Systematic reviews of complementary therapies – an annotated bibliography. Part 2: Herbal medicine

Background Complementary therapies are widespread but controversial. We aim to provide a comprehensive collection and a summary of systematic reviews of clinical trials in three major complementary therapies (acupuncture, herbal medicine, homeopathy). This article is dealing with herbal medicine. Potentially relevant reviews were searched through the register of the Cochrane Complementary Medicine Field, the Cochrane Library, Medline, and bibliographies of articles and books. To be included articles had to review prospective clinical trials of herbal medicines; had to describe review methods explicitly; had to be published; and had to focus on treatment effects. Information on conditions, interventions, methods, results and conclusions was extracted using a pre-tested form and summarized descriptively. Results From a total of 79 potentially relevant reviews pre-selected in the screening process 58 met the inclusion criteria. Thirty of the reports reviewed ginkgo (for dementia, intermittent claudication, tinnitus, and macular degeneration), hypericum (for depression) or garlic preparations (for cardiovascular risk factors and lower limb atherosclerosis). The quality of primary studies was criticized in the majority of the reviews. Most reviews judged the available evidence as promising but definitive conclusions were rarely possible. Conclusions Systematic reviews are available on a broad range of herbal preparations prescribed for defined conditions. There is very little evidence on the effectiveness of herbalism as practised by specialist herbalists who combine herbs and use unconventional diagnosis.


Introduction
In this second part of our series on systematic reviews in complementary therapies we report our findings on herbal medicines. Herbal medicines (defined as preparations derived from plants and fungi, for example by alcoholic extraction or decoction, used to prevent and treat diseases) are an essential part of traditional medicine in almost any culture [1]. In industrialized countries herbal drugs and supplements are an important market. Some countries like Germany have a long tradition in the use of herbal preparations marketed as drugs and figures for prescriptions and sales are stable or slightly declining [2]. In the US and the UK herbal medicinal products are marketed as "food supplements" or "botanical medicines". In recent years sales of such products have been increasing strongly in these countries [3,4]. In the Third World herbs are mainly used by traditional healers [5].

Methods
A detailed description of the methods used in this review of reviews is given in the first part of this series [6]. For searches in Medline 50 single plant names and the 'exploded' term 'medicinal plants' were combined with the standard search strategy for systematic reviews. As a specific intervention-related inclusion criterion we required that reports reviewed prospective (not necessarily controlled) clinical trials of substances extracted from plants in humans. Reviews dealing with single substances (e.g., artemisin derivatives) derived from plants were excluded on the grounds that such agents are comparable to conventional drugs. Disease-oriented reviews including a variety of interventions were included only if they reviewed at least 4 herbal medicine trials.
More than half of the reports reviewed gingko, hypericum or garlic preparations. No less than 13 systematic reviews dealed with ginkgo (Ginkgo biloba) extracts (see table 1). Seven of these reviewed trials (total number of trials covered in any of the reviews 15) in patients with intermittent claudication [7][8][9][10][11][12][13]. Most of these reviews concluded that ginkgo extracts were significantly more effective than placebo in increasing measures like walking distance but the clinical relevance of the effects was felt to be moderate by some reviewers. The five reviews dealing with dementia and cerebral insufficiency (total number of trials included about 50) all draw positive conclusions [13][14][15][16][17]. However, many of the older trials were in patients with minor cognitive impairment and more evidence is needed to decide whether ginkgo ex-tracts have clinically relevant beneficial effects in more severe forms of dementia. Finally, one review found that ginkgo extracts might be effective in the treatment of tinnitus [18] and another found insufficient evidence for efficacy in patients with macular degeneration [19].
The effectiveness of St. John's wort (Hypericum perforatum) extracts in depression was investigated in nine reviews [20][21][22][23][24][25][26][27][28][29][30] (total number of trials covered 29; see  table 2). Mainly due to slight differences in the inclusion criteria (for example, restriction to trials with a minimum of 6 weeks observation or with a minimum quality score) the respective study collections differed to a considerable amount. However, the conclusions were very similar. Hypericum extracts have been shown to be superior to placebo in mild to moderate depressive disorders. There is growing evidence that hypericum is as effective as other antidepressants for mild to moderate depression and causes fewer side effects but further trials are still needed to establish long-term effectiveness and safety.
Eight reviews have been performed on garlic (Allium sativum) for cardiovascular risk factors [31][32][33][34][35][36][37][38] (total number of trials covered about 50) and lower limb atherosclerosis [39] (see table 2). A modest short-term effect over placebo on lipid-lowering seems to be established but the clinical relevance of these effects is uncertain. Data from randomised trials on cardiovascular mortality are not available. Effects on blood pressure seem to be at best minor. The available results on fibrinolytic activity and platelet aggregation are promising but insufficient to draw clear conclusions. A specific problem in research on garlic is the great variety of garlic preparations used: the exact content of bioactive ingredients in these is often unclear.
The only review which focused on a herbal intervention which is not marketed as a drug or food supplement was on cabbage leaves for breast engorgement and included a single small-scale trial [68]. Chinese herbal therapy for atopic eczema [69] and a variety of herbs for lowering blood glucose [70] and for analgesic and anti-inflammatory purposes [71] have also been reviewed. For some of these herbal preparations the evidence is promising but further studies are considered necessary to establish efficacy in almost every case.  [19] degeneration y/-improvement recommend ginkgo for age-related macular degeneration Features: 1 = comprehensive search, 2 = explicit inclusion criteria, 3 = formal quality assessment, 4 = summary of results for each included study, 5 = meta-analysis; y = yes, p = partly, n = no, -= not applicable, ? = unclear review on all pharmacologic treatments for the respective condition RCT = randomized controlled trials, CCT = non-randomized controlled trials, CS = cohort studies, UCS = uncontrolled studies; OR = odds ratio, RR = rate ratio

