Regulating Herbal Products: An Historical Canadian Perspective
By Dennis V. C. Awang, PhD, FCIC
This is a revised version of the author’s presentation to the Canadian Herbalist’s Association of British Columbia, Vancouver, June 13, 2010.
Several years before the Natural Products Section, of which I was the head, was canceled in 1993, and prior to elimination of the entire Bureau of Drug Research of Health & Welfare Canada (HWC), I circulated a discussion paper titled “A Drug Identification Number (DIN) Ought to Mean Something” and proposed that natural products should not be granted DINs but rather TMNs (Traditional Medicine Numbers)—unless there were acceptable clinical trials in support of specific therapeutic claims for marketed product forms.
At the time, I successfully promoted the granting of the first such DIN to feverfew (Tanacetum parthenium, Asteraceae)* whole leaf for prevention of migraine attacks. Then all other DINs for herbal products had been granted based on acceptance of the claims of traditional medicine; however, few of these products bore much resemblance to products prepared by traditional methods, which are mostly whole plant material or water extracts. Nevertheless, the regulatory authority granted DINs to a variety of preparations, including combination products, with no assurance of botanical identity or consistent method of preparation.
Several instances of adverse reactions were observed during that period, resulting from adulteration and/or substitution. The adverse effects were relatively mild, despite the occasional need for hospitalization in more serious cases, such as contamination by tropane alkaloid-containing plant material—likely belladonna (Atropa belladonna, Solanaceae), also known as deadly nightshade, which was indicated in 5 different plants resulting in hallucination, CNS and respiratory depression. A widely publicized case of botanical substitution, popularly described as “The Hairy Baby Case,” resulted from Chinese silk vine (Periploca sepium, Asclepiadaceae) being consumed by a pregnant nurse in Toronto, instead of the apparently innocuous intended eleuthero (Eleutherococcus senticosus, Araliaceae), labeled “Siberian ginseng.”
In 1990, in Belgium, the formula of an established slimming regimen was modified by inclusion of extracts of 2 Chinese herbs imported from Hong Kong, where there was no legal regulation of Traditional Chinese Medicine (TCM). One of the intended herbs was han fang ji (Stephania tetrandra, Menispermaceae), but the herb supplied—either by accident or possibly due to the unfortunate belief that a substitution was appropriate—was guang fang ji (Aristolochia fangchi, Aristolochiaceae), which contains the nephrotoxic aristolochic acid, known to be mutagenic and carcinogenic in laboratory animals. Prolonged ingestion of the slimming treatment, administered by doctors untrained in herbal medicine, led to more than 100 cases of kidney failure in women in Belgium and France.1-4
The foregoing examples, as well as more recent occurrences of adverse health effects (AHEs), including reports of serious adverse reactions to purported black cohosh (Actaea racemosa syn. Cimicifuga racemosa, Ranunculaceae) products, popular for treatment of menopausal complaints, reveal some unfortunately related aspects of herbal regulation. Notably, almost invariably, occasions of adulteration/substitution are revealed by observation of AHEs reported via the medical community. For example, in the case of 4 serious adverse effects reported in Canada and attributed to a specific black cohosh product, a subsequent analytical investigation resulted in recall of such products from at least 7 companies supplied with the wrong plant species, probably the Asian species A. cimicifuga, but possibly A. podocarpa.
Identity and Quality
The underlying situation responsible for all these observed AHEs is the failure of the various regulatory systems to ensure proper botanical identity and quality of marketed plant products. Simple declarations of manufacturers on license application forms and elaborate product labels cannot assure identity and quality.
In the current climate, judicious consumer choice can be advanced only by education regarding medicinal effects, their relation to the type of preparation, and, arguably most importantly, knowledge of the experience and scientific competence of manufacturers.
Quality assurance (QA) is aided by promotion of Good Manufacturing Practices (GMPs) which, if effectively enforced, should address most purity issues, including contaminants such as pesticides and pollutants, toxic metals (e.g., arsenic, cadmium, lead, and mercury), bacteria, molds and mycotoxins, processing impurities and solvent residues, as well as adulteration with undeclared pharmaceuticals. Quality issues may also involve botanical identity and the use of incorrect plant parts.
