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Papaya

Scientific Name(s): Carica papaya L.
Common Name(s): Betik petik, Chichput, Fan kua, Fermented papaya, Gandul, Gantung, Katela, Kates, Kavunagaci, Kepaya, Kuntaia, Kuo, Lechoso, Lohong si phle, Mamao, Maoaza, Melon tree, Mu kua, Papailler, Papaw, Papaya, Papayer, Paw paw, Pepol, Tinti, Wan shou

Clinical Overview

Use

Traditional uses of papaya in some developing countries are being investigated; papaya may provide an alternative to standard treatments for a variety of ailments. C. papaya has a wide range of purported medicinal properties, including antiseptic, antimicrobial, antiparasitic, anti-inflammatory, antihypertensive, diuretic, antihyperlipidemic, antidiabetic, and contraceptive activity. While there are limited data to support most of these uses, there is some clinical evidence for use in treating decubitus ulcers, wounds, and intestinal worms. There is increasing interest in investigating fermented papaya preparations (FPPs) as a nutraceutical.

Dosing

Various topical applications of papaya have been used for wound healing, particularly in developing countries. There are very little data available to make specific recommendations regarding systemic doses of papaya.

One study used 20 mL of an elixir containing air-dried papaya seeds in honey (prepared by mixing 500 g of air-dried, machine-blended seeds with honey, for a total preparation volume of 1,000 mL [ie, 0.2 g of dried C. papaya seeds per milliliter]) to treat helminthiasis in children.

In clinical studies, FPPs have been used at 6 to 9 g per day in divided doses to evaluate effects in patients with diabetes or hypothyroidism.

A commercial papaya preparation (Caricol; 20 mL) has been used for 40 days in a trial evaluating effects in GI disorders.

In the United States, the papaya fruit has "generally recognized as safe" (GRAS) status when used as a food.

Contraindications

Papaya is contraindicated in patients with known hypersensitivity to any of its components (eg, papain). Papaya may induce severe allergic responses in sensitive people.

Pregnancy/Lactation

Avoid use. Papaya may be unsafe depending on the part of the plant being used and dose administered.

Interactions

None documented.

Adverse Reactions

Papaya may cause severe allergic reactions in sensitive people. Topically, papaya latex can be a severe irritant and vesicant. Papaya juice and papaya seeds are unlikely to cause adverse effects when taken orally; however, papaya leaves at high doses may cause gastric irritation.

Toxicology

No data.

Botany

Papaya is a small, bushy tree that grows 4 to 8 m in height, with a hollow trunk, large palmate leaves, and oblong, smooth-skinned fruits (melons). The melons are usually picked in a mature green state and allowed to ripen. When ripe, the flesh is sweet and juicy, and similar in taste to other melons.Hewitt 2002

History

Papaya, a tropical plant believed to have originated in southern Mexico and Central America, is now cultivated in tropical and subtropical regions worldwide for its edible ripe fruit; its juice is a popular beverage, and its young leaves and shoots are cooked as vegetables.Duke 1983, Hewitt 2002, Monti 2004 The fruits are a source of flavoring used in candies, jellies, preserves, and ice cream. Shallow cuts on the surface of fully grown but unripe fruits cause the exudation of a milky sap or latex that is collected, dried, and termed "crude papain."Foster 1999 Papain, a proteolytic enzyme, has a wealth of industrial uses, including milk-clotting (rennet) and protein-digesting properties. Nearly 80% of American beer is treated with papain, which digests the precipitable protein fragments and causes the beer to remain clear upon cooling.Duke 1983 Commercially, papain is most commonly used in meat tenderizers and chewing gums.Duke 1983, Foster 1999 Cosmetically, papain is used in some dentifrices, shampoos, and facial creams.Duke 1983

