Cranberry

• How It Works

  Cranberry juice or extracts have not been shown to treat or prevent cancer. It may be helpful for urinary tract infections (UTIs) in limited populations, but there is not enough evidence to recommend it for UTI prevention.

  Cranberries contain compounds known as proanthocyanidins that have been shown to prevent bacteria from attaching to the bladder wall, which could cause UTIs. Human studies suggest it may be helpful for this purpose in some limited populations, including prostate cancer patients, but overall evidence is conflicting. Cranberry may also prevent bacteria from attaching to the stomach lining and areas in the mouth. Although lab studies suggest activity with several types of cancer cells, this has yet to be confirmed in human studies.

  In patients who are prone to kidney stones, regular use of cranberry should be limited as it contains oxalates, a compound found in the most common form of kidney stones.

• Purported Uses
  • Prevention and treatment of urinary tract infections (UTIs)
    The evidence for this claim is mixed.
  • Anticancer effects
    Lab studies show that cranberry juice extract and isolated compounds can inhibit various types of cancer cells, but this has not been confirmed by clinical trials.
  • Prevention of stomach ulcers
    Cranberry juice may help to prevent or suppress H. pylori infection.
  • Prevention of atherosclerosis
    Although one study in healthy volunteers does not suggest benefit, another study in diabetic men suggests cranberry juice may help to reduce heart disease risk factors.
  • Prevention of gum disease/cavities
    In the lab, cranberry juice prevents bacteria from attaching to one another thereby slowing down plaque formation.
• Do Not Take If
  • You are taking warfarin: Because data is mixed on whether cranberry juice may increase bleeding, usage of cranberry juice should be monitored by a healthcare professional, if not avoided. Case reports of bleeding and death in 2 elderly patients who used cranberry juice and warfarin have occurred.
  • You are taking CYP450 substrate drugs: Cranberry may increase blood levels of these drugs or their adverse effects.
  • You are taking UGT substrate drugs: Cranberry may increase the risk of side effects for these drugs.
  • You have a history of kidney stones: Cranberry contains high concentrations of oxalate, a component common to kidney stones.
  • You are taking Tacrolimus: The serum levels of tacrolimus dropped when taken along with cranberry extract. The levels returned to desired range after stopping cranberry intake.
• Side Effects
  • Nausea, vomiting and diarrhea have occurred with large amounts of cranberry juice (3 cups daily).

  Case reports

  • Increased International Normalized Ratio (INR) and/or bleeding: Several cases were due to suspected interactions between cranberry juice and warfarin.
  • Internal hemorrhage resulting in death: In 2 patients, following concurrent use of warfarin and cranberry juice.
• Scientific Name

  Vaccinium macrocarpon

• Clinical Summary

  Cranberry is an evergreen shrub that is grown in North America and Europe. The processed fruit and juice, both rich in vitamin C, are widely consumed as food. The juice extract is marketed as a dietary supplement for urinary tract health and to prevent urinary tract infections (UTIs). It has also been used for oral and gastrointestinal infections, cardiovascular diseases, and against cancer. In preclinical studies, cranberry juice extracts and constituents exhibited antibacterial ⁽¹⁾, antimicrobial ⁽⁴⁵⁾, antifungal ⁽⁴⁶⁾, anti-inflammatory ⁽⁴⁷⁾, antioxidant ⁽⁴⁸⁾, and antiadherence ⁽⁴⁹⁾ properties.

  Clinical studies demonstrate that cranberry extracts can help prevent UTIs in adults ^(2) (3), children ⁽⁴⁾, in prostate cancer patients undergoing radiation therapy ^(5) (50), and in patients following urostomy ⁽⁶⁸⁾. A large double-blind study of older adults with high-baseline UTI risk also showed benefit ⁽⁵¹⁾, but another similar study reported negative findings ⁽⁵²⁾. A subsequent analysis revealed increased costs with no meaningful reduction in UTI rates in a geriatric nursing home environment ⁽⁵³⁾. Studies of cranberry juice for recurrent UTIs have also been mixed, with one study finding no benefit among college-aged women ⁽⁶⁾, and another observing significant reductions in UTI relapse in women over age 50 ⁽⁵⁴⁾. Cranberry was not as effective or cost-effective as trimethoprim-sulfamethoxazole in preventing UTIs in premenopausal women, but patients were less likely to develop antibiotic-resistant bacteria ^(8) (55). In volunteers from different regions, anti-adhesion activity with cranberry powder was found to be dose-dependent ⁽⁷⁾ . Overall, a systematic review determined that cranberry juice was more effective than capsules or tablets  ⁽⁵⁶⁾, but despite some support for recurrent UTI prophylaxis ⁽⁶⁹⁾, there is not enough evidence to recommend cranberry juice for UTI prevention ^(9) (70).

