Apart from being efficacious, the safety assurance of a medicinal herb and its formulation are important considerations. The World Health Organization (WHO) Global Report on Traditional and Complementary Medicine (2019) outlined that the safety of herbal medicines is often required to be assessed thoroughly, in most countries, under processes similar to those for conventional medicine, including postmarketing surveillances [
As
This review was conducted according to the York Framework of scoping studies by Arskey and O’Malley [
This review was conducted based on the primary research question “How safe is the oral consumption of What is the documented safe dose range of What is the safety profile of What are the potential herb-drug interactions of
The following Population, Intervention, Comparison, and Outcomes (PICO) framework was applied to address the study’s research questions (Table
Population, Intervention, Comparison, and Outcomes (PICO) framework.
Elements | Details |
---|---|
Population | 1. Human patients of all ages and diseases, healthy and unhealthy |
Intervention | |
Comparator | Placebo, no treatment, or control treatment |
Outcome | Primary outcome: |
A systematic search was conducted by two independent investigators for published and grey literature with predetermined keywords. In general, a combination of keywords consisting of “papaya,” “leaf,” “leaves,” “side effect,” “health effect,” “adverse effect,” “toxic,” “safety,” “herb interaction,” and “drug interaction” was used, catered, and adapted to each search engine. An example of the keywords search used for MEDLINE is presented in the supplementary material (
Title and abstract screening, as well as full-text paper inclusion, was performed by two independent investigators. A third investigator was involved in cases of disagreements. Studies were selected based on the inclusion and exclusion criteria with reference to the research questions identified and PICO elements (Table
Inclusion and exclusion criteria.
2A: clinical studies | |
---|---|
a) Clinical articles and reports on primary human data | |
a) Review papers or reports on secondary data | |
2B: animal toxicity studies | |
a) Primary articles of | |
a) Review papers or reports on secondary data | |
2C: herb-drug interaction studies | |
a) Articles and reports on the primary data of any potential herb-drug interaction | |
a) Review papers or reports on secondary data |
Data extraction was carried out and then agreed on by two independent reviewers while disparities were reviewed by a third. Four different data extraction tables (supplementary material:
In general, the categories of main data extracted include the following: Article identifier: designated number; title; and author Article characteristics: year; country; type of study (randomised controlled trials, case series, Study population: sample size; drop outs; and details of study population (age, gender, comorbidities, diagnosis, animal model, cells, and assay) Intervention: plant part used; form; formulation; quality details, e.g., quantitative analysis, chemical fingerprinting, standardisation, voucher specimen, and source; dose; duration; and cointervention Comparator: intervention description; formulation; dose; duration; and cointervention Outcomes: adverse events or reactions; herb-drug interaction; mechanism of herb-drug interaction; and method of assessment Others: limitations; funding details; other reference identified (for tracing of additional papers); and remarks (reasons for exclusion must be stated)
For unpublished ADR reports, the following information was requested from the official providers to enable critical appraisal and descriptive analysis of causality: Name and details of the ingested Purpose of Details of concomitant intervention Description of an adverse event Causality score/assessment Patient demographics (age, gender, comorbidities, and diagnosis)
Due to the versatility in types of studies and results acquired, descriptive numerical analysis was carried out for the country and type of study. A list of ongoing studies and their latest status were tabulated. The toxicity profile of
Specifically for randomised controlled and quasiexperimental trials, the reporting quality of the herbal intervention investigation was assessed using the Consolidated Standards of Reporting Trials (CONSORT) extension for herbal trials, item No. 4 [
From a total of 322 records identified from the initial search, final 41 articles were included in this scoping review for descriptive analysis, from which 13 randomised controlled and quasiexperimental trials were analysed for risk of bias and test item (herbal intervention) reporting quality (Figure
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of included studies.
Table
Demographics of included articles.
