Resveratrol as an Adjunct Therapy in Periodontal Disease: A Systematic Review and Meta-Analysis.

Background/Objectives: Resveratrol, a natural polyphenol with anti-inflammatory and antioxidant properties, has emerged as a promising adjunctive agent in periodontal therapy. This systematic review and meta-analysis evaluated evidence from in vitro, in vivo, and human clinical studies regarding the effects of resveratrol on periodontal disease, with the clinical component focusing on systemically healthy non-smoking patients. Methods: Electronic searches of MEDLINE/PubMed, Scopus, Embase, and Web of Science were conducted for studies published between 2000 and 2025. Eligible studies included periodontal-related in vitro cell models, in vivo experimental periodontitis models, and randomized clinical trials assessing resveratrol as an adjunctive therapy. Data extraction, risk-of-bias assessment, and meta-analyses were conducted in accordance with PRISMA guidelines. Results: Fifteen studies were included (five in vitro, six in vivo, and five human randomized controlled trials). Meta-analysis showed the inhibitory effect of resveratrol on the lipopolysaccharide-induced protein expression of IL-1β, IL-6, TNF-α, and IL-8 in vitro, with low to moderate heterogeneity. In animal studies, resveratrol significantly attenuated ligature-induced dental alveolar bone loss, IL-1β protein, and relative mRNA expression. However, reductions in relative mRNA expressions of TNF-α and IL-6 were inconsistent and highly heterogeneous; in contrast, nanoparticle- and liposomal-modified resveratrol consistently and significantly reduced these mRNA levels. In human trials, adjunctive resveratrol was associated with improvements in probing pocket depth and clinical attachment level compared with root planing alone in patients with periodontitis, as well as reductions in bleeding and plaque indices in patients with periodontal diseases, including gingivitis and periodontitis. Conclusions: Resveratrol suppresses pro-inflammatory cytokine expression in vitro and attenuates alveolar bone loss in vivo, with enhanced and more consistent molecular effects observed using modified formulations. Preliminary clinical evidence suggests that resveratrol may be associated with modest adjunctive effects on periodontal outcomes in systemically healthy non-smokers. However, given the limited number of clinical trials, small sample sizes, heterogeneity among studies, short follow-up periods, and limited certainty of the evidence, these findings should be interpreted cautiously. Further well-designed RCTs with longer follow-up periods are required to determine their clinical relevance.