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 For example, in Germany, almost all botanical medicines are considered medicinal agents and require medical authorisation. In the United Kingdom, some herbal medicines require registration under the Traditional Herbal Medicinal Products Directive or full medicines authorisation, whereas others considered not medicinal by function are permitted in supplements and foods.¹²

The classification of Ginkgo biloba in different countries provides a further example: in the United Kingdom and the Netherlands, Ginkgo biloba can be sold as a food supplement; in Germany and France it is a registered OTC medicine; in Ireland it is available as ‘prescription only’.¹²

HERBAL SAFETY AND ADVERSE REACTIONS

The World Health Organization (WHO) defines an adverse drug reaction (ADR) as a ‘response to a medicine which is noxious and unintended that occurs at doses normally used in humans’. When two medicines interact in a way that produces an unwanted effect, this is also referred to as an adverse drug reaction. Factors associated with an increased likelihood of developing an ADR to a drug or herbal medicine include: advanced age, polypharmacy, dementia or confusion, history of atopic disease, prolonged and frequent therapy, and compromised hepatic and/or renal function.¹

ADRs can arise due to an intrinsic or an extrinsic effect. An intrinsic effect refers to the active ingredient itself, such as the herbal medicine present within a product. An extrinsic effect relates to product characteristics resulting from poor manufacturing and quality control, such as contamination or adulteration.

Herbal adverse effects can be categorised in a similar way to pharmaceutical medicines and are mainly type A or type B reactions. Type A reactions are anticipated and predictable reactions and tend to be dose related. A herbal example is halitosis and dyspepsia caused by garlic, and a pharmaceutical example is bleeding caused by warfarin or hepatotoxicity from paracetamol. Type B reactions are idiosyncratic and uncommon, difficult to predict and not dose related. They tend to have higher morbidity and mortality than Type A reactions and are often immunologically mediated.¹³ A herbal example is hepatotoxicity caused by black cohosh, and a pharmaceutical example is interstitial nephritis with the use of NSAIDs.

When manufactured, prescribed and used appropriately, the safety of over-the-counter herbal medicines is high. Serious adverse effects and dangerous interactions are rare, particularly when one considers the millions of doses taken around the world each year. Even so, practitioners should consider the likelihood and potential consequences of an adverse reaction for each patient before prescribing any herbal medicine.

EVIDENCE AND SCIENTIFIC VALIDATION

Over the centuries, empirical knowledge about herbal medicines has slowly accumulated to form a body of evidence commonly referred to as ‘traditional evidence’. This form of evidence is based on the basic tenets of good clinical practice: careful observation of people, their environment and the diseases they acquire. While there is now a stronger focus on scientific evidence in Western countries, the accumulation of traditional evidence continues today in many parts of the world.

Over the past 40 years, scientific evidence has extended the traditional evidence base and enabled a better understanding of phytomedicines to emerge. Research has been conducted to isolate and identify key active constituents in botanical medicines and their mechanisms of action. This field of enquiry is appropriately termed phytochemistry. Efficacy and safety studies have also been conducted and there is now good evidence from systematic reviews and meta-analyses (including Cochrane reviews) of randomised controlled trials for the efficacy of certain standardised herbal extracts. Three examples are provided in Table 4.2.

Although these studies have been useful in broadening our knowledge of herbal medicine, randomised trials using a standard ‘one size fits all’ treatment approach do not accurately reflect ‘real world’ practice. Phytotherapy relies on individual diagnosis and treatments, which often comprise multiple-ingredient formulations together with diet and lifestyle advice. Investigation of a single extract in a poorly defined population (by phytotherapy standards) will only go part of the way towards supporting or disputing the clinical significance of this approach.

Until recently, most phytomedicine research was conducted in Europe and Asia, where there is a rich tradition of use. Research in this area in the United States remained stagnant until the 1990s, when rapid growth and public interest in phytotherapy motivated the government to start dedicating more funds to research. Interestingly, by 1997, the Office of Alternative Medicine in the United States was renamed the National Center for Complementary and Alternative Medicine (NCCAM), indicating greater acceptance of therapeutic approaches such as phytotherapy.²⁰ Notwithstanding these efforts, a relative lack of resources, infrastructure, government funding and financial incentives for investment in non-patentable medicines research has impeded herbal research worldwide.

Phytomedicine research in Australia continues to struggle due to a severe lack of funds despite its enormous public popularity. In 2007 the Australian Government earmarked $5 million for complementary medicine research via a National Health and Medical Research Council special call. Over 140 submissions were made, indicating enormous interest among researchers. In the same year, the National Institute of Complementary Medicine (NICM) was created using seed money provided by the Commonwealth Department of Health and Ageing together with the New South Wales Office for Science and Medical Research (OSMR) (www.nicm.org.au). The aim of the NICM was to build the capacity of complementary medicine research across Australia, effectively connecting complementary medicine researchers and professionals with the broader research community, industry and other stakeholders, to provide strategic focus and foster excellence in research. However, funding was suspended in 2009.

PHILOSOPHY AND THE HERBALIST’S APPROACH

The practice of phytotherapy is based on a synthesis of traditional and modern philosophies of health and disease. The person-centred approach is standard practice and highly individualised treatment plans are the norm. Attention is paid to a patient’s individual presentation, their diet and lifestyle choices, past history, general constitution, overall vitality and particular environmental circumstances.