Papaya has been widely used in folk medicine for many ailments: The juice has been used for warts, corns, cancers, tumors, and indurations of the skin; the roots or their extracts for uterine tumors, syphilis, yaws, or hemorrhoids, and to remove urine concretions; the unripe fruit for mild laxative or diuretic properties, and to stimulate lactation, labor, or abortion; the ripe fruit for rheumatism and alkalinizing the urine; the seeds for their anthelmintic properties or to stimulate menstruation or abortion; the leaves as a poultice for nervous pains and elephantoid growths, or smoked for asthma relief; and the latex for psoriasis, ringworm, or dyspepsia, or applied externally as an antiseptic or to heal burns or scalds, or smeared on the cervix as an ecbolic.Duke 1983, Gill 1992, Oderinde 2002

An ointment, each gram containing 8.3×105 units of papain and 100 mg of urea,Singhal 2001 is available by prescription in the United States to debride necrotic tissue and liquefy slough in a variety of short- and long-term lesions, including pressure ulcers.

Chymopapain has been used to aid in the healing and recovery of surgical wounds.Heinerman 1988

In the early 1980s, chymopapain was approved for intradiscal injection in patients with documented herniated lumbar intervertebral discs who had not responded to conservative therapy.Chymopapain 1982 This procedure is effectiveJavid 1980, Javid 1996, but remains controversial, particularly regarding safety of the administration of the enzyme.Diagnostic 1989

Chemistry

The stems, leaves, and fruits of papaya contain copious amounts of latex.Gill 1992, Hewitt 2002

The latex from unripe papaya fruit is rich in 2 enzymes: papain (also known as "vegetable pepsin") and chymopapain.Hewitt 2002 Other constituents include a mixture of other cysteine endopeptidases, such as papaya endopeptidase II (also known as caricain), papaya endopeptidase IV, omega endopeptidase,Azarkan 2003 chinitases, protease inhibitors, linamarase, and proteins without known functions.Azarkan 2004, Oloyede 2005 As the fruit ripens, papain and chymopapain dissipate and neither is present in the ripe fruit.Heinerman 1988 Papain is primarily a mixture of protein-degrading enzymes,Dubois 1988 but other components of papain can degrade carbohydrates and fats. Chymopapain has been fractionated into subcomponents designated "A" and "B."Barrett 1985 It is very similar to papain in the spectrum of its proteolytic activity, although it is less potent with respect to protein degradation.Leung 1980 Carpaine, an alkaloid compound, is also found in the unripe fruit and young leaves of papaya.Hewitt 2002, Spoerke 1980 The leaves contain the glycoside carposide.Duke 1983

The seeds contain sinigrin and caricin, both glycosides, and the enzyme myrosin.Duke 1983 When caricin is combined with myrosin, it produces a mustard-like odor.Duke 1983, Seigler 2002 Papaya seeds and pulp contain benzyl glucosinolate that is hydrolyzed by the enzyme myrosinase to produce benzyl isothiocyanate.Kermanshai 2001

A preliminary phytochemical analysis of C. papaya leaves revealed the presence of alkaloids, flavonoids, saponins, tannins, cardiac glycosides, anthraquinones, reducing sugars, steroids, phenolics, and cardenolides.Owoyele 2008

Uses and Pharmacology

C. papaya has a wide range of purported pharmacological effects, including antiseptic, antimicrobial, antiparasitic, anti-inflammatory, antihypertensive, diuretic, antihyperlipidemic, antidiabetic, and contraceptive activity. While limited data exist for most of these effects, there is some clinical evidence supporting its use in healing decubitus ulcers and other wounds, and for treating intestinal worms.

Benzyl isothiocyanate found in the pulp and seeds of papaya is a potent inducer of glutathione S-transferase, a phase 2 enzyme involved in the cellular detoxification of xenobiotics and reactive metabolites.Nakamura 2000 Aqueous extracts of C. papaya caused a concentration-dependent and statistically significant inhibition of root growth in onion bulbs. The extracts exhibited mitodepressive effects on cell division and mitotic spindle disturbance in Allium cepa.Akinboro 2007

Anthelmintic/antiparasitic/antiprotozoal activity

C. papaya contains proven anthelmintic chemical agents such as benzyl isothiocyanate and papain.Duke 1983, Kermanshai 2001, Kumar 1991, Siddiqui 1987 However, papain is unstable in the presence of digestive juices, which may account for its lack of efficacy as an anthelmintic in clinical studies.Foster 1999 Benzyl isothiocyanate is therefore considered to be the chief or sole anthelmintic in papaya seed extracts.Barrett 1985, Kermanshai 2001, Kumar 1991

