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

Table 4

Details of published clinical safety data of C. papaya leaf consumption in humans.

Author, year [ref.]	Study design	Recruited sample size, n (analysed sample size, n)	Sample description (age; gender; comorbidities)	Indication for C. papaya leaf	Intervention details (formulation; dose; frequency; duration)	Comparator/cointervention	Safety data reported (yes/no)	Adverse reactions (number, n, OR percentage patient in analysed population, %)
Hettige, 2008 [32]	Case series	12 (12)	5–44 y; 50% M, 50% F; NS	Dengue	Fresh C. papaya leaf juice; 2.5–5 mL; 2 doses 8 hours apart	NA/; Routine dengue supportive treatment except steroids, blood products, and nonsteroidal anti-inflammatory drugs	Yes	Rash (n = 5)
Ahmad, 2011 [33]	Case report	1 (1)	45 y; M; NS	Dengue (diagnosed based on signs and symptoms and risk factors, without a serology test)	Fresh C. papaya leaf juice; 25 mL; Twice daily; 5 days	NA/; Broad-spectrum antibiotics and antimalarial drugs	No	—
Assir, 2012 [34]	RCT	39 (NS)	Adult (age NS); 72% M, 28% F; NS	Dengue	CPLE syrup; 5 mL; Twice daily; 5 days	Placebo/; NS	Yes	No significant adverse event occurred in either group
Kala, 2012 [35]	Case series	5 (5)	19–52 y; NS; NS	Dengue (diagnosed based on signs and symptoms and risk factors, without a serology test)	Fresh C. papaya leaf juice; 30 mL; 3 times daily; NS (but the observation duration was 2 days)	NA/; Not mentioned	No	—
Yunita, 2012 [36]	RCT	80 (80)	15–34 y; 56% M, 44% F; NS	Dengue	C. papaya leaf 70% ethanolic extract in capsule; 1100 mg; 3 times daily; 5 days	Control group without placebo/routine dengue supportive treatment	No	—
Subenthiran, 2013 [6]	RCT	290 (228)	Mean 28.4 y ± SD 8.8; 85% M, 15% F; None	Dengue	Fresh C. papaya leaf juice; 50 g leaves; Once daily; 3 days	Control group without placebo/routine dengue supportive treatment	No	—
Gowda, 2014 [37]	RCT	30 (30)	18–55 y; 73% M, 27% F; NS	Dengue	CPLE tablet (Caripill, Microlabs); 1100 mg; 3 times daily; 5 days	Control group without placebo/routine dengue supportive treatment	Yes	Gastrointestinal disturbances, e.g., nausea and vomiting which were similar across groups
Siddique, 2014 [38]	Case report	1 (1)	23 y; M; None	Dengue	Fresh C. papaya leaf juice; 150 mL (1 and a half leaf); Once daily; 5 days	NA/; Commercial fruit juices (NS)	No	—
Abhishek, 2015 [39]	RCT	60 (60)	18–55 y; 73% M, 27% F; NS	Dengue	CPLE tablet; 1100 mg; 3 times daily; 5 days	Control group without placebo/Routine dengue supportive treatment	Yes	Gastrointestinal disturbances, e.g., nausea and vomiting which were similar across groups
Gadhwal, 2016 [40]	RCT	400 (400)	>16 y; 69% M, 31% F; NS	Dengue	Dried C. papaya leaf crude aqueous extract in capsule; 500 mg; Once daily; 5 days	Control group without placebo/routine dengue supportive treatment (antipyretic paracetamol, intravenous 0.9% normal saline, antiemetic)	Yes	None
Kasture, 2016 [41]	RCT	300 (292)	18–55 y; 55% M, 45% F; NS	Dengue	CPLE tablet (Caripill, Microlabs); 1100 mg; 3 times daily; 5 days	Placebo/; Routine dengue supportive treatment except corticosteroids	Yes	Nausea (n = 26) and vomiting (n = 17) which were evenly distributed across groups; Rash (n = 9) in the intervention group
Singhai, 2016 [42]	RCT	80 (NS)	>18 y; NS; NS	Febrile thrombocytopaenia	CPLE capsule; 2 capsules (strength NS); 3 times daily; 9 days	NS/none reported	No	—
