Carica papaya L. Leaf: A Systematic Scoping Review on Biological Safety and Herb-Drug Interactions

Abstract

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.

The Future of Carica papaya Leaf Extract as an Herbal Medicine Product

“…In conclusion, papaya leaf consumption by adults is most likely safe for short-term use, but should be carefully managed when it is given to pregnant women and people with liver impairments. Furthermore, potential herb-drug interactions could occur with oral hypoglycaemic agents, P-glycoprotein substrates, and antibiotics with cation-chelating properties [133]. As previously mentioned, a papaya leaf extract produced by Sido Muncul showed non-sub-chronic toxicity even for long periods of consumption when it was evaluated in an animal study.…”

In-vitro antiviral activity of Carica papaya formulations against dengue virus type 2 and chikungunya virus

“…Scientific studies have demonstrated the use of papaya for its anti-bacterial, anti-inflammatory, nephroprotective, antiparasitic, antidiabetic, hepatoprotective, and anti-dengue properties [ 13 ]. Although comprehensive investigation on the bioactive compounds is needed to understand the mechanism of action, positive conclusions are reported from various studies to validate the use of papaya leaves for the dengue fever treatment and have shown effectiveness in refining thrombocytopenia using in-vitro and in-vivo systems [ 14 ]. Multiple small-scale studies and case reports suggest a rapid increase of platelet count in the patients after management of papaya leaf extract and attribute its erythrocyte membrane-stabilizing potential as a possible reason for this effect [ 14 , 15 ].…”

“…Although comprehensive investigation on the bioactive compounds is needed to understand the mechanism of action, positive conclusions are reported from various studies to validate the use of papaya leaves for the dengue fever treatment and have shown effectiveness in refining thrombocytopenia using in-vitro and in-vivo systems [ 14 ]. Multiple small-scale studies and case reports suggest a rapid increase of platelet count in the patients after management of papaya leaf extract and attribute its erythrocyte membrane-stabilizing potential as a possible reason for this effect [ 14 , 15 ]. Direct antiviral activity has been demonstrated in the in-vitro studies wherein THP-1 cells treated with papaya leaves extract (PLE) showed a significant decrease in DENV envelope and NS1 protein expression, decreased viral load, and an increase in the expression of Type I interferons (IFN-α) [ 10 ].…”

A Case Study Using Papaya Leaf Extract to Reverse Chemotherapy-Induced Thrombocytopenia in a GBM Patient

“… 9 Additional studies on post-chemotherapy populations have mirrored the results of these studies and have found no treatment-related adverse events; however, a recent review has reported that the most common side effect of CPLE use is minor gastrointestinal disturbance. 10 , 11 Recently, a case report of a neonate with persistent refractory thrombocytopenia concluded that CPLE treatment may even be applicable in this population. 12 …”