St John's wort (SJW) is a herbal remedy also known as hypericum. It is extracted from the flowers and leaves of the plant Hypericum perforatum and has been used over many centuries as a traditional medicine for wound healing and mental health problems. It remains popular with the public, bought over-the-counter from health food shops and chemists as a treatment for depression. However, it should strictly be considered a drug since it contains pharmacologically active agents, including hypericin. SJW's mechanism of action is unknown but it may inhibit the reuptake of serotonin and noradrenaline, inhibit monoamine oxidase, up-regulate serotonin receptors, and decrease serotonin receptor expression.¹

Whilst many clinically important drugs have their origins in herbal medicine, issues concerning safety (possible toxicity, drug interactions and teratogenicity) and efficacy have arisen with the use of herbal remedies in modern times. The regulatory framework for herbal remedies is different and less rigorous compared with that applied to pharmaceutical medicines. They may:

• Be unlicensed, where they are not industrially produced.
• Be registered under the Traditional Herbal Medicines Registration Scheme which requires specific standards of safety and quality. Much commercially available SJW falls under this category with a need only to prove traditional use rather than efficacy.
• Hold a product license, which additionally requires evidence of efficacy.

See separate article Complementary and Alternative Medicine for further details.

Problems also occur with variation in potency between brands and batches:

• Some of the proprietary preparations are standardised for hypericin, making them more consistent than products that are not standardised.
• It is likely that other ingredients (for example, flavonoids and flavonoid derivatives, xanthone derivatives, amentoflavone, biapigenin, volatile oil) in the preparation have some effect on depression and, whilst these are not standardised, potency may vary between batches.²
• Different brands have different amounts of hypericin and other ingredients, so it is best to choose a standardised brand and to stick with the same brand.

There is some debate as to the correct dose - the usual recommended dose is about 900 mg a day of hypericum extract, but much higher doses have been used in trials.³

Efficacy

St John's wort (SJW) is usually recommended for low mood or mild depression. Its use in somatoform disorders is also being explored.⁵ Problems with clinical trials investigating the use of SJW in depression have included heterogeneity, short follow-up (often for only 4-8 weeks) and small numbers resulting in underpowering.⁶ Trials from German-speaking countries tend to report more positive results, possibly reflecting a cultural bias to its use. However, a Cochrane Review from 2008 found SJW to be superior to placebo in patients with major depression and as effective as standard antidepressants but with better tolerability and concluded that it was an effective treatment.⁷

SJW is not recommended for use in children or adolescents as there are no robust trials on which to base clinical decision making.⁸ There is no evidence of benefit in attention deficit and hyperactivity disorder (ADHD)⁹ or bipolar disorder.¹⁰ One recent RCT failed to show evidence of benefit for SJW in irritable bowel syndrome.¹¹

Contra-indications

• St John's wort (SJW) should be avoided in pregnancy or lactation due to lack of high-quality, human-based studies demonstrating safety. Animal studies suggest that use during pregnancy does not affect cognitive development or cause long-term behavioural defects, but may cause lower birth weight. There is very limited evidence that use of SJW during lactation does not affect milk production but may cause colic, drowsiness or lethargy. ¹².
• It should not be taken at the same time as other antidepressants, especially the selective serotonin reuptake inhibitors (SSRIs), venlafaxine and duloxetine, as there is risk of a serotonergic crisis.¹³
• For the same reason it should not be used with the triptans including sumatriptan, naratriptan, rizatriptan and zolmitriptan
• It should not be used in bipolar disease as it may be associated with mania.¹⁴
• SJW is a cytochrome P450 3AE inducer.¹⁵ This and other mechanisms underly a large number of potentially significant drug interactions including:^16,17
  • Oral contraceptives - avoid use with oestrogen-based or progestogen-based contraceptives and ulipristal.
  • Warfarin - avoid concurrent use.
  • Ciclosporin - avoid concurrent use.
  • Calcium-channel blockers - reduced plasma concentration of amlodipine, nifedipine and verapamil with concurrent use.
  • Anticonvulsants including carbamazepine, phenobarbital and phenytoin - avoid concurrent use.
  • Simvastatin - plasma concentration reduced by concurrent use.
  • Methadone - plasma concentration reduced by concurrent use.
  • HIV treatments including indinavir, nelfinavir, ritonavir, saquinavir, efavirenz and nevirapine.
  • Digoxin - avoid concurrent use.
  • Theophylline - avoid concurrent use.

Patient interaction warnings are frequently inadequate on products for sale.¹⁸

Initiation of treatment

Before a patient is started on a licenced antidepressant, they must see a doctor for a diagnosis. A prescription is issued and follow-up arranged. None of this is obligatory for St John's wort (SJW) in the UK as it can be bought freely, without consultation regarding diagnosis or safety advice. This is clearly unsatisfactory in the management of a serious and potentially fatal disease like depression.

• Ideally patients should consult a doctor first, discuss treatment options and be followed up regardless of what treatment they elect to follow. Sometimes the use of complementary and alternative medicine (CAM) is perceived as a barrier to open communication between doctor and patient. Doctors should enquire about the current and intended use of herbal remedies and over-the-counter medication.
• When switching from a conventional antidepressant to SJW, a 'washout' period should be allowed. This will vary depending on half-life of the drug being stopped.
• The patient should be warned about drug interactions, including antidepressants and oral contraceptives if appropriate.