Animal data

Various studies in animals confirm the effectiveness of C. papaya seeds as an anthelmintic effective against nematodes found in animals.Burke 2009, Chota 2010, Satrija 1995, Stepek 2006, Stepek 2007, Stepek 2007

C. papaya has documented activity against protozoa in addition to intestinal parasites in animal models. These include antiamebic,Tona 1998 antitrichomonal,Calzada 2007 antimalarial,Bhat 2001, Ghosh 1998, Yarnell 2004 and leishmanicidalValadeau 2009 properties.

Clinical data

In one study, 60 asymptomatic Nigerian children with microscopic evidence of intestinal parasites in their stools were randomized to either treatment with 20 mL of elixir containing air-dried C. papaya seeds and honey (prepared by mixing 500 g of air-dried, machine-blended seeds with honey, for a total preparation volume of 1,000 mL [ie, 0.2 g of dried C. papaya seeds per milliliter]) or 20 mL of honey alone (placebo). Stools were cleared of parasites in more subjects given C. papaya seeds and honey elixir than those given placebo (76.7% vs 16.7%).Okeniyi 2007 The high stool clearance rates (between 71.4% and 100%) affirm the effectiveness of C. papaya seeds against intestinal parasites. Organisms cleared included Ascaris lumbricoides (84.6%), Strongyloides stercoralis (100%), Trichuris trichiura (100%), Giardia lamblia (100%), Taenia saginata (100%), Entamoeba histolytica (71.4%), and Necator americanus (80%).Okeniyi 2007

Anti-inflammatory activity

The leaves of papaya have been used for the treatment of inflammatory conditions such as asthma, rheumatism, arthritis, and wound healing.Owoyele 2008 However, there have been few studies investigating the biological activity of the dried leaves, which have been used traditionally for the treatment of inflammatory conditions.Owoyele 2008, Pandey 2016

Animal and in vitro data

The results of a Nigerian study in rats showed that an ethanolic extract of C. papaya leaves reduced carrageenan-induced paw edema and also reduced the amount of granuloma formed. Likewise, the extract reduced edema in the formaldehyde-induced arthritis model.Owoyele 2008 A study of C. papaya leaf extract using a mouse model of allergic asthma noted reductions in inflammatory reactions and decreased levels of interleukins 4 and 5 and tumor necrosis factor alpha (TNF-alpha), among other proinflammatory cytokines.Inam 2017 Further studies are required to identify the exact active ingredient(s) or mechanisms responsible for the anti-inflammatory actions. A review of in vitro and animal studies has been published.Pandey 2016

Clinical data

Markers of inflammation (including TNF-alpha) were reduced in a small clinical study evaluating effects of fermented papaya over a 6-month period in patients with liver cirrhosis.Marotta 2011 The same group of researchers have reported effects of FPPs on immunological and inflammatory biomarkers in respiratory disease.Marotta 2012

Papain solutions have produced therapeutic effects in patients with inflammatory disorders of the genitals, intestine, liver, and eye.Rakhimov 2000

Antimicrobial activity

Papaya may exert a proteolytic effect on bacteria resulting from the production of a coagulum that immobilizes microorganisms and protects the host against bacterial infections.Wimalawansa 1981 In addition, papaya may improve the efficiency of phagocytic cells that destroy bacteria.Gurung 2009 Papaya also contains the alkaloid carpaine, which has antibacterial properties.Hewitt 2002

In vitro data

In laboratory tests, extracts from skin, flesh, and seeds of both ripe and unripe papaya showed in vitro antibacterial activity against several microorganisms, including Bacillus cereus, Bacillus subtilis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri, and Staphylococcus aureus.Emeruwa 1982, Osato 1993, Yismaw 2008

Clinical data

There are no clinical data regarding the use of papaya as an antimicrobial agent in humans, although it is postulated that its antimicrobial activity may play a role in its efficacy in treating ulcers, burns, and wounds.Starley 1999

Antioxidant activity

Papaya contains antioxidant components, such as vitamin C, malic acid, and citric acidMurcia 2001, Wimalawansa 1981; a limited number of studies have examined the antioxidant potential of papaya.

