Resveratrol

Scientific Name(s): 3,4′,5-trans-trihydroxystilbene, 3,5,4′-cis-trihydroxystilbene, 3,5,4′-trihydroxy-trans-stilbene
Common Name(s): Darakchasava, Phytoalexin, Piceatannol (analogue), Resveratrol

Medically reviewed by Drugs.com. Last updated on Jan 12, 2023.

Clinical Overview

Use

Researchers have suggested that consumption of resveratrol may potentially benefit numerous clinical conditions, including cancer, cardiovascular disease, obesity and related conditions including diabetes and non-alcoholic fatty liver disease, and neurological diseases. However, current evidence is insufficient to support a definitive place in therapy for resveratrol in these conditions. Resveratrol improved lumbar bone mineral density and bone resorption in post-menopausal women; however, the whole-body risk of major factures was unaffected. The adverse effects associated with higher dosages limit its applications.

Dosing

Lumbar bone mineral density: 75 mg (more than 98% trans-resveratrol) twice daily was used for 12 months. Evidence from other clinical studies is insufficient to provide dosing guidelines.

Contraindications

Depending on the formulation, some products are contraindicated in growing children, menstruating females, and in the presence of anemia due to binding of resveratrol to copper and iron.

Pregnancy/Lactation

Avoid due to lack of clinical data.

Interactions

Resveratrol may interact with carbamazepine and other substrates of CYP3A4.

Adverse Reactions

Adverse events for lower doses and shorter courses of treatment have been rare. Higher dosages (more than 1 g/day) may result in GI symptoms; a case of serious leukopenia and thrombocytopenia has also been reported. Resveratrol may negate exercise-induced cardiovascular benefit.

Toxicology

Limited animal studies suggest that resveratrol is noncarcinogenic and nontoxic at lower dosages, although renal toxicity has been observed at higher doses. No toxicity data for long-term administration in humans is available.

Source

Resveratrol is a naturally occurring phytoalexin produced by plants in response to stress such as injury, ultraviolet radiation, ozone exposure, and fungal attack. Commercial preparation of resveratrol is possible, although low yield and purity result. Extraction from plant sources is an intensive process. Microorganisms are used to produce resveratrol via genetic manipulation. Plant and dietary sources include purple grapes, the dried roots of Japanese knotweed, blueberries, cranberries, mulberries, rhubarb, pistachio, groundnuts, and cocoa.1, 2, 3

History

The traditional Ayurvedic medicine darakchasava contains resveratrol in its formulation. Resveratrol was initially identified in the roots of Veratrum grandiflorum (false hellebore) in 1940, and then later in Japanese knotweed in 1963, when interest was focused primarily on its potential in cardiovascular disease. Resveratrol's possible activity against carcinogens was identified in 1997, and research now also includes interest in its activity in inflammation, aging, diabetes, and neurological diseases.1, 2

Although World Health Organization data associate fat consumption with coronary heart disease, among certain populations where high-fat intake is observed with daily consumption of wine (eg, Italy, Switzerland, France), low coronary heart disease mortality rates exist. Termed the "French paradox," it is attributed in part to the presence of resveratrol in wine.1, 2, 4

Chemistry

Resveratrol is found in nature as cis-resveratrol and trans-resveratrol. Of the 2 isomers, research has been focused on the trans-resveratrol isomer because it is thought to be more abundant and more biologically active than the cis-resveratrol form. However, trans-resveratrol is highly photosensitive and easily converts to cis-resveratrol.1

Several analogues and encapsulated formulations exist that may have a greater bioavailability than resveratrol, including piceatannol, M8, pterostilbene, viniferin, and piceid.1, 5

Uses and Pharmacology

Data from animal studies should be extrapolated cautiously to humans because bioavailability of orally administered resveratrol is poor, and the matrix in which resveratrol is delivered may exert an influence on bioavailability.(3) Efficacy has largely been attributed to antioxidant activity; however, antioxidant activity has not been demonstrated in all in vivo studies.(3, 5) Activity of resveratrol in the sirtuin system has been described.(6, 7, 8)

Antiaging

Animal data

Numerous studies have explored the molecular biology and antiaging activity of resveratrol.(9, 10) Resveratrol was reported to slow aging and increase life span in simple organisms such as yeast, fish, and mice.(11, 12, 13) Trans-resveratrol concentrations in plasma and tissues after oral administration of red wine to rats or humans are similar to concentrations that have been active in vitro, usually in the range of 1 to 30 mcmol.(9)

