Wednesday, 6 November 2013

Herb-Drug Interactions

Herbal medicine has become an increasingly popular health-care choice and this growing trend has attracted the attention of the orthodox medical community who consider herbs as pharmaceutical agents which need to meet the safety and efficacy criteria that medical drugs are expected to meet within the modern paradigm of evidence based medicine (EBM).

From my own experience as a herbal practitioner and as an officer in a professional association many herbalists I encounter seem concerned about the potential of losing the traditional aspects of their practice by having herbal medicine evaluated solely by EBM, and in particular the reductionist philosophy at its centre which appears ill-equipped to evaluate the holistic paradigm upon which traditional herbalism rests. Consequently there is a growing tendency among herbalists to disregard clinical research.

I would contend that this position is untenable because although herbal medicine has 'worked' for centuries without any such 'research' per se, the issue of herb-drug interactions presents a case for reconsideration. I examine this issue within the wider context of epistemological conflicts.

I suggest pause for thought with the risks associated with herb-drug interactions out of concern for patient safety. There is no experience within the herbal tradition with herb-drug interactions upon which to draw until recently. In reconsidering research from this perspective I have informed my practice and developed a more mulch-perspective approach. This has led me to consider what other types of research may be useful and highlighted the need to consolidate perspectives as herbal medicine moves into the 21st century.


Herbal medicines are becoming increasingly popular with demand increasing exponentially in the last 20 years especially (Camber, 2007; Bent, 2008), while in developing nations some 80% of population still use botanicals as their primary source of healthcare (World Health Organization, 2008). This surge of interest in herbs has attracted the attention of the scientific establishment and with the advent of Evidence Based Medicine (EBM) as the dominant philosophy in modern science there is a call for a thorough evaluation of herbal medicines through controlled research. EBM has dominated clinical research since the 1990's establishing published research as the true currency of clinical decision making (Claridge & Fabian 2005; Hunt & Ernst, 2009). However the use of clinical research as a sole evidence base has met with criticism. Sehon & Stanley (2003) have described this definition of EBM as the gold standard of research as 'vacuous' and 'overly broad' and question the epistemological basis of such claims. Proponents of EBM appear to reject other methodologies as if to suggest there was no evidence behind them (Little, 2003).

In this article I examine these various attitudes towards clinical research from the perspective of a herbalist and I argue that while there are certainly tensions between the scientific establishment and traditional herbalism which need to be addressed, there can be a tendency among some herbalists to dismiss the EBM model entirely. I will argue that this is not a useful position to take, and using the example of herb-drug interaction I suggest a re-examining of the herbalist approach to EBM. In order to illustrate this point it will be necessary to examine what underpins both herbal and medical paradigms and what has led to the tension between them. I will then examine the area of herb-drug interaction itself and point out the need, from both a safety perspective and a drive for consilience (Wilson, 2001), to a reconsideration of scientific research.

Herbal Medicine as an Evidence House

The practice and art of traditional herbal medicine is based on the employment of crude-herb extracts, such as tinctures, decoctions and infusions (the practice), and their application to individual patients, considered to have unique idiosyncrasies, via the consultation process (the art). The practice and art of herbal medicine is informed by a combination of ancient tradition, clinical observation and modern research which form the foundation of an 'evidence house' with various 'rooms' (Jonas, 2001).

Herbalist practitioners contend that their tradition is justified from a number of evidence bases, knowledge which is gained from experience and in use since antiquity. Collectively these various 'rooms' constitute an 'evidence house' (Jonas, 2001). EBM tends to proceed from the perspective of reductionism employing a hierarchy of evidence dominated by RCTs and consequently it may be unsuitable as a measure for the holistic premise of herbal medicine; for which a broader and more circular perspective is required (Walach et al. 2006). Evidence garnered from multiple sources is appropriate to an understanding of holistic medicine (Jonas, 2001; Walach et al. 2006). Below are the 'rooms' which make up the evidence house of herbal medicine:

• Anthropological, ethnobotanical and archeological evidence reveal the long use of plants employed as medicines, dating back to the earliest civilizations.
• These historical precedents have formed the bedrock of herbal traditions for example, the Western Herbal Tradition (WHT) or Traditional Chinese Medicine (TCM).
• Practitioners from these traditions have documented their clinical experience in a series of herbals (the earliest known source being the Shén Nóng Běn Cǎo Jīng, 2800 BCE) which have continued to the present day and have become increasingly academic and specialized.
• Herbals are based on botany, horticulture, pharmacy, correspondences, oral tradition, philosophy and direct clinical experience. They have become the basis of modern herbal training, centered on the concepts of holism and vitalism.
• Clinical research into herbal medicine began in the 1950's - some 40% of modern drugs are based upon or derived from herbal medicines e.g. digoxin, morphine, vinblastine and aspirin. Randomised controlled trials, systematic reviews and research into phytochemistry, pharmacodynamics and pharmacokinetics have become the bedrock of herbal EBM and have been adopted by some herbalists as central to modern practice, but not by all.

