St. John's wort (Hypericum perforatum)

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, very little clinical evidence related to St. John’s wort in cancer has so far emerged.

Anticancer treatment

Tumour burden: Two uncontrolled studies, one in skin cancer and the other in brain tumours reported positive responses to St John’s wort treatment. As neither trial included a control, the findings are preliminary at best.

Supportive cancer care

Skin toxicity:  A small, uncontrolled study assessed effects of St John’s wort used topically to prevent skin toxicity during radiotherapy for head and neck cancer. As it was used in combination with neem oil, any contribution to the reported beneficial effects is unclear.

Prevention of cancer

Evidence for any preventive effect of St John’s wort in skin, colorectal and breast cancer is not convincing due to a negative outcome, use of an observational study design and lack of relevant research respectively.


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.


Karen Pilkington, Edzard Ernst, CAM Cancer Collaboration. St. John's wort (Hypericum perforatum) [online document], Dec 19, 2022.

Document history

Latest update: December 2022

Next update due: December 2025

Description and background

Hypericum perforatum L. (Hypericaceae) (St. John’s wort) is a perennial flowering plant, with yellow star-shaped flowers, that is native to Europe and which has been used medicinally for millennia (NMD 2022). 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. Preparations are popular as an anti-depressant and are also being promoted as an alternative cancer therapy.


Hypericum, Hypericum subsp. veronese Schrank, H., Hypericum noeanum Boiss., Millepertuis (Barnes 2007), Hyperici herba (EMA 2022).

Ingredients and quality issues

Extracts contain naphthodianthrone (=hypericin/pseudohypericin), phloroglycinderivatives (=hyperforin/adhyperforin) flavonoids, tannins, volatile oils, xanthones and many other ingredients. The major known constituents originally considered to be responsible for the antidepressant activity were hypericin and hyperforin (Ernst 2006, Butterweck 2003, Butterweck 2007).  More recently, hyperforin, adhyperforin, and several related chemicals have been considered the main constituents with antidepressant activity (NMD 2022). Extracts to study the anticancer activities have been mostly characterised by these two ingredients.

According to the 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 drug (EDQM 2022).

Alleged indications

Traditionally, St. John’s wort was employed for pain control, wound healing, melancholy, insanity and many other ailments (Ernst 2006). Today it is mainly used as an anti-depressive agent, and there is good evidence that it is effective for that purpose (Linde 2008).

In the context of cancer, 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.

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 in clinical trials: 240-1800 mg daily (most commonly 500-1200mg daily in 3 doses; equivalent to varying concentrations of hypericin and hyperforin), typically taken for 4 to 6 weeks but up to 12 weeks in some trials (Linde 2008).

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 system (Butterweck 2003, Butterweck 2007). Other known mechanisms of action include the modulation of interleukin-6 activity and gamma-aminobutyric acid receptor binding and antioxidant effects (Ernst 2006, Grundmann 2010, Jungke 2011). There is preliminary evidence from in-vitro studies to suggest that constituents of St. John's wort have anti-cancer effects (Liu 2011, Sackova 2011, Zaher 2012). 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 lines (Schempp 2002, Liu 2011, Sackova 2011, Zaher 2012). They thus inhibit the growth of leukaemia and glioblastoma prostate cancer cells in vitro (Hostanska 2003, Martarelli 2004). Ex-vivo experiments have demonstrated anti-angiogenic activity (Quiney 2006) which theoretically could contribute to anticancer effects (Schempp 2002, Doná 2004). These effects may not be linked purely to hypericin but also to other ingredients of St. John’s wort (Roscetti 2004).

Animal experiments have shown that St. John’s wort inhibits pro-inflammatory cytokines (Hu 2006). Hypericin also has phototoxic effects, and St. John’s wort could thus have potential as a photodynamic agent for some types of skin cancer (Olivo 2006). Collectively the evidence indicates that the threshold for phototoxicity of hypericin is between 100 and 1000 ng/ml (Schempp 2003). Since serum and skin concentrations of hypericin after oral administration of recommended doses are below 100 ng/ml, photosensitivity is unlikely (Barnes 2007). 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 keratinocytes (Davids 2008).

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 so (Habermann 2009). 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 cancer (Satia 2009). A similar prevalence of use (2.7%) was reported in a UK survey (Damery 2011) while a 2022 Spanish survey reported a much lower prevalence (0.05%) (Escudero-Vilaplana 2022).

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.

Very little clinical evidence related to St. John’s wort in cancer has so far emerged. This includes three uncontrolled trials in cancer patients, one trial in healthy volunteers, an observational study and a systematic review in which no relevant studies were found.  

Anticancer treatment

Tumour burden: Two uncontrolled studies, one in skin cancer and the other in brain tumours reported positive responses to St John’s wort treatment. As neither included a control, the findings are preliminary at best.

Supportive cancer care

Skin toxicity: A small, uncontrolled study assessed effects of St John’s wort used topically to prevent skin toxicity during radiotherapy for head and neck cancer. As it was used in combination with neem oil, its contribution to the reported beneficial effects is unclear.

Prevention of cancer

Evidence for any preventive effect of St John’s wort in skin, colorectal and breast cancer is not convincing due to a negative outcome, use of an observational study design and lack of relevant research respectively.

Description of included studies

Anticancer treatment

Tumour burden

Skin cancer: Kacerovsk 2008 conducted an uncontrolled, prospective open-label study with 39 patients suffering from actinic keratosis, basal cell carcinoma or Bowen disease. An extract of St John’s wort applied topically followed by photodynamic therapy was administered on a weekly basis. Complete disappearance of tumour cells was reported in histology samples from 11% of patients with superficial basal cell carcinomas and 80% of patients with Bowen’s disease.  While these are promising responses, the nature of the study including lack of a control prevents firm conclusions. In addition, side effects were an issue as all patients complained of burning and pain sensations during irradiation.

