08 Aug 2017 15 Sep 2017
Despite using plants for medicinal purposes for over 5,000 years, not much is known about the efficacy, mechanism, or safety of herbs' pharmacological activity. Although herbal medicines are not a new threat, they are becoming an increasing concern due to their growing popularity around the world.
Use of traditional medicine has expanded globally and has gained popularity. Not only is it used for primary health care of the poor in developing countries, it is also used in countries where conventional medicine is predominant in the national health care system. Three quarters of the world population is estimated to rely on herbal and traditional medicine as a basis for primary health care1. With this increase in popularity, an awareness of the efficacy, quality control, and safety of herbal medicines have become important concerns.
Plants have been recorded as being used for medicinal purposes over 5,000 years2. For most of history, herbal medicine was the only treatment. As early as 1890, 59% of the listings in the US Pharmacopeia were from herbal products, and it is estimated that one third to one half of currently used drugs were derived from plants1. Today, thousands of herbal products are available over the counter and are commonly used by patients globally. Public dissatisfaction with the cost of prescription medications, combined with an interest in returning to natural or organic remedies, has led to an increase in herbal medicine consumption1. This is particularly true in individuals with chronic or incurable diseases. Herbal medicines are not a new threat, but they are an important and misunderstood threat.
According to the World Health Organization, an herb is any form of a plant or plant product, including leaves, flowers, fruit, seed, stems, roots, and seeds2. These plants can either be sold raw or as extracts, where the plant is softened with water, alcohol, or other solvents to extract some of the chemicals. The resulting products contain dozens of chemicals, including fatty acids, sterols, flavonoids, alkaloids, and glycosides3.
Echinacea plant is widely used primarily for treatment of the common cold. Assessing the effectiveness of different Echinacea preparations is complicated because of the many extraneous variables. There are three different species of Echinacea in medical use, which include Echinacea purpurea, Echinacea pallida, and Echinacea angustifolia4. As well, not only are different parts of the plant are used (root, herb, flower, or whole plant), different methods of extraction are used. Lastly, other plant extracts or homeopathic components are added in some preparations. Making comparisons and pooling data of different preparations of Echinacea is methodologically questionable, so interpreting the plant's effectiveness needs caution due to the heterogeneity of the preparations.
Furthermore, the exact mechanisms of action for the immunomodulating effects of Echinacea preparations are unclear. There are four classes of compounds that are known to contribute to the immunomodulatory activity of Echinacea extracts: alkamides, glycoproteins, polysaccharides, and caffeic acid derivatives4. Different concentrations of different compounds are found in the three species of Echinacea. Subsequently, the pharmacologic effects associated with the elements in Echinacea may result from independent or synergistic interactions with single or multiple elements. As well, even if Echinacea extracts and constituents have demonstrated pharmacological activities in various biological assays, there is no evidence-based conceptual framework to explain how Echinacea might effectively prevent or treat acute respiratory infections4.
Karsch-Volk et al. investigated in a systemic review the effectiveness of different Echinacea preparations for preventing and treating common colds or induced rhinovirus infections4. Different preparations were compared to a placebo in twenty-four double-blind randomized control trials with 4631 participants. It was not possible to apply a standard definition of the common cold across the trials, so the participants included in this study were individuals with non-specific viral upper respiratory tract infections (URTIs) with a clinical diagnosis of common cold, influenza-like syndrome, or viral URTI; volunteers without acute URTIs but treated for preventative purposes; or volunteers without acute URTIs but challenged with rhinovirus treated for preventative and/or therapeutic purposes. The researchers only included trials of oral Echinacea with one preparation versus a placebo and excluded trials of combinations of Echinacea with other herbs and trials comparing Echinacea with no treatment or a treatment other than placebo. A large proportion of the preparations used in the trials were pressed juices (stabilized with alcohol), alcohol tinctures or tablets made from dried extracts.
The heterogeneity of the preparations tested did not allow a strong conclusion. The different preparations of Echinacea contained different amounts of bioactive components; therefore, the different preparations were not comparable. Karsch-Volk et al did conclude that some Echinacea products were more effective than a placebo for treating the common cold, but the overall evidence for clinically relevant treatment effects was weak. In general, Echinacea preventing colds did not show statistically significant reductions in illness occurrence; however, nearly all prevention trials suggested small preventative effects. Studies investigating the effects of herbs cannot draw strong conclusions unless heterogeneity and reproducibility are controlled.
