- 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.
Assessed as up to date in January 2019 by Barbara Wider.
Fully revised and updated in March 2017 by Karen Pilkington.
First published in January 2013, authored by Karen Pilkington.
Karen Pilkington, CAM-Cancer Consortium. Pomegranate (Punica granatum) [online document]. March 1, 2017.
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 USA1,2. 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 andjuice3. Common names include dadim fruit, dadima, granada, grenade, Shi Liu Pi3.
The juice contains polyphenols, mainly anthocyanidins and tannins (including ellagic acid, punicalagin and punicalin), and minerals1,4,5,39. It also contains ascorbic acid (vitamin C), citric acid, oxalic acid and tartaric acid1. The seeds contain polyphenols as well as various fatty acids and non-steroidal, oestrogen-like substances6. The fatty acid component comprises over 95% of the seed oil1. Tannins are found in the fruit peel3. The peel also contains substantial amounts of phenolic compounds including flavonoids1.
Application and dosage
In general, there is no consensus on dosage3. 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 used7,8. The larger dose was administered as capsules with each capsule containing 1g of polyphenol extract comparable to approximately 8 ounces of juice8. However, this dose was associated with more frequent adverse effects, specifically diarrhoea (see Is it safe?). 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 symptoms9.
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 arms10. Thought to have originated in Iran and Afghanistan, cultivation and use of the pomegranate spread through Asia, Mediterranean countries and parts of America1,10. 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 problems2. 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 disease11,12. Pomegranate has been used in the Indian subcontinent for the treatment of intestinal worms, nosebleeds, ulcers, sore throats12. 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 health11.
Claims of efficacy/Alleged indications
The antioxidant, anti-carcinogenic, and anti-inflammatory properties of pomegranate have provided a focus for research1,12. 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 resistance2. 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 worms3. Oestrogenic activity, albeit weak, has led to interest in its potential benefits in menopausal symptoms1,9. 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 vitro12.
Mechanisms of action
The major effects of constituents of pomegranate extracts are anti-inflammatory, antioxidant and anticancer activity1. In cancer prevention, the relevant activities include those on carcinogenesis, the cell cycle, differentiation and enzyme activity, including inhibition of carbonic anhydrase and aromatase1. Activity relevant to treatment of cancer includes effects on angiogenesis, apoptosis, tumour cell invasion and proliferation1. 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 invasion13. Similar inhibition in tumour growth was shown in a subsequent animal study14. 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 proliferation15. 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 apoptosis1. The juice appears to have great bioactivity than the single purified active ingredients16.
Pre-clinical studies have demonstrated a range of effects on various cancer cell lines, including breast, colon and prostate cells1. 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 effects24 and a possible effect in sensitising cells to the cancer drug tamoxifen25, 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 pomegranate17. A more recent survey, also in the UK, reported use by 13.6% of women with breast cancer18.
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 pharmacist19. 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 letter20.
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.
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 studies31,32, one dose comparison study33 and an uncontrolled open study22 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 inflammation36. 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.
A detailed review of the phytochemistry and pharmacological actions of all pomegranate components was published in 20071. The authors concluded that ‘the actions of Punica granatum components 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 cancers21. 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 agents35. 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.
A further three randomized clinical trials have been published since the publication of the above reviews and are not included in those.
No statistically significant differences were seen in the most recent RCT which compared pomegranate juice and placebo on PSA levels34. 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 biomarkers37. Interpretation of the results was complicated by the effects of surgery.
No trials in patients with breast cancer were located although one RCT assessed the effect of consumption of pomegranate juice on breast cancer risk38. 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.
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 size3. 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 effect36. Diarrhoea was reported more frequently in patients taking a larger dose (3g) than in those taking a smaller dose (1g) in one trial8. The fruit or seeds may cause allergies, more frequently in those with allergies to other plants3. Allergic reactions have been reported with oral and topical use and anaphylaxis has been reported on rare occasions3. The dried peel may contain a potential toxin3. There have been isolated reports of genotoxicity, for example in mice treated with high doses of whole fruit hydroalcoholic extract35.
