Are you using herbal medicines as a primary or supplemental treatment, and are you aware of possible drug-herb interactions?

I listened to the lecture of professor Dr. Bill J. Gurley titled “Clinically relevant herb-drug interactions: past, present, and future” at the National Center for Complementary and Integrative Health, National Institutes of Health of the U.S.A. I was impressed with the presentation from one pharmacy professor who is highly specialized in the pharmacokinetics and pharmacodynamics (metabolism of medications and supplements) of conventional medicines and supplemental herbal products. After the lecture, I started wondering what we really know about herbal remedies or their combination with conventional prescription medications as a part of complementary treatment. How many people are aware and knowledgeable about that? Indeed, we learned about herbal medicine a lot, but how about its combination with conventional therapeutics in the form of complementary therapy?

Did we learn something from the case of ephedra (Ephedra sinica)?

Clearly was stated in the lecture that, for example, ephedra (Ephedra sinica) was used in Traditional Chinese Medicine for over 5000 years for the treatment of asthma and nasal congestion for only 7 – 10 days, and that’s it, either a patient is healed or not, but not chronic use of ephedra was considering and proper treatment by ephedra in Traditional Chinese Medicine. However, in the U.S.A., from 1994 until 2004, ephedra was used chronically as a potent stimulant, not as a remedy for bronchial asthma, nasal congestion, cold, flu, fever, cough, and wheezing. In response to substantially collected evidence of adverse effects and deaths related to ephedra, the U.S. Food and Drug Administration (FDA) banned the sale of supplements containing ephedrine alkaloids in 2004. Ephedrine is a potent sympathomimetic that stimulates alpha, beta one, and beta two adrenergic receptors. It excites and stimulates the sympathetic nervous system, causes tremendous vasoconstriction and cardiac stimulation, and produces effects similar to epinephrine (adrenalin). Ephedra extracts that do not contain ephedrine have not been banned by the FDA and are sold legally today. Yet, Chinese and others who know how to use ephedra effectively cure some acute diseases in short-term treatment, NOT chronically.

Do we really use herbal remedies correctly in our Western culture and conventional treatment with prescription medications and then call that complementary treatment?

Do we consider numerous factors regarding combining conventional medicines and herbal remedies in complementary therapy, such as patient characteristics, gender, age, ethnicity, co-morbidity, frailty, rare genotypes, and others? Also, the fact that the majority of currently available dietary and supplemental herbal remedies are products containing multiple herbal components, that their formulation utilizes highly concentrated herbal (botanical) extracts, which is not a proper way of preparing herbal remedies in alternative medicine, that many commercially available supplemental herbal products have the presence of numerous phytochemicals that have not been tested for pharmacological activities. These facts do not “sound” like traditional herbal therapy and their proper use as supplemental therapy in complementary and conventional medicine by using prescribed medications.

What is the level of the current clinical evidence?

The next surprise, when I was searching for the scientific literature data, results of clinical studies regarding using herbal remedies as a supplement therapy to conventional therapeutics, calling that complementary treatment, mostly they are isolated case studies or case series, case reports, and results of in vitro analysis performed on cell cultures expressing human genes (for example). Mostly, clinical evidence has been on the level of preliminary case studies, case reports, an adverse event unlikely from a pharmacological viewpoint, and case reports providing some evidence for interaction; however, other cases not entirely excluded, case series, some pharmacokinetic trials in patients or healthy people, there are numerous contradictory data, or adverse events are highlighted by case reports but not confirmed by clinical trials or mega clinical trials. Most authors were allowed to generalize. Generally, generalization is acceptable only if you perform experimental clinical research design. No doubt, scientifically, case studies are a useful “tool” to set up a future hypothesis in clinical research and to conduct further research in that particular field.

