St. John's wort (Hypericum perforatum) | Cam-Cancer

St. John's wort (Hypericum perforatum)

Abstract and key points
  • St. John’s wort is an effective anti-depressive agent.
  • Some people also promote it as a cancer drug but there is no good evidence to support this claim.
  • St. John’s wort is generally a safe remedy but can powerfully interact with several drugs used for cancer patients.

Hypericum perforatum (St. John’s wort) is a perennial flowering plant, preparations of which are popular as an anti-depressant and are also being promoted as an alternative cancer therapy. Even though some preliminary pre-clinical investigations have generated encouraging findings, there are no clinical studies to show that St. John’s wort would change the natural history of any type of cancer. St. John’s wort may reduce the blood levels of many conventional drugs, including some cancer medicines. Rare adverse effects include psychological symptoms, allergic reactions and visual disturbances.

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

Document history

Assessed as up top date in May 2019 by Barbara Wider
Summary updated in September 2016 by Karen Pilkington.
Summary assessed as up to date in September 2013 by Edzard Ernst.
Most recent update and revision in May 2012 by Edzard Ernst.
Summary first published in April 2011, authored by Edzard Ernst.

Citation

Barbara Wider, Karen Pilkington, Edzard Ernst, CAM-Cancer Consortium. St. John's wort (Hypericum perforatum) [online document], http://cam-cancer.org/en/st-johns-wort. September 21, 2016.

What is it?

Scientific name

Hypericum perforatum L. (Guttiferae/Clusiaceae).
Synonym(s): Hypericum, Hypericum veronese Schrank, H., Hypericum noeanum Boiss., Millepertus1, Hyperici herba2-3.

Ingredients

Extracts contain naphthodianthrone (=hypericin/pseudohypericin), phloroglycinderivatives (=hyperforin/adhyperforin) flavonoids, tannins, volatile oils, xanthones and many other ingredients. The major known constituents considered to be responsible for the antidepressant activity are hypericin and hyperforin4-6. Extracts to study the anticancer activities have been mostly characterised by these two ingredients.

Application and dosage

Usually, St. John’s wort is taken orally. The dosage of commercial preparations varies according to the specifics of each product. Typical doses are as follows:
Dried herb: 2-4g as an infusion three times daily.
Liquid extract: 2-4 ml (1:1 in 25% alcohol) three times daily.
Standardised dried extracts applied in clinical trials: 240-1800 mg daily (equivalent to varying concentrations of hypericin and hyperforin), typically applied for 4 to 6 weeks.

According to the British and European Pharmacopoeias, St. John`s wort herb should contain not less than 0.08% of total hypericins, expressed as hypericin, calculated with reference to the dried drug2-3.

History/providers

St. John’s wort has been used medicinally for millennia. Today herbalists, naturopaths, and in some countries, doctors might prescribe or recommend St. John’s wort preparations. However, most of its usage is based on self-prescription as products are available in pharmacies and health food shops.

Claims of efficacy

Traditionally, St. John’s wort was employed for pain control, wound healing, melancholy, insanity and many other ailments4. Today it is mainly used as an anti-depressive agent, and there is good evidence that it is effective for that purpose7.

Mechanism of action

The anti-depressive effects of St. John’s wort seem to rely on the inhibition of the re-uptake of serotonin, noradrenalin, glutamate and dopamine in the central nervous system5-6. Other known mechanisms of action include the modulation of interleukin-6 activity and gamma-aminobutyric acid receptor binding and antioxidant effects4,8-9. There is preliminary evidence from in-vitro studies to suggest that constituents of St. John's wort have anti-cancer effects33-35. A range of mechanisms have been proposed based on results of pre-clinical studies, e.g. cytotoxic, apoptosis-inducing and anti-angiogenic effects.

St. John’s wort extracts exhibit cytotoxic and apoptosis-inducing effects in neoplastic cell lines11,33-35. They thus inhibit the growth of leukaemia and glioblastoma prostate cancer cells in vitro12-13. Ex-vivo experiments have demonstrated anti-angiogenic activity14 which theoretically could contribute to anticancer effects15-16. These effects may not be linked purely to hypericin but also to other ingredients of St. John’s wort17.

