Written by Karen Pilkington and the CAM-Cancer Consortium.
Updated March 1, 2017

Pomegranate (Punica granatum)

Abstract and key points

  • Pomegranate (Punica granatum) is an edible fruit traditionally used to treat a range of ailments
  • Pomegranate juice and extracts have been used in trials in prostate cancer
  • Evidence on effectiveness in cancer is insufficient
  • Few adverse effects have been reported with the juice but there is limited safety data on other extracts

Pomegranate (Punica granatum) is an edible fruit originating in the Middle East, the juice of which is widely available commercially. Various parts of the fruit including the juice have been used traditionally to treat a range of ailments.

The juice and other extracts have shown a wide range of bioactivity in pre-clinical studies, such as anti-inflammatory, anti-infective and anti-oxidant effects.

On the basis of this research, beneficial effects are claimed in cancer, specifically in the prevention and treatment of prostate cancer.

Few clinical trials in cancer have been conducted to date: an uncontrolled trial showed promising beneficial effects on prostate specific antigen (PSA) doubling time in prostate cancer but subsequent randomised controlled trials have failed to show any difference between pomegranate and placebo. One small randomized clinical trial did not show an effect of pomegranate consumption on breast cancer risk.

Pomegranate juice has been widely consumed for many years. It has been used in studies lasting up to 3 years and appears to be safe. A small number of cases of allergic reactions and possible interaction with warfarin have been reported although causation has not been proven. Limited safety data is available on extracts. There has been a report of genotoxicity in an in vivo study using very high doses of whole fruit extract.

There is insufficient evidence from clinical studies to draw conclusions about possible effectiveness in cancer but there do not appear to be any serious concerns as to the safety of pomegranate juice extracts with usual therapeutic doses.

Read about the regulation, supervision and reimbursement of herbal medicine at NAFKAMs website CAM Regulation.

What is it?

Scientific names, brand names, common names

Pomegranate (Punica granatum Lythraceae) is the edible fruit of the pomegranate plant, a small tree native to parts of Southeast Asia and cultivated in China, India, the Mediterranean region and parts of the USA 1,2. The outer leathery skin (pericarp) encloses numerous seeds, each surrounded by a translucent sac that contains the juice. Thin, bitter-tasting membranes form a network throughout the fruit. Various parts of the fruit can be utilised or consumed; most commonly the seeds andjuice 3. Common names include dadim fruit, dadima, granada, grenade, Shi Liu Pi 3.

Ingredients/Components

The juice contains polyphenols, mainly anthocyanidins and tannins (including ellagic acid, punicalagin and punicalin), and minerals 1,4,5,39. It also contains ascorbic acid (vitamin C), citric acid, oxalic acid and tartaric acid 1. The seeds contain polyphenols as well as various fatty acids and non-steroidal, oestrogen-like substances 6. The fatty acid component comprises over 95% of the seed oil 1. Tannins are found  in the fruit peel 3. The peel also contains substantial amounts of phenolic compounds including flavonoids 1.

Application and dosage

In general, there is no consensus on dosage 3. In trials in prostate cancer, doses of juice equivalent to between 240ml (8 ounces, 570 mg total polyphenol gallic acid) to 720ml (24 ounces, approximately 3000 mg of polyphenol extract) daily have been used 7,8. The larger dose was administered as capsules with each capsule containing 1g of polyphenol extract comparable to approximately 8 ounces of juice 8. However, this dose was associated with more frequent adverse effects, specifically diarrhoea (see Safety section). Other parts of the plant have also been used. For example, two daily doses of 30mg seed oil (containing 127 μg of steroidal phytoestrogens per dose) was used to treat women with menopausal symptoms 9.

History/providers

The pomegranate has been described in ancient texts including those of Greek mythology, has been held sacred by many of the world’s religions and is featured in several medical coats of arms 10. Thought to have originated in Iran and Afghanistan, cultivation and use of the pomegranate spread through Asia, Mediterranean countries and parts of America 1,10. Pomegranate has been part of folk medicine in many cultures and is used in several systems of medicine, including Ayurvedic and Unani medicine, for a variety of health problems 2. Parts of the plant, such as its bark, petals and peel continue to be used in the Middle East, Asia and South America to treat conditions ranging from diarrhoea and dysentery to gum disease 11,12. Pomegranate has been used in the Indian subcontinent for the treatment of intestinal worms, nosebleeds, ulcers, sore throats 12. In the West, interest in the medical potential of pomegranate began slowly in the 1990s, stimulated by researchers in Israel who reported benefits on cardiovascular health 11.

