Introduction. The Carica papaya L. leaf is gaining interest as a potential therapeutic agent for alleviating dengue- and non-dengue-associated thrombocytopaenia. In that regard, safety considerations are as important as efficacy potential. The safety evaluation of botanical products for human use is complicated by variable formulations, complex phytochemical composition, and extrinsic toxicants. This review aimed to systematically collate related safety clinical and preclinical data, as well as reports on herb-drug interactions of C. papaya leaf consumption. Methods. A systematic search using predetermined keywords on electronic databases (MEDLINE, Cochrane Library Central, LILACS, and Web of Science) and grey literature was conducted. Relevant clinical and preclinical studies were identified, screened, and analysed to present an overall safety profile of C. papaya leaf consumption. Results. A total of 41 articles were included (23 clinical, 5 ongoing trials, and 13 preclinical) for descriptive analysis on study characteristics, adverse reactions, toxicity findings, and herb-drug interactions, from which 13 randomised controlled and quasiexperimental trials were further assessed for risk of bias and reporting quality. Overall, C. papaya leaf consumption (in the form of juice and standardised aqueous extract) was well tolerated by adult humans for short durations (<five days) while one randomised controlled trial reported safe consumption of C. papaya leaf standardised aqueous extract in children (aged 1–12 years). Minor gastrointestinal side effects were most commonly reported. There are concerns about hepatotoxicity and reproductive toxicity in long-term use, supported by animal studies. Unfavourable herb-drug interactions with metformin, glimepiride, digoxin, ciprofloxacin, and artemisinin were accounted. Conclusion. C. papaya leaf consumption in adults is generally safe for short-term use though cautioned in pregnancy and people with liver impairment. It has potential herb-drug interactions with oral hypoglycaemic agents, p-glycoprotein substrates, and antibiotics with cation chelating properties.

A combined polyherbal formulation containing tongkat ali (Eurycoma longifolia) and kacip fatimah (Labisia pumila) aqueous extracts was evaluated for its safety aspect. A repeated dose 28-day toxicity study using Wistar rats was conducted where the polyherbal formulation was administered at doses 125, 500 and 2000 mg/kg body weight to male and female treatment groups daily via oral gavage, with rats receiving only water as the control group. In-life parameters measured include monitoring of food and water consumption and clinical and functional observations. On day 29, blood was collected for haematological and biochemical analysis. The rats were necropsied and the organs were collected for histopathological examination. This study showed that the combined formulation did not induce any significant toxicity effect at any dose level in terms of morbidity, mortality, behaviour, functional observation, body weight, food and water consumption, whole blood haematology and serum biochemistry. However, there were some microscopic changes in the histopathological examinations of some organs given 2000 mg/kg body weight, which may suggest an early response to the polyherbal formulation. From this study, the no observed adverse effect level is estimated to be more than 500 mg/kg body weight but not exceeding 2000 mg/kg body weight. The observed effects at the highest dose indicate the need for further study of longer dosing duration.