Complementary medicine is teamwork between conventional (Western medicine) specialists and alternative herbal medicine specialists

Well, where we are regarding understanding herbal medicine, do we really appreciate them, maybe we misuse them, how properly they should be used, and how can they be applied as an additional therapy with conventional medications in the form of complementary medicine? Also, there is one more question, if we do not know how to use them properly, why we do not leave it to the patient to make a decision either to use herbal medicine (correctly) or conventional drugs to treat their diseases or provide prescription authorities with additional education regarding a complementary approach for therapy. Certainly, complementary medicine is teamwork. Indeed, the “street” is in two directions, a two-way street, not one. It looks like some bigger picture is behind all these facts.

Current clinical evidence of interactions between herbal (botanical) and conventional medications

Herbal medicines have been well known worldwide, in European countries, America, Russia, China, India, and Arabic countries for centuries. Currently, Western herbal medications can be classified into botanical-derived conventional medicines and dietary supplements. However, over the past two decades, intensive interest in herbal medicine has overgrown in all countries. In addition, due to cultural diversities in the EU and Russia, traditional herbal remedies of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular (Sammons H.M. et al., 2016).

The typical scenario today is a combination of herbal medicines used in conjunction with conventional drugs in the form of complementary treatment. Unfortunately, this condition may give rise to the potential for harmful herb-drug interactions.

Some clinically critical herb-drug interactions have been reported in the literature. Still, many are from case studies, case reports, and limited clinical observations or literature searches and reviews of published case reports. Common herbal medicines that exhibited some interactions with conventional medications (prescription medications) include St John’s wort (Hypericum perforatum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John’s wort could significantly reduce the area under the plasma concentration-time curve, and blood concentrations of conventional medications prescribed by medical specialists such as cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon, and theophylline. The standard drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus, and irinotecan.

Herbal medicines may interact with medications in the intestine, liver, kidneys, and action targets. Most of them are actually substrates for specific metabolizing enzymes such as cytochrome P450s and P-glycoprotein. Well, the underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and pharmacodynamic events are implicated in many of these interactions but not fully understood and investigated. In particular, enzyme induction and inhibition may be essential in some herb-drug interactions. Because herb-drug interactions can significantly affect circulating levels of conventional medications and alter the clinical outcome, identifying herb-drug interactions has important implications (Chen X.W. et al., 2012).

Clinical consequences of herbal/botanical medicine-drug interactions depend on various factors, such as the co-administered drugs, the patient characteristics, general patient conditions, the origin of the herbal medicines, the composition of their constituents, and the applied dosage regimens. Therefore, to optimize the proper use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and delineate the underlying mechanisms (Shi S. et al., 2012, Singh D., 2012).

Various clinical and other medical literature reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. For example, The World Health Organisation indicated that approximately 80% of the Asian and African populations rely on traditional herbal medicine as the primary method for treating various diseases (Neergheen-Bhujun V.S., 2013).

The use of botanical/herbal dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, their concentration in the final product, mechanisms of action, efficacy, and safety. An essential but under-investigated safety concern is the potential for popular botanical/herbal dietary supplements to interfere with the absorption, transport, and metabolism of conventional medications prescribed by prescription authorities. Therefore, clinical trials of drug-botanical interactions should be the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical in vitro studies.

For example, phase one clinical trials have confirmed preclinical studies and clinical case reports that St. John’s wort (Hypericum perforatum) induces CYP3A4/CYP3A5. However, clinical studies of most botanicals predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 (Sprouse A.A., 2016). The complementary use of medications and herbal/botanical products is becoming increasingly prevalent over the last decade as a highly concentrated supplemental product (Cho H.J. et al., 2015). Herb-induced enzyme inhibition and induction may result in enhanced and decreased tissue, plasma, bile, and urine drug concentrations, leading to a change in a conventional medication’s pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects (Li B. et al., 2016). Cytochrome P450 enzymes metabolize many FDA-approved pharmaceuticals (conventional medications) and herbal supplements. This metabolism of medicines and supplements can be augmented by concomitant use. For example, the xenobiotic receptors androstane receptor (CAR) and the pregnane X receptor (PXR) could respond to xenobiotics by increasing the expression of many genes involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s enzymes. Induction of the expression or inhibition of the action of CYP450s enzymes can result in drug-drug interactions and toxicity (Brewer C.T.et al., 2017).

