Mills & Bone 2: The Sequel
 The Essential Guide to Herbal Safety
by Simon Mills and Kerry Bone
Five years after the publication of their major textbook Principles And Practice Of Phytotherapy,1 Mills and Bone have produced a sequel to that original collaboration - a companion volume called The Essential Guide to Herbal Safety, (hereafter MB2) also published by Churchill Livingstone. The coauthors are both respected phytotherapists, Simon Mills from the University of Exeter in the UK has a long involvement in European phytomedicine, and Kerry Bone from Australia, a practitioner and scientist with extensive background in the herbal product industry. Given the current intensifying focus of international debate in both regulatory and medical circles about the safety of botanical medicines, this is a timely publication, and credit is due to the authors for anticipation of the need for proponents of herbal medicine to frame the context of this complex and controversial subject.
Any comprehensive treatment of the subject of herbal safety must address the fact that there are really several distinct components to the whole topic, several of which pose conceptually challenging problems. Firstly, the process that might best be described as the "mainstream manufacture of misinformation" has to be addressed.* Secondly, specific herbs at any given time may be targets of negative publicity, often in concert with regulatory/political efforts to restrict their availability. Obvious recent examples are kava, or in the USA ephedra. These attacks not only require systematic, detailed, science-based rebuttal but invariably are played out within a wider political theatre, which requires integrating political strategy as well as science into the counterplay. Thirdly, terminology, classification, description and mechanisms of herbal adverse effects and herb-drug interactions have to be clarified in relation to the conventional sciences of toxicology, epidemiology, pharmacovigilance and so on. A common language and conceptual framework is a prerequisite for rational communication and scientific debate on issues which are often controversial and politically charged. Then there are important questions relating to the herb industry, such as quality control, good manufacturing practises, standardization, methods and forms of preparation, many of which are controversial within as well as outside the herbal community. Finally, the overall literature on herbal safety is heterogenous, widely varying in quality, quantity, and methodological approach. This renders any attempt at compilation into a meaningful and consistent format extraordinarily challenging in itself.
How does MB2 measure up to this rather formidable set of tasks?
The good news is that fully the first third of the entire book is devoted to an overarching discussion of most of the areas outlined above. MB2 begins with twelve separate essay chapters that set out a framework of conceptual, clinical and methodological issues while clear-cutting the residual theoretical debris, junk science and opinionated bias. Simon Mills is the main theoretician, providing several key essays on Adverse Placebo and Transient Treatment Reactions; Idiosyncratic Drug reactions and a contextualizing "medical-anthropological" overview of human-plant interactions. Kerry Bone demystifies the topic of herbs for pregnancy and lactation, and proposes the official Australian system of classification as superior to the more or less arbitrary "herb lists" that have previously dominated this topic. Bone also uses his considerable experience in herb industry R&D to review safety issues in herbal product manufacture, including adulteration and contamination by synthetic drugs and heavy metals, and microbiological, pesticide and herbicide contamination with reference to GMPs.
At this point it should be mentioned this first part also includes contributions from several co-writers. Among these, Mathias Schmidt's stands out in more ways than one. The only non Anglo-Australian of the co-writer team, Dr Schmidt is a German expert in phytopharmacy and pharmacovigilance who will be known to many for the maintenance of an invaluable web site resource on the kava hepatoxicity issue ever since it first broke in Germany.2 Thus the kava chapter contains for the first time in print a compilation and cross-referenced resource of all the available hepatotoxicity case reports with full details (or more often lack thereof) from the various national authorities together with an analysis of every case. Arguably, the conclusions of the MB2 chapter on kava pulls its political punches, but if the authors opted for diplomacy rather than political polemic, the chapter still provides invaluable ammunition for those currently fighting the irrational restrictions on kava.
There is a collaborative 40 pp chapter on herb-drug interactions. This contains some much-needed corrective analysis of the problems of misinformation detailed at the start of this review. The demolition of the infamous error-laden 1998 article by pharmacist Lucinda Miller from Archives of Internal medicine is overdue but still thoroughly enjoyable (sadly this appalling article is still heavily quoted in secondary literature, an example of the previously mentioned "mainstream manufacture of misinformation").3 The authors rightly point out that herbalists themselves are not always immune from subscribing to or propitiating herbal myths - such as "plant coumarins interact with warfarin". Two tables concisely summarizing possible herb-drug, and conversely drug-herb interactions are provided.
