J. Cosmet. Sci., 71, 439–454 (November/December 2020) 439 Effi cacy and Safety of Centella Asiatica (L.) Urb. on Wrinkles: A Systematic Review of Published Data and Network Meta-Analysis CHUENJID KONGKAEW, PEERAPONG MEESOMPERM, C. NORMAN SCHOLFIELD, NARTTAYA CHAIWIANG, and NETI WARANUCH , Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand (C.K., C.N.S. ), Department of Pharmacy Practice, Research Centre for Safety and Quality in Health, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand (C.K., P.M., C.N.S.), Research Department of Practice and Policy, UCL School of Pharmacy, London WC1N 1AX, United Kingdom (C.K. ), Medical Division of General Support Offi ce, Armed Force Development Command, Bangkok, Thailand 10210 (P.M.), Faculty of Optometry, Ramkhamhaeng University, Bangkok 10240, Thailand (N.C.), Department of Pharmaceutical Technology, Cosmetics and Natural Products Research Center, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand (N.W.) Accepted for publication May 22, 2020. Synopsis Centella asiatica has many applications in cosmetics, including wrinkle treatments, but its effectiveness remains to be clarifi ed. This systematic review study aimed to demonstrate the effi cacy and safety of C. asiatica for reducing facial wrinkles. PubMed, Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of clinical trials, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Thai Library Integrated System, and Thai university database/journals were searched until May 2019. Five double-blinded randomised controlled trials, including 172 Asian females, were included. Endpoints were wrinkling measured by visual score, image analysis, and participant satisfaction. Two placebo-controlled studies applied gel/creams containing C. asiatica or asiaticoside for 12 w to periorbital skin. Two studies applied tretinoin or Pueraria mirifi ca contralaterally and by network meta- analysis C. asiatica appeared more effective than P. mirifi ca but possibly less than tretinoin. Asiaticoside applied as a lipstick for 8 w reduced lip wrinkling. Skin hydration was markedly raised by C. asiatica but not tretinoin. One study reported 10 adverse events for C. asiatica and 35 for tretinoin. Cochrane risk of bias was generally low, reporting was weak, and lack of C. asiatica standardization prevents general application. From the reported data, it is possible to conclude that C. asiatica improved lip and periocular wrinkles, and may replace retinoids if its long-term safety is established and C. asiatica is standardized. Address all correspondence to Chuenjid Kongkaew at chuenjidk@nu.ac.th or chuenjid@googlemail.com.

JOURNAL OF COSMETIC SCIENCE 440 INTRODUCTION Cutaneous wrinkling is commonly associated with aging, mechanical and chemical in- sults, and radiation. The reduced skin thickness and resilience arise from the failure of fi broblast reconstruction of the dermal extracellular matrix (1). To date, the most effective and commonly used treatments are topical retinoids that bind to their nuclear receptors, thereby increasing collagen I and III production, and reducing infl ammation among other actions (2). But these compounds have side effects, a narrow therapeutic window, and are available only on prescription in some countries, a barrier to cosmetic applications. Several herbal preparations have been reported to curtail or reverse wrinkle formation, including Centella asiatica. Centella asiatica (L.) Urban (Apiaceae), commonly called Asiatic pennywort, Gotu kola, or Indian pennywort,is a leafy rampant creeper that grows pre- dominantly in wetlands across southern and eastern Asia. Its leaves in particular are used as food in varying forms while also enjoying widespread application in medicines to treat a diverse range of ailments (3). These include peptic ulcer (4), diarrhea (5), fl atulence (5), convulsions (6), and cognitive impairment (7). For cosmetic purposes, C. asiatica has been reported to ameliorate bruising, to retard loss of skin elasticity (8,9), to improve postpar- tum stretch marks (10), to reduce skin wrinkling (11), and to promote wound healing (12). The active ingredients of C. asiatica are several pentacyclic triterpenoids and their glycosides including asiatic acid, asiaticoside, madecassic acid, and madecassoside which collectively comprise 2–8% dry weight of the plant (13) and are responsible for the me- dicinal actions (3) of cosmetics (14). Lesser amounts of other terpenes and many secondary metabolites are found in C. asiatica but too little for pharmacological action C. asiatica. C. asiatica has been added to numerous formulations for the aforementioned conditions which are described in several reviews about C. asiatica, but there is a paucity of those focusing on the effi cacy and safety data when present in cosmetics. This study aimed to address this issue, specifi cally by systematically reviewing studies on facial wrinkles. METHODS ELIGIBILITY CRITERIA This systematic review and network meta-analysis (NMA) used characteristics following the participants, interventions, comparisons, outcomes, study design criteria: the partici- pants were healthy volunteers the intervention groups received C. asiatica as the sole active ingredient, and applied topically the comparator groups did not receive C. asiat- ica outcome measures were (i) skin wrinkling, (ii) adverse events (AEs), or (iii) partici- pant opinion/satisfaction and the study design was randomized controlled trials (RCTs). SEARCH STRATEGY We searched PubMed, Embase, the Cochrane Central Register of clinical trials, Allied and Complementary Medicine Database, CINAHL, the Thai Library Integrated System, and Thai university databases/journals (Chulalongkorn, Mahidol, and Naresuan Universities), and also screened the WHO clinical trials registry, Clinicaltrials.gov, “grey” literature