Animal data

In one study, Wistar rats were divided into 1 of 5 groups: control; 100 mg/kg/day of C. papaya juice; 200 mg/kg/day of C. papaya juice; 400 mg/kg/day of C. papaya juice; or vitamin E (alpha-tocopherol). The study demonstrated that the antioxidative stress potential of the juice was comparable with alpha-tocopherol.Mehdipour 2006

Clinical data

A study of elderly patients supplemented with FPP exhibited an enhancement in antioxidant protection, suggesting that FPP may improve antioxidant defense in elderly patients, even in those without overt antioxidant deficiency states.Marotta 2006]

Another study in patients with hepatitis C suggested a potential supportive role of FPP or vitamin E. Both treatments improved redox status; however, only FPP decreased 8-hydroxy-deoxy-guanidine. The improvement of cytokine balance with FPP was better than with vitamin E treatment.Marotta 2007

Based on clinical studies, antioxidant activity has been postulated as the mechanism of action for improved healing rates in diabetes-associated wounds and reduced deleterious reactive oxygen species in persons with type 2 diabetes.Dickerson 2015

Reduced oxidative stress in individuals with hereditary spherocytosis following treatment with FPP for 3 months has been reported.Ghoti 2011

In women with subclinical or mild hypothyroidism (N=60), fermented papaya produced normalization of the redox markers examined.Tomella 2014

Antitumor activity and immunomodulatory effects

In vitro data

Another study reported that aqueous extract of C. papaya leaves exhibits antitumor activity and immunomodulatory effects, suggesting that the C. papaya leaf extract may have a role in treatment of cancer and various allergic disorders.Otsuki 2010

Cardiovascular effects

Animal data

Diuretic activity is associated with the aqueous extracts of C. papaya. Adult male Sprague-Dawley rats were given an oral dose of 10 mg/kg of C. papaya root extracts. The demonstrated increased urine output (P<0.01) was similar to effects with hydrochlorothiazide 10 mg/kg.Sripanidkulchai 2001

Antihypertensive activity is associated with ethanolic extracts from the unripened fruit of C. papaya. Both hydralazine (200 mcg per 100 g intravenously [IV]) and C. papaya extract (20 mg/kg IV) produced depression of mean arterial pressure in renal hypertensive, deoxycorticosterone acetate-salt hypertensive, and normotensive rats. The papaya extract decreased mean arterial pressure 28% more than hydralazine in the hypertensive groups. The papaya extract also produced relaxation of vascular tone that was attenuated by phentolamine. It was concluded that the fruit of C. papaya likely contains antihypertensive agent(s) that exhibit mainly alpha-adrenoceptor activity.Eno 2000

The raw fruit of C. papaya displayed antihyperlipidemic activity in Sprague-Dawley rats with hyperlipidemia induced by IV injection of triton WR1339 or a high-fat diet.Banerjee 2006 The fresh juice of C. papaya exerted a lowering of serum cholesterol and triglycerides within the first 24 hours in the triton model. Similarly, the aqueous and methanolic extracts of C. papaya markedly reduced levels after 7 days of repeated oral treatment compared with control (atorvastatin and fenofibrate–treated) group.Banerjee 2006

Clinical data

There are no clinical data regarding the use of papaya in cardiovascular disease. However, a clinical study evaluating antioxidant activity of FPP found no effect on total lipid profile. Participants consumed FPP 9 g/day over 6 weeks.Dickerson 2015 A further clinical study (N=127) found reductions in blood pressure and a limited effect on lipid profiles following supplementation with 6 g/day of FPP for 14 weeks.Somanah 2012

Contraceptive properties

Anecdotal evidence suggests that eating unripe papaya for 3 consecutive days may induce abortion and that the papain in ripe fruit may have contraceptive-like activity when consumed daily. It has been suggested that papain suppresses progesterone, which is needed for conception and pregnancy.Natural Way 1994

The seeds of C. papaya are being considered in the development of an antifertility agent for men.Lohiya 2006, Verma 2006

Animal data

Various investigators have reported antifertility effects of C. papaya seeds in laboratory mammals.