Herbal medicines are often promoted as natural and therefore harmless; however, these remedies are not free from adverse effects. Much of the United States' botanical industry's products are unlicensed and are not required to demonstrate efficacy, quality, or safety1. Lack of regulation and loose distribution channels may attribute to poor quality of herbal products which will result in adverse reactions. Regulation is difficult since different cultures in different regions of the world have developed various practices of traditional medicine without a parallel international standard and appropriate method for evaluating traditional medicine.
Pharmacologically Active Ingredients
Natural products contain pharmacologically active molecules which can potentially cause danger to human health. Examples of toxicity associated with herbal use include the hepatotoxicity due to pyrrolizidine alkaloids-containing plants, acting by a characteristic veno-occlusive disease that may be rapidly progressive and fatal, Aconitum poisoning due to Aconitum alkaloids, which are highly toxic cardiotoxins and neurotoxins, and the severe and lethal cardiovascular side effects associated with Ephedra sinica6. However, other studies have clearly shown that adverse events due to herbal remedies are relatively infrequent if assessed for causality and that although the number of severe clinical reactions was small, fatalities have been described7.
The objective of this review was to collect available data on the following: (i) adverse effects observed in humans from the intake of plant food supplements or botanical preparations; (ii) the misidentification of poisonous plants; and (iii) interactions between plant food supplements/botanicals and conventional drugs or nutrients.
Biological contamination and chemical contamination of medicinal herbs and herbal products are very common. Impurities in medicinal herbs and their preparations and products refer to biological contamination8. They may involve living microbes such as bacteria and their spores, yeasts and molds, viruses, protozoa, insects (their eggs and larvae), and other organisms. Microbial contamination of herbs may result from improper handling during production and packaging. Sources of contamination are microbes from the ground and processing facilities (contaminated air, microbes of human origin). Cross contamination is also a possibility from extraneous materials such as glass, plastic, and other materials which contact the herbs, herbal preparations, or products. Human excrement, animal manure and feces used as fertilizers are other sources of biological contamination. As well, contamination of herbs with bacterial strains resistant to known antibiotics poses human health risks and infection. Additionally, because molds are widespread in the atmosphere, they are a natural contaminant of medicinal herbs. Molds are potent allergens and producers of mycotoxins. Products of microbial metabolism, such as toxic, low-molecular-weight metabolites from molds, are chemical contaminants. Furthermore, herbal products can be contaminated by heavy metals and pesticides as well.
Case reports, case series, and pharmacokinetic trials have highlighted that herbal medicines can interact with prescribed medicines6. Interactions can have either a pharmacokinetic and pharmacodynamics basis or both, and herbal medicines may interact with prescribed drugs at the intestine, liver, kidneys, and targets of action. Herbal remedies involved in drug interactions have been shown to up-regulate or down-regulate cytochrome P450s and/or P-glycoprotein6. The roles of drug transporters, including the organic anion and cation transporters and the nuclear pregnane-X receptor, are apparent9. However, most of the evidence for herb-drug interactions come from case reports; therefore, it is difficult to establish a cause and effect relationship.
Izzo reviewed the clinical data regarding the interactions between herbal remedies and prescribed drugs. Since herbal medicines are a mixture of more than one bioactive ingredient, such combinations of many substances increase the likelihood of interactions taking place; therefore, theoretically, the likelihood of herb-to-drug interactions is higher than drug-to-drug interactions, if only because synthetic drugs usually contain single chemical entitities10. Therefore, it is difficult to rule out what causes the interaction. The review investigated the clinical data for 27 herbal remedies known to interact with conventional medicines, such as Aloe vera, Echinacea, and St John's Wort.
Also examined in the review were characteristics of the patient. Age, frailty, infrequent genotypes, ethnicity, gender, and comorbidity should be accounted for when considering herb-to-drug interactions. This is important since polymorphisms in the genes for drug-metabolizing enzymes or transporters may influence herb-to-drug interactions. As well, the concomitant use of prescription medications and herbal products by older adults is a common situation in western countries10. Since older adults typically have multiple health problems, they are at particular risk for herb-to-drug interactions. Despite this gravity, clinical studies investigating the potential of drug interactions in elderly patients are rare. Additionally, it is well established that the pharmacokinetics of many drugs vary between men and women. Gender differences in herb-to-drug interactions have been reported both experimentally and in clinical trials10.