  In other studies, cranberry juice inhibited the adhesion of H. pylori to human gastric mucosa ⁽¹⁸⁾, and regular consumption may suppress H. pylori infection ^(19) (20), a major factor in peptic ulcer disease and gastric cancer. When used with standard treatment, cranberry juice helped eradicate H. pylori ⁽²¹⁾. It was shown to prevent plaque formation and the development of gum disease as well due to its anticolonizing and antiadhesion properties ^(22) (23).

  Cranberry extracts and proanthocyanidins also exhibited antiproliferative effects against prostate ^{(10) (11) (12)}, liver ⁽¹³⁾, lung ⁽⁵⁷⁾, neuroblastoma ⁽⁵⁸⁾, breast ⁽¹⁴⁾, ovarian ⁽¹⁵⁾, gastric ⁽⁵⁹⁾, colon ^(12) (16), esophageal ⁽⁶⁰⁾, and oral ⁽¹²⁾ cancer cells. Although cranberry juice consumption did not lower oxidative status in humans, suggesting lack of protective effect against cancer or heart disease ⁽¹⁷⁾, it did appear to improve cardiovascular disease (CVD) risk factors in diabetic men ⁽⁶¹⁾. However, cranberry juice has high concentrations of oxalate, a common component of kidney stones, and should be limited in patients with a history of nephrolithiasis ⁽⁴⁰⁾. Other data suggest it may be helpful in uncommon forms including struvite stones, which are associated with bladder infections ^{(33) (62) (63)}.

• Food Sources

  Cranberry can be consumed as juice, sauce, or dried fruit.

• Purported Uses
  • Urinary tract infections
  • Cancer prevention and treatment
  • Ulcers
  • Atherosclerosis
  • Gum disease
• Mechanism of Action

  The A-type linkages in cranberry proanthocyanidins C-PACs may enhance urinary bacterial antiadhesion activities to prevent UTIs ^{(25) (26) (27) (28) (64)}. Similarly, the bioactivity against C. albicans biofilm formation is due to anti-adherence properties and/or iron chelation ⁽⁴⁶⁾. In susceptible populations, improved preventive effects with cranberry juice over capsules or tablets may be related to better hydration with liquid, and/or additive effects with additional compounds in juice not contained in supplements ⁽⁵⁶⁾. Anti-adhesion properties were also demonstrated in other microenvironments. Cranberry prevented H. pylori-induced stomach ulcers by inhibiting bacterial adhesions in the stomach lining ^(18) (29), decreased adherence of oral streptococci strains to saliva-coated hydroxyapatite ⁽²³⁾ and glucan-coated hydroxyapatite, and impaired biofilm formation ^(22) (30) indicating it may slow development of dental plaque and protect against plaque-related diseases. Cranberry also regulated aggressive human periodontitis fibroblast inflammatory responses via nuclear factor-kappaB and matrix metalloproteinase-3 (MMP3) inhibition ⁽⁴⁷⁾.

  Additional studies have shown that C-PACs may play a role in enhancing host innate immunity. In a worm model, a standardized cranberry extract mediated host immune response via p38 MAPK signaling, insulin/insulin-like growth factor 1 signaling, and heat shock factor 1 ⁽⁴⁵⁾. Antiatherogenic effects of cranberry juice occur via reductions in serum glucose and apoB, and increases in serum and apoA-1 and paraoxonase, associated with stabilizing HDL ⁽⁶¹⁾.

  Mechanisms underlying the anticancer effects of cranberry extracts and C-PACs have also been investigated. A cranberry extract inhibited prostate cancer cell growth by decreasing cyclins, cyclin-dependant kinase expression ⁽¹⁰⁾ , and MMP activity ⁽³¹⁾. Dose-response inhibition of gastric cancer cells to cranberry is in part due to decreased proliferating cell nuclear antigen expression and apoptotic induction ⁽⁵⁹⁾. A proanthocyanidin isolate was shown to arrest ovarian cancer cell growth by inhibiting vascular endothelial growth factor and generating reactive oxygen species ⁽¹⁵⁾. C-PACs were also found to induce cell death in esophageal adenocarcinoma via microRNA modifications within cancer cells ⁽⁶⁰⁾, and in human lung cancer cells, they altered gene expression, induced apoptosis, and modulated cell-cycle processes ⁽⁵⁷⁾. In high-risk neuroblastoma cells, a purified C-PAC induced apoptosis and ROS generation, and encouraged cyclophosphamide retention with synergistic cytotoxic benefits ⁽⁵⁸⁾.

  Cranberry juice increases the risk of uric acid stone formation because of its acidifying effect and slowing of urate synthesis, thereby decreasing urinary pH ^(32) (33).

• Contraindications

  • Cranberry products can increase urine oxalate excretion and may promote the formation of the most common type of kidney stones ^{(32) (33) (40)}. Its use should therefore be limited in patients with a history of nephrolithiasis ⁽⁴⁰⁾.