Other chapters in Part 1 include essays on the safety concerns of Chinese herbal medicines, allergic reactions to botanicals, and pharmacovigilance. London hospital based toxicologist Debbie Shaw's introductory chapter on "The Case to Answer" makes the obvious but often overlooked important pointÉ that while natural is not safe, a familiarity with basic phytochemistry and phytopharmacology can minimize the risk of occurrence of predictable adverse effects. (this is often overlooked in mainstream discussion of herbal safety where ignorance is actually often to blame for an ADR or HDI precipitated by inappropriate use of the herb).
The second two thirds of the book consists of individual safety monographs on 125 herbs. These monographs are the core of the book and likely to constitute an authoritative textual reference for the foreseeable future. Mills and Bone, probably well aware from historical precedent how the written word tends to become 'set in stone', have strategically chosen to err on the progressive rather than conservative side of known controversies. For example, throughout MB2 the Commission E positions (from the outdated official German handbook presented as authoritative but in fact unreferenced and often speculative) where unsupported are rightly indicated as such.
Dosage data in the monographs is thoughtfully presented; on the whole dose ranges given are a higher than those found in many texts, and often include useful additional information. For echinacea for example, the upper dose given for E. angustifolia root 1:5 tincture is given as 15 mL/day, compared to say the latest ESCOP monograph dose of 60 drops tid.4 The MB2 text also mentions the relevant detail that much higher doses are often recommended by herbalists in acute conditions; meanwhile the typical doses for different echinacea species, parts and preparations are tabulated together for quick reference. It is refreshing to see more sensible and realistic dose information derived from practitioner experience rather than the habit of reproducing (often way too low) clinical trial dose data as authoritative. Hopefully this practice will be followed by others such as the American Herbal Pharmacopoeia.
The monographs are well referenced, but like all the references in the book (and other Mills and Bone texts) the bibliographic formatting of the citations is irritatingly inconvenient. Original article titles are omitted, and only abbreviated journal names supplied. If one wants to quickly validate a reference by locating its abstract, the process can be frustratingly difficult if not almost impossible.
What are the shortcomings of MB2? One problem, actually inherent in any text that aims at comprehensiveness, is the perennial issue of striking balance between the amount of detail and constraints of overall length of a book. When confronted by pressing questions of safety in clinical practice, it is always more valuable to have a resource with more rather than less detail, more discussion of mechanisms, more analysis of available studies and other relevant literature. For example, the Schmidt chapter on Kava is illustrative of the kind of depth that is really required to get to grips with safety questions posed by the herb by examining different mechanisms, analyzing different case reports, possible explanations of the observed data and so on. Obviously, a fifty-page monograph on all 125 herbs is impossible, but there are at least a handful of controversial herbs that merit really extended discussion, including obvious examples such as St. John's wort and black cohosh. Perhaps the monographs could have been more varied in length to deal more with these appropriately. The discussion of St. John's Wort interactions is particularly weak, merely listing the drugs that have been reported to interact with the herb without elaborating the underlying mechanisms; this simply does not enable prediction or management of potential but to date unreported interactions.
On the topic of which herbs made the cut for the 125 monographs, some of the omissions and inclusions are puzzling. Why include monographs on the "safety" of such benign botanicals as elder-flower, bilberry fruit, cranberry, nettle and raspberry leaf, but not on the more problematic aconite, belladonna, convallaria, chelidonium, henbane, lobelia, or even cayenne? This omission of the low dose or "toxic" botanicals is disconcerting, and arguably ominous if the book is targeting future regulatory developments. The monograph list suggests more than a hint of neutered "euroherb" blandness, and one hopes it does not portend a future where valuable low dose herbs are prohibited by Brussels bureaucracy. On a similar theme, it really is time that Euro-Australian phytotherapy acknowledged the enormous therapeutic value of the medicinal mushrooms by including them in their monograph collections Ð they are conspicuously absent in MB2.
Discussion of pharmacogenomic and pharmacogenetic variability (and its role in determining variability of individual response to herbs (and drugs) is lacking in the text. Polymorphisms in drug metabolizing enzymes give rise to pharmacokinetic variations in drug bioavailability, but the subject also embraces a wide variety of pharmacodynamic issues due to receptor polymorphisms and other "metabolomic" variations. In addition to modulation of drug metabolizing enzymes, several herbal compounds are also substrates of the same enzymes, and undergo bioactivation to form toxic intermediates eg comfrey (Symphytum spp.), germander (Teucrium chamaedrys L.). At very least the impact of specific herbs on different CYP450 isoforms, Phase 2 conjugases and Phase 3 transporters such as P-glycoprotein is significant, and should be properly covered in any comprehensive discussion of safety and herb-drug interactions.
