Written by Steve Woodley
Quality control has been an issue for as long as humans have used herbs to heal. Herbal medicines can be adulterated for a variety of reasons, both accidental from a lack of knowledge by foragers, handlers, market traders and buyers, and deliberate where the drive to maximise profits eclipses the need for high quality materials. In the historical development of quality assessment it is apparent that as the division of labour becomes more specialised, so does the concern for adulteration as the physician must rely on others for high quality materials. Technological advancements have enhanced the methods of detecting adulteration but so have the methods of adulteration become more subtle and harder to detect.
However, one of the oldest forms of poor standards (which is to sell poor quality, low potency herbs of the correct species), has remained a problem as they pass the majority of examinations. This is especially true where active ingredients are complex or unknown as is the case with many herbs and formulated products. Until recently this has only been possible through evaluation of their clinical effects on live subjects but an alternative method has now become feasible through the use of functional mitochondrial testing in cultured cell lines.
Adulteration in Ancient Rome
The first to highlight the problem of herbal adulteration was Dioscorides in 50 CE, who authored the first systematic pharmacopoeia De Materia Medica (Περὶ ὕλης ἰατρικῆς). He described over 40 tests to examine the quality of herbal products bought from traders in ancient Rome (1). Most of these were organoleptic but some used simple chemico-physical tests, such as flame tests, solubility, measurements of weight and displacement and other unique properties of authentic herbs such the ability of balsam (probably Commiphora gileadensis (L.) C.Chr., Burseraceae) to be washed clean from a woolen cloth while its adulterants stain (2).
Later Roman authors such as Pliny the Elder (23 – 79 CE) also documented widespread adulteration in food and drugs in his Natural History with methods to detect them (3,4). The physician Galen (131 – 201 CE) was also aware of adulteration in his supplies, often complaining of fraudulent merchants and asserting the need for a physician to know his materials (5) , even suggesting animal testing for the formulated antitoxin theriac (θηριακή) to determine its authenticity (6).
Ancient China and functional adulteration
A similar trend emerged in China. In the 5th century, as medicine developed into increasingly specialised roles of harvesters, market-traders and physicians, scholar-hermit Tao Hongjing (陶弘景) wrote his Collected Annotations to the Materia Medica (Ben Cao Jing Ji Zhu, 本草經集注) where he lamented the poor quality of herbs in his day, accusing the market traders of deliberately selling low quality products for profit, and the physicians of being only concerned with looks and unable to recognise genuine potency (7). To remedy this state of affairs, he hoped his detailed additions to each entry of the earlier 1st century classic, the Divine Farmer’s Materia Medica (Shen Nong Ben Cao Jing, 神農本草經), would help physicians to recognise true potency and value it over cosmetic appearance. In particular he highlighted the issue of correct species from poor growing regions, lacking the potency of the genuine article, being sold as the real thing. This problem of functional adulteration is very difficult to detect and still pertinent today.
In 659, during the Tang dynasty the world’s first national pharmacopoeia, the Newly Revised Materia Medica (Xin Xiu Ben Cao, 新修本草) was published (8). The whole country was surveyed for specimens and detailed colour drawings were included to complement textual descriptions. Improvements to authenticating herbal medicines continued with the Extension to the Materia Medica (Ben Cao Yan Yi, 本草衍義) by Kou Zongshi (寇宗奭), an expert in authentication, compiled in 1116 being one of the first printed texts that focused on differentiating authentic from inauthentic herbal medicine (9). However, it was not until the Origins of the Materia Medica (Ben Cao Yuan Shi, 本草原始) in 1788 that pictures of the prepared herbal materials were included rather than just the live plants.
The medieval period saw little development in the technology for detecting adulteration but instead relied on the development of ethical and legal frameworks to ensure the purity of medicinal herbs. As the Islamic Golden Age dawned under the Abbasid Caliphate in 9th century Baghdad, a new class of professional pharmacists started writing new pharmacopoeias, beginning with Yuhanna Ibn Masawayh (يوحنا بن ماسويه, Romanised: Johannes Mesue), who focused one work on aromatics, including methods of detecting their adulteration (10). A code of ethics was established for this emerging class who were held to higher standards than regular spice traders and enforced by a government appointed official, al-Muhtasib (محتسب), who inspected pharmacies for potential adulteration, degradation, fraud and excessive profiteering (11).