Izzo's review article had many limitations. Only clinical reports were considered, and preclinical studies, including human in vitro experiments, were excluded. This and other unpublished articles could lead to underestimation. As well, most of the evidence on herb-to-drug interactions discussed in the article was based on case reports, which are sometimes incomplete and do not allow inferences for a causal relationship. However, it should be noted that even documented case reports can never establish a causal relationship between drug administration and an adverse event since there are so many extraneous variables. Also, the extract type, standardization of extract, part of the plant used and the scientific name of the plant were not specified in the papers reviewed. This is important because preparations obtained from the same plant may have different chemical compositions and therefore different biological actions, as previously highlighted. This leads to uncertainty as to what causes the adverse effects. Furthermore, herbal preparations are not subject to the same regulations as prescription drugs, so the content of active ingredients may vary among manufacturers, potentially causing a large variation in efficacy and safety. The under-regulated quality of herbal medicines is another limitation and safety issue since contamination or adulteration of herbal medicines, including adulteration with synthetic drugs, may cause drug interactions. Therefore, a contaminant/adulterant, and not an herbal ingredient, can theoretically cause the drug interactions. Lastly, it is difficult to identify most herb-to-drug interactions because many countries do not have a central mechanism for mandatory reporting, and many people conceal their use of herbal medicines to their physicians or pharmacists, believing that herbal products are natural and therefore safe10.
Izzo concluded that clinical reports clearly indicate that herbal medicines can interact with conventional drugs. While most of these interactions have a negligible clinical significance, some may pose a serious threat to public health. Herbal medicines may be used by patients concomitantly receiving conventional drugs, which can result in misunderstood adverse events.
Important changes to the regulation of herbs are needed to improve the safety and appropriate use of herbal products. These include requiring manufacturers to register with the FDA, requiring safety tests like those required for over-the-counter drugs, requiring all health claims to be supported by data approved by the FDA, and ensuring that product labels provide an accurate list of all ingredients1. These changes will help the safety of herbal products, but additional changes are needed to improve and promote high-quality research. Defining specific standards for herbal products to ensure consistency between studies is critical. Once a well-established standard of the chemical fingerprint exists for herbs, the formulation of the herbal product can become clear.
Additionally, symptoms of illnesses are subjective. Operational definitions need to be addressed to make strong comparisons. Ideally, a robust study design would be able to show all preparations of a plant showing either positive or negative effects.
Because of the current regulatory structure and limited available data on safety and efficacy, there is high risk using herbal medicine, including severe side effects from pharmacologically active ingredients, contaminants, or drug interactions. On the other hand, the benefits using herbal medicine lack evidence or have inconsistent evidence, so more high-quality research needs to be conducted, especially regarding high-risk patients such as older adults.
Assessing the efficacy, quality, and safety of herbal medicines is problematic because of inadequate or inconsistent study methods being used. Herbal research should be conducted with the same meticulous care as any other medical research, and all herbal products administered to patients should ideally be chemically characterized, standardized, and of known quality. Extraneous variables from different herbal preparations do not allow for generalizations about the efficacy and safety of herbal remedies, and findings of clinical studies must be interpreted cautiously because many studies were performed without sufficient rigor and recorded detail.
Additionally, the current regulation of herbs does not ensure that available products are safe, and false and illegal marketing claims are common. Changes to the regulation of herbal products could dramatically improve the appropriate use of herbs. High quality research in this field is needed to firmly establish the efficacy and safety of many herbal products.
The biggest threat regarding herbal medicines is that it continues to be misunderstood. It is unknown which exact chemical, or combination of chemicals, in an herb produces a biological effect. Hence, it is difficult to create the ideal herbal product that is precise, controlled, and standardized. Also, it is not known if a single chemical component of the herb or the synergistic combination of chemicals in the plant would produce the desired effect. Which constituent of the herb produces an herb-to-drug interaction is not understood either, allowing for adverse reactions. These ambiguous fallouts result from the many different preparations of herbal products. Standardized, robust study designs are required to address the uncertainty of these findings.
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