Animal experiments have shown that St. John’s wort inhibits pro-inflammatory cytokines18. Hypericin also has phototoxic effects, and St. John’s wort could thus have potential as a photodynamic agent for some types of skin cancer19. Collectively the evidence indicates that the threshold for phototoxicity of hypericin is between 100 and 1000 ng/ml20. Since serum and skin concentrations of hypericin after oral administration of recommended doses are below 100 ng/ml, photosensitivity is unlikely1. Nevertheless, it was reported that 3 µM of activated hypericin induced a necrotic mode of cell death in pigmented melanoma cells and melanocytes and an apoptotic mode of cell death in non-pigmented cells and keratinocytes21.

Alleged indications

The claim is that St. John’s wort may exert direct effects on cancer cells (see below) and thus influence the natural history of the disease.

Prevalence of use

In most countries, St. John’s wort is a popular anti-depressant. Many cancer patients might thus try it to improve their mood by using this herbal extract. One survey suggested that 5% of lymphoma patients do so10. There are only scarce data to show how many cancer patients might take St. John’s wort to treat their malignancy. One study suggested that 2-5% of US lung/colorectal cancer patients took St. John's wort supplements. These data, however, do not imply that they took it for treating cancer24.

Legal issues

In most countries, St. John’s wort is available as a food supplement. In other countries (e.g. Germany), full licences have been issued for St. John’s wort as an anti-depressant. St. John’s wort is listed by the Council of Europe as a natural source of food flavouring.

Cost and expenditure

The cost of one week’s supply varies considerably from ~€15 to €25. High quality preparations tend to be at the higher end of this range.

Does it work?

Clinical trials

Very little clinical evidence related to St. John’s wort in cancer has so far emerged. Kacerovsk et al.22 conducted an uncontrolled, prospective open-label study with 39 patients suffering from actinic keratosis, basal cell carcinoma or Bowen disease. They found promising responses but the nature of the study prevents firm conclusions.

A study on healthy volunteers suggested that hypericum-induced photosensitization might enhance UVB-induced cutaneous damage23. The relevance of this finding to patients with cancer is, however, as yet unclear.

Proposed anti-inflammatory effects of St John’s wort on the skin were assessed in the treatment of acute skin toxicity in patients undergoing radiotherapy or chemo-radiotherapy for head and neck cancer37.  A preparation containing St John’s wort and neem oil was used during radiotherapy treatment and follow-up. Beneficial effects were reported but the trial was small (28 patients), a convenience sample was used and there was no control group. Thus, the findings can be considered preliminary at best, particularly as neem oil is also suggested to have anti-inflammatory properties and may have contributed to any effects observed.

Observational studies

A recent update on the data of the VITAL (Vitamins and Lifestyle) study reported a reduced risk for colorectal cancer (CRC) upon consumption of St. John’s wort24. This observational study, however, cannot establish cause and effect.

Is it safe?

Adverse events

Numerous studies of St. John’s wort as an anti-depressant suggest that the adverse effects of oral St. John’s wort at recommended doses to treat depression are minimal and rare ranging in frequency from 0.1% to 2.4%25-26. However, the safety of St John’s wort products taken as self-treatment without supervision by a healthcare professional requires further study. A small number of studies exploring the effects of self-treatment with St. John’s wort products report adverse effects including psychological symptoms, allergic reactions and visual disturbances, which participants believed to be related to the use of St. John’s wort4.

Contradictions

Photosensitivity, allergy, pregnancy and lactation.

Interactions

St. John’s wort powerfully interacts with a wide range of drugs, including some cancer medications27,36 e.g. topoisomerase II cancer chemotherapy, cyclosporine, tacrolimus, amitripyline, irinotecan , digoxin, oral contraceptives or HIV-protease inhibitors. The mechanisms of these interactions include an induction of cytochrome P-450 microsomal oxidase enzymes (e.g. CYP3A4, CYP1A2, CYP2C9 , CYP2C19) and P-glycoprotein transporter pathway28-30. The effect can lead to clinically relevant effects in cancer patients31-32.

Warning

The elimination half-life of hypericin is about 24 to 27 hours. Repeated doses have been reported to lead to a steady state concentration after 4 days1.