Demographic categories | Frequency (n) | Percentage (%) |
---|---|---|
Clinical evidence (published and unpublished) ( | ||
Randomised controlled trial | 12 | 52.17 |
Quasiexperimental trial | 1 | 4.35 |
Retrospective audit | 1 | 4.35 |
Case report/series | 7 | 30.43 |
Other unpublished reports | 2 | 8.70 |
Dengue | 15 | 65.22 |
Chemotherapy-induced thrombocytopaenia | 3 | 13.04 |
Cancer | 1 | 4.35 |
Chronic immune thrombocytopaenia purpura | 1 | 4.35 |
Febrile thrombocytopaenia | 1 | 4.35 |
General health | 1 | 4.35 |
Neonatal thrombocytopaenia | 1 | 4.35 |
India | 12 | 52.17 |
Malaysia | 3 | 13.04 |
Pakistan | 3 | 13.04 |
U.S.A | 2 | 8.70 |
Bangladesh | 1 | 4.35 |
Indonesia | 1 | 4.35 |
Sri Lanka | 1 | 4.35 |
Preclinical | ||
General toxicity | 5 | 71.43 |
Specific toxicity | 1 | 14.29 |
Combination (general and specific) | 1 | 14.29 |
Rodent | 5 | 71.43 |
Nonrodent | 2 | 28.57 |
Malaysia | 3 | 42.86 |
Nigeria | 2 | 28.57 |
Ghana | 1 | 14.29 |
Brazil | 1 | 14.29 |
Herb-drug interaction studies ( | ||
Pharmacokinetic | 2 | 33.33 |
Pharmacodynamic | 4 | 66.67 |
| 3 | 50.00 |
| 2 | 33.33 |
Combination ( | 1 | 16.67 |
Nigeria | 3 | 50.00 |
Italy | 2 | 33.33 |
Japan | 1 | 16.67 |
Details of clinical evidence on the safety profile of
Details of published clinical safety data of
Author, year [ref.] | Study design | Recruited sample size, | Sample description (age; gender; comorbidities) | Indication for | Intervention details (formulation; dose; frequency; duration) | Comparator/cointervention | Safety data reported (yes/no) | Adverse reactions (number, |
---|---|---|---|---|---|---|---|---|
Hettige, 2008 [ | Case series | 12 (12) | 5–44 y; | Dengue | Fresh | NA/ | Yes | Rash ( |
Ahmad, 2011 [ | Case report | 1 (1) | 45 y; | Dengue (diagnosed based on signs and symptoms and risk factors, without a serology test) | Fresh | NA/ | No | — |
Assir, 2012 [ | RCT | 39 (NS) | Adult (age NS); | Dengue | CPLE syrup; | Placebo/ | Yes | No significant adverse event occurred in either group |
Kala, 2012 [ | Case series | 5 (5) | 19–52 y; | Dengue (diagnosed based on signs and symptoms and risk factors, without a serology test) | Fresh | NA/ | No | — |
Yunita, 2012 [ | RCT | 80 (80) | 15–34 y; | Dengue | Control group without placebo/routine dengue supportive treatment | No | — | |
Subenthiran, 2013 [ | RCT | 290 (228) | Mean 28.4 | Dengue | Fresh | Control group without placebo/routine dengue supportive treatment | No | — |
Gowda, 2014 [ | RCT | 30 (30) | 18–55 y; | Dengue | CPLE tablet (Caripill, Microlabs); | Control group without placebo/routine dengue supportive treatment | Yes | Gastrointestinal disturbances, e.g., nausea and vomiting which were similar across groups |
Siddique, 2014 [ | Case report | 1 (1) | 23 y; | Dengue | Fresh | NA/ | No | — |
Abhishek, 2015 [ | RCT | 60 (60) | 18–55 y; | Dengue | CPLE tablet; | Control group without placebo/Routine dengue supportive treatment | Yes | Gastrointestinal disturbances, e.g., nausea and vomiting which were similar across groups |
Gadhwal, 2016 [ | RCT | 400 (400) | >16 y; | Dengue | Dried | Control group without placebo/routine dengue supportive treatment (antipyretic paracetamol, intravenous 0.9% normal saline, antiemetic) | Yes | None |
Kasture, 2016 [ | RCT | 300 (292) | 18–55 y; | Dengue | CPLE tablet (Caripill, Microlabs); | Placebo/ | Yes | Nausea ( |
Singhai, 2016 [ | RCT | 80 (NS) | >18 y; | Febrile thrombocytopaenia | CPLE capsule; | NS/none reported | No | — |
Adarsh, 2017 [ | RCT | 100 (100) | 21–65 y: | Dengue | CPLE capsule; | Placebo/ | Yes | No severe adverse events; |
Hussain, 2017 [ | Quasiexperimental trial | 60 (58) | 28–80 y; | CIT | Fresh papaya leaf granules in capsule; | Control group without placebo/ | Yes | None; |
Sundarmurthy, 2017 [ | RCT | 40 (40) | Mean 42.5 | CIT | CPLE tablet (marketed product, brand (NS)); | Control group without placebo/NS | Yes | Diarrhea (15%), dizziness (10%), vomiting (15%), headache (10%), and dysgeusia (20%) the in intervention group; |
Rahmat, 2018 [ | Case report | 1 (1) | 76 y; | Prostate cancer | CPLE tea and elixir; | NA/ | Yes | None |
Hampilos, 2019 [ | Case series | 4 (4) | 21–67 y; | Chronic immune thrombocytopaenic purpura | NA/ | Yes | Increased glucose levels ( | |
Pandita, 2019 [ | Case report | 1 (1) | Neonate (30 weeks preterm 23 days of life); | Sepsis thrombocytopaenia | CPLE syrup (Caripill, Microlabs); | NA/ | Yes | None; |
