechanisms of action of resveratrol have been documented? Results The term ‘‘resveratrol’’ is found in title, abstract or MESH word in 5425 or 3650 publications following searching on ISI Web of Science or PubMed, respectively. The substantially higher number of hits found in ISI Web of Science was due to abstracts or papers with focus on identification of sources of Resv. All the publications relevant for this systematic review were present in both data bases and the refinement of the search using PubMed is indicated in Figure 1. To identify the cancer Table 3. Recommendations for the use of resveratrol – part 3. What is the relevant dose of resveratrol? N A relevant or optimal dose for resveratrol has yet to be established by human studies and will almost certainly vary depending on the effect being studied. N Doses in the range of hundreds of mg to several g per day have been proposed based on animal studies, but more human studies are needed to confirm these estimates. N Chronic human intake above the concentrations contained in natural food should be considered experimental until long-term human studies have been performed. doi:10.1371/journal.pone.0019881.t001 doi:10.1371/journal.pone.0019881.t003 PLoS ONE | www.plosone.org 2 June 2011 | Volume 6 | Issue 6 | e19881