Another issue concerns the challenge posed by different patient subgroups in relation to different therapeutic herbs or plant compounds. In clinical practice safety issues are generally manifest relative to a particular set or subset of patients and are not resident in the herb (daisies are only allergenic for people with daisy allergies). Currently, perhaps the most controversial of these is the phytoestrogens, particularly in relation to individual differences in gender, menopausal status, a history past or present of reproductive cancer and so on. Neither soy, nor the leguminous isoflavones are included in the monograph section, however there is arguably sufficient confusion and controversy as well as patient concern over phytoestrogens for them to merit a chapter of their own.
It would be disingenuous to nit-pick ones way through the individual monographs even if space allowed, but there are a couple of points worth making. It seems that the monograph details could have been more thoroughly cross-checked during line-editing or proofing stages. Taking a random example such as turmericÉ it does not really make sense to warn against using "high" doses > 15 gms/day of turmeric in combination with antiplatelet or anticoagulant medications when the upper dose range has already been specified earlier in the monograph as a from 3 gm to a maximum of 9 gm/day. There is a significant difference between 9 and 15 grams. Staying with turmeric, its monograph does not mention solid extracts standardized to >90% curcumin as a form of this herb (standardized extracts are included for others such as milk thistle, ginkgo, St. John's wort) but given the notably low bioavailability of the curcuminoids, such extracts are almost obligatory for therapeutic effects beyond the beyond GI mucosa. Finally, curcumin is a potent inhibitor of p-glycoprotein, and will impact the bioavailability of drugs which are its substrates - this has in fact been demonstrated for several chemotherapeutic agents, whereas interaction with anticoagulants has not been reported.
Despite the admirable debunking of junk science literature in the earlier part of the herb-drug interactions section, it was really not hard to find an instance where the original data had clearly not been sufficiently reviewed Ð for example the suggested interaction between Panax ginseng and MAO inhibitors. The main "citation" for this alleged interaction consist of a couple of side remarks made en passant by a journal editor which referred to a "ginseng-containing" product Natrol High.5 In fact this product does not contain any Panax ginseng at all, although did have small quantities of the unrelated adaptogens eleutherococcus and ashwagandha. Mills and Bone themselves point out quite correctly in their Panax ginseng monograph how many reports of claimed "ginseng" interactions and ADRs are based upon mistaken identity, particularly with eleuthero, so here they seem to be hoisted by their own petard. Whether this lapse is an isolated case or illustrative of a more pervasive problem with the text is a matter that will only become clear given a closer reading over time given the large amount of reference material contained in the volume.
Given impending EU legislation that requires approved "herbal medicine products" to have authoritative safety monographs, the lasting value MB2 is likely to be its strategic impact in the politico-regulatory environment where it will serve as benchmark reference on the subject of herb safety written from a pro-herbal medicine perspective. Hopefully MB2 will rapidly displace the use of the archaic Commission E text at least with regards safety and dosage information, and become recognized as a standardized reference in the field. The introduction claims that the book is intended for practitioners, but practical answers to many questions that can arise everyday in the clinic are not provided by this text. Those wanting to know, for example, how much lobelia to safely administer to a case of pediatric asthma or whether black cohosh is safe with to use with aromatase inhibitors will have to look elsewhere. For sure, Mills and Bone have again stepped up to the plate and delivered another major opus, and it is hard to think of anyone else who could have done the job at all, let alone better. In risk/benefit jargon, the book is a safe bet. It is a library must-have volume, and may be useful for pharmacists, but it is questionable whether professional herbalists will find it "essential" to their daily practice.
* "mainstream manufacture of misinformation" characterizes the process whereby inaccurate negative information about herb safety, adverse effects and herb-drug interactions in the mainstream medical literature is propitiated largely as an artifact of the MEDLINE indexing system, which logically equates miscellaneous editorial correspondence with peer reviewed articles via the database's *title* field.
References
1. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.
2. Schmidt M. Is kava really hepatotoxic? accessed February 27th, 2005; http://www.uni-muenster.de/Chemie.pb/Kava/kavaframe.html.
3. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 1998;158:2200-2211.
4. ESCOP. ESCOP Monographs:The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK: European Scientific Cooperative on Phytotherapy & Thieme; 2003.
5. Shader RI, Greenblatt DJ. Phenelzine and the dream machine--ramblings and reflections. J Clin Psychopharmacol 1985;5:65.
© 2005 Jonathan Treasure
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