What are the dangers of drug interactions with herbal medicines?

KEYWORDS:

• Adverse effects
• herb-drug interaction
• herbal medicine
• pharmacokinetic interactions
• pharmacodynamic interactions

1. Introduction

Plants have been used in the treatment of many diseases since ancient times, while also having served as a major source of modern single compound drugs. Herbal medicines continue to be widely used globally due to specific health beliefs [1,2] and due to scientific information becoming more and more available on their benefits to patients as well as their safety [3]. It is true that many plants that have been used traditionally for therapeutic and culinary applications are generally safe, but it is also important to know that some plants are highly toxic and can even be deadly [3].

When patients take herbal medicines in conjunction with their prescribed allopathic medicines, interactions may occur between the phytochemicals in the herbal medicines and active ingredients of prescription drugs through several mechanisms, which can be defined as either pharmacokinetic or pharmacodynamic in nature. These interactions can impact on the pharmacological activity, blood levels, metabolism or toxicity of allopathic drugs [1,2]. Herb-drug interactions are based on the same pharmacological principles as drug-drug interactions [4]. In contrast to single compound-containing allopathic medicinal products, herbal medicines usually contain a complex mixture of phytochemicals that are produced as secondary metabolites. An herbal medicine (e.g. extract or plant material) can easily contain more than 150 ingredients, which makes identification of the causing factor for adverse effects and interactions difficult [5]. In addition, adverse effects due to herb-drug interactions are in general poorly reported and documented, a problem exacerbated by the lack of disclosure by patients of its use to their healthcare providers [2].

Pharmacokinetic interactions specifically refer to changes (i.e. enhancement or inhibition) in the absorption, distribution, metabolism, and excretion of drugs instigated by the co-administered herbal medicine [1], while pharmacodynamic interactions include synergistic or antagonistic pharmacological effects [6].

2. Risks associated with herb-drug interactions

In general, the outcomes of drug interactions can range from insignificant with no inconvenience to the patient up to treatment failure and life-threatening effects or even death [7]. Unfortunately, unreasonable conclusions have been drawn on the risks of certain herbal medicines based on anecdotal evidence as well as misunderstandings and misquoted published articles. One example of such a case is that of Melilotus officinalis (known as sweet clover) that contains coumarin and it was initially believed that this herb caused a bleeding disorder as a result of containing coumarin. However, the condition was later discovered to be caused by dicoumarol, which is a chemical substance formed from coumarin by bacteria in damaged hay. When sweet clover is dried properly it does not contain dicoumarol and therefore has no anticoagulant activity [8]. Well recorded and reliable cases of harm by herbal medicine usage remain remarkably low, even when underreporting of adverse reactions in the herbal sector is taken into consideration. Nevertheless, there are safety issues associated with herbal medicines that need to be realistically assessed based on reliable information [9].

The importance of herb-drug interactions in the safety assessment of herbal products is demonstrated by the fact that the second edition of the American Herbal Product Association’s Botanical Safety Handbook [3] includes a separate herbal medicine safety classification system that focusses mainly on pharmacokinetic herb-drug interactions. The severity of pharmacokinetic herb-drug interactions is generally based on the toxicity of the co-administered drug when its plasma level is increased beyond the minimum toxic concentration or the consequences when its therapeutic plasma level is not achieved. Patients taking drugs with narrow therapeutic windows are at greater risk since relatively small changes in the blood levels of these drugs may lead to toxic effects or therapeutic failure. Furthermore, certain circumstances and conditions may require that patients are monitored on a regular basis when they use herbal medicines in conjunction with prescribed medicines. These patient populations are most vulnerable and include those that are treated with medicines having narrow therapeutic indices (e.g. digoxin, warfarin, immunosuppressive drugs, some anti-retroviral drugs, theophylline, phenytoin and phenobarbital), those with liver and kidney impairment, elderly patients, neonates, pregnant women, organ transplant patients and those with certain genetic disorders [8].

Some patients are especially desperate for alternative and additional treatments to assist in curing their ailments or to reduce the severe side-effects of conventional treatments. In this regard, cancer patients are particularly vulnerable, since they use alternative medicines concurrently with prescribed medicines more often than the general population [1,2]. Some cancer patients use as many as eight herbal supplements while receiving chemotherapeutic treatment [6]. Complementary medicines (including herbal medicines) are frequently associated with polypharmacy. When patients take more than one allopathic medicine (polypharmacy) together with herbal medicines (sometimes more than one herbal medicine), it translates to an increased risk for interactions [10].

Several reliable sources have become available in recent years that are based on scientific evidence, to classify herbal medicines with respect to their safety when used in conjunction with prescribed drugs. It is interesting to observe that only a relatively small percentage of commonly used herbal medicines are contraindicated for use in combination with allopathic drugs when used in normal doses, which is based on confirmed cases and clinical studies. Authoritative sources have become available that can be consulted for herbal medicine safety when used in conjunction with other medicines [3,11–14], however, it is important to note that healthcare workers and patients should obtain the newest information on the topic and consult resources that are continuously updated. The Web version of the Natural Medicines Comprehensive Database is one of the most comprehensive and reliable natural medicine resources available that is frequently updated. It has a search function under ‘Interaction Checker’ that provides up to date information on interactions between herbs and prescription medicines as well as over-the-counter medicines [15].