Abortifacient properties have been reported in female rats,Bodhanker 1974, Garg 1971 while decreases in sperm motility and count have been reported in male ratsChinoy 1985, Das 1980, Fansworth 1982, Lohiya 1994, Lohiya 2006, Manivannan 2009, Pathak 2000 and rabbits.Pathak 2001

Histologic examination of sections of pituitary gonadotrophs (follicle-stimulating hormone and luteinizing hormone cells) in male Wistar rats treated with C. papaya extract 200 mg/kg/day for 1 and 8 weeks revealed pronounced hypertrophy, while those treated with 50 mg/kg showed mild hypertrophy and hyperplasia. The testes of rats treated with C. papaya revealed gradual degeneration of the germ cells, Sertoli cells, and Leydig cells, as well as germinal epithelium. Tubules of epididymis of rats treated with 200 mg/kg of extract appeared empty, indicating the degeneration of sperm cells in the lumina. These results suggest C. papaya extract interfered with the pituitary-gonadal axis to influence male reproductive functions.Udoh 2005

Results of another study in which rats were given oral doses of 50, 100, 250, and 500 mg/kg of methanolic extract of papaya seeds for 28- and 90-day periods support antifertility effect findings. Sperm density decreased in all 28-day and 90-day–treated rats, whereas total sperm motility inhibition was observed at 250 and 500 mg/kg dose levels at the 28-day interval and in all dose groups at the 90-day interval.Lohiya 2006

Studies have also been performed to evaluate the toxicological effects of papaya seed extract and whether this effect is reversible even after high concentrations and long-term administration. One such study in mice revealed a dose-dependent suppression of sperm motility coinciding with a decrease in sperm count and viability with high dosages of aqueous C. papaya seed extract. Forty-five days after withdrawal of treatment, complete normalcy was restored.Verma 2006 Another study in mice administered 50 mg/kg/day showed 100% sterility after 60 days, and safety was demonstrated after 360 days based on unaltered health status, organ weight, hematology, and clinical chemistry, and by an increase in body weight. All altered parameters, including percent fertility, were restored to control levels 120 days after treatment withdrawal.Manivannan 2009

In other studies, no signs of toxicity were observed in rats receiving a single oral dose of a methanolic extract of papaya seeds at 2,000 mg/kg,Lohiya 2006 or in those receiving 5,000 mg/kg of aqueous and methanolic extracts of whole, unripe C. papaya fruit.Ezike 2009

Another study in albino rats concluded that long-term daily oral administration of a methanolic extract of C. papaya seeds affects sperm parameters (count, viability, motility) and shows efficacy as a male contraceptive without causing adverse effects.Goyal 2010

Decubitus ulcers, burns, and wound healing

Papain has demonstrated an ability to dissolve dead tissue without damaging living cells.Hewitt 2002

Animal data

A study investigating the healing efficiency of papaya latex on burns induced in Swiss albino mice concluded that dried papaya latex 1% and 2.5% formulated in carbogel are both effective in the treatment of burns.Gurung 2009 There was an increase in the percentage of wound contraction observed from day 12 in the papaya 2.5%–treated group, and from day 20 in the papaya 1%–treated group and the standard treatment (silver sulfadiazine/chlorhexidine cream) group. Epithelization time was shorter in the papaya 2.5% group.Gurung 2009

In a study in streptozotocin-induced diabetic rats, aqueous extracts of C. papaya fruit (100 mg/kg for 10 days) applied to excision and dead space wound models exhibited a 77% reduction in wound area compared with controls (59%). The papaya extract–treated wounds epithelized faster.Nayak 2007 Another study compared the effects of aqueous extracts of unripe versus ripe papaya on wound healing. Unripe papaya induced complete healing in shorter periods than ripe papaya (13 vs 17 days).Anuar 2008 A study examining the effects of FPP oral supplementation for wound healing in adult obese diabetic mice provided the first evidence that FPP may specifically influence the response of wound site macrophages and subsequent angiogenic response.Collard 2010

Clinical data

C. papaya is used in the pediatric unit at the Royal Victoria Teaching Hospital, located in The Gambia in West Africa, as a major component of burn dressings. The pulp of the papaya fruit is mashed and applied daily to full thickness on infected burns. It appears to be effective in sloughing necrotic tissue, preventing burn wound infection, and providing a granulating wound suitable for split thickness skin grafting.Starley 1999 Postulated mechanisms of action include activity of the proteolytic enzymes, papain, and chymopapain, and antimicrobial activity. Further studies are needed.

