St. John's wort (Hypericum perforatum)

Abstract and key points

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.

Safety

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.

Citation

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

Document history

Last updated in November 2022 by Karen Pilkington.
Assessed as up to 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.
Update and revised in May 2012 by Edzard Ernst.
Summary first published in April 2011, authored by Edzard Ernst.

What is it?

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.

Synonyms

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.

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?

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.

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% (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).

Contradictions

Photosensitivity, allergy, pregnancy and lactation.

Interactions

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).

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 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”.

References

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