Brain tumours: In an open study, patients with recurrent or progressive malignant gliomas were treated with gradually increasing doses of oral synthetic hypericin for up to 3 months. (Couldwell 2011). Tumour status was assessed via magnetic resonance scanning at 3 months and any toxicity noted. Tumour volume stabilised or at least slightly reduced in 9 (22%) of 42 patients. Hypericin was well tolerated with the mean maximum tolerated dose of 0.40 ± 0.098 mg/kg daily. Lack of a control group was a serious limitation in this study so that the results are indicative only.

Supportive cancer care

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 cancer (Franco 2014).  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.

Prevention of cancer

A systematic review included searches for trials of St John’s wort for the promotion or prevention of breast cancer in menopausal women alongside other possible outcomes such as effects on hot flushes (Ghazanfarpour 2016). Only 3 trials of St John’s wort were found, two using a combination product and one comparing two herbal treatments, and none assessed promotion or prevention of breast cancer.

A study on healthy volunteers suggested that hypericum-induced photosensitization might enhance UVB-induced cutaneous damage (Kerb 2002). The relevance of this finding to patients with cancer is, however, as yet unclear.

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 wort (Satia 2009). This observational study, however, cannot establish cause and effect.

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% (Schulz 2006, Anon 2001). 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 wort (Ernst 2006).


Photosensitivity, allergy, pregnancy and lactation.


St. John’s wort powerfully interacts with a wide range of drugs, including some cancer medications (Lemachatti 2009, Caraci 2011) 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 pathway (Yang 2010, Perloff 2001, Zhou 2004). The effect can lead to clinically relevant effects in cancer patients (Mathijssen 2002, Thiele 1994) For example, reduced effectiveness of docetaxel caused by St John’s wort has been reported (Escudero-Viliplana 2022).


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 days (Barnes 2007). There is a theoretical concern that St John’s wort may interfere with surgical procedures due to its effects on serotonin levels (NMD 2022).

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”.

Anon. 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.

Barnes J, Anderson LA, Phillipson JD. Herbal medicines (3rd ed). London: Pharmaceutical Press. 2007.

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.

Butterweck V. Mechanism of action of St John's wort in depression: what is known? CNS Drugs 2003; 17(8):539-562.

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.

Couldwell WT, Surnock AA, Tobia AJ, Cabana BE, Stillerman CB, Forsyth PA, Appley AJ, Spence AM, Hinton DR, Chen TC. A phase 1/2 study of orally administered synthetic hypericin for treatment of recurrent malignant gliomas. Cancer. 2011 Nov 1;117(21):4905-15. doi: 10.1002/cncr.26123.

Damery S, Gratus C, Grieve R, Warmington S, Jones J, Routledge P, Greenfield S, Dowswell G, Sherriff J, Wilson S. The use of herbal medicines by people with cancer: a cross-sectional survey. Br J Cancer. 2011 Mar 15;104(6):927-33. doi: 10.1038/bjc.2011.47. Epub 2011 Mar 1. PMID: 21364591; PMCID: PMC3065283.

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.

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 

EDQM, European Directorate for the Quality of Medicines. European Pharmacopoeia Online, 11th ed. 2022. [requires subscription]

EMA 2022, European Medicines Agency. Hyperici herba [online]. EU monograph. Last updated 29th November 2022.

Ernst E, Pittler MH, Wider B, Boddy K. The desktop guide to complementary and alternative medicine. Edinburgh; 2nd edition. Edinburgh: Mosby/Elsevier. 2006.

Escudero-Vilaplana V, Collado-Borrell R, Gómez Martínez-Sagrera P, Villanueva-Bueno C, Revuelta-Herrero JL, Gonzalez-Haba E, Hoyo-Muñoz Á, Jerez Gilarranz Y, Marzal-Alfaro B, Herranz A, Martin M, Sanjurjo M. Complementary and alternative medicine in cancer patients: characteristics of use and interactions with antineoplastic agents. J Cancer Res Clin Oncol. 2022 Jul 6. doi: 10.1007/s00432-022-04172-1.

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. 

Ghazanfarpour M, Sadeghi R, Latifnejad Roudsari R, Khadivzadeh T, Khorsand I, Afiat M, Esmaeilizadeh M. Effects of flaxseed and Hypericum perforatum on hot flash, vaginal atrophy and estrogen-dependent cancers in menopausal women: a systematic review and meta-analysis. Avicenna J Phytomed. 2016 May-Jun;6(3):273-83.

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.

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.

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.

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.

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.

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.

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.

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.

Linde K, Berner MM, Kriston L. St. John's wort for major depression. Cochrane Database of Systematic Reviews 2008, Issue 4, Art.No.: CD000448.

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.

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.

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.

NMD 2022, Natural Medicines Database. St John’s wort (Hypericum perforatum. Professional monograph [online database, requires subscription]. Accessed 12th December 2022.

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.

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.

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.

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.

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.

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.

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.

Schempp CM, Simon-Haarhaus B, Simon JC. Phototoxic and apoptosis-inducing capacity of pseudohypericin. Planta Med 2002; 68(2):171-173.

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.

Schulz V. Safety of St. John's wort extract compared to synthetic antidepressants. Phytomed 2006; 13(3):199-204.

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Thiele B, Brink I, Ploch M. Modulation of cytokine expression by hypericum extract. J Geriatr Psychiatry Neurol 1994; 7(Suppl 1):S60-62.

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.

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.

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.


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