The Pharmaceutical Journal
Vol 274 No 7340 p302-303
12 March 2005

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Developing evidence-based PILs to inform the public about St John’s wort

In this article, Michelle King describes how, in response to requests from the public, a group in Grampian reviewed the evidence, dealt with uncertainties and produced patient information leaflets on the herbal remedy St John’s wort

St John’s wort is commonly used by members of the public to treat depression. Despite the need for authoritative and independent advice about this herbal remedy, information can be patchy and is often inaccessible to the public.

Repeated requests for information on St John’s wort were anecdotally reported by the local Healthpoint, an NHS centre, which provides a wide range of advice on health-related matters to the public. The Healthpoint policy, at the time, was not to recommend St John’s wort; however the information to justify this recommendation or to allow the enquirer to make an informed choice was limited. This was further complicated by uncertainties about the extent of existing evidence for St John’s wort and whether it was not being recommended because of perceptions of risk, lack of efficacy or for other reasons. Healthpoint staff approached the Grampian specialists in pharmaceutical public health to ask if we could help clarify the issue and develop evidence-based patient information to help them deal with enquiries from the public.

Finding the evidence?

The first step in the task was to identify the evidence. This included evidence for efficacy, side effects, drug-drug interactions and drug-disease interactions and was in the context of using St John’s wort as a self-help treatment for mild depression. We searched a number of databases, including Cochrane, Pubmed, International Pharmaceutical Abstracts and Cumulative Index to Nursing and Allied Health Literature, to find entries on St John’s wort. We were particularly interested in systematic reviews and randomised controlled trials comparing St John’s wort with other treatments and with placebo. We consulted standard texts, for example, the British National Formulary¹ and Martindale², and we visited the website of the Medicines and Healthcare products Regulatory Agency to identify safety issues. Other issues associated with the use of St John’s wort were identified and investigated by reading texts on herbal medicine and articles identified in the initial searches or their references. We used “Google” to search for useful internet sites and, more importantly, to examine the information an informed member of the general public could access. Finally, we contacted a drug information specialist with a personal interest in the toxicology of herbal medicines.

Sharing the evidence

The evidence we collated was summarised in a briefing paper, which also identified issues for discussion. The briefing paper was used to provide background information for stakeholder health professionals who would either be affected by the provision of advice on St John’s wort or whose expertise was in the area of mental health. We sent it, along with an invitation to attend a meeting to discuss the evidence and agree on the advice, to pharmacists from a variety of backgrounds (including community pharmacists, mental health pharmacists and public health pharmacists), a GP, mental health consultants and staff from Health Promotions (a sub-division of the department of public health, NHS Grampian) and the Healthpoint.

This early involvement of stakeholders was important to address concerns before they became barriers, to make the policy relevant to those involved, to raise awareness of the policy and to incorporate a variety of views.

The briefing paper presented evidence in a referenced format with links to e-resources where possible. It also identified areas where evidence was lacking along with important issues that needed to be dealt with. This allowed those involved to form their own evidence-based opinions, to go back to the literature if necessary and to have time to think about the issues identified in the briefing paper before attending the meeting. The issues were:

· The distinction between mild to moderate and severe depression
· Effectiveness of St John’s wort compared with placebo and existing therapies
· Side effects
· Drug interactions
· Strength of preparations used in trials
· Quality and consistency of St John’s wort products

The meeting started with a general discussion of the evidence. In subjects with mild to moderate depression, there appeared to be evidence of efficacy compared with placebo, tricyclic antidepressants and, although it was limited, selective serotonin reuptake inhibitors. There was hardly any evidence to support the use of St John’s wort in subjects with severe depression. Comparisons of exercise and St John’s wort were not identified in the literature, leaving the question “Is exercise a better treatment for depression?” unanswered. Exercise certainly had many other benefits to offer with limited potential for adverse outcomes.

Two aspects of the use of St John’s wort were quickly focussed upon: reality and risk.

The reality is that people can buy St John’s wort from a variety of outlets, often take it without consulting a health professional and do not inform their doctor or pharmacist that they are taking it.

The risk is that severe depression is an illness where delay in treatment can have tragic consequences. And, although the side effects of St John’s wort are not particularly alarming, drug-drug interactions can be life threatening and the concentration of both antidepressant and enzyme inducer in the product is almost always unknown.

St John’s wort is standardised on hypericin content. However, hyperforin and, possibly, other substances contribute to the antidepressant effect³ and enzyme induction.⁴ Tests on commercial products show wide variation between the hypericin content stated on the label and that extracted from these products.⁵ Indeed, the BNF warns about variation in St John’s wort preparations.¹ Theoretically, different batches of the same brand can also vary owing to variations in the source of the plant material and its growing conditions, or the practice by some brand holders of contracting out the manufacture of the product to different manufacturers; unfortunately there is no published research to clarify this.

