8. Research in herbal medicine
Simon Y. Mills
Chapter contents
Introduction151
The evidence fragments152
Prospects from herbal research162
Conclusions and recommendations167
Introduction
Although herbal or plant-based remedies are extremely popular treatments around the world, their use in developed countries invokes complex regulatory and academic issues. In some parts of the world, notably the USA, they are supplied as dietary supplements with relatively few regulatory or scientific standards. In other countries they may hold default medicinal status. In Europe particularly, where herbal remedies are referred to as ‘herbal medicinal products’, ‘phytomedicines’ or ‘plant drugs’, they are regulated alongside conventional medicines, at least as far as standards of quality and safety are concerned. In some countries phytomedicines are actually orthodox pharmaceuticals, prescribed by doctors and dispensed or supplied primarily by pharmacists.
Herbal medicines are perhaps the most tangible targets among complementary treatments for research and investigation. The leading manufacturers in Europe have a long history of providing clinical data in the orthodox forum and there is a relatively good stock of scientific literature. Herbs can also be the origin of new synthetic medicines. They may even be the basis of patentable extracts. All this means that research into their activity can be commercially justified. There is a vast record of scientific papers in which plants or their constituents have been subject to laboratory studies to investigate their prospects for leads in pharmaceutical research. Even though the trend in pharmaceutical research is moving away from plant leads and the long-term prospects here are not promising, the levels of published papers show no signs of reducing.
However, there is a difference between plants as leads for pharmaceutical development and as herbal medicines used by humans. Unfortunately the clinical evidence base for the use of plants as medicines has at best been patchy. The use of herbal medicines as elements in considered clinical strategies, as applied by qualified herbal practitioners for example, has as poor a publication record as any other complementary discipline. Establishing efficacy of herbal products in law has usually been a pragmatic exercise. Undemanding requirements in lieu of clinical evidence have recently been adopted in Europe and the future prospect for research investment by herbal medicine manufacturers has unfortunately been diminished.
Experience of herbal remedies within a modern medical culture does confirm that they have distinguishing features. They have been used continuously for many decades or centuries, often in ways much different from those of modern prescription. Their modern and traditional descriptions are often very different. Plants consist of many chemical constituents with inherent variability and with complex pharmacological effects on the body. There are different issues of both efficacy and safety and it is unwise to compare them directly to medicines made up of single chemical entities. To be consistent to this difference the research methods employed should also be adapted.
One research area of promise is the massive human experience of herbal remedies. Even today the World Health Organization considers that the majority of remedies consumed by humans around the world are plant-based in a traditional context, and historically the dominance of plants in medicine must have been overwhelming. The vast majority of this human use is unrecorded and most of the available data are not rigorously collated. However, there is still a rich vein of material to be mined and proposals are outlined here.
The evidence fragments
There are four major types of research data on medicinal plants or their constituents (Table 8.1). As these are more than are available for other complementary treatments it is fair to subject them to a robust test of relevance. They may be reviewed from the perspective of a herbal remedy user, whether through self-prescription or in herbal practice. Do they help to make an informed decision about the safe and beneficial use of a herbal remedy? Most of these sources of data fail this test and remain barely useful fragments.