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 study26.
A potential for interaction with herbs, supplements and drugs that reduce blood pressure has been suggest due to pomegranate’s possible antihypertensive effects3. Pomegranate juice is also reported to have ACE inhibitor-like effects suggesting caution in those being treated with this class of drugs3. Human studies show that pomegranate juice has no effect on the bioavailability or pharmacokinetics of representative CYP2C9 and CYP3A4 substrates40,41. Several individual cases of potential interaction with warfarin have been reported27,28. 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 juice29. 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.
- Lansky EP, Newman RA. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J Ethnopharmacol. 2007;109(2):177-206.
- Jurenka JS. Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev. 2008;13(2):128-44.
- Natural Medicines Comprehensive Database: professional version. Pomegranate monograph. Stockton (CA): Therapeutic Research Faculty. Available online. Accessed 28th February 2017.
- Schubert SY, Lansky EP, Neeman I. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J Ethnopharmacol 1999;66:11-7.
- Wang RF, Xie WD, Zhang Z, et al. Bioactive compounds from the seeds of Punica granatum (pomegranate). J Nat Prod 2004;67:2096-8.
- Moneam NM, el Sharaky AS, Badreldin MM. Oestrogen content of pomegranate seeds. J Chromatogr 1988 438:438-42.
- Pantuck AJ, Leppert JT, Zomorodian N, Aronson W, Hong J, Barnard RJ et al.. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res. 2006 12(13):4018-26.
- Paller CJ, Ye X, Wozniak PJ, Gillespie BK, Sieber PR, Greengold RH et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013;16(1):50-5.
- Auerbach L, Rakus J, Bauer C, Gerner C, Ullmann R, Wimmer H, Huber J. Pomegranate seed oil in women with menopausal symptoms: a prospective randomized, placebo-controlled, double-blinded trial. Menopause. 2012;19(4):426-32.
- Langley P.BMJ. Why a pomegranate? BMJ. 2000;321(7269):1153-4.
- Longtin R. The pomegranate: nature's power fruit? J Natl Cancer Inst. 2003;95(5):346-8.
- Ismail T, Sestili P, Akhtar S. Pomegranate peel and fruit extracts: A review of potential anti-inflammatory and anti-infective effects. J Ethnopharmacol. 2012;143(2):397-405.
- Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A, Mansel RE, Neeman I, Geldof AA, Campbell MJ. Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food. 2004;7(3):274-83.
- Malik A, Afaq F, Sarfaraz S, Adhami VM, Syed DN, Mukhtar H. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci USA. 2005;102(41):14813-8.
- Adams LS, Zhang Y, Seeram NP, Heber D, Chen S. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila). 2010;3(1):108-13.
- Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem. 2005;16(6):360-7.
- Zavery B, Appleton L, Sandiford K, Wong H, Hughes J. Complementary and alternative medicine use amongst oncology patients attending a large cancer centre in England. Progress in Palliative Care 2010;18(2): 89-93.
- McLay JS, Stewart D, George J, Rore C, Heys SD. Complementary and alternative medicines use by Scottish women with breast cancer. What, why and the potential for drug interactions? Eur J Clin Pharmacol. 2012;68(5):811-9.
- Medicines and Healthcare products Regulatory Agency (MHRA). Banned and r restricted herbal ingredients (2014). Available online. Accessed 31st January 2017.
- US Food and Drug Administration (FDA) 2010. Pom Wonderful: Warning Letter. Available online. Accessed 29th February 2017.
- Adhami VM, Khan N, Mukhtar H. Cancer chemoprevention by pomegranate: laboratory and clinical evidence. Nutr Cancer. 2009;61(6):811-5.
- Pantuck AJ, Zomorodian N, Belldegrun AS. Phase-II Study of pomegranate juice for men with prostate cancer and increasing PSA. Curr Urol Rep. 2006;7(1):7.
