CHEMICAL DIVERSITY

As herbal medicines are not produced synthetically and contain a myriad naturally occurring components, chemical diversity is always present. In herbal medicine, it is essential to use the correct species and type of plant, and plant part, and understand the growing, harvesting and manufacturing processes involved that influence the chemical make-up of the final product.

Interestingly, the wine and beer industries manipulate these same factors to achieve the multitude of variations available for their products. And as any wine drinker knows, wine produced one year from a particular vineyard will be different from one produced the following year, and wines of the same grape variety will also differ between vineyards.

Many commercial herbal medicine manufacturers are also using sophisticated methods of evaluating the influence of various growing, harvesting and extracting techniques as a means of producing consistently high-quality herbal medicines. In order to detect variations between batches, manufacturers use laboratory techniques such as thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC), both of which provide a visual characterisation of the presence of different chemical constituents within the herb. The graphs produced from TLC and HPLC testing are often referred to as ‘fingerprints’ and used to determine the identity of herbal material and the integrity of the extraction process, as well as to measure quantities of individual constituents.

CLINICAL RELEVANCE

Having an appreciation of the chemical diversity of herbal medicines is vital when interpreting findings from clinical trials.

Readers should identify the particular herbal extract used, because the composition of products varies between manufacturers, and evidence of efficacy (and safety) should be considered extract specific. At best, evidence can be extrapolated only to preparations of the same herb with a very similar phytochemical profile, although even this is not completely accurate.

Unfortunately, many early trials did not provide sufficient details about the herb or extract used and some did not test samples to confirm the identity of the plant or that samples actually contained sufficient active constituents. This is a critical oversight. Clinical trials using herbal extracts that have not been adequately defined in phytochemical terms are of questionable value because we cannot know whether a negative result was because the herb was lacking in activity or because the extract was of inadequate quality. This requires a shift of thinking in Western research, which is used to dealing with pharmaceutical drugs that tend to consist of only one standardised chemical entity and need relatively little description.

Phytochemical analysis is also important when case reports of adverse events are evaluated, to ensure the authenticity of the herbal medicine and identify whether confounding influences such as contamination or adulteration are present. Until testing is performed, conclusions regarding herbal medicines are open to error.

The herb St John’s wort is a useful example of the clinical relevance of chemical diversity, the importance of intra-herbal interactions and the accumulating evidence base surrounding phytomedicines.

St John’s wort has been used as a treatment for neuralgic conditions since the time of Ancient Greece and as a treatment for psychiatric disorders since the time of Paracelsus.⁴ It was traditionally used as a tea, an aqueous extract, and it is included in the national pharmacopoeias of many European countries. In 2005 a Cochrane systematic review of 37 clinical trials, including 26 comparisons with placebos and 14 comparisons with synthetic antidepressant drugs, confirmed its effectiveness for mild to moderate depression, thereby providing strong support for one of its main traditional uses.⁵

St John’s wort contains several active constituents, but it is generally accepted that the hyperforin and hypericin constituents are chiefly responsible for its antidepressant and anxiolytic effects.¹ In the past 5 years, researchers have identified that an extract devoid of both hypericin and hyperforin still has antidepressant effects, suggesting that other constituents in the extract are also pharmacologically active.⁶ Current research has identified several new active constituents, but others remain elusive. In addition, several other components previously considered devoid of activity have been found to alter the pharmacokinetics of key active constituents. For example, procyanidin B₂ and hyperoside increase the oral bioavailability of hypericin by 58% and 34% respectively.⁷ Therefore, current scientific knowledge has demonstrated that the total extract has to be considered the active substance, and that the herb’s pharmacological effects cannot be described as simply due to one or two active constituents.

In the late 1990s, the extraction method used by some commercial producers was modified, resulting in higher hyperforin concentrations than previously seen.⁸ A St John’s wort extract known as LI 160 is one of these higher-hyperforin types. Since this time, numerous reports and studies have identified pharmacokinetic drug interactions with St John’s wort based on its ability to induce cytochromes and P-glycoprotein, and the hyperforin constituent has been identified as the key constituent responsible for these induction effects.¹ Meanwhile, studies with low-hyperforin St John’s wort preparations, such as Ze 117, have not found evidence of the same interactions.⁸ Unfortunately, the distinction between preparations is not well appreciated in the literature and many reference texts fail to mention this important point.