Claims of efficacy/Alleged indications

The antioxidant, anti-carcinogenic, and anti-inflammatory properties of pomegranate have provided a focus for research 1,12. It has been suggested that pomegranate has potential in the treatment and prevention of cancer, cardiovascular disease, diabetes, oral and dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance 2. It has been used orally for a wide range of conditions including atherosclerosis, congestive heart failure (CHF), hyperlipidaemia, hypertension, myocardial ischaemia, acidosis, haemorrhage, HIV disease and intestinal worms 3. Oestrogenic activity, albeit weak, has led to interest in its potential benefits in menopausal symptoms 1,9. The main interest in the area of cancer has been in the prevention of prostate cancer based on early reports of in vitro activity. Pomegranate is also suggested for other cancers including breast, colon and liver cancers, again based primarily on its activity in vitro 12

Mechanisms of action

The major effects of constituents of pomegranate extracts are anti-inflammatory, antioxidant and anticancer activity 1. In cancer prevention, the relevant activities include those on carcinogenesis, the cell cycle, differentiation and enzyme activity, including inhibition of carbonic anhydrase and aromatase 1. Activity relevant to treatment of cancer includes effects on angiogenesis, apoptosis, tumour cell invasion and proliferation 1. Pomegranate extracts have shown significant anti-tumour activity against human prostate cancer cells: cold-pressed oil and polyphenols extracted from the juice and pericarp (peel) suppressed the proliferation, pericarp polyphenols and seed oil inhibited growth of xenografts and various extracts suppressed invasion 13. Similar inhibition in tumour growth was shown in a subsequent animal study 14. A significant decrease in serum prostate-specific antigen levels was also demonstrated. In breast cancer ellagitannin-derived compounds inhibited aromatase activity as well as cell proliferation 15. Ellagitannins also reduced inflammatory cell signalling in colon cancer1 while quercetin has been shown to inhibit lung cancer cell growth with effects via the cell cycle and induction of apoptosis 1. The juice appears to have great bioactivity than the single purified active ingredients 16.

Pre-clinical studies have demonstrated a range of effects on various cancer cell lines, including breast, colon and prostate cells 1. Pomegranate juice, peel and oil have been shown to interfere with tumour cell proliferation, cell cycle, invasion and angiogenesis1. Recent studies have also reported anti-oestrogenic effects 24 and a possible effect in sensitising cells to the cancer drug tamoxifen 25, both potentially of benefit in breast cancer .

Prevalence of use

Pomegranate juice is widely used as a beverage. A survey of patients attending a cancer centre in England revealed that 1.7% (7 out of 422 patients) used pomegranate 17. A more recent survey, also in the UK, reported use by 13.6% of women with breast cancer 18.

Legal issues

Pomegranate juice and fruits are widely available in most countries. Pomegranate seed oil and capsules or tablets containing pomegranate extract can be purchased from health food shops and some pharmacies, as dietary supplements. In the UK, preparations containing pomegranate bark can only be sold in registered pharmacies and by or under the supervision of a pharmacist 19. In a case of a manufacturer making claims of effectiveness of pomegranate preparations without sufficient supporting research being available, this led to the FDA issuing a warning letter 20.

Costs and expenditures

The cost of pomegranate products varies considerably. Pomegranate juice can be purchased for between 2 and 16 Euros per litre depending on the quality and source. The cost of pomegranate seed oil varies between 5 and 15 Euros per 10ml. Pomegranate extract tablets or capsules cost 4 to 20+ Euros per 30.

Does it work?

Systematic reviews, meta-analyses

Two reviews described as systematic have been published. The first included ‘one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety’ 30. Four clinical studies were found on the effectiveness of three pomegranate products. Two controlled studies, 31,32 one dose comparison study 33 and an uncontrolled open study 22 were identified (see Table 1 for further details). These were assessed against a set of criteria derived from previous reviews and judged to be poor quality.

The total number of studies included in the review that related to safety is not entirely clear but included animal studies, clinical studies and case reports which were described narratively. The conclusions were that there is evidence of an anticancer effect in prostate cancer and that pomegranate can safely be used in high doses. There appears to be a contradiction regarding its effects on liver enzymes: in the abstract, this is stated as induction but, in the discussion, inhibition is described.  The authors also reported that commercial pomegranate products vary greatly in their content of coactive ingredients. The limitations of the search (PubMed only, limited search terms) suggests that relevant studies may not have been located and so the comprehensiveness of this review is uncertain.

A second review focused on pomegranate juice on plasma C-reactive protein concentrations, a marker of inflammation 36. SCOPUS, Medline and two Iranian bibliographic databases were searched for prospective trials. The review methods appear rigorous: data extraction was carried out by two independent reviewers who also assessed the risk of bias of each trial. Five RCTs with a total of 432 participants were included and a meta-analysis conducted. Evidence of a significant effect on plasma C-reactive protein was not found.

Narrative reviews

A detailed review of the phytochemistry and pharmacological actions of all pomegranate components was published in 2007 1. The authors concluded that ‘the actions ofPunica granatumcomponents suggest a wide range of clinical applications for the treatment and prevention of cancer…’ However, this conclusion was based on the results of pre-clinical studies and only one clinical trial was mentioned.

Subsequently, a review summarised the research relating to the effects of pomegranate in prevention of various cancers, including breast, colon, lung, prostate and skin cancers 21. Research showing inhibition of the growth of cancer cells in culture and in preclinical animal studies was described but, again, only one clinical trial was mentioned.