Herbal medications, herbal dietary supplements, and other nutritional supplements are highly prevalent among older people

Herbal medications and other dietary supplements (herbal, vitamin-minerals, and probiotics) are prevalent in older people. Physicians, particularly primary care physicians, are often unaware that their patients use herbal remedies and other nutritional supplements concomitantly with conventional medicines. Herbal remedies and other dietary supplements contribute to high rates of polypharmacy, particularly among older people with multimorbidity. Herbal medicines and other nutritional supplements can interact with conventional drugs and be associated with various adverse side effects. Physicians should be patient-centered and non-judgmental when initiating discussions about herbal medicines and other dietary supplements. Maintaining and developing patient empowerment and self-management skills (Pitkälä K.H. et al., 2016) is vital. In addition to conventional medicine prescribed by a physician(s), many patients regularly use alternative therapies as a self-directed complementary treatment. Communication between patients and providers about complementary therapy use is not consistent. There is an extreme demand for interventions in health care that provide timely, integrative communication support. Delivering herb-drug-disease alerts through multiple channels could help meet critical patient information needs (Christensen C.M. et al., 2017). It is essential to state that conventional medicine specialists should consult alternative medicine specialists if the patient is determined to undergo complementary treatment.

Clinical professionals and specialists, as well as alternative medicine specialists, should enhance risk management on herbal-medication interactions such as increasing awareness of potential changes in therapeutic risk and benefits, inquiring patients about all currently used conventional medicines and herbal medicines and supplements, automatically detecting highly substantial significant herbal/medication interaction by computerized reminder system, selecting the alternatives, adjusting the dose, reviewing the appropriateness of physician orders, educating patients to monitor for drug-interaction symptoms, and paying attention to follow-up visit and consultation (Zhang X.L. 2017).

Severe herb-drug interactions were noted for St. John’s wort (Hypericum perforatum) and mistletoe (Viscum album). The most severe interactions resulted in transplant rejection, delayed emergence from anesthesia, cardiovascular collapse, renal and liver toxicity, cardiotoxicity, bradycardia, hypovolaemic shock, inflammatory reactions with organ fibrosis, and death. Moderately severe interactions were noted for ginkgo (Ginkgo biloba), ginseng (Panax ginseng), kava kava (Piper methysticum), saw palmetto (Serenoa repens), and green tea (Camellia sinensis). Antiplatelet agents and anticoagulants were the most commonly interacting drugs (Posadzki P. et al., 2013).

Although (unfortunately) several studies on pharmacokinetic and pharmacodynamic herb-drug interactions have been conducted in healthy volunteers, there is tremendous uncertainty on the validity of these studies. Unfortunately, a qualitative review and a meta-analysis were performed to establish the clinical evidence of these interaction studies. According to the literature data, out of 4026 screened abstracts, 32 studies were included in the qualitative analysis. The meta-analysis was performed on only eleven additional studies (Awortwe C. et al., 2019).

Many patients treated with cardiovascular medication like to drink green tea because of their cultural tradition or because of its beneficial effects on general wellness and health. However, green tea may affect the pharmacokinetics and pharmacodynamics of many cardiovascular medications and compounds. Some recent data showed that green tea and some cardiovascular medications interact, and drug interactions were reported for rosuvastatin, sildenafil, and tacrolimus. Putative mechanisms involve inhibitory effects of green tea “catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol, and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, data on green tea interaction with cardiovascular substances with a narrow therapeutic index, such as warfarin and tacrolimus, are derived from single case reports. Conversely, green tea interactions with simvastatin, rosuvastatin, nadolol, and sildenafil were documented through pharmacokinetic studies” (Werba J.P. et al., 2018).