Other problems

There is an abundance of St. John’s wort preparations and only some are of high quality.  Commercial products should adhere to Good Agricultural Practice (GAP), Good Manufacturing Practice (GMP) and in Europe to the European guidelines “Quality of Herbal Medicinal Products”.

References
  1. Barnes J, Anderson LA, Phillipson JD. Herbal medicines (3rd ed). London: Pharmaceutical Press. 2007.
  2. European Directorate for the Quality of Medicines (EDQM). Euopean Pharmacopoeia, 5th ed and Supplements 5.1-5.7. Strasbourge: Council of Europe 2004-2007. 2007.
  3. The British Pharmacopoeia. British Pharmacopoeia Commission, London, Her Majesty's Stationery Office. 2007.
  4. Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine. Edinburgh; 2nd edition. Edinburgh: Mosby/Elsevier. 2006.
  5. Butterweck V. Mechanism of action of St John's wort in depression: what is known? CNS Drugs 2003; 17(8):539-562.
  6. Butterweck V, Schmidt M. St. John's wort: role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr 2007; 157(13-14):356-361.
  7. Linde K, Berner MM, Kriston L. St. John's wort for major depression. Cochrane Database of Systematic Reviews 2008, Issue 4, Art.No.: CD000448.
  8. Grundmann O, Lv Y, Kelber O, et al. Mechanism of St. John's wort extract (STW3-VI) during chronic restraint stress is mediated by the interrelationship of the immune, oxidative defense, and neuroendocrine system. Neuropharmacol 2010; 58(4-5):767-773.
  9. Jungke P, Ostrow G, Li J-L, Norton S, Nieber K, Kelber O et al. Profiling of hypothalamic and hippocampal gene expression in chronically stressed rats treated with St. John’s wort extract (STW 3-VI) and fluoxetine. Psychopharmacol 2011; 213:757-772.
  10. Habermann TM, Thompson CA, LaPlant BR, Bauer BA, Janney CA, Clark MM et al. Complementary and alternative medicine use among long-term lymphoma survivors: a pilot study. Am J Hematol 2009; 84(12):795-798.
  11. Schempp CM, Simon-Haarhaus B, Simon JC. Phototoxic and apoptosis-inducing capacity of pseudohypericin. Planta Med 2002; 68(2):171-173.
  12. Hostanska K, Reichling J, Bommer S, Weber M, Saller R. Hyperforin a constituent of St. John's wort (Hypericum perforatum L.) extract induces apoptosis by triggering activation of caspases and with hypericin synergistically exerts cytotoxicity towards human malignant cell lines. Eur J Pharm Biopharm 2003; 56(1):121-132.
  13. Martarelli D, Martarelli B, Pediconi D, Nabissi MI, Perfumi M, Pompei P. Hypericum perforatum methanolic extract inhibits growth of human prostatic carcinoma cell line orthotopically implanted in nude mice. Cancer Lett 2004; 210(1):27-33.
  14. Quiney C, Billard C, Mirshahi P, Fourneron JD, Kolb JP. Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells. Leukemia 2006; 20(4):583-589.
  15. Schempp CM, Kirkin V, Simon-Haarhaus B, Kersten A, Kiss J, Termeer CC et al. Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis. Oncogene 2002; 21:1242-1250.
  16. Doná M, Dell'Aica I, Pezzato E, Sartor L, Calabrese F, Della Barbera M et al. Hyperforin inhibits cancer invasion and metastasis. Cancer Res 2004; 64:6225-6232 
  17. Roscetti G, Franzese O, Comandini A, Bonmassar E. Cytotoxic activity of Hypericum perforatum L. on K562 erythroleukemic cells: differential effects between methanolic extract and hypericim. Phytother Res 2004; 18(1):66-72.
  18. Hu ZP, Yang XX, Chan SY, Xu AL, Duan W, Zhu YZ et al. St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis. Toxicol Appl Pharmacol 2006; 216(2):225-237.
  19. Olivo M, Du HY, Bay BH. Hypericin lights up the way for the potential treatment of nasopharyngeal cancer by phtodynamic therapy. Curr Clin Pharmacol 2006; 1(3):217-222.