The above evidence bases, collectively considered, form the foundation for the herbal medicine tradition from an epistemological perspective however the scientific establishment argues that the EBM model should be accepted as the only reliable evidence base for identifying the safety, efficacy and effectiveness of herbal medicines; or indeed as 'truth' while the rest are archaic, anecdotal or have 'haphazard ancient roots' (Ernst & Singh, 2008). EBM prefers to model itself on best-evidence; knowledge gained from systematic reviews of randomised controlled trials (RCTs) for example, and yet clinical outcomes are multifactorial processes which cannot be isolated in a controlled environment like the RCT. The real world of clinical practice offers a window: while a single case history may be considered as anecdotal a case series (10 or more cases) offers a basis for further investigation (Fugh-Berman, 1996) and is a methodology which has been neglected in epidemiological theory (Dekkers, Egger, Altman & Vandenbroucke, 2012). Herbalists know what works and what doesn't through experience.

Distrust of the Medical Paradigm: Where Does It Come From?

Practitioners of Western Herbal medicine have a historical tendency to be cautious of the orthodox medical fraternity in general. Antagonism between the two philosophies has at times been especially strong such as in the wake of the 1910 Flexner Report. This report by Abraham Flexner on the standards of medical education across the United States at the time was the result of a collaboration between a number of pharmaceutical companies and the recently incorporated American Medical Association. Dominated by science and pharmaceutical interests the report effectively put an end to most herbal schools in North America (Haller, 1994) and instigated the decline of the eclectic and physio-medicalist traditions which had been the major influences in American herbal medicine for the previous century (Treasure, 2005).

The physio-medicalist tradition was introduced to the UK in 1838 by Albert Coffin (1798-1866) while the concepts of the eclectics were imported by Wooster Beech (1794-1868) in the 1850's - both became amalgamated within the British tradition and the resulting groups formed the National Association of Medical Herbalists in 1864. Brown (1985) quotes a UK government report on unqualified medical practice in 1910 in which herbalists are tarnished: "A large number sell drugs for the purpose of procuring abortion, often at exorbitant prices". Herbalism in England was significantly affected by a number of acts of parliament from the Apothecaries Act of 1815 culminating in the Pharmacy and Medicines Act of 1941 which more-or-less outlawed the practice altogether while the professional herbal associations faced repeated failure over any attempt for legitimation and recognition (Brown, 1985; Church, 2009).

The 1941 Act was eventually replaced by the 1968 Medicines Act of which Section 12 and 56 (and subsequently reincorporated in 2012 by the Human Medicines Act) gave a caveat to herbal practitioners, however in more modern times European legislation has created a period of legal uncertainty and transition. The consequence of this historical tension has seen a tendency for some herbalists to not only be cautious of EBM but to question if the entire paradigm of modern clinical research is generally destructive to the tradition.

These are just two historical examples of how herbalists have come to be traditionally cautious of orthodox medicine and yet this caution is not solely the reserve of herbalists. The Thalidomide scandal of the late 1950's and early 1960's saw thousands of birth defects in children whose mothers had consumed the pharmaceutical drug Thalidomide. Since this time similar instances have occurred in which medical drugs have had to be withdrawn from the market because of serious side effects including multiple fatality despite being extensively and rigorously trialed. In 2004 the pharmaceutical drug Vioxx was withdrawn after it had been linked to an increase in cardiovascular events (Rotthoff, 2010). Research into the controversial area of iatrogenic deaths (deaths caused by inappropriate medication or surgery for example) has shown that iatrogenesis is one of the leading causes of death (Lazarou, Pomeranz, & Corey, 1998; Leape & Yessian 1999; Null et al. 2006) while there is growing evidence that trust in the medical establishment and doctor/patient relationships have been eroded and issues of accountability raised (Betz & O'Connell, 1983; Thomson, 2012). Issues of bias within the pharmaceutical industry have also been examined (Lexchin, 2012; Seife, 2012).

Deconstructing Holism

If EBM can be said to be a modern paradigm then the holistic paradigm which is central to herbal medicine theory is one which has endured for thousands of years and has had to weather many storms. The term holism was first coined by Smutts (1927) in his book Holism and Evolution in which he describes 'wholeness' as an 'inherent character of the universe' (Smutts, 1927). Yet the concept rides upon much more ancient philosophies. An examination of the Ayurvedic tradition for example discusses the notion that humans are made up of three attributes - the physical, the subtle and the casual which can be extrapolated to imply body, mind and spirit and any medical interventions must encompass all of these attributes in order to treat the whole person (Gerson, 1993). This approach stimulates the vitilistic principle, the body's innate ability to self-heal.