At present, the predominant methods for botanical identity testing rely on the plant’s morphological features or phytochemical profiles. Historically, morphological identification could be reliably accomplished by macroscopic examination of whole plants and/or plant parts, essentially intact after harvest, by an experienced botanist or trained herbalist. However, a botanist at the herbarium of the University of Texas at Austin wrongly identified a voucher specimen as German chamomile (Matricaria recutita, Asteraceae), purportedly of Argentinian origin and containing 7.3% of anthecotulid—a noxious, highly allergenic sesquiterpene lactone.
Examination of the specimen by German researchers revealed the plant material to be, in fact, derived from dog’s chamomile (Anthemis cotula, Asteraceae). M. recutita contains variable, but much lower levels of anthecotulid.†6 Commercial raw material can be available in various forms, from cut and powdered, otherwise untreated plant parts, to extracts using a variety of solvents. Definitive species diagnosis from solid plant material is often elusive by macroscopic and/or microscopic means, making identification increasingly reliant on phytochemical procedures, mainly of the chromatographic and spectroscopic/spectrometric varieties. Largely reliable, well-established chemical separation techniques can provide distinctive profiles without necessarily identifying individual phytochemical compounds. However, complete reliance on chemical profiles for botanical identification is problematic since marker compounds may exhibit wide variation in concentration of the naturally occurring chemical constituents of plants. Definitive comparative data on plant-to-plant, population-to-population, and species-to-species are prerequisite to reliable taxonomic diagnoses. Also, the preponderance of processed botanical material in the herbal supply chain precludes the broader reliable application of macroscopic and microscopic morphology-based identity testing, and by default the herbal community relies largely on phytochemical measurements to ascertain sample identity.‡
DNA-based approaches appear to be particularly useful for deconstructing plant mixtures to confirm the identity of components in blended herbal products.7 Nucleotide-based methodology has been used to overcome many of the shortcomings associated with morphological and chemical identification techniques, including identification of both single herb and mixed plant preparations: St. John’s wort (Hypericum perforatum, Clusiaceae) has been effectively differentiated from morphologically and chemically similar species, as have other species such as Korean/ Chinese or Asian ginseng (Panax ginseng, Araliaceae) from American ginseng (P. quinquefolius), and Chinese star anise (Illicium verum, Illiciaceae) from Japanese star anise (I. anisatum). Further, the time and cost surrounding DNA-based analytical techniques have steadily decreased over the last 20 years: Data collection which once required days or weeks can now be completed in a matter of hours, with service pricing in the neighborhood of morphological and phytochemical methods.
A Prescription for Improved Regulation
After a decade of virtual dormancy of HWC herbal regulatory programs, the promulgation of the Natural Health Products Regulations in 2003 and the staffing-up of the Natural Health Products Directorate (NHPD) as part of a renovated Health Canada (HC) to administer these regulations created a regulatory framework and process to replace herbal DINs with Natural Product Numbers (NPNs). A website developed since publishes plant species monographs (webprod.hc-sc.gc.ca/nhpid-bdipsn/monosReq.do? and also elaborates extensive specifications required for licensing finished products. However, a seminal—and critical—deficiency of NHPD’s regulatory process is the lack of a confirmatory aspect, respecting both botanical identity and chemical analysis.
Low Dog et al.8 acknowledge that both Canada and the United States require manufacturers of herbal products to report to their respective “appropriate government agencies” “serious adverse effect reports,” and regard the Canadian system as superior to that of the US because the former requires market authorization of each NHP before it can be legally sold. However, the Canadian judgment of safety, efficacy, and “high quality” is based solely on consideration of an application form—and “on the basis of evidence of compliance with current GMPs.”
A Registry of Certified Growers (obedient to Good Agricultural and Collection Practices [GACP])/Suppliers, based on established competence in Botanical Authentication of Raw Material, who can be identified at all subsequent stages of supply and processing.