| Fragment | Positives | Problems |
|---|---|---|
| Controlled clinical trials |
Highest-quality evidence of the specific effects of a remedy
Particularly relevant to the remedy and to the main use of herbs for self-medication
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Economics not suited to trials in non-proprietary products
Methodological challenges for herbal remedies
Clinical trial findings may be inappropriate for self-medication
Reduced incentives of new legislation
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| Animal studies |
Prominent in herbal scientific literature
May allow insight into pharmacological and physiological processes
|
Ethically unacceptable to many who might choose the herbal option
Many trials compromised by unrealistic dosing
Interspecies differences in metabolism of key plant constituents
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| In vitro studies |
Vast proportion of literature, linked mainly to pharmaceutical development
May allow insight into cellular processes, particularly where plant products are administered externally or by injection
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Cannot account for the fact that most plant constituents are metabolically altered on oral consumption
Usually other unrealistic dosage regimens
Distorting effects of using glassware on plant materials chosen for research
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| Traditional use evidence |
Overwhelming human medical experience through history
Relates to actual dose and human use of herbs
With systematic organization collective experiences may be extracted and linked to evidence in other fragments
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Uncontrolled observations masked by non-specific and cultural effects and observer bias
Records usually of poor quality
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Fragment 1: controlled clinical trials
In the case of clinical trial evidence, the literature is mixed. There are increasing well-conducted random-assigned, double-blind controlled studies, and even systematic reviews of these. The literature on ginkgo (Ginkgo biloba) (The European Scientific Cooperative on Phytotherapy 2003), which has been among the most widely prescribed of all drugs in continental Europe, and on St John’s wort (Hypericum perforatum) (The European Scientific Cooperative on Phytotherapy 2003), many hundreds of papers in each case, with dozens of these being full clinical trials.
There is little doubt that orthodox evidence requirements are potentially appropriate for most herbal medicines consumed by the public. Over-the-counter (OTC) herbal use in Europe far outstrips practitioner prescription, probably by a factor of more than 20:1 (IMS/PhytoGold 1998). For researching OTC label indications for discrete medicinal products, in which individual responses to remedies are not the critical issue, the double-blind controlled clinical trial is clearly the most applicable method. In addition, as the ‘patient’ is in many cases not being diagnosed professionally and is determining his or her own treatment and prognosis, self-assessment questionnaires are often an appropriate measure of progress. These are not expensive to administer. As this is often ‘outpatient’ medicine research, costs can be saved as close clinical supervision need not be always be necessary throughout the trial.
There are however practical problems in pursuing good clinical research in herbal medicine:
1. Herbal medicine in the west can boast few teaching hospitals or research institutes, nor support from public resources. Industrial investment has been limited to a few larger manufacturers used to working in a pharmaceutical culture. In most parts of the sector the necessary infrastructure is lacking. Neither can the costs of undertaking research studies easily be commercially justified: it is difficult to patent herbs and the size of the market for any individual product is only occasionally comparable to that for any patentable conventional drug. Commercial investment in clinical trials costing many hundreds of thousands of euros per product can only be justified if manufacturers can recover their investment in the market. A crude herbal is free for anyone to copy. Leading phytomedicine manufacturers therefore produce new extracts from plants that they can commercially protect. For example, there are almost no clinical trial data for ginkgo leaves as such: the research has been conducted on patented extracts of ginkgo (notably one known as EGb761) (Kressman et al. 2002). The same is largely true for black cohosh, saw palmetto, St John’s wort, horse chestnut and kava. It is difficult for the wider herbal community to claim efficacy for non-standardized products based on these clinical data. The very high and rapidly escalating costs of conducting clinical trials to modern ethical standards and regulatory requirements put off all but the most promising prospects.
2. The indications often claimed for herbal medicines include many without robust outcome measures. Most are destined for the self-medication OTC market so are by definition directed at lesser degrees of morbidity where hard measures are elusive. By contrast, most synthetic OTC medicines on the market have ‘switched’ from prescription status and have acquired their efficacy evidence on harder clinical indications and in hospital or similar settings. Without hard or acceptably validated outcome measures, with more variable and lower-grade symptoms among the patient population, and with a greater likelihood of self-limiting or other spontaneously changing conditions, clear treatment effects are harder to establish. The result is that it is usually particularly necessary to recruit large patient samples and to devise tight exclusion criteria to constrain variation in the sample. All this places extra logistical demands on those wishing to set up effective clinical trials for these products.
3. Herbs are compound medicines, occupying an unusual position as being medicines with many of the characteristics of foods. As a complex of pharmacologically active chemicals, the whole package will have different properties from that of any single constituent acting alone. Knowing the action of the latter will not itself be predictive on the effect of the former, particularly if the experimental evidence is based on work done on laboratory animals (see below). It is therefore rare to find the satisfactory preclinical evidence often required by ethics committees for the approval of major clinical studies.
