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Alternative Medicine

Hypericum perforatum (St John's wort) in depression: pest or blessing?
Joseph M Rey and Garry Walter
Image of St John's wort

St John's wort (SJW) was introduced into Australia during the 1880s for medicinal purposes, but was subsequently declared a noxious weed. There is now a resurgence of interest in the therapeutic properties of this herb. In particular, use of SJW as an antidepressant has increased in recent months owing to reports of its effectiveness and safety. Nevertheless, the controlled trials available have limitations. Increasing use of SJW in the community poses a variety of questions. For example, should medical practitioners become more knowledgeable about the effects and interactions of alternative remedies? What are the ethical and medical implications of "antidepressant" prescribing by non-medical persons? Who is to fund further research and treatment studies? How can quality of SJW preparations be guaranteed? (MJA 1998; 169: 583-586)

Introduction - Botany - Active constituents - Antidepressant? - Mechanism of action - "First, do no harm" - Other health claims - Preparations - Precautions - Implications - Acknowledgements - References - Authors' details
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"What is a weed? A plant whose virtues have not been discovered"
- Ralph Waldo Emerson, Fortune of the Republic.
 

Introduction Although a considerable proportion of the Australian population uses herbal medicines regularly,1,2 most medical professionals distrust herbal remedies and know little about them.3 This scepticism may be related to the perception that many of the claims of herbalists are unproven or fanciful. One of the current health crazes in Europe and the United States concerns Hypericum perforatum, more commonly known as St John's wort (SJW). Used to treat a range of ailments for more than 2000 years, and said to have been prescribed by Hippocrates himself,4 it is the apparent value of SJW as an antidepressant that has captured most recent attention, and been the subject of a recent meta-analysis.5

In the past year alone, 10 books extolling the antidepressant effects of SJW were published. The titles are eloquent enough, among them St John's wort: nature's blues buster6 and The natural Prozac program: how to use St John's wort, the antidepressant herb.7 There have also been many review articles published in botanical and herbal medicine journals.8 An article in Time9 in 1997 elevated the herb to superstar status in the United States, and sales of SJW in that country skyrocketed. In Germany, SJW is used more extensively than conventional antidepressants for treating depression.10 In Australia, SJW has been attracting increasing media attention. Undoubtedly, consumption of this herb will become more prevalent.

Are assertions about the antidepressant effects of SJW justified? The fact that the National Institute of Mental Health (NIMH) in the United States recently funded a US$4 million trial gives some credence to the claims. The NIMH study is testing whether SJW is more effective than a placebo or a selective serotonin reuptake inhibitor in the treatment of depression. If SJW does reduce depressive feelings, should we recommend its use? Are the extracts from SJW safe for human consumption? In this article, we seek to answer these questions and to inform clinicians about this herbal treatment, particularly in relation to depression.

Botany The genus Hypericum contains more than 300 species. Hypericum perforatum is the species most often used in herbal remedies. It is an upright bush, growing to a metre tall, with oblong, perforated leaves and bright yellow flowers (see Figures). The leaves are dotted with translucent glands. There are many explanations for the appellation "St John's wort" (wort means "plant" in Old English); one is that the plant was named after St John the Baptist because the flowers were said to bloom on the anniversary of his execution.

SJW is native to Europe, Asia and Africa, but not Australia. It has been introduced to parts of Queensland, New South Wales, Victoria, South Australia and Tasmania. The original introduction has been traced to the Ovens Valley in Victoria during a gold boom in the 1880s, when a German woman imported seed of the plant and established it for medicinal purposes.11 It soon overran her garden and spread to the nearby racecourse, from where it attracted the local name of "racecourse weed". As the goldminers moved out seeking new fields, the plant went with them, mainly in chaff for their horses. SJW has been declared a noxious weed in most areas; however, in some quarters the attitude towards the herb has changed and it is beginning to be seen as a cash crop. Earlier this year, the St John's Wort Landholders' Association was launched in Bathurst, NSW, to encourage harvesting of the weed.12 Australia expects to provide up to 20 per cent of the 7000 tonnes of SJW used worldwide each year.12