Srikanth, 2019 [ | RCT | 294 (285) | Mean 7.75 | Dengue | CPLE syrup (Caripill, Microlabs); 275–550 mg; | Control group without placebo/ | Yes | Nausea ( |
Sathyapalan, 2020 [ | RCT | 50 (50) | Mean 52.5 | Dengue | CPLE tablet (Caripill, Microlabs); | Placebo/ | Yes | No serious adverse events reported up to 2 weeks after intervention cessation |
Sreelatha, 2020 [ | Single-arm retrospective audit | 50 (50) | 19–75 y; | CIT | CPLE tablet; | NA/temozolomide, paclitaxel, docetaxel, gemcitabine, doxorubicin, cyclophosphamide, rituximab, vincristine, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, and capecitabine | Yes | Dysgeusia and nausea |
Based on published clinical evidence, overall, no major adverse reactions related to
Two cases of unpublished ADR reports retrieved from the MADRAC database reported hepatic enzyme derangements, with a MADRAC causality score [
Details of unpublished adverse drug reaction (ADR) reports of
Report no. | Gender | Age (years) | ADR description | Indication for | Intervention details (formulation; dose; frequency; duration) | Additional laboratory evaluation (adulteration and heavy-metal analysis) | Potential confounding factors (e.g., concomitant medications/comorbidities) | MADRAC causality assessment |
---|---|---|---|---|---|---|---|---|
1 | Male | 17 | Deranged liver enzymes after 6 days of consumption reported in a patient diagnosed with dengue fever | Dengue | Negative detection for paracetamol and nonsteroidal anti-inflammatory drugs; heavy-metal levels within allowable limits | Not specified | Possible | |
2 | Female | 37 | Transaminitis with accompanying symptoms of fever, vomiting, diarrhea, loss of appetite, and lethargy | General health | Negative detection for steroids; heavy-metal levels within allowable limits | Not specified | Possible |
Source: Pharmacovigilance Section, Centre for Compliance and Quality Control, National Pharmaceutical Regulatory Agency, Malaysia; ADR = adverse drug reaction; MADRAC = Malaysian Adverse Drug Reactions Advisory Committee.
Analysis of reporting quality on the herbal intervention/test item based on CONSORT checklist item No. 4 is presented in
Overall, 61% of the included articles mentioned the type of extract used as an intervention. The most commonly investigated formulation in the clinical articles included was juice (26%) followed by a commercialised standardised aqueous extract of
For the two unpublished ADR reports of liver enzyme derangements, the dose of
Risk of bias analysis (Figure
Risk of bias analysis of included randomised controlled and quasiexperimental trials (
Risk of bias analysis summary for individual randomised controlled and quasiexperimental trials (
Details and findings of animal toxicity studies of the oral
Author, year [ref.] | Animal model (species; gender) | Intervention details (formulation; dose; frequency; duration; quantitative analysis of content) | Comparator | Quantitation of toxic/safe dose | Description of toxicity findings |
---|---|---|---|---|---|
Akinloye, 2010 [ | Rat (Wistar; Male) | Air-dried | 0.9% sodium chloride | NA | (i) Male reproductive toxicity |
Omonkhua, 2011 [ | Rabbits (New Zealand; NS) | Water | NA | (i) Transient elevation of liver enzymes (ALP, GGT, and bilirubin) at initial periods of treatment (3 to 5 weeks); | |
Halim, 2011 [ | Rat (Sprague Dawley; female) | Freeze-dried | Water | NS | (i) No mortality and acute adverse events at all doses; |
Afzan, 2012 [ | Rat (Sprague Dawley; male and female) | Lypohilised fresh | Water | NS | (i) No mortality and acute adverse events at all doses; |
Ismail, 2014 [ | Rat (Sprague Dawley; male and female) | Freeze-dried fresh | Water | NOAEL = 2000 mg/kg (male and female) | (i) No mortality and acute adverse events, no changes in body weight and food and water intake at all doses; |
Ansah, 2015 [ | Rat (Sprague Dawley; male and female) | Air-dried | Distilled water | LD50 > 2000 mg/kg | (i) No mortality and acute adverse events; |
Nghonjuyi, 2016 [ | Chicks (Kabir; male and female) | Air-dried | Distilled water | LD50 > 5120 mg/kg | (i) No mortality and acute adverse events, no changes in body weight, food, and water intake at all doses; |
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transferase; HGB = haemoglobin; HCT = haematocrit; HDL = high-density lipoprotein; LD50 = median lethal dose; LDH = lactate dehydrogenase; NA = not applicable; NOAEL = no-observed-adverse-effect level; NS = not specified; RBC = red blood cell counts; TG = triglyceride; WCC = white blood cell counts.
