BACKGROUND: The ethanol extract of Gynostemma pentaphyllum Makino leaves (EGP) has been reported recently to have anxiolytic effects on chronically stressed mice models. PURPOSE: We aimed to investigate the efficacy and safety of EGP on anxiety level in healthy Korean subjects under chronic stressful conditions. STUDY DESIGN: Double-blind, placebo-controlled trial. METHODS: This study was conducted with 72 healthy adults who had perceived chronic stress and anxiety with a score on the State-Trait Anxiety Inventory (STAI) from 40 to 60. Participants were randomly assigned to receive either EGP (200鈥痬g, twice a day, N鈥?鈥?6) or placebo (N鈥?鈥?6). All participants were exposed to repetitive loads of stress by performing the serial subtraction task for 5 min every second day during the 8-week intervention. Primary outcome of Trait-STAI and secondary outcomes of State-STAI, total score of STAI, Hamilton Anxiety Inventory (HAM-A), Beck Anxiety Inventory (BAI), blood norepinephrine and adrenocorticotropic hormone (ACTH), salivary cortisol and alpha-amylase, cardiovascular autonomic nervous system (ANS) functional test, and heart rate variability (HRV) test were measured before and after intervention. RESULTS: After the 8-week intervention, the EGP significantly lowered the score of the Trait Anxiety Scale of the STAI (T-STAI) by 16.8% compared to the placebo (p鈥?鈥?.041). The total score on the STAI decreased by 17.8% in the EGP group and tended to improve compared with that of the placebo group (p鈥?鈥?.067). There were no significant differences in the changes in score of S-STAI, HAM-A, BAI, and other parameters from baseline between the two groups. There was no causal relationship between the ingestion of EGP and adverse drug reactions. CONCLUSION: We found that supplementation with EGP reduced "anxiety proneness" in subjects under chronic psychological stress, as shown by a decrease in the score of T-STAI and the tendency for decrease in the total score of STAI. This result suggests that EGP supplementation can be used as a regimen to safely reduce stress and anxiety; however, more studies are needed to establish the long-term safety and effectiveness.