Active constituents Many constituents with potential biological activity have been extracted from the flowers and leaves, the parts of the plant used for medicinal purposes.4,8 These include naphthodianthrones, flavonoids, phloroglucinols and xanthones. Hypericin, one of the naphthodianthrones, has traditionally been considered the main active ingredient, but it is not known whether it is the antidepressant compound. The amount of hypericin varies widely in different parts of the plant, under different growth conditions, and at different times of the year.4,8

Is St John's wort antidepressant? Most of the research on SJW has been performed in Germany and published in Continental journals. There have been numerous open trials of SJW in depression and 24 double-blind studies: eight randomised, double-blind studies comparing SJW to other active medications (desipramine,13 imipramine,14,15 amitryptiline,16,17 diazepam18,19 and maprotiline20) and 16 randomised, double-blind studies comparing SJW to placebo. In two studies13,21 SJW was used in combination with valerian. There have been no head-to-head trials with newer antidepressants. As noted, an NIMH study is currently comparing SJW with a selective serotonin reuptake inhibitor and a placebo.

A meta-analysis assessing 23 of the double-blind trials was published recently,5 and will not be replicated in this article. In summary, most patients in the reports had mild to moderately severe depression. (In mild depression the patient is distressed by depressive symptoms but will probably be able to perform most activities; symptoms are more numerous and intense when depression is of moderate severity, and the patient is likely to have significant difficulty in continuing with ordinary activities.)22 Three trials included patients with severe depression. Most trials lasted four to eight weeks. Across all reports, 50%-80% of patients improved with SJW, a rate similar to that achieved with conventional antidepressants. Patients with mild to moderate depression fared best. Vorbach et al found SJW superior to imipramine (75 mg/day) in severe depression,15 but the dose of imipramine was inadequate. SJW was found to be as effective as phototherapy in patients with seasonal affective disorder.23

 

Image of the weed
A field of St John's wort. Declared a noxious weed in most areas of Australia, St John's wort is now being seen as a cash crop. Inset: Details of the flower. Photos courtesy of NSW Agriculture.

 
Linde et al concluded that these studies had significant limitations.5 Most of the trials were small and used heterogeneous patient groups. Classification of depression was not uniform and none of the studies lasted longer than 12 weeks. Dosages of antidepressant in the comparison trials were subtherapeutic or in the low therapeutic range.

Mechanism of action Although the exact mechanism of action remains obscure, substances contained in SJW extracts have been found to interact with a number of neurotransmitter systems implicated in depression and in psychiatric illness generally. SJW inhibits uptake of serotonin, noradrenaline and dopamine. Crude extract of SJW has a potent affinity for g-aminobutyric acid (GABA) receptors and inhibits monoamine oxidase.24 Recently, it has been postulated that the antidepressant effect of SJW may be due to its effect on interleukin-6.25 It is also of interest that the plant has high concentrations of melatonin,26 increases nocturnal production of melatonin,4 and increases deep sleep.27 Melatonin is thought to play a role in the aetiology of seasonal affective disorder and sleep.28

"First, do no harm" The popular belief that "natural products are safe" has not always been vindicated, as the tragic experience with royal jelly revealed.29 However, SJW has not been associated with serious adverse events in humans and appears well tolerated. The rates of adverse events with placebo (4.8%) and SJW (4.1%) in placebo-controlled trials are comparable.5 Fewer than 2% of patients in studies have stopped taking SJW.30 In an open trial of 3250 patients taking hypericum, side effects were reported by 2.4% of subjects.30 The most commonly noted adverse events were gastrointestinal symptoms (0.6%), allergic reactions (0.5%), fatigue (0.4%) and restlessness (0.3%). Other adverse reactions reported were emotional vulnerability, pruritus, weight gain and dizziness.4 Severe phototoxicity has been reported in cattle and sheep grazing on the plant8 (the veterinary term is "hypericism"), but not in humans taking therapeutic (antidepressant) doses. However, photosensitivity does appear to be a common problem for AIDS patients treated with high doses of hypericum in studies of the antiviral properties of SJW.4

During the past 25 years there have been three reports, all in the past few months, to the Australian Adverse Drug Reactions Advisory Committee (ADRAC) relating to SJW (Dr Patrick Purcell, Acting Head, ADRAC, personal communication). These comprised hyperaesthesia in a 38-year-old woman; a combination of dyspnoea, flushing, headache, hyperventilation, mydriasis, nausea, pain, palpitations, rhinitis and tremor in a 47-year-old woman; and a fall in cyclosporin levels to 25% of previous levels in a woman in her mid-twenties (enzyme induction?). The low rate of reports to ADRAC may be due to under-reporting, insufficient identifying information about many of the herbs reported, uncommon use (until recently), or a low actual rate of adverse effects.31