Clinical data

Research reveals no clinical data regarding resveratrol's use in antiaging. The reported antiaging activity of resveratrol has been promoted in the marketing of skin care formulations, although unproven.(14)

A 9-year prospective cohort study (InCHIANTI) of 783 Italian community-dwelling adults 65 years or older utilized a food questionnaire and found no association between total urinary resveratrol metabolite concentrations and all-cause mortality; however, a higher proportion of participants who lacked urinary resveratrol died compared with those with urinary measurements. Urinary resveratrol was strongly associated with alcohol intake.(71)

Anti-inflammatory

Resveratrol inhibits the synthesis and release of proinflammatory mediators, modifies eicosanoid synthesis, inhibits activated immune cells, and inhibits cyclooxygenase (COX)-1 and COX-2 in vitro.(15, 16, 17)

Animal data

In rat models of chronic colitis, resveratrol reduced neutrophil infiltration and proinflammatory cytokines, and NF-kappaB protein expression was reduced.(18, 19) Resveratrol suppressed inflammation and inhibited lipid peroxidation in glycerol-induced renal injury in rats.(20)

Clinical data

In a meta-analysis, data pooled from 6 randomized controlled trials (N=415) that enrolled patients with cardiovascular disease revealed that administration of resveratrol significantly reduced levels of tumor necrosis factor (TNF)-alpha (mean difference [MD] −0.55; 95% confidence interval [CI], −1.04 to −0.063; P=0.027) and C-reactive protein (CRP) (MD, −0.63; 95% CI, −1.133 to −0.128; P=0.014) but not those of interleukin (IL)-6. Heterogeneity was not significant for any of the outcomes. Subgroup analyses revealed that doses more than 15 mg/day, but not less than that, produced significant reductions in both TNF-alpha (P<0.01) and CRP (P=0.01). However, only TNF-alpha reductions remained significant when the duration of supplementation was 9 weeks or less (P=0.04) but for CRP it was only significant at more than 9 weeks (P=0.01). Resveratrol was dosed at 20 mg/day or less (range, 8.1 to 20 mg/day) in all but 2 studies, which used 100 and 500 mg/day, and was given for durations that ranged from 4 to 52 weeks. The studies were published between 2012 and 2019, categorized as good (n=4) or fair (n=2) quality with sample sizes that ranged from 9 to 30 subjects in each study.(118)

Resveratrol inhibited basal release of the inflammatory cytokine IL-8 from alveolar macrophages in patients who smoke and in those with chronic obstructive pulmonary disease.(21)

An author-funded study reported reduction in facial redness in subjects (n=16) treated topically twice daily for 8 to 12 weeks with a combination product containing resveratrol, green tea polyphenols, and caffeine. Subjective evaluation by trained observers and clinicians documented improvement in 100% and 81% of subjects’ clinical photographs and spectrally-enhanced red images, respectively. The preliminary split-face study (with and without resveratrol) demonstrated decreased redness only when resveratrol was added to the treatment.(65)

A 9-year prospective cohort study (InCHIANTI) of 783 Italian community-dwelling adults 65 years and older utilized a food questionnaire and found no association between total urinary resveratrol metabolite concentrations and inflammatory markers (ie, serum c-reactive protein, IL-6, IL-1-beta, TNF); however, participants with no urinary resveratrol metabolites were more likely to have higher levels of IL-1-beta and TNF. Urinary resveratrol was strongly associated with alcohol intake.(71)

Cancer

Resveratrol has been reported to be effective in blocking all 3 stages of carcinogenesis (ie, initiation, promotion, progression).(22) Numerous molecular mechanisms of anticancer activity are associated with resveratrol, including blocking carcinogen activation by inhibiting phase I enzymes, enhancing antioxidant capacity and inducing phase II carcinogen detoxifying enzymes, arresting cell proliferation by modulating cell cycle regulatory machinery, inducing apoptosis of damaged or transformed cells, turning off the angiogenic switches and blocking neovascularization in tumor tissues, suppressing invasion and metastasis, and sensitizing tumor cells for chemotherapy-induced apoptosis.(23, 24, 25)