In an attempt to document papaya's use, a 15-item questionnaire was used to interview 9 nurses in Jamaica who used papaya to treat pressure ulcers.Hewitt 2002 It was discovered that nurses used grated unripe papaya blended into a paste for application twice daily, once daily, or on alternate days to the ulcers. The ulcers were cleaned with normal saline, Eusol, or soap and waterHewitt 2002, Singhal 2001 prior to application and then covered with gauze to keep the papaya in place.Hewitt 2002, Sieggreen 1997 The interviewees reported that the slough was easily removed from the ulcer after the papaya had been applied for about 1 week, at which time granulation tissue was evident. When healing was slow, papaya was used in conjunction with systemic antibiotics or topical Eusol, tetracycline, or mupirocin.Hewitt 2002, Singhal 2001 All participants interviewed were convinced that applying unripe papaya to pressure sores was effective.Hewitt 2002

A home treatment for pressure ulcers that involved soaking gauze in the "milk" from the trunk or unripe fruit of the papaya plant and then packing it into the pressure sore 3 times daily has been described.Burns 1997

Based on clinical studies, antioxidant activity has been postulated as the mechanism of action for improved healing rates in diabetes-associated wounds and reduced deleterious reactive oxygen species in individuals with type 2 diabetes.Dickerson 2015

Diabetes

Animal data

An antidiabetic effect of C. papaya has been demonstrated in streptozotocin-induced diabetic rats, possibly due to flavonoid content.Tanveer 2017

Clinical data

A study compared the effects of FPP in a group of patients with type 2 diabetes being treated with the hypoglycemic agent glibenclamide (ie, glyburide) and a group of healthy subjects. All participants were given 3 g of FPP daily during lunch for 2 months. The results of this study confirmed the empirical experience that fermented papaya use can decrease plasma glucose levels in both healthy individuals and those with type 2 diabetes. This hypoglycemic effect, associated with clinical signs, led to dosage reductions in patients' oral glibenclamide therapy; 1 patient was able to discontinue glibenclamide completely.Danese 2006

Another study evaluating the antioxidant activity of FPP found no effect on blood glucose. Participants consumed 9 g/day of FPP over 6 weeks.Dickerson 2015 A further clinical study (N=127) found nonstatistically significant decreases in fasting blood glucose with FPP 6 g/day for a period of 14 weeks.Somanah 2012

GI activity

Animal data

A study in experimental rat models revealed the antiulcer potential of aqueous and methanolic extracts of unripe papaya fruit. The extracts reduced the ulcer index, with the methanolic extract demonstrating better protection against indomethacin-induced ulcers and the aqueous extract demonstrating better protection against ethanol-induced gastric ulcers.Ezike 2009 The cytoprotective and antimotility properties may account for the antiulcer properties of unripe fruit.Ezike 2009

Clinical data

Limited clinical studies have demonstrated effects of consumption of papaya preparations (including papain and chymopapain) in digestive disorders.Leung 1980 A clinical study (N=126) documented reductions in self-reported symptoms, particularly constipation, flatulence, and heartburn, following daily consumption of a commercial papaya preparation (Caricol) 20 mL for 40 days.Muss 2013

Gluten intolerance

In vitro data

Caricain, and to a lesser extent, chymopapain, from papaya latex are gluten-detoxifying enzymes that may provide a basis for suitable enzyme therapy in gluten intolerance.Cornell 2010

Dosing

Various topical applications of papaya have been used for wound healing, particularly in developing countries.Burns 1997, Hewitt 2002, Sieggreen 1997, Singhal 2001, Starley 1999 There are very little data available to make specific recommendations regarding systemic doses of papaya.