Other health claims SJW is being promoted as a treatment for a range of other ailments besides depression, including anxiety and "stress", sleep problems, nocturnal enuresis, bacterial and viral infections, respiratory conditions, peptic ulceration, inflammatory arthritis, cancer, and skin wounds.4 It is also said to increase libido, an application dating from the Middle Ages: Take the ash of starlizard, civet oil and St John's wort oil. Smeared on the toe of the left foot and on the loins, the ointment will serve to reinvigorate.32 Tradition further had it that the herb would be most effective for stimulating sexual desire when picked at night while the picker was naked!32

Preparations, dosage and administration SJW is available as tablets, capsules, drops and teas and is produced by many manufacturers. An oil form is available for external use but has no place in treating depression. The optimum adult dose of SJW for treating depression, based on available studies, appears to be 300 mg of plant extract orally three times daily. However, doses used varied considerably among studies, and there are no systematic studies on the minimum therapeutic dose. Furthermore, the amount of active substances might vary depending on factors such as the extraction process, season, and plant part used. As with prescription antidepressants, there is a lag in onset of action. If side effects are intolerable, or if at six weeks SJW is deemed to be ineffective, the patient can be weaned off SJW and another antidepressant considered. Unfortunately, there are no data about "washout periods" following discontinuation of SJW. A conservative approach is to wait two weeks after ceasing SJW before commencing another agent.

Precautions Because SJW may potentiate monoamine oxidase inhibitors (MAOIs), its combination with these compounds is best avoided. At this stage, combining SJW with other antidepressants is strongly discouraged for the same reasons. To our knowledge, there are no reports of dietary interactions with SJW, similar to those found with MAOIs, and no empirical studies dealing with this issue. Uterotonic activity has been reported in animal experiments,33 and for this reason SJW is not recommended in pregnancy. SJW has not been evaluated in children and adolescents. Because of the potential risk of phototoxicity, it has been suggested that patients should be advised not to sunbathe (naturally or artificially) while taking SJW and not to concurrently use photosensitising drugs such as chlorpromazine or tetracyclines.

Implications for practice, research and policy Over the past few years the physical treatment of depression has been bolstered by the emergence of a number of new classes of antidepressant (such as selective serotonin reuptake inhibitors, reversible inhibitors of monoamine oxidase type A, serotonin and noradrenaline reuptake inhibitors, and 5-HT2 antagonists). A variety of augmenting agents are available and electroconvulsive therapy retains a place for more severe cases. Cognitive-behaviour therapy is also effective. Nevertheless, not all patients benefit from "standard" treatments and some people experience troublesome side effects. Further, antidepressant drugs are yet to meet with uniform community acceptance. A recent national survey found that, for depression, conventional antidepressants were perceived as helpful by 29% of respondents and harmful by 42%.34 In contrast, the treatment category that included vitamins, minerals, tonics and herbal medicines was considered helpful by 57% of respondents and harmful by 3%.

Clearly, there is scope for alternative antidepressants if they can be shown to be safe and effective. SJW is the best known of several herbs being touted as antidepressant.24 However, available evidence for SJW is insufficient at this stage. Indeed, one of the aims of treating depression, the prevention of suicide, could be compromised by using a treatment that is yet to be fully investigated. If SJW is to consolidate a place in the medical armamentarium, several issues relating to clinical practice, research and policy will need to be addressed:

  • Acknowledgement by medical practitioners of the existence of an alternative treatment system. The presence of another therapeutic system cannot be ignored.3,34,35 We need to routinely ask our patients about their use of SJW and other herbal preparations. This is particularly important as concurrent use of SJW and other antidepressant drugs may be harmful.