By contrast the reductionist theory of EBM prefers to bring explanations to a more simple level but it can be argued that in so doing it avoids the fact that health is a morally based enterprise with the reductionist approach pulling emphasis away from the moral and towards the material (Little, 2003) evidenced by the market-driven basis of the pharmaceutical industry and funding bias (Chimonas et al. 2007). Scott (1999) argues that holistic medicine in contrast can be seen as 'socially and politically progressive' (Scott, 1999).

Ernst and Singh (2008) refer to early reductionist scientists in the 18th century isolating active ingredients from plants so as to 'improve upon nature'. They determine this methodology as scientific herbalism as opposed to alternative herbalism which they condescendingly suggest rests on the notion that 'Mother Nature knows best' (Ernst & Singh, 2008). They imply that a religiosity or nature-superstition is inherent in holistic traditions which is metaphysical and therefore incongruous as an evidence-base. Their theory then rests on the principle that only plants which have been investigated by EBM can be characterised as safe and effective (Ernst & Singh, 2008).

In the holistic tradition the use of whole herb extracts is central while in the reductionist ethos the standardized active ingredient is employed as the agent of research (a case of cutting the feet to fit the boots in this author's eyes) and yet in discussing Hypericum perforatum (St John's Wort) the same authors mention that attempts to isolate an active agent (thought to be hypericin) proved to be not as effective a therapeutic agent as the whole plant (Ernst & Singh, 2008). Ernst & Singh's work has done much to alienate herbalists and other alternative practitioners from the scientific model (Alderson, 2009). The authors also commit the philosophical fallacy of confusing absence of proof (lack of clinical evidence) with proof of absence (there is no evidence) and in so doing encourage scientism. Holism offers a multi-dimensional approach to healthcare which brings the patient centre-stage whereas the reductionist perspective tends to see the individual in terms of a disease or a statistic and in so doing dehumanizes them (Little, 2003).

The EBM Model

In EBM the safety, efficacy and effectiveness of a herb is largely determined by the use of a single extract, thought to be the main 'active constituent' and which should be applicable in all cases as has been discussed. Herbal extracts are standardised so the active constituent is constant. This reductionist model, argue herbalists, does not describe the synergy of the many active components found in a crude extract, and so EBM is unsuitable as a methodology, or needs reworking to take holistic principles into account.

Research takes several lines of inquiry however. There is research to determine the collective phytochemistry of a plant which may allow an evaluation of pharmacological potential; there is research into pharmacodynamics (the effect of the agent on the body) and pharmacokinetics (what the body does with the agent); as well as research aimed at establishing whether a herb is safe, whether it works and how effective it is but there is also research into the interaction of herbs with modern drugs. To dismiss all forms of research as merely the hegemony of scientism however is to ignore the useful possibilities it may offer as herbal medicine enters the 21st century. Some herbalists have considered that drawing on and utilising the widest range of perspectives is a necessary prerequisite to preserve the tradition itself (Conway, 2011).

Herb Drug Interactions

Modern pharmaceutical drugs are a recent phenomenon and their origins can be traced back to the development of aspirin in 1899. However these drugs were not around when many of the great herbals were written and so there are no points of reference in the herbal tradition to evaluate their interaction with herbs until relatively recently.

Investigations into herb-drug interactions (HDIs) began from research in 1989 into the hypotensive drug Felodipine in combination with alcohol. Grapefruit juice was used as a placebo as part of the blinding process in the randomised controlled trial carried out by Bailey, Malcolm, Arnold and Spence (1989) who made the novel discovery that grapefruit had an inhibitory effect on the CYP450 pathways in the liver. This notable interaction created an interest in the following decade and speculations began into HDIs as a consequence (Dharmananda, 2000).

Despite the widespread use of herbs documented HDIs are uncommon and yet in some situations they could have serious clinical implications (Izzo & Ernst, 2001; Williamson, 2003).

Hypericum perforatum) was one of the first herbs to be associated with HDIs. Some convincing research into St John's Wort interaction with the drugs cyclosporine, digoxin and indinivar has been established (Treasure, 2005). St John's Wort is now known to act upon the Cytochrome P450 mixed oxidase system by decreasing plasma concentrations in a significant way (Bauer, Stormer, Kerb, Johnne, Brockmoller & Roots, 2002; Hojo, Echizenya, Ohkubo & Shimizu, 2011).