Animal data

Resveratrol induces differentiation and apoptosis in cancer cell lines, including leukemia, colon, breast, and prostate cancers, and esophageal cells and radiation-induced chromosome aberration. Several review articles report on resveratrol's anticancer activity,(22, 23, 24, 25, 26, 27) and the publication of experimental studies is exponential. Studies evaluating the effects of combinations of resveratrol and chemotherapeutic agents and other polyphenols have been published.(27)

Clinical data

Limited clinical trial data is available beyond dose-escalation tolerability and safety studies in healthy volunteers.(2, 5, 27) Several trials are currently listed in the ClinicalTrials.gov database of publicly and privately supported clinical studies of human participants conducted around the world, but results are not yet available.(28) The effect of resveratrol on cell proliferation in colorectal epithelial cells was positively reported in a small study (N=6).(27) In a study of 24 patients with refractory multiple myeloma, investigators noted minimal efficacy together with unacceptable adverse events following the administration of resveratrol SRT501 5 g daily.(29) Another small clinical study (N=39) evaluated the effect of resveratrol 100 mg daily for 12 weeks on markers of breast cancer.(30) While another, conducted in 34 overweight postmenopausal women, documented some favorable effects of resveratrol 1 g/day for 12 weeks on hormone-related breast cancer risk factors including estrogen metabolism, sex steroid hormone-binding globulin, and urinary 2-hydroxyestrone levels.(73)

A 9-year prospective cohort study (InCHIANTI) of 783 Italian community-dwelling adults 65 years and older utilized a food questionnaire and found no association between total urinary resveratrol metabolite concentrations and prevalence of cancer; urinary resveratrol was strongly associated with alcohol intake.(71)

Cardiovascular disease

Animal data

Numerous mechanisms have been suggested for the observed beneficial cardiovascular effects of resveratrol based on in vitro and animal studies.(31, 32) Resveratrol 5 to 25 mmol/L may have antifibrotic activity; it inhibits growth paths stimulated by angiotensin II, epidermal growth factor, or transforming growth factor beta, all of which are essential in fibroblast proliferation and differentiation.(32) Resveratrol reduced infarct size and improved left systolic and diastolic function following myocardial ischemia in rats, possibly by reducing atrial natriuretic peptide and transforming growth factor beta1, both of which protect the heart from detrimental remodeling.(33) Prevention of ischemic reperfusion injury has also been documented in other studies.(34)

Clinical data

Despite evidence to support a reduction in hypertension, heart failure, and ischemic heart disease in rodents, clinical trial data for the use of resveratrol in human pathology are limited.(26) Small trials have reported increased flow-mediated vasodilation following administration of resveratrol doses up to 270 mg and increased cerebral blood flow following doses of resveratrol 500 mg.(2) Flow-mediated vasodilation (FMD) was also significantly improved in a small double-blind crossover trial in 28 obese, otherwise healthy, patients who took trans-resveratrol 75 mg/day for 6 weeks; extent of benefit was negatively correlated with baseline FMD. No benefit was noted in cognitive performance.(68)

One clinical trial demonstrated improvement in ventricular function marker (brain natriuretic peptide) following administration of resveratrol 20 mg/day over 60 days,(35) and another found improved biomarkers among patients with stable coronary artery disease who took resveratrol 10 mg daily for 3 months.(36) Similar effects with resveratrol 350 mg daily over 6 months have been reported in studies conducted in Spain.(37, 38, 39)

High-dose resveratrol (1,000 mg daily × 1 week then 2,000 mg daily × 1 week) reduced intestinal and hepatic lipoprotein particle production in overweight or obese men with mild hypertriglyceridemia in a double-blind, cross-over randomized clinical trial (n=8). ApoB-48 and apoB-100 production were significantly reduced by 22% and 27%, respectively; however, insulin sensitivity, fasting, and fed plasma triglyceride levels were not significantly affected. No adverse effects were reported.(64) A systematic review and meta-analysis evaluated 7 trials (N=282) and determined that, overall, resveratrol supplementation had no significant effect on any lipid concentrations. Subgroup analyses based on coronary heart disease risk and duration of therapy yielded results consistent with the overall analysis.(67)