Certification of analytical laboratories qualified to conduct chemical testing of both raw material and finished products. (The most recent refinements of analytical methodology should be provided in a timely manner to prospective license applicants.)
A schedule of rotational random manufacturer product testing should be established (such as operated biannually in France); product candidates ought to be prioritized for selection, as in the earlier Natural Products program, on the basis, mainly, of sales volume, severity of associated health conditions, and recognition of past incidences of adulteration/substitution.
Development of a database of DNA analytical profiles, as an aid to characterizing herbal products, especially the components of blended finished products.
Dennis V.C. Awang, PhD, FCIC, is President of MediPlant Natural Products Consulting Services and an ABC Advisory Board member.
* The author notes his reluctant adherence to the ABC/HerbalGram style convention for scientific notation of botanicals in which the accepted and/or preferred Latin binomial is employed with the family name, but without the attribution of the botanical authority, as was formerly the ABC/HG style. The author hereby notes his preference for the latter, despite ABC’s decision to discontinue the use of authorities, as is still employed elsewhere, e.g., in professional botanical journals. —DVCA
† Anthecotulid is responsible for the commonly observed primary irritant contact dermatitis specific A. cotula, is absent from bisabolol chemotypes of German chamomile flowers; its low yield in the bisabolol oxide -B chemotype does not induce primary irritations, although specific hypersensitivity might rarely be induced by that and other known chemotypes.
‡ Recent advances in metabolomics and chemometrics for medicinal plants involve applying multivariate statistical treatments (e.g., Principal Components Analysis, Hierarchical Cluster Analysis, or Partial Least Squares and its extensions such as Orthogonal PLS) to the “fingerprint” results obtained from phytochemical analyses. The data may come from simple broad-spectrum extracts, e.g., from deuterate solvents (single or mixed) subjected directly to nuclear magnetic resonance (NMR) spectroscopic analysis, or from any of the wide variety of chromatographic separation techniques (e.g., HPLC, GC) combined with detection and analysis by mass spectrometry, NMR, diode-array UV, etc. The advantages of the metabolomic/chemometric approach are that it allows one to work with complex extracts rather than a limited number of marker compounds that may or may not be relevant to the medicinal properties of the plant, and one has systematic, objective, reproducible conclusions on the similarity of samples with a reference standard, revealing the degree of natural variability in the species compared to significant differences from other species. Applications of medicinal plant metabolic fingerprinting with chemometrics for both quality control and bioactivity assessment have been reviewed recently by Verpoorte et al. 9,10
- Depierreux M, Van-Damme B, Vanden-Houte K, Vanherweghem JL. Pathological aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis. 1994;24(2):172-180.
- Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet. 1993;341:387-391.
- Vanherweghem JL. Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy). J Altern Complement Med. 1998;4:9-13.
- Chen JK. Nephropathy associated with the use of Aristolochia. HerbalGram. 2000;48:44-45.
- Mahady GB, Dog TL, Barrett ML, et al. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause. 2008;15:628–38.
- Hausen BM, Busker E, Carle R. The sensitizing capacity of Compositae plants. VII. Experimental investigations with extracts and compounds of Chamomilla recutita (L.) Rauschert and Anthemis cotula L. Planta Medica. 1984;50:229-234.
- Cimino M. Ensuring the specific identity and quality f herbal products by the power of DNA. HerbalGram. 2010;86:50-57.
- Low Dog T, Marles R, Mahady G et al. Assessing safety of herbal products for menopausal complaints: an international perspective. Maturitas. 2010;66:355-362.
- van der Kooy F, Maltese F, Choi YH, Kim HK, Verpoorte R. Quality control of herbal material and phytopharmaceuticals with MS and NMR based metabolic fingerprinting. Planta Medica. 2009;75;763-775.
- Yuliana ND, Khatib A, Choi YH, Verpoorte R. Metabolomics for bioactivity assessment of natural products. Phytotherapy Res. 2010 DOI: 10.1002/ ptr.3258.