Pomegranate (Punica granatum)

Abstract and key points

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.

Anti-tumour treatment

Prostate cancer:

• Tumour burden: one small randomised controlled trial (RCT) failed to find an effect of pomegranate on biopsy metrics including extent of tumour

• Prostate specific antigen (PSA) levels: One uncontrolled trial showed promising effects on PSA doubling time but subsequent RCTs have failed to show any difference between pomegranate and placebo.

• Other biomarkers: changes in relevant biomarkers have been reported but results from individual trials have not yet been replicated

Colorectal cancer:

• Several biomarkers and biological changes have been measured in a trial in patients with colorectal cancer but the clinical significance of these is unclear

Supportive cancer care

• Pain: One trial in advanced prostate cancer did not find an effect on pain.

Cancer prevention

• Breast cancer: 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.

Citation

Karen Pilkington, CAM-Cancer Consortium. Pomegranate (Punica granatum) [online document], http://cam-cancer.org/en/pomegranate. December 13, 2021.

Document history

Fully revised and updated in November 2021 by Karen Pilkington.
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.

What is it?

Description and background

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 (Lansky 2007, Jurenka 2008). 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 and juice (NMD 2021). Common names include dadim fruit, dadima, granada, grenade, Shi Liu Pi (NMD 2021).

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 (Langley 2000). Thought to have originated in Iran and Afghanistan, cultivation and use of the pomegranate spread through Asia, Mediterranean countries and parts of America (Lansky 2007, Langley 2000). 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 (Jurenka 2008). 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 (Longtin 2003, Ismail 2012). Pomegranate has been used in the Indian subcontinent for the treatment of intestinal worms, nosebleeds, ulcers, sore throats (Ismail 2012). 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 (Longtin 2003).

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 (Zavery 2010). Another survey, also in the UK, reported use by 13.6% of women with breast cancer (McLay 2012).

Ingredients and quality requirements

The juice contains polyphenols, mainly anthocyanidins and tannins (including ellagic acid, punicalagin and punicalin), and minerals (Lansky 2007, Schubert 1999, Wang 2004, Zafershany 2014). It also contains ascorbic acid (vitamin C), citric acid, oxalic acid and tartaric acid (Lansky 2007). The seeds contain polyphenols as well as various fatty acids and non-steroidal, oestrogen-like substances (Moneam 1988). The fatty acid component comprises over 95% of the seed oil (Lansky 2007). Tannins are found in the fruit peel (NMD 2021). The peel also contains substantial amounts of phenolic compounds including flavonoids (Lansky 2007).

Alleged indications

The antioxidant, anti-carcinogenic, and anti-inflammatory properties of pomegranate have provided a focus for research (Lansky 2007, Ismail 2012). 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 (Jurenka 2008). It has been used orally for a wide range of conditions including atherosclerosis, congestive heart failure (CHF), hyperlipidaemia, hypertension, myocardial ischaemia, metabolic syndrome and rheumatoid arthritis (NMD 2021). Oestrogenic activity, albeit weak, has led to interest in its potential benefits in menopausal symptoms (Lansky 2007, Auerbach 2012).

Applications and dosage

In general, there is no consensus on dosage (NMD 2017). 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 (Pantuck 2006, Paller 2013). The larger dose was administered as capsules with each capsule containing 1g of polyphenol extract comparable to approximately 8 ounces of juice (Paller 2013). This dose was associated with more frequent adverse effects, specifically diarrhoea (see Is it safe?). However, a similar dose in another study was reported to be well-tolerated (Jarrad 2021). 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 (Auerbach 2012).

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 (Ismail 2012).

Mechanisms of action

The major effects of constituents of pomegranate extracts are anti-inflammatory, antioxidant and anticancer activity (Lansky 2007). In cancer prevention, the relevant activities include those on carcinogenesis, the cell cycle, differentiation and enzyme activity, including inhibition of carbonic anhydrase and aromatase (Lansky 2007). Activity relevant to treatment of cancer includes effects on angiogenesis, apoptosis, tumour cell invasion and proliferation (Lansky 2007). 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 (Albrecht 2004). Similar inhibition in tumour growth was shown in a subsequent animal study (Malik 2005). 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 (Adams 2010). Ellagitannins also reduced inflammatory cell signalling in colon cancer while quercetin has been shown to inhibit lung cancer cell growth with effects via the cell cycle and induction of apoptosis (Lansky 2007). The juice appears to have great bioactivity than the single purified active ingredients (Seeram 2005).

Pre-clinical studies have demonstrated a range of effects on various cancer cell lines, including breast, colon and prostate cells (Lansky 2007). A summary of the research on the effects of pomegranate in prevention of various cancers, including breast, colon, lung, prostate and skin cancers showed inhibition of the growth of cancer cells in culture and in preclinical animal studies (Adhami 2009). Pomegranate juice, peel and oil have been shown to interfere with tumour cell proliferation, cell cycle, invasion and angiogenesis (Lansky 2007). Recent studies have also reported anti-oestrogenic effects (Sturgeon 2010) and a possible effect in sensitising cells to the cancer drug tamoxifen (Banerjee 2011), both potentially of benefit in breast cancer.

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 (MHRA 2014). In a case of a manufacturer making claims of effectiveness of pomegranate preparations without sufficient supporting research being available, this led to the US Food and Drug Administration issuing a warning letter (FDA 2017). The European Food Safety Authority (EFSA) has also rejected various health claims from manufacturers (e.g. EFSA 2010).

Costs

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?

Clinical trials of pomegranate have mainly focussed on prostate cancer but few trials are available and most are of low quality. All trials are described in Table 1.