One study used 20 mL of an elixir containing air-dried papaya seeds in honey (prepared by mixing 500 g of air-dried, machine-blended seeds with honey, for a total preparation volume of 1,000 mL [ie, 0.2 g of dried C. papaya seeds per milliliter]) to treat helminthiasis in children.Okeniyi 2007

In clinical studies, FPPs have been used at 6 to 9 g per day in divided doses to evaluate effects in patients with diabetes or hypothyroidism.Dickerson 2015, Somanah 2012, Tomella 2014

A commercial papaya preparation (Caricol; 20 mL) has been used for 40 days in a trial evaluating effects in GI disorders.Muss 2013

The papaya fruit has GRAS status when used as food.

Pregnancy / Lactation

Possibly unsafe. Avoid use. A 1978 report suggested that papain was teratogenic and embryotoxic in rats.Singh 1978 Several studies have investigated whether papaya consumption is safe during pregnancy. Rats given a ripe papaya blend in place of water showed no difference in the number of implantation sites and viable fetuses. However, unripe or semiripe papaya, which contains a higher concentration of latex, could be unsafe during pregnancy.Cherian 2000 The crude papaya latex induced spasmodic contraction of the uterine musclesCherian 2000 similar to oxytocin and prostaglandin F2-alpha.Adebiyi 2002 No adverse effects on prenatal development were observed in female Sprague-Dawley rats administered a low-dose, crude, aqueous extract of papaya seeds.Oderinde 2002 Some authors have postulated that papain may affect a vital membrane involved in the development of the fetus.Natural Way 1994

Interactions

None documented. It is possible that papain, which is found in the papaya leaves and unripe fruit, may affect the international normalized ratio in patients maintained on warfarin.Shaw 1997

Adverse Reactions

Papaya is contraindicated in patients with known hypersensitivity to any of its components (eg, papain).

Papaya may induce severe allergic responses in sensitive people. A case report of immediate hypersensitivity reaction after contact with C. papaya has been reported; total serum immunoglobulin E in this patient was 2,500 units/mL, and prick tests with papaya extracts were positive.Ezeoke 1985 Cross-sensitivity between papain and papaya latex has been described, suggesting patients who exhibit an allergic reaction to papaya latex may have a similar reaction to papain.Diez-Gomez 1999, Soto-Mera 2000

Topically, the papaya latex can be a severe irritant and vesicant.Duke 1983

Orally, high-dose extracts from the leaves may cause gastric irritation (extracts from unripe fruit have shown antiulcer activity in animal models).Ezike 2009 The results of an ulcerogenic study showed an ethanolic extract of C. papaya leaves produced gastric mucosal irritation at high doses (200 mg/kg in rats). A dose of 800 mg/kg produced a comparable ulcerogenic effect with a standard ulcerogenic dose of indomethacin (20 mg/kg).Owoyele 2008 However, in another study investigating the anthelmintic efficacy of C. papaya seeds in a honey elixir, no adverse effects occurred. Two of the 30 children in that study complained of transient nausea, and an episode of loose stools was reported on the day treatment was given. All participants in this study had intestinal parasitosis that may have caused these symptoms.Okeniyi 2007

Toxicology

An acute toxicity test (median lethal dose) in adult male Wistar rats demonstrated that papaya juice (from the ripe fruit) was not lethal, with no signs of toxicity observed in rats receiving up to and including doses as high as 1,500 mg/kg after oral administration. Thus, papaya juice is considered nontoxic.Mehdipour 2006

Oral administration of aqueous and methanolic extracts of whole, unripe C. papaya fruit of up to 5,000 mg/kg in mice did not produce lethality or signs of acute toxicity after 24 hours.Ezike 2009

Papaya seed extract may exert potentially toxic effects on mammalian vascular smooth muscle. Benzyl isothiocyanate, the chief bioactive ingredient in seeds, irreversibly inhibits the contraction of dog carotid artery.Wilson 2002 Papaya extract, when present in high concentrations, was cytotoxic by increasing the membrane permeability to calcium.Wilson 2002

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