Cardiovascular benefit in 27 men 60 to 72 years of age induced by intensive exercise training was negated by the administration of trans-resveratrol 250 mg/day over 8 weeks. Mean arterial blood pressure, certain cholesterol parameters (ie, total cholesterol:high-density lipoprotein ratios, low-density lipoprotein, and triglycerides), and maximal oxygen uptake were significantly higher in men randomized to exercise plus placebo. Additionally, the vasodilator prostacyclin was significantly higher in the exercise plus placebo group, indicating a vasoconstrictive state in the resveratrol group.(69) A 2015 meta-analysis of data from 6 randomized clinical trials (N=247) investigating the effect of at least 2 weeks of resveratrol supplementation on blood pressure identified a significant benefit by subgroup analysis only on systolic blood pressure [SBP] (−11.9 mm Hg, P=0.01) and only at "higher" doses (at least 150 mg/day). Of the 6 included studies, 1 trial enrolled healthy volunteers, while the others included patients with type 2 diabetes mellitus, cardiovascular disease, metabolic syndrome, and obesity. Overall, significant publication bias was documented and no significant dose effects of resveratrol on SBP or diastolic blood pressure (DBP) were found.(77)

A 9-year prospective cohort study (InCHIANTI) of 783 Italian community-dwelling adults 65 years and older utilized a food questionnaire and found no association between total urinary resveratrol metabolite concentrations and prevalence of cardiovascular disease; however, a significantly higher proportion of participants who lacked urinary resveratrol had strokes compared with those with urinary resveratrol measurements. Urinary resveratrol was strongly associated with alcohol intake.(71)

CNS

Clinical data

The effect of adjunctive resveratrol on irritability in 62 children with autism spectrum disorder concurrently treated with risperidone was explored in a double-blind, randomized, placebo-controlled trial. After 10 weeks, both resveratrol (250 mg twice daily) and placebo resulted in significant improvements from baseline in 4 of the 5 total measures: irritability, lethargy, stereotypic behavior, and inappropriate speech (P<0.001 for all) with no significant difference between groups. In contrast, the hyperactivity/noncompliance score was significantly improved with resveratrol compared to placebo (mean difference, 4.51; 95% confidence interval, 0.1 to 8.92; P=0.04).(114)

Diabetes

Animal data

Studies in animals (largely in rodents) support a role for resveratrol in the treatment of obesity and diabetes, with improved glucose metabolism and lipid profiles observed. In addition, weight loss has been reported in some studies, with possible increases in metabolic rate.(2, 5, 26)

Clinical data

Although improved insulin sensitivity has been reported following higher doses of resveratrol, some studies have produced equivocal results.(2, 5) Clinical studies have primarily been conducted in nondiabetic obese volunteers or have been pilot or open-label studies.(40, 41, 42, 43, 44)

A meta-analysis of 11 randomized clinical trials (N=388) published through March 2014 and evaluating the effects of resveratrol on glucose control and insulin sensitivity revealed a significant effect in diabetic, but not nondiabetic, participants. Resveratrol dosing ranged from 8 to 1,500 mg/day for a duration of 2 weeks to 6 months. Trials were conducted in participants with type 2 diabetes (n=3), cardiovascular disease (n=3), obesity (n=3), metabolic syndrome (n=1), and healthy volunteers (n=1); 8 of the studies included overweight or obese patients with a body mass index of 25 or more (in kg/mg²). Diabetic patients experienced significant reductions in fasting glucose (−35.22 mg/dL; P<0.01), fasting insulin concentrations (−4.55 microunits/mL; P<0.01), HbA_1c (−0.79%; P=0.02), and insulin resistance (homeostatic model assessment - insulin resistance [HOMA-IR]; −2.25; P<0.01). Significant between-study heterogeneity was observed for blood glycemic measures of diabetics.(74)