QUALITY CONTROL AND PRODUCT REGULATION

There are considerable differences in the classification and regulation of herbal products in the world market. Regulation tends to be influenced by ethnological, medical and historical factors. Because herbal medicines do not fall easily into the legal categories of food or drug, they often inhabit a grey area between the two.

In Australia there is an international best-practice, risk-based regulatory system for both complementary and pharmaceutical medicines.¹ The Commonwealth Department of Health and Aged Care delegates responsibility for the regulation of complementary medicines to the Therapeutic Goods Administration (TGA), which has an office dedicated to this role (Office of Complementary Medicines). The TGA is responsible for product quality, safety, claims, registration, post-marketing monitoring and setting standards for manufacturing. All herbal products manufactured commercially in Australia must be produced according to the code of Good Manufacturing Practice (GMP). In 1997, the Parliamentary Secretary to the Minister for Health and Family Services established a new ministerial advisory committee, the Complementary Medicines Evaluation Committee (CMEC), which advises the TGA and government on the regulation of complementary medicines.

All complementary medicines imported into, supplied in or exported from Australia are entered onto the Australian Register of Therapeutic Goods (ARTG) and allocated an AUST L number if considered low risk and generally safe (most herbal products) or AUST R number if considered high risk (most prescription drugs). For both AUST L and AUST R products, there are statutory guidelines, stringent labelling requirements and regulations regarding advertising and compliance of the manufacturing process with a recognised code of good manufacturing practice. Penalties are imposed for manufacturers found to be in breach of these regulations.

In 2004, Health Canada officially added a new term to the global list of synonyms for dietary supplements: natural health products (NHP), with the release of its Natural Health Products Regulations (the NHP regulations). The regulations are applicable to the sale, manufacture, packaging, labelling, importation, distribution and storage of NHP, and are administered by the recently formed Natural Health Products Directorate (NHPD) within Health Canada. Herbal medicines fall into the NHP category. One of the main components of the NHP regulations is product licensing. Under the new regulations, all NHP are required to undergo pre-market review to obtain a product licence and a corresponding Natural Product Number (NPN). In addition to providing data on the safety, efficacy and quality of NHP ingredients, each manufacturer applying for a product licence must provide information regarding the site of manufacture, packaging, labelling, distribution or importation, with corresponding site licence (SL) numbers, acquired through the submission of a site licence application (SLA). A site licence provides some assurance that current good manufacturing practice is being undertaken.⁹

In the United States, the Food and Drug Administration (FDA) has treated dietary supplements, such as herbal medicines, as foods since 1994 with the enactment of the Dietary Supplement Health Education Act (DSHEA). The DSHEA resulted from a grassroots campaign protesting against the ongoing efforts of the FDA to regulate dietary supplements as drugs, not foods. The DSHEA led to the existence of two sets of regulatory standards, one for foods (including dietary supplements) and the other for drugs (medicines). It also transferred to manufacturers the responsibility for ensuring product safety and the requirement that any therapeutic claims be substantiated by adequate evidence.¹⁰

Regulation of herbal products differs substantially between Australia, Canada and the United States in that, under the DSHEA, a manufacturer is not required to obtain approval from the FDA prior to marketing its product, although other provisions must be satisfied to ensure a reasonable expectation of safety. Because the FDA has no regulatory control over what products are on the market, it can only remove a dietary supplement from the market if it can prove that the product has violated the regulations governing product safety, information and labelling, or claims after the product reaches the market. To withdraw a product, the FDA must also prove that the product places the consumer at ‘significant or unreasonable risk’.¹⁰

Unlike Australia, Canada and the United States, in several European countries botanical medicines have always been part of mainstream medicine and therefore have been included in the regulations of each country from the beginning. Herbal medicines fall within the scope of the European Directive 2001/83/CE, but there is still little harmonisation between countries in regards to regulation.¹¹ In some European Union (EU) countries, herbal products are sold as foods, or incorporated in functional/fortified foods or as food supplements, meaning that no medicinal claims are made, whereas in other EU countries these preparations are registered by full or simplified registration procedures. In some countries, the medicinal product status is automatically linked to pharmacy-only status.¹²