• Adverse Reactions

  Ingesting large amounts of cranberry juice (3 cups daily) has been associated with gastrointestinal upset including nausea, vomiting, and diarrhea ⁽⁶⁶⁾.

  Case Reports

  Recurrent stones: In a 47-year-old man with severe right renal colic and hematuria who took cranberry concentrate tablets twice daily over 6 months ⁽⁴⁰⁾.

  Several cases of increased International Normalized Ratio (INR): Due to suspected interactions between warfarin and cranberry juice ^(36) (37).

  Internal hemorrhage and subsequent death: In 2 patients with concurrent use of warfarin and cranberry juice ^(38) (39).

• Herb-Drug Interactions

  Warfarin: Cranberry juice may potentiate warfarin-induced anticoagulation, but data are conflicting ^{(34) (41) (65)}. Although consumption of cranberry juice in large quantities (1–2 L daily or supplements for >3–4 weeks) may alter warfarin effects, monitoring intake rather than total avoidance of cranberry juice by warfarin users in other cases may be warranted ⁽⁶⁷⁾.

  Cyclosporin: A randomized controlled trial has shown that 240 mL of cranberry juice had no clinically significant effect on the disposition of a 200 mg dose of cyclosporin ⁽⁴²⁾.

  UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrates: Cranberry modulates UGT enzymes in vitro and can increase risk of side effects of drugs metabolized by them ⁽³⁵⁾.

  Cytochrome P450 substrates: Cranberry inhibits enteric CYP3A activities and may interfere with the absorption of substrate drugs ⁽⁴³⁾. Cranberry inhibits CYP2C9 in vitro, but this activity was not observed in humans ⁽⁴⁴⁾.

  Tacrolimus: Concurrent use with cranberry extracts resulted in sub-therapeutic serum levels of tacrolimus in a renal transplant patient ⁽⁷¹⁾. The levels returned to desired range following cessation of cranberry.

• Herb Lab Interactions

  Urinary pH has been shown to decrease after drinking cranberry juice ^(32) (33).

• References

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  2. Stothers L. A randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women. Can J Urol. Jun 2002;9(3):1558-1562.

  3. Kontiokari T, Sundqvist K, Nuutinen M, et al. Randomised trial of cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in women. BMJ. Jun 30 2001;322(7302):1571.

  4. Ferrara P, Romaniello L, Vitelli O, et al. Cranberry juice for the prevention of recurrent urinary tract infections: a randomized controlled trial in children. Scand J Urol Nephrol. 2009;43(5):369-372.

  5. Bonetta A, Di Pierro F. Enteric-coated, highly standardized cranberry extract reduces risk of UTIs and urinary symptoms during radiotherapy for prostate carcinoma. Cancer Manag Res. 2012;4:281-286.

  6. Barbosa-Cesnik C, Brown MB, Buxton M, et al. Cranberry juice fails to prevent recurrent urinary tract infection: results from a randomized placebo-controlled trial. Clin Infect Dis. Jan 1 2011;52(1):23-30.

  7. Howell AB, Botto H, Combescure C, et al. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study. BMC Infect Dis. 2010;10:94.

  8. Beerepoot MA, ter Riet G, Nys S, et al. Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women. Arch Int Med. Jul 25 2011;171(14):1270-1278.

  9. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2012;10:CD001321.

  10. Deziel B, MacPhee J, Patel K, et al. American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell cycle regulators. Food Funct. May 2012;3(5):556-564.

  11. Ferguson PJ, Kurowska E, Freeman DJ, et al. A flavonoid fraction from cranberry extract inhibits proliferation of human tumor cell lines. J Nutr. Jun 2004;134(6):1529-1535.

  12. Seeram NP, Adams LS, Hardy ML, et al. Total cranberry extract versus its phytochemical constituents: antiproliferative and synergistic effects against human tumor cell lines. J Agric Food Chem. May 5 2004;52(9):2512-2517.

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  18. Burger O, Ofek I, Tabak M, et al. A high molecular mass constituent of cranberry juice inhibits helicobacter pylori adhesion to human gastric mucus. FEMS Immunol Med Microbiol. Dec 2000;29(4):295-301.

  19. Zhang L, Ma J, Pan K, et al. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial. Helicobacter. Apr 2005;10(2):139-145.

  20. Gotteland M, Andrews M, Toledo M, et al. Modulation of Helicobacter pylori colonization with cranberry juice and Lactobacillus johnsonii La1 in children. Nutrition. May 2008;24(5):421-426.

  21. Shmuely H, Yahav J, Samra Z, et al. Effect of cranberry juice on eradication of Helicobacter pylori in patients treated with antibiotics and a proton pump inhibitor. Mol Nutr Food Res. Jun 2007;51(6):746-751.