There has been substantial interest lately in using herbs to treat hypertension and cardiovascular disease.

“Herbs and other botanicals contain numerous phytochemicals that effectively treat cardiovascular diseases and hypertension. Accumulating scientific evidence provides a reason for the use of herbs by health practitioners for treating their patients. The rationale for this expanding use of herbs is patients’ belief in a “holistic medicine” and that herbs are natural, safe, and effective. However, there are reasons for concern with the use of herbs because they are not regulated or supervised carefully, and their use could lead to severe complications or interactions with their combination with traditional medicines. Also, their use is associated with significant out-of-pocket expenses because their use is not compensated by health insurance providers” (Chrysant SG et al., 2017).

Malongane F. and colleagues stated in 2017 in their article: “Tea is one of the world’s most widely consumed non-alcoholic beverages next to the water. It is classified as Camellia sinensis and non-Camellia sinensis (herbal teas). The common bioactive compounds found mainly in green teas are flavan-3-ols (catechins) (also called flavanols), proanthocyanidins (tannins), and flavonols. Black tea contains theaflavins and thearubigins, white tea contains l-theanine and gamma-aminobutyric acid (GABA), while herbal teas contain diverse polyphenols. Phytochemicals in tea exhibit antimicrobial, anti-diabetic, and anti-cancer activities that are perceived to help manage chronic diseases linked to lifestyle. Many of these phytochemicals are reported to be biologically active when combined. Knowledge of the synergistic interactions of tea with other teas or herbs in terms of biological activities will benefit therapeutic enhancement. There is evidence that various types of teas act synergistically in exhibiting health benefits to humans, improving consumer acceptance and economic value. Similar observations were made when combined with teas, herbs, or medicinal drugs.” (Malongane F et al., 2017).

St. John’s wort is a common medicinal herb for treating mild to moderate depression.

Hyperforin, one of the main components of St. John wort, plays an essential role in the induction of cytochrome P450 enzymes and P-glycoprotein transporter and consequentially affects the pharmacokinetics of various drugs. Several clinical studies demonstrate the interaction of St. John wort with the metabolism of conventional medications, which may cause life-threatening events such as probably serotonin syndrome if combined with SSRI antidepressant therapy (Soleymani S et al., 2017).

In one article published in 2017, Asher G.N. and colleagues stated: “Nearly 25% of U.S. adults report concurrently taking prescription medications with dietary supplements. Some supplements, such as St. John’s wort and goldenseal, are known to cause clinically significant drug interactions and should be avoided by most patients receiving any pharmacologic therapy. However, many other supplements are predicted to cause interactions based only on in vitro studies that have not been confirmed or have been refuted in human clinical trials. Some supplements may cause interactions with a few medications but are likely safe with other medications (e.g., curcumin, echinacea, garlic, Asian ginseng, green tea extract, and kava kava). Some supplements have a low likelihood of drug interactions and, with certain caveats, can safely be taken with most medications (e.g., black cohosh, cranberry, ginkgo, milk thistle, American ginseng, saw palmetto, valerian). Clinicians should consult reliable dietary supplement resources, or clinical pharmacists or pharmacologists, to help assess the safety of specific herbal supplement-drug combinations. Because most patients do not disclose supplement use to clinicians, the most crucial strategy for detecting herb-drug interactions is to develop a trusting relationship that encourages patients to discuss their dietary supplement use” (Asher GN et al., 2017). Izzo A.A. and colleagues published data in 2016. They stated: “Systematic reviews/meta-analyses suggest preliminary or satisfactory clinical evidence for agnus castus (Vitex agnus castus) for premenstrual complaints, flaxseed (Linum usitatissimum) for hypertension, feverfew (Tanacetum partenium) for migraine prevention, ginger (Zingiber officinalis) for pregnancy-induced nausea, ginseng (Panax ginseng) for improving fasting glucose levels as well as phytoestrogens and St John’s wort (Hypericum perforatum) for the relief of some symptoms in menopause. However, firm conclusions about efficacy cannot be generally drawn.”