3. Prejudices and inaccuracies with respect to herbal safety

When assessing the clinical significance of herb-drug interactions, it is important to take into consideration the complexity and interplay of factors that may be involved. Patient factors that may play a role include comorbidities, genetic polymorphism and the number and type of allopathic medications consumed by the person in conjunction with the type and number of herbal medicines. Drug factors include the drug’s therapeutic index, potency, plasma protein binding capacity and susceptibility to cytochrome P450 enzymatic metabolism as well as affinity for efflux transporters. Herb factors include the dosage of the herbal medicine that is taken by the patient, adulteration of the herbal product with other substances (including active pharmaceutical ingredients), misidentification of the plant and contamination with impurities such as heavy metals. Other factors related to the herbal medicine include the location where they were grown (which include aspects such as soil type, weather conditions), the presence of contaminants such as pesticides and bioburden, the harvesting methods and the extraction methods. These aspects are critically important when adverse reactions are reported during herbal medicine use or when clinical trials are planned [3].

The benefit-risk assessment of herbal medicines can easily be distorted by the lack of proof of efficacy of the specific herbal medicine. It is therefore of importance to first obtain convincing, scientific evidence of the benefit of herbal medicines before the risk can be weighed against the beneficial effects [8].

It is important to note that the effects caused by an overdose of allopathic medicines are not considered as adverse drug reactions. However, since herbal medicines are often used during self-treatment by making use of over-the-counter products, these patients can easily overdose with the intention of increasing the product’s beneficial effects. As a consequence, the overdose effects may then be reported as adverse effects [16].

The regulation of herbal medicines vary substantially between countries, which ranges from applying the same strict laws as for registration of prescription medicines to the use of less strict laws such as those applicable for dietary supplements and health foods. Depending on the legal framework applied to register herbal medicinal products, the following aspects may contribute to herbal safety inaccuracies in some countries namely the poor quality of herbal medicinal products in terms of the herbal ingredients and their phytochemical composition, misidentification of the plant species, adulteration with other substances, substitution of herbal ingredients, incorrect processing of plant material or contamination during manufacture. Furthermore, adverse effects of herbal medicines are often based on single cases with incomplete data and it is not always possible to exclude other causes such as an underlying disease or presence of toxic substances due to adulteration or intake of the wrong plant species due to misidentification or substitution [16].

4. Conclusion

Some herbal medicines have been used since ancient times for the effective treatment of disorders, and modern scientific scrutiny has confirmed the benefit of some herbal medicines based on pharmacological principles. This proof of efficacy of herbal medicines have made them serious contenders in primary healthcare provision, not only through self-treatment but also through rational prescription by medical doctors and other healthcare professionals. The use of herbal medicines is not without risk and when they are administered together with allopathic medicines, it can lead to herb-drug interactions. The outcome of these interactions ranges from negligible to life threatening. The potential dangers associated with herb-drug interactions cannot be ignored, but should be rationally managed. Safety concerns of herbal medicines have stimulated development of pharmacovigilance and drug monitoring programs around the world that include comprehensive reporting of adverse reactions. In addition, well planned clinical trials have been conducted on herbal medicines alone and in combination with prescribed allopathic medicines. As a result, several professional databases have become available as guidelines for healthcare professionals to manage the use of herbal medicines together with prescribed allopathic medicines.

However, certain challenges make it difficult to obtain reliable data on herbal medicine safety such as the variability in the quality control of herbal medicinal products, especially in countries where less strict regulatory requirements for herbal medicines exist. Other issues that complicate the determination of the safety of herbal medicines include misidentification, adulteration, substitution and contamination. Despite these challenges, data have become available that can be used to guide healthcare professionals in advising patients regarding the safe use of herbal medicines when taken in conjunction with conventional medicines.

5. Expert opinion

There is no doubt that there are dangers associated with the use of herbal medicines, which include potential adverse effects and interactions with allopathic medicines. Unfortunately, some misconceptions with respect to this important topic have appeared based on speculation, prejudices, theoretical possibilities and inconclusive studies. Fortunately, accurate and reliable information on herb-drug interactions are becoming more and more available based on well planned clinical studies and rational herbal pharmacovigilance programs that can be used to ensure the safe use of herbal medicines by patients.

The assessment of the risk that is associated with herb-drug interactions should take several factors into consideration. One such factor is the quality of the evidence provided for the herb-drug interaction. For example, results obtained from in vitro experiments may only indicate potential interactions, while double-blind placebo controlled clinical trials with clinical relevant endpoints can be regarded as having a high level of accuracy. Quality aspects of the herbal medicine that caused the interaction should be considered, which include factors such as adulteration, proper plant identification and origin, dose and phytochemical composition. Other factors to consider include the severity of the adverse effects and/or toxic effects, the duration of the symptoms, if failure of therapy occurred due to the herb-drug interaction and the frequency of the incidence (e.g. number of case reports). Furthermore, herb-drug pharmacokinetic interactions should be evaluated on the same principles as for drug-drug interactions such as the determination of no-effect boundaries based on the maximum tolerated dose. Furthermore, statistically significant alterations of drug plasma levels by herbal medicines may occur without significant clinical effects.

Herb-drug interactions can be avoided or managed by giving the correct advice to patients based on information from reliable sources. On rare occasions, herbal medicines are contraindicated when patients are using certain prescribed allopathic medicines for which harmful herb-drug interaction effects have been identified (e.g. St John’s Wort with certain anticoagulant drugs). In other cases, it can be managed by closely monitoring the patient or taking the herbal medicine at another time as the prescribed drug, while taking special precautions in most vulnerable patient populations as listed above.

By educating and making health care providers aware of the dangers associated with herb-drug interactions through accurate resources and publications based on scientifically sound studies can contribute to managing the situation and thereby reduce harmful and adverse effects.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.