  22. Weiss EI, Lev-Dor R, Kashamn Y, et al. Inhibiting interspecies coaggregation of plaque bacteria with a cranberry juice constituent [published erratam appear in J Am Dent Assoc 1999 Jan;130(1):36 and 1999 Mar;130(3):332]. J Am Dent Assoc. Dec 1998;129(12):1719-1723.

  23. Yamanaka A, Kimizuka R, Kato T, et al. Inhibitory effects of cranberry juice on attachment of oral streptococci and biofilm formation. Oral Microbiol Immunol. Jun 2004;19(3):150-154.

  24. Neto CC. Cranberry and its phytochemicals: a review of in vitro anticancer studies. J Nutr. Jan 2007;137(1 Suppl):186S-193S.

  25. Foo LY, Lu Y, Howell AB, et al. A-Type proanthocyanidin trimers from cranberry that inhibit adherence of uropathogenic P-fimbriated Escherichia coli. J Nat Prod. Sep 2000;63(9):1225-1228.

  26. Foo LY, Lu Y, Howell AB, et al. The structure of cranberry proanthocyanidins which inhibit adherence of uropathogenic P-fimbriated Escherichia coli in vitro. Phytochemistry. May 2000;54(2):173-181.

  27. Howell AB, Reed JD, Krueger CG, et al. A-type cranberry proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry. Sep 2005;66(18):2281-2291.

  28. Howell AB, Vorsa N, Der Marderosian A, et al. Inhibition of the adherence of P-fimbriated Escherichia coli to uroepithelial-cell surfaces by proanthocyanidin extracts from cranberries. New Engl J Med. Oct 8 1998;339(15):1085-1086.

  29. Burger O, Weiss E, Sharon N, et al. Inhibition of Helicobacter pylori adhesion to human gastric mucus by a high-molecular-weight constituent of cranberry juice. Crit Rev Food Sci Nutr. 2002;42(3 Suppl):279-284.

  30. Koo H, Nino de Guzman P, Schobel BD, et al. Influence of cranberry juice on glucan-mediated processes involved in Streptococcus mutans biofilm development. Caries Res. 2006;40(1):20-27.

  31. Deziel BA, Patel K, Neto C, et al. Proanthocyanidins from the American Cranberry (Vaccinium macrocarpon) inhibit matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in human prostate cancer cells via alterations in multiple cellular signalling pathways. J Cell Biochem. Oct 15 2010;111(3):742-754.

  32. Gettman MT, Ogan K, Brinkley LJ, et al. Effect of cranberry juice consumption on urinary stone risk factors. J Urol. Aug 2005;174(2):590-594; quiz 801.

  33. Kessler T, Jansen B, Hesse A. Effect of blackcurrant-, cranberry- and plum juice consumption on risk factors associated with kidney stone formation. Eur J Clin Nutr. Oct 2002;56(10):1020-1023.

  34. Greenblatt DJ, von Moltke LL, Perloff ES, et al. Interaction of flurbiprofen with cranberry juice, grape juice, tea, and fluconazole: in vitro and clinical studies. Clin Pharm Ther. Jan 2006;79(1):125-133.

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  42. Grenier J, Fradette C, Morelli G, et al. Pomelo juice, but not cranberry juice, affects the pharmacokinetics of cyclosporine in humans. Clin Pharm Ther. Mar 2006;79(3):255-262.

  43. Kim E, Sy-Cordero A, Graf TN, et al. Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. Planta Med. Feb 2011;77(3):265-270.

  44. Ushijima K, Tsuruoka S, Tsuda H, et al. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects. Brit J Clin Pharmacol. Aug 2009;68(2):194-200.

  45. Dinh J, Angeloni JT, Pederson DB, et al. Cranberry extract standardized for proanthocyanidins promotes the immune response of Caenorhabditis elegans to Vibrio cholerae through the p38 MAPK pathway and HSF-1. PLoS One. 2014;9(7):e103290.

  46. Rane HS, Bernardo SM, Howell AB, et al. Cranberry-derived proanthocyanidins prevent formation of Candida albicans biofilms in artificial urine through biofilm- and adherence-specific mechanisms. J Antimicrob Chemother. Feb 2014;69(2):428-436.

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  66. Wing DA, Rumney PJ, Preslicka CW, et al. Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study. J Urol. Oct 2008;180(4):1367-1372.

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  70. Gunnarsson AK, Gunningberg L, Larsson S, Jonsson KB. Cranberry juice concentrate does not significantly decrease the incidence of acquired bacteriuria in female hip fracture patients receiving urine catheter: a double-blind randomized trial. Clin Interv Aging. 2017 Jan 13;12:137-143.

  71. Dave AA, Samuel J. Suspected Interaction of Cranberry Juice Extracts and Tacrolimus Serum Levels: A Case Report. Cureus. 2016 May 16;8(5):e610