The most recent narrative review aimed to provide a ‘comprehensive analysis of known targets and mechanisms’ and an evaluation of the potential of pomegranate polyphenols as anticancer agents 35. Evidence on prostate cancer was considered the strongest with some indications of a beneficial effect on PSA doubling time. However, a risk of genotoxicity was also highlighted based on results of two studies: a study of high doses of whole fruit extract in mice and a study of the fruit skin extract on breast cancer cells (the latter being a beneficial effect). The authors recommend an accurate assessment of risk-benefit before any recommendations could be made on its potential in cancer treatment.

Clinical trials

A further three randomized clinical trials have been published since the publication of the above reviews and are not included in those.

Prostate cancer

No statistically significant differences were seen in the most recent RCT which compared pomegranate juice and placebo on PSA levels 34. In this trial, the initial intention was to compare placebo, pomegranate extract and standard pomegranate juice but, due to slow recruitment, the study was converted to a two arm (pomegranate extract versus placebo) 1 year after the study was started. The power of the study was reported to be unaltered by this change as the sample size of 183 was sufficient for the 2 way comparison.  Most participants were Caucasian, had surgery or radiation therapy as primary treatment, and were initially staged as T2c or less, Groups were well-matched at baseline and although only 128 completed the 12 months of treatment, rates and reasons for early termination were similar across the groups. Most adverse events were judged not to be related to the pomegranate product except for 3 cases of gastrointestinal events such as nausea, constipation and decreased appetite (definitely related) and, teeth discoloration and abdominal bloating (posibly related). A preplanned subgroup analysis of men with the MnSOD AA genotype suggested that these may be a group more sensitive to the effects of antioxidants

Another recent RCT investigated the effects on specific biomarkers 37. Interpretation of the results was complicated by the effects of surgery.

Breast cancer

No trials in patients with breast cancer were located although one RCT assessed the  effect of consumption of pomegranate juice on breast cancer risk 38.  Sixty-four postmenopausal women were assigned to either a commercial pomegranate juice or to apple juice for 3 weeks. Serum levels of estradiol, estrone, testosterone, androstenedione, and sex hormone binding globulin serum were measured and no significant differences between groups found. The study was small and it is not clear if it was of sufficient size to detect differences. A further analysis indicated a significant reduction in estrone and testosterone in normal weight as compared with overweight women taking pomegranate. However, estrone levels in this group were higher than the control group at baseline so the relevance of this finding is unclear.

Is it safe?

Adverse events

In general, the pomegranate fruit and its components are considered safe for human consumption with over several thousand years of use as a food product. Orally, pomegranate is generally well tolerated, the juice is widely consumed and no serious adverse events have been reported in clinical trials although those in cancer patients have been limited in number and size 3. One trial found similar rates of mild to moderate adverse events for pomegranate extract and placebo with only 3 cases of gastro-intestinal disturbances definitely attributed to the extract while tooth discolouration was considered a possible adverse effect 36. Diarrhoea was reported more frequently in patients taking a larger dose (3g) than in those taking a smaller dose (1g) in one trial 8. The fruit or seeds may cause allergies, more frequently in those with allergies to other plants 3. Allergic reactions have been reported with oral and topical use and anaphylaxis has been reported on rare occasions 3. The dried peel may contain a potential toxin 3. There have been isolated reports of genotoxicity, for example in mice treated with high doses of whole fruit hydroalcoholic extract 35.

Contraindications

Due to the potential for anaphylaxis, it is suggested that pomegranate is avoided in those who are allergic to pomegranate. There are no controlled studies on the safety of pomegranate juice in pregnancy and lactation. There is also insufficient reliable information on safety of pomegranate extracts in pregnancy and lactation and potential genotoxicity of one whole fruit extract has been reported in an animal study 26.

Interactions

A potential for interaction with herbs, supplements and drugs that reduce blood pressure has been suggest due to pomegranate’s possible antihypertensive effects 3. Pomegranate juice is also reported to have ACE inhibitor-like effects suggesting caution in those being treated with this class of drugs 3. Human studies show that pomegranate juice has no effect on the bioavailability or pharmacokinetics of representative CYP2C9 and CYP3A4 substrates 40,41. Several individual cases of potential interaction with warfarin have been reported 27,28. However, other variables were presented in each of these reports that may have contributed to the abnormal INR results. One case was also reported of a patient being treated with the statin rosuvastatin and ezetimibe who developed rhabdomyolysis after starting to drink pomegranate juice 29. Causation could not be established in this case as the patient had pre-existing risk factors and rhabdomyolysis could also have been caused by a drug-drug-interaction of rosuvastatin and ezetimibe.

Evidence tables

Please view the PDF listed below for the table on uncontrolled clinical trials included in this summary.

Table 1: Controlled clinical trials of Pomegranate for cancer

Citation

Karen Pilkington, CAM-Cancer Consortium. Pomegranate (Punica granatum) [online document]. http://cam-cancer.org/The-Summaries/Herbal-products/Pomegranate-Punica-granatum. March 1, 2017.

Document history

Fully revised and updated in March 2017 by Karen Pilkington.

First published in January 2013, authored by Karen Pilkington.

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