Similar results were found in a small randomized, double-blind, placebo-controlled trial (n=24) in adults with metabolic syndrome and a body mass index (BMI) between 30 and 39 such that patients who received resveratrol 1,500 mg/day for 90 days experienced significant reductions in total weight (P=0.007), BMI (P=0.006), fat mass (P=0.001), waist circumference (P=0.004), and insulin secretion (P=0.004). No differences were observed in the placebo group. Treatment was well tolerated and no serious adverse events were noted.(75) In men with metabolic syndrome, 2 doses of resveratrol were investigated for effects on cellular inflammation and glucose metabolism in a randomized, double-blind, placebo-controlled trial (n=74). Participants randomly received resveratrol 75 mg or 500 mg twice daily or placebo for 16 weeks. No significant improvements in inflammatory biomarkers, insulin sensitivity, lipids, or subcutaneous fat accumulation were observed. Instead, a significant worsening of glucose and lipid metabolism were observed in the high-dose resveratrol group compared to placebo as reflected by increases in fructosamine (+11.8 micromol/L; P<0.0113), LDL cholesterol (+0.61 mmol/L; P<0.006), and total cholesterol (+0.69 mmol/L; P<0.002).(86) Similarly, a slight increase in total cholesterol and triglycerides was observed with 6-month administration of 500 mg/day, but not 40 mg/day, of resveratrol in adults with type 2 diabetes managed with oral medications. This double-blind, randomized, placebo-controlled trial (n=192) found no significant effect of resveratrol on C-reactive protein, BMI, waist circumference, BP, IL-6, fasting glucose, HbA_1c, HOMA-IR, C-peptide, AST, ALT, GGT, uric acid, adiponectin, free fatty acids, or lipid parameters. Compared to placebo, subgroup analysis revealed a significantly higher reduction in C-reactive protein in patients taking the higher dose (500 mg/day) who had a shorter duration of diabetes (less than 8 years), were of a younger age (65 years), used aspirin, and smoked. Additionally in the 40 mg/day group, a significant interaction effect was found with duration of diabetes and C-reactive protein values, such that values decreased with a duration of disease of less than 8 years and increased with a longer history of disease. Both doses were well tolerated with no major adverse effects reported.(87)

As an adjunct to pharmacological treatment in patients with type 2 diabetes mellitus, resveratrol supplementation ranging from 10 to 5,000 mg/day for 4 weeks to 12 months duration was found to be significantly more effective than placebo or control for improving SBP, hemoglobin A_1c, and creatinine (P<0.05 for each) in a systematic review and meta-analysis that included data from 6 clinical trial registries (N=196). No significant effects were found for fasting glucose, DBP, insulin, trigylcerides, low-density lipoprotein (LDL), high-density lipoprotein, or homeostatic model assessment of insulin resistance.(78) In a meta-analysis of 31 randomized controlled trials (N=1,722), the effects of resveratrol on lipid and liver enzymes in patients with metabolic syndrome and related disorders was investigated. Dosages ranged from 20 to 3,000 mg/day given for 4 to 48 weeks. A significant benefit for resveratrol was reported only for total cholesterol (weighted mean difference [WMD]= −7.65 mg/dL; 95% CI, −12.93 to −2.37; P<0.01) and GGT (WMD= +1.76 units/L; 95% CI, 0.58 to 2.94; P<0.01) but not for triglycerides, LDL, HDL, ALT, or AST. Subgroup analysis revealed no significant differences based on dose, duration of therapy, or type of disease (ie, overweight/obese, type 2 diabetes, other).(116)

In a double-blind, randomized, placebo-controlled study (n=110) conducted in type 2 adult diabetics on oral hypoglycemic agents for at least a year, administration of resveratrol 200 mg/day for 24 weeks significantly improved fasting blood glucose (by 7.56%), HgA_1c (by 6.31%), fasting insulin (9.96%), insulin resistance (HOMA-IR by 17.96%; P<0.05 each). In addition to improvement seen in glycemic parameters with resveratrol, anti-inflammatory and redox markers also improved and included TNF-alpha, IL-6, malondialdehyde, and microalbuminuria by 13.67%, 13.27%, 8.46%, and 13.48%, respectively (P<0.05). Non-significant changes in lipids were observed between groups.(119)

The safety and efficacy of adjunctive resveratrol have also been investigated in patients with type 1 diabetes. Resveratrol 500 mg twice daily was supplemented for 2 months in patients 12 to 45 years of age who were currently on oral antidiabetic therapy and insulin injection in an exploratory uncontrolled trial. Compared to baseline, HbA_1c and fasting blood glucose were statistically significantly reduced by −0.52% (P=0.033) and by −79.31 mg/dL (P<0.001), respectively. The antioxidant measure of malondialdehyde and total antioxidant capacity were also significantly improved (P<0.002 and P<0.001, respectively). No other parameters (ie, anthropomorphic, insulin resistance, C-reactive protein, liver function tests) were significantly affected.(117)

Exercise capacity

Clinical data

In a phase 2 randomized, double-blind, placebo-controlled, crossover pilot study in 13 healthy sedentary adults, the effect of resveratrol on exercise capacity was assessed via exercise duration on constant load at 75% max and peak oxygen uptake on incremental exercise testing. Oral resveratrol was initiated at 500 mg twice daily for 1 week then increased to 1,000 mg twice daily for 3 more weeks, if tolerated, with a 2-week washout. No significant effect was found on exercise capacity. All but 1 participant was able to tolerate the 2 g/day dose; however, GI complaints were significantly more common (77%) with resveratrol than placebo (15%) and included diarrhea, nausea, and cramping.(83)