Saffron (Crocus sativus L., Iridaceae) adulteration was a particular concern due to its culinary and medicinal use in many healing traditions. Often ascribed with magical properties, with its labour intensive harvesting procedure, made it worth its weight in gold (12). From the 5th to the 15th centuries, an armed guard was charged with inspecting saffron supplies coming into port in Venice and in 1358 the first known food law was enacted in Nuremberg, punishing the adulteration of saffron with death, sometimes by being burnt alive with your own adulterated products.
The scientific revolution
The scientific revolution ushered an age of using technology to enhance the senses. Magnifying lenses had been known to the ancient Greeks and Romans (13) but the invention of the compound microscope allowed Nehemiah Grew to provide the first vivid descriptions of plant anatomy in 1682 (14,15). Over time new technologies such as fluorescence, confocal microscopy and imaging techniques have added new dimensions to what we can see in order to differentiate plant materials (16).
In 1735 Linnaeus applied scientific methodology to taxonomic classification in his Systema Naturae (17), developing the binomial nomenclature still used today (18). This initiated a systematic method of classifying species and therefore determining which species should be considered authentic or adulterants, and clarifying which species referred to by traditional or local names have the medicinal benefits required of them (19).
The industrial age and the birth of chemometrics
The industrial revolution saw a new wave of advances in botanical sciences. The age of chemometric testing began when Mikhail Tsvet demonstrated the first chromatographic technique to separate plant pigments in 1903 (20). Spectroscopic analysis, observing the unique interactions of the separated compounds with energy from ultraviolet or infrared radiation, or from magnetic or ionising charges, could be used to speculate on their structures with far greater accuracy than smell or taste alone, even detecting deliberate adulteration with drugs, dyes or similar herbal materials designed to be undetectable by routine methods of examination (21).
With increased sensitivity, it became possible to detect new potential contaminants that would have escaped detection or even consideration in the past. This includes both naturally occurring toxic compounds in plants which can arrive in the supply chain by being inherently present in a species, or by contamination with plants that contain them, heavy metals drawn from the environment, or contamination with artificial substances such as pesticides. Pyrrolizidine alkaloids caused particular concern in herbal medicine, being discovered in several plants considered safe for centuries, such as borage (Borago officinalis L., Boraginaceae), comfrey (Symphytum officinale L., Boraginaceae) and coltsfoot (Tussilago farfara L., Asteraceae). These have no obvious toxic effects in moderate doses but long term use can cause irreparable liver and lung damage, even leading to cancer (22). The use of these herbs has since been voluntarily suspended by most professional herbalist associations (23) but potential contamination of other herbs and foods with plants that contain PAs is harder to control. These toxins are too widely distributed in nature to ever make total eradication feasible and as little as one ragwort (Senecio sp. L., Asteraceae) per hectare of St. John’s Wort (Hypericum perforatum L., Hypericaceae) is enough to exceed the suggested threshold of 1.0 μg PAs daily (24). However, through implementation of Good Agricultural and Collecting Practices combined with batch testing using a combination of chromatography and spectroscopy, it is hoped that exposure can be kept within safe limits. Tropane alkaloids have caused a similar concern, often ending up in the supply chains through accidental contamination with Datura sp. or Convolvulus sp. and these too are managed with chemometric and spectroscopic analysis to ensure levels are below the regulatory limits (25). Likewise, pesticides are monitored with published reports containing chromatographic-spectroscopic analysis (26,27) with similar monitoring of heavy metals (28).
This field continues to advance with more refined techniques and computing power to analyse the data providing even more sophisticated models (29). Initiatives like the High Performance Thin Layer Chromatography Atlas of plants (30) aim to publish the chemical fingerprint of every species, against which unknown samples can be compared to determine the species or the presence of adulterant chemicals.