On the other hand, inconclusive evidence of effectiveness or contradictory results has been reported for Aloe vera in the treatment of psoriasis, cranberry (Vaccinium macrocarpon) in cystitis prevention, ginkgo (Ginkgo biloba) for tinnitus and intermittent claudication, echinacea (Echinacea spp.) for the prevention of common cold and pomegranate (Punica granatum) for the prevention/treatment of cardiovascular diseases. A critical evaluation of the clinical data regarding the adverse effects has shown that herbal remedies are generally better tolerated than synthetic medications. Nevertheless, potentially dangerous adverse effects, including herb-drug interactions, have been described. This suggests the need to be vigilant when using herbal remedies, particularly in specific conditions, such as during pregnancy and in the pediatric population” (Izzo AA et al., 2016).

Ginkgo biloba leaf extracts are popular herbal remedies for the treatment of Alzheimer’s dementia, tinnitus, vertigo (Meniere’s disease), and peripheral arterial disease

Unger M., in an article published in 2013, stated: “As ginkgo biloba leaf are taken regularly by older people, who are likely to also use multiple other drugs for the treatment of, e.g., hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest.” (Unger M., 2013).

The statement that many people have the mistaken notion that natural, all herbs and foods are safe; is not so. Why?

The market contains highly concentrated dietary, supplemental products from botanical/herbal sources, aromatherapy, vitamin-minerals, additional products, and probiotics. Indeed, these herbal remedies are far different than the ones supposed to be administered; they are diverse, concentrated, and combined with conventional medicines and compete for metabolism with our xenobiotic metabolizing enzymes from a family of cytochrome CYP450 s and others. The patient should decide in consultation with a traditional/conventional medicine specialist (Western medicine) or alternative medicine specialist what treatment would be the best option for a patient. The complementary aspect should be conducted carefully with synchronized conventional and alternative medicine administration. A pharmacist should be a great source of knowledge with their knowledge of pharmacokinetics, pharmacodynamics, and pharmacognosy. Unfortunately, many people use Internet resources for consultation and so-called self-healing instead of using the practices of conventional medicine specialists and alternative medicine specialists.

Also, as you can see from this short review, there are no reliable scientific data on herbal/medicine interaction and side effects; all data are from isolated case reports with suspicion of conflict of interests. However, during the last twenty years, the practice of herbalism and the production of highly concentrated herbal remedies as supplemental products has become mainstream worldwide. Again, this is due to recognizing the value of conventional medical practice globally. Herbal remedies traditionally are mixtures of more than one active ingredient or single herbal sources such as a tincture or tea, but they are not highly concentrated. In addition, they should be administered for a certain period, NOT chronically, as explained in the case of ephedra.

Undoubtedly, the possibility of herb-drug interactions is theoretically higher than drug-drug interactions because synthetic drugs usually contain a single chemical entity, even though it is not scientifically confirmed. As Hussain M.S. explained in the article published in 2011: “Case reports and clinical studies have highlighted the existence of some clinically significant interactions, although cause-and-effect relationships have not always been established. Herbs and drugs may interact either pharmacokinetically or pharmacodynamically. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in significantly reduced drug pre-systemic metabolism. An additional mechanism is the inhibition of P-glycoprotein. This transporter carries the drug from the enterocyte back to the gut lumen, further increasing the fraction of the drug absorbed. Some herbal products (e.g., St. John’s wort) have been shown to lower the plasma concentration (and the pharmacological effect) of some conventional drugs, including cyclosporine, indinavir, irinotecan, nevirapine, oral contraceptives, and digoxin” (Hussain MS., 2011).

Respectfully,

References:

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