Anti-tumour treatment
Prostate cancer:

  • Tumour burden: one small randomised controlled trial (RCT) failed to find an effect of pomegranate on biopsy metrics including extent of tumour
  • Prostate specific antigen (PSA) levels: One uncontrolled trial showed promising effects on PSA doubling time but subsequent RCTs have failed to show any difference between pomegranate and placebo.
  • Other biomarkers: changes in relevant biomarkers have been reported but results from individual trials have not yet been replicated

Colorectal cancer:

  • Several biomarkers and biological changes have been measured in a trial in patients with colorectal cancer but the clinical significance of these is unclear

Supportive cancer care

  • Pain: One trial in advanced prostate cancer did not find an effect on pain.

Cancer prevention

  • Breast cancer: One small randomized clinical trial did not show an effect of pomegranate consumption on breast cancer risk.

Anti-tumour treatment

Prostate cancer

One systematic review included four clinical studies on pomegranate products in prostate cancer (Vlachojannis 2015). Two were controlled studies (Freedland 2013, Stenner-Liewen 2013), one was a dose comparison study (Paller 2013) and one was an uncontrolled open study (Pantuck 2006). All were judged to be poor quality and the evidence of overall clinical effectiveness was also assessed as poor. Several of the studies described below were also included in a more recent systematic review (Gimenez-Bastida 2021). The authors concluded that limited scientific evidence (few studies, variation and short duration) makes conclusions difficult. All trials are included in Table 1 and each of the relevant outcomes is discussed below.

Biopsy metrics (presence of tumour, extent of tumour, and Gleason score)

One small RCT involved 30 men with organ-confined, favourable-risk prostate cancer who were treated with pomegranate fruit extract 1000 mg or placebo daily for twelve months (Jarrad 2021). The extract was well-tolerated with no significant toxicities but no differences were found in biopsy metrics. It is unclear that the study had sufficient power to detect differences in these outcomes.


Prostate-specific antigen(PSA) levels

One RCT assessed the effects of 500 ml of pomegranate juice or 500 ml of placebo given daily for 4 weeks to 102 advanced prostate cancer patients (Stenner-Liewen, 2013). No differences between groups in PSA kinetics were measured.

No statistically significant differences were seen in another RCT, which compared pomegranate juice and placebo in 183 men with rising PSA levels after primary therapy for prostate cancer (Pantuck 2015). 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 (possibly related). A pre-planned subgroup analysis of men with the MnSOD AA genotype suggested that these may be a group more sensitive to the effects of antioxidants

A further RCT in 30 men with organ-confined, favourable-risk prostate cancer compared 12 months treatment with pomegranate fruit extract with placebo (Jarrad 2021).  The trial appeared reasonably well-designed. No differences were found in PSA doubling time.


Other biomarkers

Several trials have assessed the effects of pomegranate products on various biomarkers. These include intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG (a DNA damage marker), and cancer pS6 kinase, NF-kappaB, and Ki67 (Freedland 2013). Plasma levels of insulin-like growth factor1 (IGF1), testosterone and IGFBP3 were not influenced by pomegranate extract in a trial in 30 prostate cancer patients (Jarrad 2021). Reductions from baseline were seen, however, in 8‐OHdG (a DNA damage marker) (p = 0.01) and androgen receptor expression (p = 0.04). These findings have not yet been replicated and the impact on clinical outcomes is not Clear.


Colorectal cancer

Several biomarkers and biological changes have been measured in a trial of pomegranate in patients with colorectal cancer. These include effects on microRNAs (Nuñez-Sánchez 2015), gene expression changes (Nuñez-Sánchez 2017), plasma lipopolysaccharide-binding protein levels, a marker of metabolic endotoxemia (González-Sarrías 2018). These findings have not yet been replicated and the impact on clinical outcomes is not Clear.

 

Supportive cancer care

Pain

The above-mentioned RCT in 102 advanced prostate cancer patients assessed effects on pain (Stenner-Liewen, 2013). No differences in pain scores were observed between 4 weeks of pomegranate juice compared with a placebo drink.

Cancer prevention

A systematic review focused on pomegranate juice on plasma C-reactive protein concentrations, a marker of inflammation linked to cancer risk (Sahebkar 2016). 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. None of the trials involved cancer patients.

Breast cancer

One RCT assessed the effect of consumption of pomegranate juice on breast cancer risk (Kapoor 2015).  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

Pomegranate fruit and their components are generally considered safe for human consumption and have been used for several thousand years 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 (NMD 2021). 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 (Sahebkar 2016). Diarrhoea was reported more frequently in patients taking a larger dose (3g) than in those taking a smaller dose (1g) in one trial (Paller 2013). Pomegranate may lower blood pressure and this may be a concern in those with hypotension or undergoing surgery.

The fruit or seeds may cause allergies, more frequently in those with allergies to other plants (NMD 2021). Allergic reactions have been reported with oral and topical use and anaphylaxis has been reported on rare occasions (NMD 2021). The dried peel may contain a potential carcinogen and toxin and the bark contains alkaloids (NMD 2021). There have been isolated reports of genotoxicity, for example in mice treated with high doses of whole fruit hydroalcoholic extract (Nuñez-Sánchez 2015).

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 (Sánchez-Lamar 2008).

Interactions

A potential for interaction with herbs, supplements and drugs that reduce blood pressure has been suggested due to pomegranate’s possible antihypertensive effects (NMD 2021). Pomegranate juice is also reported to have ACE inhibitor-like effects suggesting caution in those being treated with this class of drugs (NMD 2021). Human studies show that pomegranate juice is unlikely to affect the bioavailability or pharmacokinetics of CYP2C9 and CYP3A4 substrates (Park 2016, Abdlehawy 2016) but inhibition of CYP2D6 is possible in theory. Several individual cases of potential interaction with warfarin have been reported (Jarvis 2010, Komperda 2009). 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 (Sorokin 2006). 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.
 

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