Macular degeneration

Clinical data

Three case studies in octogenarians with age-related macular degeneration demonstrated dramatic anatomic retinal restoration and visual improvement, in addition to unexpected systemic benefits, subsequent to daily administration of a resveratrol-based nutritional supplement. The product contained 100 mg micronized/microencapsulated trans-resveratrol combined with quercetin, ferulic acid, vitamin D₃, and a copper-iron-calcium binding molecule (inositol hexaphosphate). Objective retinal imaging suggested improvements in both anterior and posterior retinal photoreceptor structural health that was accompanied by superior acuity and greater comprehensive visual function (ie, contrast sensitivity, scotoma resolution). Improvements occurred bilaterally, less in the more severely diseased eye, and were noticeable within 4 days of supplementation and continued for more than 1 year with daily use. Medically documented improvements in comorbidities as well as physical stamina were also reported during supplement administration. Lab development funding was provided by the product sponsor.(66)

Memory performance

Clinical data

A double-blind, placebo-controlled interventional study (n=46) evaluated the effects of resveratrol supplementation on memory performance in healthy overweight adults. Resveratrol 200 mg/day for 26 weeks significantly improved specific memory function (ie, word retention over a 30-minute delay; P=0.038), increased hippocampal functional capacity (P<0.05), reduced HbA_1c (P=0.014), and increased leptin (P<0.001) compared with placebo. Compared with baseline, the resveratrol group also experienced significant benefit on the delayed recall and recognition score (P<0.05); however, the difference between groups was not significant. Improved cognitive function was positively correlated to improvements in leptin and HbA_1c; the latter suggesting improved glucose metabolism (even within normal limits) as a potential underlying mechanism.(70)

Neurodegenerative conditions

Animal data

Most evidence supports resveratrol's role in activating the SIRT1/PGC-1 pathway, which improves mitochondrial function.(45) A role for resveratrol in Alzheimer, Huntington, and Parkinson diseases, as well as in neurological injury, has been suggested on the basis of studies in rodents.(26, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57)

Clinical data

A randomized, double-blind, placebo-controlled, within-subjects crossover trial (n=23) found that the combination of piperine 20 mg with trans-resveratrol 250 mg, but not resveratrol alone, significantly improved central blood flow but not cognitive performance in healthy young adults.(72) In a 9-year prospective cohort study (InCHIANTI) of 783 Italian community-dwelling adults 65 years and older, a food questionnaire was utilized to examine the relationship between urinary resveratrol levels and all-cause mortality. Although no association was found for the primary end point, a significantly higher proportion of participants had cognitive impairment (Mini-Mental State Examination score, <24) who had no urinary resveratrol metabolites compared with those who did have urinary resveratrol measurements. Urinary resveratrol was strongly associated with alcohol intake.(71) Statistically significant improvements in performance of a single cognitive task on day 1 and subjective ratings of fatigue throughout the 28 day study were observed in healthy, young adults who received trans-resveratrol 500 mg/piperine10 mg for 28 days in a double-blind, randomized, placebo-controlled, parallel-group study. Additionally, a significant increase in diastolic blood pressure was observed in the resveratrol group. No effect was found on mood, sleep quality, general health, or other cognitive tasks.(81) A double-blind, randomized, placebo-controlled multicenter phase 2 trial examined the primary outcomes of safety, tolerability, and effects on biomarkers and volumetric magnetic resonance image of resveratrol over a 52-week period in 119 adults with mild to moderate Alzheimer disease (mini-mental state examination 14 to 26 at screening). Resveratrol was initiated at 500 mg once daily and escalated every 13 weeks to a final dose of 1,000 mg twice daily. The placebo group was noted as having a longer duration of disease from symptom onset but not in years from diagnosis. The group treated with resveratrol lost a statistically significant amount of weight resulting also in a significantly lower BMI over the study period compared to the placebo group. The cerebrospinal fluid and plasma level of biomarker Aβ40 declined significantly with resveratrol treatment as did brain volume. No serious adverse events were related to the use of resveratrol.(82)