A period of scaremongering was in evidence however in which poorly carried out research into HDIs appeared in peer-reviewed journals and were subsequently quoted in secondary research papers without critical examination of primary data, and continue to be quoted to this day (Williamson, 2003; Treasure, 2005; Mills & Bone, 2005/2008). The primary research suffered from issues of botanical identification, adulteration, contamination, lack of phytochemical knowledge, glaring inconsistencies or poor documentation for example (Fugh-Berman, 2000; Mills & Bone, 2005/2008; Williamson, 2003). The publishing of flawed data has done little to ingratiate herbalists. Issues of correct procedure and documentation need to be rigorously and independently examined in order to determine the difference between a theoretical or an actual interaction. There is also a need to improve safety-related search strategies in systematic reviews of the literature (Pilkington & Boshnakova, 2011)

One important issue here is when data is used as a template for legislation. If primary data is flawed but used as justification for legislation then we may suffer the consequences of poor science becoming law.

Clinically significant interactions have been reported for over 80 herbs (Ulbricht et al. 2008) but critical examination of primary data does not seem to be in evidence. A review by Ernst and Fugh-Berman (2001) determined that only 13% of the 108 HDI cases they examined were classified as well-documented while 68% were considered unevaluable (Fugh-Berman & Ernst, 2001). Useful work has been done in differentiating between actual, potential and theoretical HDIs however (Johns-Cupp, 1998; Brinker 1998/2001; Mills & Bone 2005/2008; Sarris & Wardle, 2010; Stargrove, Treasure & McKee, 2008). Drugs with a low therapeutic window are of general concern.

Although only a few actual interactions have been observed it is important to stress the unique idiosyncrasies of the individual which may increase risk factors and the fact that new drugs will continue to appear on the market. There is no time to be complacent in negotiating clinically significant risk factors.

There has also been a tendency to focus on herb-drug interactions from the negative perspective of adverse reactions and yet positive interactions have also been noted. Etheridge (2012) cites positive interactions between Coleus forskohlii and the asthma drug Salbutamol . Andrographis paniculata, Panax ginseng and Silybum marianum may reduce hepatic injury caused by alcohol while Withania somnifera may reduce drug tolerance and dependence to offer further examples (Sarris & Wardle, 2010). If herbs can also potentiate a drug then this may mean that the patient might need a smaller dose and therefore a reduction in side-effects and costs would be expected.

Rhetoric & Reality

This data emphasises that it is incumbent upon the herbal practitioner to appreciate the clinical implications of HDIs within their therapeutic strategy and this in turn requires an appreciation of the need for effective clinical research; but it also serves as pause for thought for those who feel that research has nothing to offer the traditional herbalist. The issue of safety and of 'do no harm' must be central to clinical practice and in an age when the use of multiple medications is common, concurrent use of herbs especially with drugs with a low therapeutic window must be carefully evaluated.

To ignore research in this regard is not only risky but arrogant. While it is certainly true there are problems with research models (Little, 2003) it becomes important for herbalists to be more directly involved in the process in order to address those problems. A look at the history of pharmacognosy in both Western Herbal Medicine and TCM reveals the knowledge and interaction of plant constituents was well-known, indeed modern medicine is based upon it (Dharmananda, 2000; Upton, 2011). There is no reason why this research should not continue in regards of HDIs.


Differences in philosophy between herbalists and the scientific establishment have been ongoing and the resulting tension has alienated some herbalists from research models. The development of phytotherapy, a type of herbalism which tends to embrace EBM has resulted in tension within the herbal community itself (Singer, 2007; Khoury, 2009). If an acceptance of EBM can help ingratiate herbal medicine with the medical establishment, for example as a means to legitimation, then at what price? What happens to concepts such as holism within the process of 'mainstreaming'? Singer describes the potential of a 'bifurcation of epistemology', a split between biomedically-informed and traditionally orientated practitioners, the risk being that patients would lose choice in approaches to their health care (Singer, 2007). By the same token the isolation of traditional herbal medicine risks estrangement and misunderstanding (Van Marie, 2002). A consilience of knowledge bases appears the best strategy.

I have raised the issue of herb-drug interaction as an important area in this context and examined the reality behind it. The rhetorical slant that herbalists cannot associate with anything which doesn't fit their paradigm risks stagnation on the one hand but brings into question aspects of safety on the other. The ongoing assessment of HDI risks presents an opportunity to look at how research might benefit herbal medicine, and by extension those persons who use it. While there are tensions between holist and reductionist paradigms exploring knowledge from a variety of bases brings to bear wider experience and multiple approaches to the clinical setting; yet it is also incumbent upon herbalists to engage with the research process and examine ways and means to make it more appropriate to the holistic perspective.

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