Adarsh, 2017 [43]	RCT	100 (100)	21–65 y: 45% M, 55% F; NS	Dengue	CPLE capsule; 500 mg; 3 times daily; 5 days	Placebo/; Routine dengue supportive treatment (intravenous fluids, paracetamol, antacids, platelet transfusion, and inotropic agents)	Yes	No severe adverse events; Gastrointestinal disturbances, e.g., nausea and vomiting reported in both treatment and control groups
Hussain, 2017 [44]	Quasiexperimental trial	60 (58)	28–80 y; 66% M, 34% F; Malignancy, ischaemic heart disease, chronic obstructive pulmonary disease, diabetes, and others (NS)	CIT	Fresh papaya leaf granules in capsule; 290 mg; Twice daily; 5 days	Control group without placebo/; Chemotherapy, single or in combination of 5-fluorouracil, bleomycin, etoposide, ifosfamide, cyclophosphamide, paclitaxel, docetaxel, carboplatin, oxaliplatin, gemcitabine, capecitabine, and cisplatin with radiation	Yes	None; No significant changes in haematological and biochemical (NS) values; No treatment-related deaths
Sundarmurthy, 2017 [5]	RCT	40 (40)	Mean 42.5 y ± SD 10.2; 62.5% M, 37.5% F; Solid tumour malignancy and others (NS)	CIT	CPLE tablet (marketed product, brand (NS)); 1100 mg; 3 times daily; 7 days	Control group without placebo/NS	Yes	Diarrhea (15%), dizziness (10%), vomiting (15%), headache (10%), and dysgeusia (20%) the in intervention group; Comparable to the control group
Rahmat, 2018 [45]	Case report	1 (1)	76 y; M; Prostate cancer, hypertension, IgG2/IgG4 subclass deficiency	Prostate cancer	CPLE tea and elixir; 4 g tea, 5 mL elixir; Twice daily (morning tea, night elixir); NS	NA/; None reported, though having a strong history of using natural products	Yes	None
Hampilos, 2019 [46]	Case series	4 (4)	21–67 y; 50% M, 50% F; Chronic immune thrombocytopaenic purpura, hyperlipidaemia, hypothyroidism, and ulcerative colitis	Chronic immune thrombocytopaenic purpura	C. papaya leaf 10:1 glycerin extract (in liquid and capsule); 600 mg–1200 mg; 3 times daily; Up to ten months	NA/; Steroids (prednisolone), gemfibrozil, and levothyroxine	Yes	Increased glucose levels (n = 1); lymphopaenia (n = 1) ; Increased appetite (n = 1)
Pandita, 2019 [47]	Case report	1 (1)	Neonate (30 weeks preterm 23 days of life); M; None	Sepsis thrombocytopaenia	CPLE syrup (Caripill, Microlabs); 20 mg/kg; 3 times daily; 19 days (tapered off)	NA/; Hospital resuscitative support	Yes	None; Baby healthy up to 18 months of age at follow-up
Srikanth, 2019 [48]	RCT	294 (285)	Mean 7.75 y ± SD 3.27; 50% M, 50% F; NS	Dengue	CPLE syrup (Caripill, Microlabs); 275–550 mg; 3 times daily; 5 days	Control group without placebo/; Routine dengue supportive treatment	Yes	Nausea (n = 2) in the intervention group
Sathyapalan, 2020 [49]	RCT	50 (50)	Mean 52.5 y ± SD 15; 61% M, 39% F; NS	Dengue	CPLE tablet (Caripill, Microlabs); 1100 mg; 3 times daily; 5 days	Placebo/; Routine dengue supportive treatment	Yes	No serious adverse events reported up to 2 weeks after intervention cessation
Sreelatha, 2020 [50]	Single-arm retrospective audit	50 (50)	19–75 y; 50% M, 50% F; Solid tumour malignancy and others (NS)	CIT	CPLE tablet; 1100 mg; 3 times daily; Up to 2 weeks	NA/temozolomide, paclitaxel, docetaxel, gemcitabine, doxorubicin, cyclophosphamide, rituximab, vincristine, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, and capecitabine	Yes	Dysgeusia and nausea

Diagnosed as haemorrhagic skin rash due to disease instead; thought to be not related to C. papaya leaf treatment but steroid treatment instead; CIT = chemotherapy-induced thrombocytopaenia; CPLE = C. papaya leaf extract; F = female; M = male; NA = not applicable; NS = not specified; SD = standard deviation; y = years.