  20. Schempp CM, Winghofer B, Müeller K, Schulte-Mönting J, Mannel M, Schöpf E et al. Effect of oral administration of Hypericum perforatum extract (St. John's Wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother Res 2003; 17(2):141-146.
  21. Davids LM, Kleemann B, Kacerovska D, Pizinger K, Kidson SH. Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells. J Photochem Photobiol B 2008; 91(2-3):67-76.
  22. Kacerovska D, Pizinger K, Majer F, Smid F. Photodynamic therapy of nonmelanoma skin cancer with topical hypercum perforatum extract--a pilot study. Photochem Photobiol 2008; 84(3):779-785.
  23. Kerb R, Brockmoller J, Schlagenhaufer R, Sprenger R, Roots I, Brinkmann U. Influence of GSTT1 and GSTM1 genotypes on sunburn sensitivity. Am J Pharmacogenomics 2002; 2(2):147-154.
  24. Satia JA, Littman A, Slatore CG, Galanko JA, White E. Associations of herbal and specialty supplements with lung and colorectal cancer risk in the VITamins and lifestyle study. Cancer Epidemiol Biomarkers Prev 2009; 18(5):1419-1428.
  25. Schulz V. Safety of St. John's wort extract compared to synthetic antidepressants. Phytomed 2006; 13(3):199-204.
  26. International Journal of Toxicology. Final report on the safety assessment of Hypericum perforatum extract and Hypericum perforatum oil. Int J Toxicol 2001; 20(Suppl2):31-39.
  27. Lemachatti J, Leveque D, Beretz L, Bergerat JP. Potential pharmacokinetic interactions affecting antitumor drug disposition in cancer patients. Anticancer Res 2009; 29(11):4741-4744.
  28. Yang AK, He SM, Liu L, Liu JP, Wei MQ, Zhou SF. Herbal interactions with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem 2010; 17(16):1635-1678.
  29. Perloff MD, von Moltke LL, Stormer E, Shader RI, Greenblatt DJ. Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure. Br J Pharmacol 2001; 134(8):1601-1608.
  30. Zhou S, Chan E, Pan SQ, Huang M, Lee EJ. Pharmacokinetic interactions of drugs with St John's wort. J Psychopharmacol 2004; 18(2):262-276.
  31. Mathijssen RHJ, Verweij J, de Bruin P, Loos WJ, Sparreboom A. Effects of St John's wort on irinotecan metabolism. J Nat Cancer Inst 2002; 94(16):1247-1249.
  32. Thiele B, Brink I, Ploch M. Modulation of cytokine expression by hypericum extract. J Geriatr Psychiatry Neurol 1994; 7(Suppl 1):S60-62.
  33. Liu JY, Liu Z, Wang DM, Li MM, Wang SX, Wang R et al. Induction of apoptosis in K562 cells by dicyclohexylammonium salt of hyperforin through a mitochondrial-related pathway. Chem Biol Interact 2011; 190(2-3):91-101.
  34. Sackova V, Kulikova L, Kello M, Uhrinova I, Fedorocko P. Enhanced Antiproliferative and Apoptotic Response of HT-29 Adenocarcinoma Cells to Combination of Photoactivated Hypericin and Farnesyltransferase Inhibitor Manumycin A. Int J Mol Sci 2011; 12(12):8388-8405.
  35. Zaher M, Tang R, Bombarda I, Merhi F, Bauvois B, Billard C. Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa. Int J Oncol 2012; 40(1):269-276.
  36. Caraci F, Crupi R, Drago F, Spina E. Metabolic drug interactions between antidepressants and anticancer drugs: focus on selective serotonin reuptake inhibitors and hypericum extract. Curr Drug Metab 2011; 12(6):570-577.
  37. Franco P, Potenza I, Moretto F, Segantin M, Grosso M, Lombardo A, Taricco D, Vallario P, Filippi AR, Rampino M, Ricardi U. Hypericum perforatum and neem oil for the management of acute skin toxicity in head and neck cancer patients undergoing radiation or chemo-radiation: a single-arm prospective observational study. Radiat Oncol. 2014 9:297. 

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