4. There are some instances in herbal research where blinding will be difficult. For example, bitter remedies, potentially mediated by the effects on digestive functions of stimulation of the bitter taste buds, have played an important part in the claims of traditional herbal medicine: this is almost impossible to blind. There will as always be a role for the good single-blind study, especially if other elements are rigorously controlled.
5. In the past clinical studies in the use of herbal medicines have often been of indifferent methodological quality. Modern studies, even those otherwise highly rated, can be undermined because they neglect basic precautions against the very variable quality of herbal products. In a surprising proportion of clinical trial papers the herbal product used is not quantified, stabilized or verified (Wolsko et al. 2005). Other studies may not relate to the herbal remedy as such but to its chemically defined ingredients. For example, the well-claimed benefits of horsechestnut (Aesculus hippocastanum) on the venous system are actually based on studies of a major constituent, aescin. Many studies on kava-kava (Piper methysticum) are actually of the pyrone kavain. It may be even more misleading: the reputation that the greater celandine (Chelidonium majus) has in liver conditions is based on commercially sponsored studies on a semisynthetic derivative Ukrain.
6. There are other unintended consequences of clinical research that can limit their benefits to manufacturers. It is surprising how even the best track record of research has failed to lead to medicine registrations outside central Europe: St John’s wort, ginkgo and hawthorn (Crataegus spp.) are prescription medicines in Germany but have no medicinal status at all in the UK and USA. In part this is linked to the indications established by such studies. In all three cases the studies point to uses that are not appropriate for unsupervised self-medication – depression, cardiovascular disease and heart disease respectively. Because self-medication is generally permitted only for minor self-limiting conditions, in those countries where herbs are more likely to be chosen by the public clinical research may actually be counterproductive.
Looking ahead there are new reasons for concern. In Europe, where so much of the herbal clinical literature has been generated, there is a new regulatory regime. The Directive on Traditional Herbal Medicinal Products permits the registration (rather than licensing) as medicines of herbal products on the basis of their traditional use rather than on proven efficacy (Directive 2004). Such products still have to comply with pharmaceutical good manufacturing practice (GMP) and safety monitoring, but there is no longer any incentive to prove their efficacy in clinical trials. In fact, as the Directive does not apply ‘where the competent authorities judge that a traditional herbal medicinal product fulfils the criteria for authorization’, any such data may bar a herbal product from the less expensive registration option and lead to a requirement that it be licensed as a full medicine. There is a concern that the new Directive will lead to a progressive devaluing of herbal medicines and a drying up of clinical research activity.
The herbal practitioner, or phytotherapist, has other reasons to note the limitations of the controlled clinical study. Herbal practitioners emphasize the individuality of their treatments; they most often mix a number of individual herbs in a prescription and in many cases construct a unique mixture. Like other complementary practitioners they might also point out that conventional clinical trials involve the homogenization of the patient population so that only an average effect is confirmed and genuinely important benefits for a minority of the population will be overlooked. Clinical trial data will help with, but still not answer, the fundamental question: ‘is this remedy going to be good for this patient?’
Nevertheless the controlled clinical trial is a notably flexible instrument and clinical trial data at least involve rigorous observations of human use of plants: of the forms of research available they are by far the most valuable in making clinical judgements. Perhaps better hopes lie with the moves towards sustainable economic development in countries around the world. Renewed interest in the potential of indigenous medical traditions, in some cases linked to emerging economies, has increased research activities in a wider range of plants (Blumenthal & Cavaliere 2006). At best standards developed for herbal research in Europe can be exported to improve the quality of investigation elsewhere and new products linked to sustainable ‘freetrade’ arrangements. There is still a hunger for beneficial natural medicines. If there is any substance in the promise, new ways will be found to service that demand.