Six preclinical studies reported several differential herb-drug interactions between oral administration of
Herb-drug interaction studies of
Author, year [ref.] | Study type (animal model, if any) | Drug candidate(s) of interaction | Outcome of interaction | Proposed type of interaction | |
---|---|---|---|---|---|
Fakeye, 2007 [ | Dried | Metformin, glimepiride | Enhanced hypoglycaemic effect | Pharmacokinetic + pharmacodynamic | |
Sanella, 2009 [ | Dried | Artemisinin | Synergisim in inhibiting growth of | Pharmacodynamic | |
Onaku, 2011 [ | Fresh | Artemisinin | Antagonism in percentage reduction of parasitaemia ( | Pharmacodynamic | |
Oga, 2012 [ | Dried | Digoxin | Inhibition of p-glycoprotein transport of digoxin | Pharmacokinetic | |
Ukpo, 2017 [ | Freeze-dried crude | Ciprofloxacin | Reduced absorption and serum half-life of ciprofloxacin | Pharmacokinetic | |
Sanella, 2019 [ | Dried | Artemisinin | Subsynergism in inhibiting | Pharmacodynamic |
NA = not applicable, NS = not specified.
Thrombocytopaenia in dengue fever remains the most investigated indication of
Oral consumption of
Two cases of liver enzyme derangements were identified from unpublished local ADR reports, which documented a “possible” causal relationship of
In herbal medicine development, it is well established that several confounding factors such as the agroclimatic factors and types of extraction solvent used can influence the final phytochemical composition of a formulation, which may, in turn, affect efficacy and toxicity [
Extrapolating from animal toxicity studies, elevated liver enzymes have been reported in rats and rabbits administered with repeated doses of
Reproductive side effects have also been reported in animal studies [
In clinical trials,
Differential interaction effects were also reported between two
An
One of the most common pathways of herb-drug interaction is through the effect on cytochrome (CYP) enzymes, a major group of liver metabolising enzymes of many drugs [
No conclusive findings on extrinsic toxicity can be drawn as most of the required quality data to assess extrinsic toxicity were not sufficiently reported based on the CONSORT reporting checklist for herbal interventions, item No. 4 [
Heavy-metal contamination from soil and the presence of pesticides in raw plants of herbs used in formulating the final herbal medicine product are important factors to consider when evaluating extrinsic toxicity [
There are several limitations of this review. Firstly, only English articles were included. However, our paper took into account all previously published randomised controlled trials which were included in the two most recent systematic reviews on efficacy and safety of
Quantitative analysis to pool incidence of reported adverse reactions was not possible in this review due to the lack of data on actual incidence of each adverse event in both treatment arms reported. Insufficient reporting on quantitative analysis on the phytochemical composition of an individual test item further contributed towards the difficulty in performing meaningful data comparison. Furthermore, as only three out of thirteen trials administered a placebo in the control group, there is a high risk for performance bias for such analysis. Lastly, this review was unable to critically evaluate the risk of extrinsic toxicity due to limited reporting on the quality of test items/herbal interventions investigated.
In conclusion,
Adverse drug reaction
Arachidonate 12-lipoxygenase
Alkaline phosphatase
Alanine transaminase
Aspartate transaminase
Consolidated Standards of Reporting Trials
Cytochrome
Follicle stimulating hormone
Gamma-glutamyl transferase
Luteinising hormone
Latin American and Caribbean Health Sciences Literature
Malaysian Adverse Drug Reactions Advisory Committee
Organization for Economic Cooperation and Development
Population, Intervention, Comparison, and Outcomes
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews
World Health Organization.
All data used to support the findings of this study are included within the article and supplementary information files.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
The authors would like to thank the Director General of Health Malaysia, Deputy Director General of Health Malaysia (Research & Technical Support), and Director of Institute for Medical Research, Head Centre of Herbal Medicine Research Centre, for their support and permission to publish this article. The authors would also like to extend their gratitude towards Dr. Azuana Ramli, Head of the Pharmacovigilance Section, Centre for Compliance and Quality Control, National Pharmaceutical Regulatory Agency, Ministry of Health, Malaysia, for providing information on ADR reports from the MADRAC database.
S1 Table. Details of ongoing trials. S1 Appendix. Sample search strategy and keywords. S2 Appendix. Data extraction tables. S3 Appendix. PRISMA-ScR checklist. S4 Appendix. CONSORT checklist for herbal trials, item No. 4.