Nonalcoholic fatty liver disease

Clinical data

A randomized, double-blind, placebo-controlled trial evaluating the effects of resveratrol supplementation on liver enzymes, inflammatory biomarkers, hepatic elasticity, and echogenecity was conducted in patients with nonalcoholic fatty liver disease (NAFLD) (n=50). Patients were randomized to either 500 mg trans-resveratrol or placebo (medium chain triglycerides) for 90 days in conjunction with lifestyle interventions that included an energy-balanced diet and physical activity. Anthropomorphic measurements, liver enzymes, and steatosis grade improved significantly in both groups (P<0.005); however, resveratrol supplementation was associated with significantly greater improvements in ALT, inflammatory cytokines, nuclear factor kappaB activity, serum cytokeratin-18 (a biomarker of hepatic apoptosis), and hepatic steatosis grade (P<0.05).(76) Similarly, resveratrol 600 mg/day for 3 months significantly decreased liver enzymes (ALT, AST), glucose, insulin resistance, LDL-cholesterol, and total cholesterol, as well as serum cytokines including TNF-alpha (an inflammatory cytokine that independently predicts histological fibrosis in NAFLD), cytokeratin 18 fragment (a biomarker of hepatic apoptosis), fibroblast growth factor 21, and elevated adiponectin levels in adults with NAFLD enrolled in a double-blind, randomized, placebo-controlled trial in China. No adverse events were reported by participants.(80) In contrast, administration of resveratrol 500 mg 3 times daily for 6 months to patients with transaminasemia, suspected NAFLD, BMI of at least 25 kg/cm², and at least 1 additional element of metabolic syndrome, but not diabetes, failed to produce significant benefit in a prospective, double-blind, randomized controlled trial (n=28). Although ALT levels and intrahepatic lipid content significantly decreased with resveratrol compared to baseline, the difference was not significant compared to placebo. The major limiting factor of the study was the small sample size. The study was underpowered; a change in plasma ALT of 25 units/L could be detected with a 2-sided 0.05 significance at 0.60. Adverse events in the resveratrol group that led to study discontinuation included 1 case with GI problems and 1 case of serious febrile leukopenia and thrombocytopenia (after 10 days of treatment that recurred upon repeated exposure).(84)

A meta-analysis of randomized controlled trials sought to determine if resveratrol supplementation was beneficial for patients with NAFLD. The 4 eligible studies were published between 2014 and 2016 and included 156 participants. Besides significant increases in total cholesterol and LDL cholesterol (P<0.05 each) observed with resveratrol supplementation in patients with NAFLD compared to controls, no other significant changes were detected for weight, body mass, blood pressure, HDL cholesterol, insulin, insulin resistance, liver enzymes, bilirubin, or tumor necrosis factor-alpha. Publication bias was not statistically significant.(85)

Osteoporosis and bone metabolism

Clinical data

Although lumbar bone mineral density (BMD) and bone resorption were significantly improved with resveratrol supplementation, the overall risk of major fractures was not in the Resveratrol for Healthy Ageing in Women (RESHAW) 24-month crossover trial conducted in 125 postmenopausal women. Supplementation with 150 mg/day of resveratrol significantly improved BMD of the lumbar spine (P<0.001) but not femur neck (P=0.058) or total hip (P=0.054) compared to placebo treatment after adjusting for false discovery rate; absolute values were significant for all 3 outcomes (P<0.001, P=0.035, and P=0.029, respectively). Bone resorption markers were also significantly lower during the resveratrol phase compared to the placebo phase (P=0.015, adjusted). Subgroup analysis showed an enhanced effect of resveratrol for women who regularly used vitamin D plus calcium supplements in lumbar BMD compared to calcium only, and in total hip BMD compared to those who consumed neither vitamin D nor calcium supplements.(115)

Sleep

Clinical data

In an observational study (n=60) of patients with hepatitis C treated with peg-IFN-alpha and ribavirin, the addition of resveratrol (19.8 mg 3 times daily × 12 months) significantly improved sleepiness scores in responders (P<0.05) compared with placebo. Scores among patients overall for general health, mood, sleep quality (P<0.001 each), and sleepiness (P<0.05) were better with resveratrol than placebo. No serious adverse events were noted; the incidence of psychological adverse events was found to be lower in the resveratrol group.(88)

Dosing

Although resveratrol is extensively absorbed orally (approximately 70%), due to rapid metabolism, bioavailability is poor. Significant person-person variability has been reported, and the presence of food in the stomach is likely to decrease absorption. Metabolism is dependent on intestinal microflora and hepatic function for sulfation.1, 2, 5, 58 The plasma pharmacokinetics of resveratrol and its metabolites in healthy volunteers have been described.59, 60

Lumbar bone mineral density

Resveratrol (more than 98% trans-resveratrol) 75 mg twice daily was used for 12 months.115

Evidence from other clinical studies is insufficient to provide dosing guidelines.