Medical herbalists are trained in basic sciences such as anatomy, physiology and biochemistry, basic pharmacology and clinical diagnosis in order to enable a comprehensive history to be taken, identifying symptoms and underlying disease. According to an Australian workforce survey, 85% of naturopaths and Western herbalists also hold first aid certification and approximately 90% regularly attend continuing education seminars.²¹ The same survey identified that nearly 40% of practitioners use Western diagnostic tests such as pathology and radiology to guide their clinical practice and nearly two-thirds perform physical examinations. In addition, most use traditional naturopathic diagnostic assessments.

Therapy is aimed at addressing the cause of disease, reducing the influence of exacerbating factors and providing symptomatic relief in an overall attempt to achieve deeper and longer-lasting healing. As a result, herbal combinations are prescribed rather than single herbs, and treatments can vary significantly between individual patients who present with outwardly similar symptoms. Preparations such as tinctures, fluid extracts, syrups, capsules and creams are all part of the treatment armoury. Education about pharmacognosy, herbal materia medica, manufacturing and botany provide Western herbalists with the foundation knowledge on which to base treatment choices.

In most cases, liquid herbal preparations are dispensed on site and commercially prepared oral dose forms are used. In recent years, awareness of drug–herb interactions has meant that practitioners are now being trained to take a full medication history and understand how to avoid inducing a negative interaction.

The herbalist’s wholistic approach also encourages patient responsibility and enlists them as a key partner in the healing process. This is a common theme in all traditional healing systems and is central to the practice of phytotherapy.

TALKING WITH PATIENTS ABOUT HERBAL MEDICINES

Studies indicate that most patients using complementary medicines (including herbal medicines) do not routinely disclose this information to their medical practitioner. In the United States, Eisenberg and colleagues identified that, in 1990, only 39.8% of complementary medicine users disclosed their use to physicians, and in 1997 this figure was 38.5%, suggesting that disclosure had remained poor.²⁵ Many other surveys have had similar findings. One review of patients attending medical clinics identified non-disclosure rates of 23–72%.²⁷ In all 12 studies reviewed, the same three themes were consistently reported as barriers to communication: patient concern about eliciting a negative response from the physician; the patient’s perception that their medical practitioner did not need to know about complementary medicine use because they would be unable to contribute useful information; and lack of clinician enquiry.

Lack of patient disclosure combined with lack of practitioner enquiry results in a ‘don’t ask, don’t tell’ culture in which communication barriers are continually reinforced.²⁸ Not only is this situation potentially dangerous, it is also a missed opportunity for practitioners to learn from patients about their reasons for using herbal medicines, whether the treatment has been effective or ineffective, and other details about their healthcare beliefs.

Clear and open communication is essential for the delivery of high-quality, safe patient care. General practitioners must be able to talk with patients about a variety of healthcare and treatment options, especially those that are commonly used by the public, such as herbal medicines. Asking a few open-ended questions in a non-judgmental way will help the clinician to assess whether a patient is taking any herbal medicines and enable a discussion to begin.

NEXT STEPS

Asking patients about their use of botanical medicines is relatively easy, but interpreting their answers can be far more difficult. The following steps are recommended:

PRESCRIBING HERBAL MEDICINES

Botanical medicines can play an important role in general practice and provide practitioners with many additional therapeutic tools. While the fully fledged practice of phytotherapy requires several years of specialised training, general practitioners can successfully integrate some simple, pre-prepared herbal treatments into their practice.

Once it has been determined that a herb is efficacious and safe for a specific patient, the patient should be encouraged to choose a high-quality product. Practitioners are advised to become familiar with their local regulations and herbal manufacturing companies, to ascertain which products present the best quality. For example, in Australia, it is important that products contain an AUST L or AUST R number on the label together with an expiry date, and any product without these should not be used. Practitioner-only companies in Australia pride themselves on producing higher-quality products which are only available in clinics under supervision.

Once the correct herbal extract has been chosen, the choice of dose follows. Doses used in clinical trials provide a useful guide but they are sometimes difficult to interpret. Doses provided by manufacturers on product labels also provide a general guide, but can be conservative and may need to be increased to reach full therapeutic effect. For more specific information, refer to reputable texts or even ring the product manufacturer about dosing schedules, as many have dedicated enquiry phone lines.

Patients should be provided with instructions about where they can find the particular product prescribed, how to take and store the medicine, and what they should expect. It is worth discussing a sensible time frame for trialling a herbal medicine so that expectations are realistic and management can be modified if the treatment is not effective. Once again, information about this can be found in clinical trials and good reference texts. For example, herbs such as Ginkgo biloba for mild dementia require a trial of at least 3 months, whereas ginger treatment should alleviate nausea within 1 hour. Box 4.2 provides a summary of these steps.

As with good food and good wine, the quality of commercially prepared herbal medicines will vary, as will the price. Learning about different company philosophies and products takes time but will help clinicians to become more confident prescribers. Most importantly, look for opportunities to learn more about herbal medicines from credible sources and become familiar with accredited medical herbalists and pharmacists who have additional herbal medicine training.

If a patient is keen to start using a herbal medicine but as their practitioner you lack confidence or knowledge about it, consider referring the patient to an accredited medical herbalist. A standard referral letter should be sufficient, and should include the names of all medications being used by the patient. If you would like the practitioner to provide correspondence about their phytotherapeutic approach, ensure that this is stated in the referral letter.