Papain and papaya enzyme

What it is

Papain is a mixture of protein-digesting enzymes from papaya. It is collected from the latex of full-grown but unripe papaya fruit and is also present in the leaves and trunk. It is used as a meat tenderiser, in brewing, in contact-lens cleaners and as an oral supplement.

What the research says

There is very little human evidence. We found no systematic review of oral papain. A small placebo-controlled trial of a fermented papaya preparation (Caricol, not pure papain) reported less constipation and bloating, but the benefits disappeared after washout and heartburn did not improve significantly. Papain is a known allergen (including in workers and people with latex allergy), and one poison-centre case linked papaya extract with a sharply raised INR on warfarin.

Evidence grade: Limited evidence.

What goes wrong

A poison-centre case report described a patient on stable warfarin whose INR rose to 7.4 after taking papaya extract containing papain; it fell to 2.0 after both were withdrawn. (Source 1)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: Adult on warfarin taking papaya extract for weight loss.
• How long: Not stated.
• Result: INR 7.4, falling to 2.0 after withdrawal; case details unpublished.
• Funding: not stated.

The patient was admitted for cardiac surgery with an INR of 7.4. After withdrawal of both papaya extract and warfarin, the patient's INR decreased to 2.0.

Papain is an allergen: in skin-prick testing of allergy clinic patients some reacted, and reported symptoms include palatal itching, eye and nasal symptoms, abdominal cramps and diarrhoea. (Source 2)

• Case series, Low certainty.
• Size: 500 allergy clinic patients skin-prick tested; 5 of 475 with seasonal allergy positive to papain and pollens.
• Who: Allergy clinic patients.
• How long: Not applicable.
• Result: 5 of 475 positive (about 1%)
• Funding: not stated.

Five of 475 subjects with seasonal allergic disease had positive skin tests to both Papain and local pollens.

People with natural rubber latex allergy can cross-react with tropical fruit allergens, which is relevant to papaya products. (Source 2)

• Official position, Low certainty.
• Size: Not applicable.
• Who: People with latex allergy.
• How long: Not applicable.
• Result: Not applicable.
• Funding: not stated.

natural rubber latex allergy can be associated with serological cross-reactivity to plant allergens, especially in tropical fruits and Ficus

What the evidence supports

In a double-blind placebo-controlled trial of a papaya preparation (Caricol), more users than placebo reported benefit for constipation and flatulence. (Source 3)

• Randomized trial, Low certainty.
• Size: 139 participants selected and divided evenly between arms; 126 completed per protocol.
• Who: Volunteers with chronic indigestion and gastrointestinal dysfunction.
• How long: 40 days (20 ml daily)
• Result: Constipation benefit 82% vs significantly fewer on placebo (p<0.031); flatulence benefit 78% (p=0.017 vs placebo)
• Funding: not stated (product-specific trial)

82% of evaluable participants in the verum group benefited from regular use. In the placebo group, the proportion was significantly lower (p<0.031).

What the evidence does not support

In the same trial, heartburn did not improve significantly and none of the benefits persisted after a washout period. (Source 3)

• Randomized trial, Low certainty.
• Size: Heartburn analysis: 13 evaluable participants (139 selected, 126 completed per protocol)
• Who: Volunteers with chronic indigestion.
• How long: 40 days plus washout.
• Result: Heartburn p=0.114 (not significant); no significant benefits after washout.
• Funding: not stated.

None of the significant benefits were observed after the washout phase.

The trial authors themselves note that little evidence exists on papaya's physiological effect and efficacy in humans. (Source 3)

• Randomized trial, Low certainty.
• Size: Not applicable.
• Who: Not applicable.
• How long: Not applicable.
• Result: Not applicable.
• Funding: not stated.

little evidence has been produced with reference to its physiological effect in humans and the proof of efficacy

How much

• Reference intake: No RDA or Adequate Intake exists: papain is a plant enzyme, not an essential nutrient. (Source 1)
• Upper limit: No tolerable upper intake level for papain as a supplement was found. (Source 1)
• Studied: Caricol papaya preparation, 20 ml daily for 40 days (Muss 2012). (Source 3)

A common belief, and what the research shows

The belief: Papaya enzyme supplements are proven to fix digestion.

What the research shows: The main trial we found tested a papaya preparation, not pure papain, and 'None of the significant benefits were observed after the washout phase.' Its authors note 'little evidence has been produced with reference to its physiological effect in humans and the proof of efficacy'.

Questions and answers

What is it?

Papain is a protein-digesting (protease) enzyme obtained from the latex of unripe papaya fruit. It is also present in the plant's leaves and trunk. (Source 2)

What does it do in the body?

It breaks down proteins, which is why it tenderises meat. People take it believing it eases swelling, inflammation and digestive complaints, but human evidence is thin. (Source 1)

Is it good or bad for you?

This source does not settle whether papain helps anything; what it addresses is one caution. For people taking warfarin or related medicines, it says excessive papaya extract or papain supplements should preferably be avoided until further data are available. The trial evidence and the allergy reports are set out in the findings. (Source 4)

How do you get more of it?

Papain comes from papaya latex and is sold as supplements and meat tenderisers; the trial product was taken as 20 ml daily. Nothing here is a recommendation. (Source 3)

If it is harmful, what reduces it?

Does not apply; the body does not make papain. In the reported warfarin case, the raised INR came down after the papaya extract was stopped. (Source 1)

Why might someone be low in it or missing it?

Does not apply. Papain is not a nutrient or a body substance, so no one is deficient in it. (Source 1)

Which whole foods contain it or feed it?

Papaya, especially unripe fruit latex; it is also in the leaves and trunk of the plant. (Source 2)

What happens if you do not have it?

Nothing is known to happen; papain is not essential. (Source 1)

How can you test for it?

There is no test for papain status. Papain allergy can be tested with skin-prick testing, which has been used in allergy clinic populations; we found no accuracy data. (Source 2)

References

1. American Journal of Health-System Pharmacy 57:1221-7 (via Medscape). Potential Interactions Between Alternative Therapies and Warfarin. 2000. Read the source
2. Thermo Fisher Scientific (ImmunoCAP allergen encyclopedia). f293 Papaya - Allergen Encyclopedia. Read the source
3. Biogenic Amines 26(1):1-17. Papaya preparation (Caricol) in digestive disorders. 2012. Read the source
4. Drugs.com. Papaya and warfarin interactions (professional monograph). Read the source