Monitoring

• The depression should be monitored to assess progress. The patient should be seen after a week or two and then at intervals dictated by the doctor's clinical acumen and usual practice. As with other antidepressants, It may take 2 to 4 weeks to have effect.
• Where a patient is taking other drugs, particularly anticoagulants, careful monitoring is required on starting and stopping St John's wort (SJW). They must be counselled that different brands and strengths of SJW are likely to cause differences in the degree of interaction and therefore ideally they should stick to one particular preparation.
• Ask the patient about side-effects. Patients on conventional drugs are usually very ready to attribute physical signs and symptoms to an adverse drug reaction. With 'natural remedies' the opposite may be true.
• The most commonly reported side-effects¹⁹ include:
  • Gastrointestinal symptoms such as nausea, vomiting or diarrhoea
  • Allergic reactions
  • Fatigue
  • Dizziness
  • Dry mouth
  Photosensitivity is uncommon and tends to be associated with high doses, but people taking it should increase their sun protection and avoid strong sunlight.
• The Medicines and Healthcare products Regulatory Agency (MHRA) is encouraging the reporting of adverse reactions to herbal medicines via the Yellow Card Scheme - patients are able to self-report or report via their pharmacist or doctor. Discontinue the SJW where side-effects are intolerable or drug interactions unacceptable.
• Where the depression becomes severe, stop the SJW and start an adequate dose of a drug of proven value in severe depression after a brief 'washout' period.

History

St John's wort is named after St John the Baptist, whose feast day on 24th June coincides with the plant's full bloom in Europe. Its five yellow petals resemble a halo, and its red sap symbolises the blood of the martyred saint. He was beheaded after criticising the morality of King Herod, the Jewish king. The name hypericum comes from the Greek, meaning 'greatest health'.

Document references

1. Depression, Clinical Knowledge Summaries (February 2010)
2. Lawvere S, Mahoney MC; St. John's wort. Am Fam Physician. 2005 Dec 1;72(11):2249-54. [abstract]
3. Szegedi A, Kohnen R, Dienel A, et al; Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non BMJ. 2005 Mar 5;330(7490):503. Epub 2005 Feb 11. [abstract]
4. Depression in adults, NICE Clinical Guideline (October 2009); Depression: the treatment and management of depression in adults
5. Muller T, Mannel M, Murck H, et al; Treatment of somatoform disorders with St. John's wort: a randomized, Psychosom Med. 2004 Jul-Aug;66(4):538-47. [abstract]
6. van der Watt G, Laugharne J, Janca A; Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry. 2008 Jan;21(1):37-42. [abstract]
7. Linde K, Berner MM, Kriston L; St John's wort for major depression. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD000448. [abstract]
8. Depression in children and young people, NICE (2005); (Identification and management in primary, community and secondary care)
9. Weber W, Vander Stoep A, McCarty RL, et al; Hypericum perforatum (St John's wort) for attention-deficit/hyperactivity disorder in children and adolescents: a randomized controlled trial. JAMA. 2008 Jun 11;299(22):2633-41. [abstract]
10. Andreescu C, Mulsant BH, Emanuel JE; Complementary and alternative medicine in the treatment of bipolar disorder - A review of the evidence. J Affect Disord. 2008 Sep;110(1-2):16-26. Epub 2008 May 5. [abstract]
11. Saito YA, Rey E, Almazar-Elder AE, et al; A randomized, double-blind, placebo-controlled trial of St John's wort for Am J Gastroenterol. 2010 Jan;105(1):170-7. Epub 2009 Oct 6. [abstract]
12. Dugoua JJ, Mills E, Perri D, et al; Safety and efficacy of St. John's wort (hypericum) during pregnancy and Can J Clin Pharmacol. 2006 Fall;13(3):e268-76. Epub 2006 Nov 3. [abstract]
13. Izzo AA; Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence. Int J Clin Pharmacol Ther. 2004 Mar;42(3):139-48. [abstract]
14. Nierenberg AA, Burt T, Matthews J, et al; Mania associated with St. John's wort.; Biol Psychiatry. 1999 Dec 15;46(12):1707-8. [abstract]
15. Markowitz JS, Donovan JL, DeVane CL, et al; Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 JAMA. 2003 Sep 17;290(11):1500-4. [abstract]
16. British National Formulary; 59th Edition (March 2010) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (link to current BNF).
17. Izzo AA, Ernst E; Interactions between herbal medicines and prescribed drugs: an updated systematic Drugs. 2009;69(13):1777-98. doi: 10.2165/11317010-000000000-00000. [abstract]
18. Clauson KA, Santamarina ML, Rutledge JC; Clinically relevant safety issues associated with St. John's wort product labels. BMC Complement Altern Med. 2008 Jul 17;8:42. [abstract]
19. MHRA Current Problems in Pharmacovigilance Volume 26, May 2000

Internet and further reading

• Mind: factsheet; St John's wort.
• MHRA Using herbal medicines: advice to consumers, March 2010

Acknowledgements