Discussion
Our overview shows that a considerable number of systematic reviews on herbal medicines is available. In the majority of cases the reviewers considered the available evidence as promising but only very rarely as convincing and sufficient as a firm basis for clinical decisions. The methodological quality of the primary studies has been criticized by many reviewers.
Our summary of the existing studies must be interpreted with caution. What we performed is a systematic review of systematic reviews which inherently bears a large risk of oversimplification. Readers who want to reliably assess the evidence for a given herb for a defined condition should read the respective reviews. Our collectionwhich to the best of our knowledge is complete up to summer 2000 -is aimed at facilitating the access and giving an idea of the amount of the available evidence.
Based on the increase of herbal medicine reviews in recent years we expect that at least ten new publications will become available in the year 2001.
Most of the currently available systematic reviews address herbal preparations which are marketed and widely used in industrialized countries. However, the widespread traditional use of herbs in the Third World is rarely ever investigated and has not been subjected to systematic reviews. The many herbs used in folk medicine or other traditional uses of herbs (for example, hypericum is used for a variety of ailments other than depression including enuresis, diarrhoea, gastritis, bronchitis, asthma, sleeping disorders etc.) seem to be rarely investigated. Furthermore, practitioners of herbal medicine often combine different herbs and use unconventional diagnostic approaches to adapt prescriptions to single patients. It seems likely that these traditional  forms of herbal medicine will remain underresearched relative to single herbal preparations due to the lack of financial incentive for sponsors and due to methodological problems.
Herbal medicines products are not, in general, subject to patent protection. This reduces the motivation for drug companies to invest in trials. Many of the existing herbal medicine manufacturers are comparably small companies, often with limited research resources and expertise. Maybe partly for these reasons, the quality of many older herbal medicine trials is low. Furthermore, negative trials which could threaten the company's survival might not become published.
A fundamental problem in all clinical research of herbal medicines is whether different products, extracts, or even different lots of the same extract are comparable and equivalent. This is a major issue in the expert research community and a major obstacle to a reliable assessment for the non-expert. For example, Echinacea products can contain other plant extracts, use different plant species (E. purpurea, pallida or angustifolia), different parts (herb, root, both), and might have been produced in quite different manners (hydro-or lipophilic extraction). Pooling studies that use different herbal products in a quantitative meta-analysis can be misleading. Health care professionals and patients considering to prescribe or take a particluar herbal product should check carefully whether the respective product or extract has been tested in the trials included in a review. On the health food store shelf the high quality, standardized products used in the trials might not be available. Only a herbal medicine expert can judge with some certainty whether the results can be extrapolated to the product of interest.
On the level of health care policies the available systematic reviews more often provide insight into the deficiencies of the evidence than guidance for decision making. Trials on hard endpoints are very rarely available and observation periods have generally been short. The clinical relevance of the observed effects is not always clear.
Herbal medicines are generally considered as comparably safe. While this is probably correct case reports show that severe side effects and relevant interactions with other drugs can occur. For example, hypericum extracts cause considerably fewer side effects than tricyclic antidepressants [92] but can decrease the concentration of a variety of other drugs by enzyme induction [93]. Several reviews summarizing side effects and interactions have been published [94][95][96][97][98].
In conclusion, the systematic reviews collected for this analysis are a good tool to get an overview of the available evidence from clinical trials in the area of herbal medicine. However, applying the findings to patients care is problematic for those who are not experts in herbal medicine. In this case it might be better to directly search the literature for clinical trials of the respective product.