Pregnancy / Lactation

Avoid due to lack of clinical data. Resveratrol is structurally similar to the synthetic estrogen diethylstilbestrol and may have estrogenic activity.61

Interactions

A pharmacokinetic study in 12 healthy males was conducted to determine the effect of resveratrol pretreatment on the pharmacokinetics of carbamazepine and on the CYP3A4 enzyme activity. Compared to control, a single 500 mg dose of resveratrol administered once daily for 10 days prior to a single dose of carbamazepine 200 mg significantly increased maximal drug concentration (by 46.2%), area under the curve (by 37.1%), and half-life (by 22.8%) of carbamazepine and significantly decreased apparent oral clearance (by 33.1%) and apparent volume of distribution (by 19.3%). However, time to reach maximum drug concentration and elimination rate constant were not significantly changed. Additionally, carbamazepine metabolite:parent ratios of C_max and AUC were also significantly decreased.79

Aripiprazole: CYP3A4 inhibitors (weak) may increase the serum concentration of aripiprazole. Further dose reductions may be recommended with concomitant use of a CYP2D6 inhibitor. Aripiprazole dose reductions may be recommended in CYP2D6 "poor metabolizers." Aripiprazole dose reduction is not recommended when used as adjunctive therapy for major depressive disorder.95, 96, 97, 98, 99

Buspirone: Resveratrol may increase the serum concentration of buspirone. Monitor therapy.100, 101, 102, 103

Carbamazepine: Resveratrol may increase the serum concentration of carbamazepine. Monitor therapy.101, 102, 103, 104

Diclofenac (systemic): Resveratrol may increase the serum concentration of diclofenac (systemic). Monitor therapy.100, 105, 106

Dofetilide: CYP3A4 inhibitors (weak) may increase the serum concentration of dofetilide. Monitor therapy.107, 108, 109

Flibanserin: CYP3A4 inhibitors (weak) may increase the serum concentration of flibanserin. Monitor therapy.110

Lomitapide: CYP3A4 inhibitors (weak) may increase the serum concentration of lomitapide. Consider therapy modification.93, 94

Losartan: Resveratrol may decrease serum concentrations of the active metabolite(s) of losartan. Resveratrol may increase the serum concentration of losartan. Monitor therapy.100, 111, 112

Nimodipine: CYP3A4 inhibitors (weak) may increase the serum concentration of nimodipine. Monitor therapy.113

Pimozide: CYP3A4 inhibitors (weak) may increase the serum concentration of pimozide. Avoid combination.89, 90, 91, 92

Adverse Reactions

Clinical studies of single doses of trans-resveratrol 5 g resulted in no observed adverse events, and adverse events for low doses (less than 1 g) or short courses of treatment (1 month) have been rare.5 However, at higher dosages, abdominal disorders (diarrhea, pain, nausea, and flatulence) have been reported, as well as elevated bilirubin levels.5, 26, 27 A case of serious fever, leukopenia and thrombyocytopenia (that recurred with rechallenge) was reported in a patient with NAFLD receiving 500 mg 3 times daily for 6 months in a randomized, controlled trial.84 (84) Doses of resveratrol SRT5021 5 g daily resulted in severe adverse events, including renal failure, in a small clinical trial.2, 29 Resveratrol is structurally similar to the synthetic estrogen diethylstilbestrol and may have estrogenic activity.61

Toxicology

Limited toxicity studies using resveratrol in large doses (2 to 4 g/kg in rodents) have suggested renal toxicity; however, lower doses (20 mg/kg) were not toxic. Toxicity studies in rats (100 mg/kg for 28 days) and dogs (up to 1,200 mg/kg/day) showed no adverse effects on histopathological analysis and no hematological effects.27, 62 No hepatic toxicity was observed in rodents following oral administration despite evidence of accumulation in the liver.1, 5

A daily dose of resveratrol 100 mg/kg did not induce chromosome aberrations after 30 days of ingestion, and no carcinogenicity was observed.1, 5, 63 No toxicity data for long-term administration in humans are available.26

References

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