- Carducci MA, Paller CJ, Wozniak P, Sieber P, Greengold R, Stockton B et al. A phase II study of pomegranate extract for men with rising prostate-specific antigen following primary therapy. J Clin Oncol 2011 (suppl 7; 11).
- Sturgeon SR, Ronnenberg AG. Pomegranate and breast cancer: possible mechanisms of prevention. Nutr Rev. 2010;68(2):122-8.
- Banerjee S, Kambhampati S, Haque I, Banerjee SK. Pomegranate sensitizes Tamoxifen action in ER-α positive breast cancer cells. J Cell Commun Signal. 2011;5(4):317-24.
- Sánchez-Lamar A, Fonseca G, Fuentes JL, Cozzi R, Cundari E, Fiore M, Ricordy R, Perticone P, Degrassi F, De Salvia R. Assessment of the genotoxic risk of Punica granatum L. (Punicaceae) whole fruit extracts. J Ethnopharmacol. 2008;115(3):416-22.
- Jarvis S, Li C, Bogle RG. Possible interaction between pomegranate juice and warfarin. Emerg Med J. 2010;27(1):74-5.
- Komperda KE. Potential interaction between pomegranate juice and warfarin. Pharmacotherapy. 2009;29(8):1002-6.
- Sorokin AV, Duncan B, Panetta R, Thompson PD. Rhabdomyolysis associated with pomegranate juice consumption. Am J Cardiol. 2006;98(5):705-6.
- Vlachojannis C, Zimmermann BF, Chrubasik-Hausmann S. Efficacy and safety of pomegranate medicinal products for cancer. Evid Based Complement Alternat Med. 2015;2015:258598.
- Freedland SJ, Carducci M, Kroeger N, Partin A, Rao JY, Jin Y et al. A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. Cancer Prev Res (Phila). 2013;6(10):1120-7.
- Stenner-Liewen F, Liewen H, Cathomas R, Renner C, Petrausch U, Sulser T et al. Daily Pomegranate Intake Has No Impact on PSA Levels in Patients with Advanced Prostate Cancer - Results of a Phase IIb Randomized Controlled Trial. J Cancer. 2013;4(7):597-605.
- Paller CJ, Ye X, Wozniak PJ, Gillespie BK, Sieber PR, Greengold RH et al. A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis. 2013 Mar;16(1):50-5.
- Pantuck AJ, Pettaway CA, Dreicer R, Corman J, Katz A, Ho A, Aronson W, Clark W, Simmons G, Heber D. A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis. 2015;18(3):242-8.
- Nuñez-Sánchez MA, Dávalos A, González-Sarrías A, Casas-Agustench P, Visioli F, Monedero-Saiz T et al. MicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: Critical issues to discern between modulatory effects and potential artefacts. Mol Nutr Food Res. 2015;59(10):1973-86.
- Sahebkar A, Gurban C, Serban A, Andrica F, Serban MC. Effects of supplementation with pomegranate juice on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials. Phytomedicine. 2016;23(11):1095-102.
- Turrini E, Ferruzzi L, Fimognari C. Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy. Oxid Med Cell Longev. 2015;2015:938475.
- Kapoor R, Ronnenberg A, Puleo E, Chatterton RT, Jr., Dorgan JF, Seeram NP, et al. Effects of Pomegranate Juice on Hormonal Biomarkers of Breast Cancer Risk. Nutrition and cancer. 2015;67(7):1113-9.
- Zarfeshany A, Asgary S, and Javanmard SH. Potent health effects of pomegranate. Adv Biomed Res. 2014; 3: 100.
- Park SJ, Yeo CW, Shim EJ, Kim H, Liu KH, Shin JG, Shon JH. Pomegranate juice does not affect the disposition of simvastatin in healthy subjects. Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):339-44.
- Abdlekawy KS, Donia AM, Elbarbry F. Effects of Grapefruit and Pomegranate Juices on the Pharmacokinetic Properties of Dapoxetine and Midazolam in Healthy Subjects. Eur J Drug Metab Pharmacokinet. 2016 Jun 13. [Epub ahead of print] DOI: 10.1007/s13318-016-0352-3