Fragment 2: evidence from animal studies
Investigations of medicinal activity in animals raise particular concerns among those who would otherwise be amenable to using herbal approaches and are therefore often discouraged in the herbal industry. However it is salutary to note that the international scientific literature on plant remedies and their constituents is still dominated by in vivo studies.
As well as challenging moral and ethical sensibilities such studies have other shortcomings. They are always undermined by interspecies differences and often by therapeutically inappropriate mode of application. Observations often relate to unrealistically high doses, and particularly to intraperitoneal or intravenous injection rather than oral administration. In the case of plants, whose constituents are usually transformed by digestive action and hepatic first-pass effect, these latter factors seriously undermine any projection to the effect of the whole plant on oral consumption in humans. Differences in liver processing among animal species add a particular extra uncertainty for complex chemical entities like plants. It has been established, for example, that critical P450 cytochrome metabolic pathways differ significantly in laboratory animals compared to humans (Blumenthal & Cavaliere 2006).
At best oral administration of plants in realistic doses to animals may help to explore some basic pharmacological processes. In most cases these data should be ruthlessly marginalized in projecting clinical effects in humans.
Fragment 3: evidence from in vitro studies
In laboratory experiments it is extremely difficult to reproduce the balance of plant constituents that will actually reach internal tissues after digestion, absorption and the hepatic first-pass effects. In cell and tissue cultures concentrations of active principles at cell membranes and receptors usually far exceed those ever reached in vivo.
Most in vitro studies are on isolated fractions of the plant. It is very doubtful that the action of the whole plant can be determined by knowing the effects of individual constituents. Interaction between dozens or even hundreds of these limits the inferences that can be drawn. There have been some calculations demonstrating the synergistic effects of plant constituents in the whole plant which reinforce this point (Bogaards et al. 2000).
One particular hurdle arises from the historical choice of glass (‘vitro’) to conduct these experiments. Some key plant constituents are adherent to glass surfaces and quickly coat glassware, so compromising observations. Plants therefore have to be ‘cleaned up’ before being tested, leaving out important principles like resins, tannins, gums and mucilages.
The best that can be claimed for this work is that it may suggest pharmacological mechanisms. It can have almost no impact on judgements in clinical practice.
Fragment 4: evidence from traditional use and practitioner experience
Accounts of other people’s use of medicines, particularly by observers outside the culture concerned, are vulnerable to observer error and usually relate to isolated cases or reputations in which non-specific influences on efficacy may be overwhelming. Without some form of confirmation any such report is at best an anecdote and when the additional cultural contexts are added it is difficult to generalize to the wider human community. Organized traditional records, as in the classic texts from earlier cultures, may be more systematized but suffer from ‘shibboleth’ status: they are very rarely subject to rigorous review and have usually been transmitted didactically in a way that may enhance the powerful impact of suggestion on efficacy. Nevertheless, even with these caveats, clinical experience is the prime source of information on which most practitioners in any tradition base their judgements. Although personal perceptions of treatment benefit are obscured by non-specific effects, including placebo, collective impressions have great potency in determining the therapeutic profile of any remedy. Indeed it has been proposed that herbal texts may provide resources for modern data-mining techniques to identify novel pharmacotherapeutic leads for bioactive compounds (Williamson, 2001 and Buenz et al., 2006). Substantial accounts, for example as seen in systematic compilations of ethnobotanic records (Moerman, 1998, Allen and Hatfield, 2004 and Buenz et al., 2004), can provide valuable sources for processing and distillation. Organized pre-modern physician texts, such as those of Eclectic physicians of 19th-century North America (Perry 1980), have relevance in modern clinical experience and should not be dismissed. The vast classical literature from China, India, Islamic and other regions is still the basis of medical practice and education in these countries today. There is potential – largely unexplored – scope for a distillation of such experiences. One form of correlation between traditional use and pharmacological research is outlined in Table 8.2 and referred to on page 161.
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