The genetic revolution
Within a few years of the first Nature papers on human DNA fingerprinting being published by Alec Jeffries in 1985, the technique had revolutionised botanical sciences (31). DNA analysis enabled faster and more precise taxonomic classification, based on snippets of genetic code, than the traditional system and could even determine distinctions between apparently identical species or from fragments that had been cut and no longer had distinguishing characteristics visible. For example, the Chinese names of some medicinal herbs, such as Mu Tong and Fang Ji, may both refer to several separate species, one of which is a toxic Aristolochia species (A. manshuriensis and A. fangchi respectively) containing aristolochic acids that cause kidney damage, while the other is not (Clematis armandii Franch., Ranunculaceae or Akebia trifoliata (Thun.) Koidzumi seu quinata (Houtt.) Decne., Ranunculaceae and Stephania tetrandra S. Moore, Menispermaceae respectively) and can be used safely (32). It can be almost impossible to tell dried, cut specimens, powders or extracts apart and while some countries have responded with outright bans on all species where confusion could happen (33), others have implemented testing and analysis to regulate imports (34). An integrated approach of chemometric testing for the presence of aristolochic acids combined with DNA barcoding to ensure correct species (35) seems to be the best option to enable herbal medicine to continue to be practiced effectively and safely without unnecessary restrictions.
Similar to, and complementing, the chromatographic atlases of plants, databases of genetic information such as the Barcode of Life Data (BOLD) (36), the NCBI Genome Database (37) and the Medicinal Materials DNA Barcode Database of Traditional Chinese Medicines (38) have been developed enabling samples to be compared against verified specimens.
The problem of testing
Modern chemometric and genetic analysis of plants have undoubtedly enhanced the quality assessment of herbs, but they are not without their drawbacks. Chemometric analysis often relies on identifying active ingredients or known adulterants and searching for these markers to determine the quality of the medicine but the effects of many herbal medicines cannot be traced to single compounds and in many cases their mechanisms remain unknown, requiring new strategies to be considered (39). DNA fingerprinting can also be problematic when applied to extracts where the DNA is often degraded after processing (40).
The ultimate purpose of herbal medicines is to have a biological effect which is difficult to determine without functional testing on a biological system. Some forms of adulteration, like that highlighted by Tao Hongjing, may pass chemometric and genetic analysis, especially where a specific drug compound is not the key to the herb’s activity, or in formulae where there may be too many markers to effectively search for them all. Until recently the only methods of functional testing were either animal experiments, which are ethically problematic (40) and only provide limited information (42), human trials, which are very expensive to run in an area that is chronically underfunded, or by observation of the effects of each batch in the clinic, which is less than ideal.
Mitochondria: A new possibility for functional assessment
Mitochondrial testing presents a new and exciting opportunity for the functional analysis of the quality of herbal medicines. Mitochondria stand at the centre of biological activity, not only providing the energy required for most biological functions but being integral to almost every aspect of multicellular life (43). Their broad range of functions has even led to suggestions that they may be behind similarly broad traditional concepts fundamental to life such as Qi (44). Changes in mitochondrial function have been implicated in many states of health and non-inheritable disease including metabolism, stress responses, inflammation, ageing, cancer, cardiovascular and neurological function (45), and immune responses to viral infections including SARS-CoV2 (46). Many of these have been traditionally attributed to Reactive Oxygen Species (“free radicals”) generated as by-products from the mitochondrial respiration process and treated with antioxidants. However, current research shows that the picture is far more complex, with antioxidants failing to show an improvement in living subjects (47), maybe even eliminating the beneficial effects of exercise triggered by a moderate rise in free radicals (48) and having contradictory results in cancer, where free radicals induce both the proliferation and the self-destruction of cancer cells (49).
Through the use of dyes that react with specific mitochondrial processes, fluorescent microscopy and highly sensitive probes that can measure the oxygen consumption rate or temperature changes in a culture of cells, it is possible to generate a mitochondrial profile of the effects of herbal substances on specific tissues (50). Besides gathering invaluable information on the potential mechanisms of many herbs, this approach also provides a novel method of functional evaluation, closer to the clinical effects than chemical or genetic profiles can provide on their own. Moreover, it could be used routinely on herbal batches for the purposes of quality, safety and efficacy assessment, while being less ethically problematic than testing on animals and less costly than running conventional human trials.
The Research Centre for Optimal Health is at the forefront of this research methodology with several PhD and postdoctoral projects currently being undertaken and papers already published (50,51,52,53,54). We have also developed a high-throughput testing pipeline that is able to rapidly determine the biological potency of individual herbs and herbal formulas as well as being able to analyse how herbal medicine may improve mitochondrial health in humans.
For further information about mitochondrial testing contact Prof. Jimmy Bell at: J.Bell@westminster.ac.uk.
Acknowledgements: Thanks to Pukka Herbs for providing the PhD scholarship funding for Steve Woodley.
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