Ultimately, the meeting decided that, since there was sufficient evidence of effectiveness to support the use of St John’s wort and because it was readily available, appropriate use and risk management were the most important issues to address. We acknowledged the role of the internet, the informed patient and patient autonomy, because many people would decide to take St John’s wort based on information obtained from the internet and could legally purchase the remedy from a supermarket or health food store. Unfortunately, internet resources rarely identified or discussed risk.

How to share evidence with the public

We agreed to produce two patient information leaflets.

The first, a credit card-sized leaflet aimed at minimising the risks associated with taking St John’s wort, was intended to be made available at the point of sale in pharmacies, supermarkets and health food stores.

The second, a tri-fold leaflet that included more information on St John’s wort along with advice on other self-help treatments for depression, was to be made available at the Healthpoint and in pharmacies. The credit-card sized leaflet was aimed at customers who self-selected St John’s wort, and the trifold leaflet was for those who wanted more information about the remedy or ways of self-managing mild depression.

Identifying risks

Advising patients when to consult a doctor was a multifactorial problem with no clear answers. There were no specific symptoms that could be used to differentiate between mild to moderate and severe depression leaving a diagnostic dilemma which, unless the person sought medical advice, could not easily be solved. Seeking medical advice for a dip in the ups and downs of normal life is unnecessary and a waste of resources; on the other hand the prevention of self-harm is extremely important. But how does one distinguish between the two?

A clear cut-off for the time a person should endure depressive symptoms before seeking medical treatment is also difficult to define, because it depends on the severity of depression and its effect on daily living. Unless there is a sensitive and specific self-administered test to separate those who need medical attention and those who do not, uncertainty must be acknowledged and the risk of a tragic outcome weighed against its likelihood and the resources available to prevent it. In other words, professional judgement is used to determine the cut-offs with the knowledge that there is no correct answer but that at a population level some answers are better than others. We agreed on the inclusion of advice to consult a doctor if the depression was severe, had persisted for more than three months or if St John’s wort had not helped within six to eight weeks.

Despite a general preference within the stakeholder group for the involvement of health professionals in a person’s decision to take St John’s wort, there was no way of ensuring this. There was also concern that unnecessary GP consultations would be generated by directing all patients to consult their doctor or pharmacist before taking St John’s wort, or to inform them they were taking it. As a result, purchasers were encouraged to inform their doctors and pharmacists at their next visit. This delay, or indeed the possibility that doctors and pharmacists might never be informed, was also of concern. Some of the interactions between St John’s wort and other medicines are potentially life threatening and we considered this to be an unacceptable risk. Therefore interaction advice that addressed the self-selection of St John’s wort without any input from a health professional was necessary. This advice also needed to consider those about to take St John’s wort for the first time and those already taking it, including those taking St John’s wort and an interacting medicine who might read the leaflet and decide to stop taking it. As a result, we included a list of the interacting medicines to help purchasers identify their need for professional advice. This was accompanied by advice to consult a doctor or pharmacist before starting or stopping St John’s wort if taking any of the listed medicines.

The potential for variation between products resulted in the explicit identification of this problem and advice to “always use the same brand”. Owing to lack of evidence, and highlighting the need for more research, the potential for batch variation was not included in the advice.

Consultation and feedback

The leaflets have been distributed for comment to health professionals and the public, and we hope the final versions will be ready soon. So far the feedback has been useful and has focused on the areas where there are no definitive answers, highlighting the variability of professional judgement. We dealt with this variability through consultation and collaboration and by explicitly recognising what the unknowns were.

In conclusion, although there are a variety of factors to consider when providing medicine-related advice, evidence, risk, discussion with others and pragmatism are useful foundations on which to build a course of action.

Acknowledgements Thanks to Alison Blenkinsopp for her comments and the idea that writing about this experience might be helpful to those dealing with uncertainties, to Anna Drew for additional drug information, to those involved in developing the leaflets and to those who provided feedback.

References

1. British National Formulary (47th edition). London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
2. Sweetman SC (editor). Martindale: The complete drug reference (34th edition). London: Pharmaceutical Press; 2004.
3. Barnes J. Herbal therapeutics: depression. Pharmaceutical Journal 2002;268:908–10 (PDF 70K)
4. Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM et al. St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proceedings of the National Academy of Sciences USA 2000;97:7500–02.
5. Wang ZJ, Lin SM, Hu ML. Contents of hypericin and pseudohypericin in five commercial products of St John’s wort (Hypericum perforatum). Journal of the Science of Food and Agriculture 2004;84:395–7.