  • Quality control of SJW preparations. The Register of Therapeutic Goods currently categorises SJW and most herbal preparations as "listed drugs", which are subject to fewer checks than "registered drugs". Apart from having to satisfy less-rigorous efficacy and safety criteria compared with registered drugs, listed drugs lack standardised preparation and are more prone to contamination, substitution, adulteration, incorrect packaging, wrong dosage, and inappropriate labelling and advertising.31 For example, in the case of SJW there is presently no way of knowing that the correct species of Hypericum is used, that the plant is harvested at the right time of year, that appropriate plant parts are chosen, dried and stored properly, and that the extraction process is uniform. All of these are known to affect biological activity.

  • Funding of further research. Several breakthroughs in therapeutics have resulted from the study of natural substances,24 and SJW also promises to be rewarding in this area. However, further research into SJW will need to be funded from outside the pharmaceutical industry, by the National Health and Medical Research Council or other institutions. Herbal treatments cannot be patented, so the financial incentives for research that drive the pharmaceutical market are limited.

  • Determination of the antidepressant component. SJW has many biologically active components. Determination of which of these are antidepressant may, in turn, contribute to the development of more refined preparations of SJW and further antidepressants, as well as increase our knowledge about the aetiology of depression.

  • New treatment studies. To date, duration of trials has ranged from two to 12 weeks. Longer-term studies should be done to assess long term effects and the effectiveness of SJW in preventing relapse. Patient populations need to be described better and therapeutic doses of comparison antidepressants need to be used.

  • Evaluation of SJW in certain subgroups. SJW has mainly been studied in adults with mild to moderate depression. There is a need to evaluate the herb in severely depressed patients. There is also a growing realisation that major depression is not uncommon in young people. Adult data cannot necessarily be generalised to the young, as the experience with tricyclic antidepressants has shown.36 Trials with children and adolescents are therefore necessary.

The current situation in which treatment of depression with SJW is initiated by non-medical persons is fraught with danger. Suicide risk has been mentioned already. Non-medical prescription and supervision may preclude patients from receiving antidepressant treatments of demonstrated effectiveness. This has ethical implications, particularly in the case of children.37 Also, medical conditions that mimic depression, some of them common (eg, hypothyroidism), may remain unidentified and untreated. On the other hand, access to an over-the-counter antidepressant might be useful for patients with subclinical depression who are unlikely to be treated otherwise.38 For these reasons, a wider debate about who should prescribe SJW may be necessary.

We find ourselves in the midst of an era in which new, better-tolerated therapeutic agents are being regularly introduced. Paradoxically, patients are turning to herbal remedies. Time will tell whether, in Australia, SJW is allowed to blossom in medicine as a bona fide antidepressant, or whether it should be weeded out.

Acknowledgements Con Spiliopoulos, Glenda Schaffer, Susie Freeman, Rachel Rees, Patrick Purcell and Helen Cameron are thanked for their assistance.

References
  1. MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 1996; 347: 569-573.
  2. Kristoffersen SS, Atkin PA, Shenfield GM. Uptake of alternative medicine [letter]. Lancet 1996; 347: 972.
  3. Thompson A. As patients embrace herbal remedies, dearth of scientific evidence frustrates clinicians. Am J Health Syst Pharm 1997; 54: 2656, 2658, 2664.
  4. Chavez ML, Chavez ML. Saint John's wort. Hosp Pharm 1997; 32: 1621-1632.
  5. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression: an overview and meta-analysis of randomised clinical trials. BMJ 1996; 313: 253-258.
  6. Cass H. St John's wort: nature's blues buster. New York: Avery Publishing Group, 1998.
  7. Zuess J. The natural Prozac program: how to use St John's wort, the antide pressant herb. New York: Three Rivers Press, 1997.
  8. Wohlmuth H. St John's wort -- phytotherapy for depression. Botanical Pathways 1997; 2: 3-5.
  9. Nash M. Nature's Prozac? Time 1997; Sep 22: 80-81.
  10. De Smet PAG, Nolen WA. St John's wort as an antidepressant. BMJ 1996; 313: 241-242.
  11. Parsons WT. Noxious weeds of Victoria. Melbourne, Inkata Press, 1973.
  12. Crossweller A. Farmers to cash in by weeding out wort. Daily Telegraph (Sydney). 1998; July 6: 5.
  13. Steger W. Depressive verstimmungen. Z Allgemeinmed 1985; 61: 914-918.
  14. Werth W. Psychotonin M versus imipramin in der chirurgie. Der Kassenarzt 1989; 15: 64-68.
  15. Vorbach EU, Hubner WD, Arnoldt KH. Effectiveness and tolerance of the hypericum extract L1 160 in comparison with imipramine: randomised double blind study with 135 outpatients. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S19-S23.
  16. Kniebel R, Burchard JM. Zur therapie depressive verstimmungen in der praxis. Z Allgemeinmed 1988; 64: 689-696.
  17. Bergmann R, Nubner J, Demling J. Behandlungen leichter bis mittelschwerer depressionen. Therapiewoche Neurologie/Psychiatrie 1993; 7: 235-240.
  18. Warnecke G. Beeinflussung klimakterischer depressionen. Z Allgemeinmed 1986; 62: 1111-1113.
  19. Panijel J. Die behandlung mittelschwerer angstustande. Therapiewoche 1985; 41: 4659-4668.
  20. Harrer G, Hubner WD, Podzuweit H. Effectiveness and tolerance of the hypericum extract L1 160 compared with maprotiline: a multi-centre double-blind study. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S24-S28.
  21. Ditzler K, Gessner B, Schatton WFH, Willems M. Clinical trial on Neuropas versus placebo in patients with mild to moderate depressive symptoms: a placebo- controlled, randomised double-blind study. Complement Ther Med 1994; 2: 5-13.
  22. World Health Organization. The ICD-10 classification of mental and behavioral disorders. Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization, 1992; 121-122.
  23. Martinez B. Hypericum in the treatment of seasonal affective disorder. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S29-S33.
  24. Cott J. Natural product formulations available in Europe for psychotropic indications. Psychopharmacol Bull 1995; 31: 745-751.
  25. Thiele B, Brink I, Ploch M. Modulation of cytokine expression by Hypericum extract. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S60-S62.
  26. Murch SJ, Simmons CB, Saxena PK. Melatonin in feverfew and other medicinal plants. Lancet 1997; 350: 1598-1599.
  27. Schulz H, Jobert M. Effects of hypericum extract on the sleep EEG in older volunteers. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S39-S43.
  28. Wirz-Justice A. Biological rhythms in mood disorders. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press, 1995; 999-1018.
  29. Bullock RJ, Rohan A, Straatmans JA. Fatal royal-jelly induced asthma [letter]. Med J Aust 1994; 160: 44.
  30. Woelk H. Benefits and risks of the hypericum extract L1 160: drug monitoring study with 3250 patients. J Geriatr Psychiatry Neurol 1994; 7 Suppl 1: S34-S38.
  31. Drew AK, Myers SP. Safety issues in herbal medicine: implications for the health professions. Med J Aust 1997; 166: 538-541.
  32. Fletcher K. Themes for herbal gardens. Ringwood, Victoria: Viking, 1996; 16.
  33. Shiplochliev T. Extracts from a group of medical plants enhancing the uterine tonus. Vet Med Nauki 1981; 18: 94-98.
  34. Jorm AF, Korten AE, Jacomb PA, et al. Mental health literacy: a survey of the public's ability to recognise mental disorders and their beliefs about the effectiveness of treatment. Med J Aust 1997; 166: 182-186.
  35. Shenfield GM, Atkin PA, Kristoffersen SS. Alternative medicine: an expanding health industry. Med J Aust 1997; 166: 516-517.
  36. Hazell P, O'Connell D, Heathcote D, et al. Efficacy of tricyclic drugs in treating child and adolescent depression: a meta-analysis. BMJ 1995; 310: 897-890.
  37. Komesaroff PA. Use of complementary medicines: scientific and ethical issues. Med J Aust 1998; 169: 180-181.
  38. Cott JM, Fugh-Berman A. Is St John's wort (Hypericum perforatum) an effective antidepressant? J Nerv Ment Dis 1998; 186: 500-501.

Authors' details Rivendell Unit, Concord West, NSW.
Joseph M Rey, PhD, FRANZCP, Director, and Clinical Professor, Department of Psychological Medicine, University of Sydney;
Garry Walter, FRANZCP, Inpatient Director, and Clinical Lecturer, Department of Psychological Medicine, University of Sydney.

Reprints will not be available from the authors.
Correspondence: Dr J M Rey, Rivendell Unit, Hospital Road, Concord West, NSW 2138.
E-mail: jreyATmail.usyd.edu.au

©MJA 1998
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