The issue of herb-drug interactions looms large over the practice of herbal medicine. Up to now there have been few incidents recorded of clinical herb-drug interactions. After the first such reports emerged in the 1990s, a concern has been raised: that we know so little about herbs and their potential for interaction with drugs that these incidents could be just the “tip of the iceberg.” In actuality, the issue has been largely overblown. The exaggerated depiction came about because evidence of interactions remains largely the result of projections from laboratory studies and from only a few case reports where the culprit often was not entirely evident. Virtually all medical writers who review the literature acknowledge the small number of reports, but conclude that the issue of herb-drug interactions is a serious one that must be pursued. In a few instances, the interactions may have been responsible for severe consequences.

Prscription_Drugs2The nature of herb-drug interactions is not a chemical interaction between a drug and an herb component to produce something toxic. Instead, the interaction most often involves having an herb component cause either an increase or decrease in the amount of drug in the blood stream. This is known as a “kinetic” effect, having to do with rate of movement of the drug into and out of the body or into and out of a particular target organ. A decrease in the amount of drug could occur as a result of herb components binding up some of the drug and preventing it getting into the blood stream from the gastrointestinal tract, or by stimulating the production and activity of enzymes that degrade the drug and prepare it for elimination. An increase in the drug dosage could occur when an herb component aids absorption of the drug or inhibits the enzymes that break down the drug or guide it out of the body. A decrease in drug level by virtue of an interaction could make the drug ineffective; an increase in drug level could produce side effects.

Alternatively, there are cases deemed to be an herb-drug interaction where the two agents are each exerting a particular action and those activities can be countering each other or adding to each other; this is known as a “dynamic” effect, having to do with the direction of each action. For example, an herb might produce an effect that is contrary to the effect desired for the drug, thereby reducing the drug effect but not interfering with the drug’s level in the blood stream or target organ. Some oncologists have proposed that herbs and nutritional supplements with antioxidant properties aimed at protecting normal cells from the harmful effects of cancer therapies might also protect cancer cells from the intended damage from radiation therapy, thereby countering the medical intervention. Or, an herb might produce the same kind of effect as the drug, perhaps by a different mechanism, and give an increase in the drug effect, without increasing the amount of the drug present. This kind of problem is often a concern when prescribing two drugs; for example, if two anti-diabetes drugs are given to a patient with elevated blood sugar, each will have an effect of lowering blood sugar; the combined effect might be to lower blood sugar too far, thus producing a dangerous situation. This problem is unusual for two anti-diabetes herbs, because the mild activity of herbs frequently requires two or more herbs with similar action to get blood sugar closer to normal; herbs forcing blood sugar below normal is unlikely. Combining a drug that lowers blood sugar with an herb that does so is sometimes thought of as having a potential for herb-drug interaction, but it is simply two methods of accomplishing the same task of reaching normal levels so does not produce clinical reports of adverse conseuqences. Some examples of concerns about herb-drug interactions that have been raised are that an herb might:

  • increase or decrease the effect of a blood thinner such as Warfarin and lead to either a bleeding episode or formation of a dangerous clot;
  • decrease the effect of a blood pressure medication, leading to high blood pressure and a stroke; or
  • decrease the effect of an anti-infection agent, letting the infection get out of control.

Such undesired responses can occur with drug-drug interactions and with food-drug interactions (especially from the impact of grapefruit juice), so the finding of some instances of herb-drug interaction would not be surprising.

In China it is common for herbs to be combined with drugs. Their combination is sometimes incidental (one doctor prescribes drugs, a different one prescribes herbs), but is often intentional and based on a prevalent favorable theory about using herbs and drugs together. The general sense of the situation among Chinese doctors has been that herbs reduce the side effects of drugs and help them to perform their function better; in turn, drugs will make an herb formula work more strongly and quickly. Together, herbs and drugs may produce a more desirable result than either taken alone. As an outcome of working within this scenario, little attention has been paid to adverse herb-drug interactions among doctors working in China.

The Chinese culture is one in which herbs were a dominant medical therapy during the first part of the 20th Century, and drugs were a relatively recent addition to the medical field. The situation was different in the West. Herbs had been almost entirely replaced by drugs during the first part of the 20th Century. Herbs were later reintroduced once drugs had become a dominant feature of modern health care. The re-introduction of herbs brings with it suspicions and concerns about unreliability and lack of adequate knowledge about them, especially compared to the well-defined nature of drugs and intensive regulation of them.

Today, doctors and pharmacists are provided courses and educational materials outlining potential problems with herbs that their patients may be using. The matter of herb-drug interactions involves a considerable amount of speculation about what might happen. A sample presentation to doctors is the following chart; it was produced for an article on herb-drug interactions for diabetes, showing the different mechanisms (first column) and effects (second column):

Her_drug_mechanism

This chart first divides interaction concerns into the broad subgroups mentioned above: pharmacokinetic (affecting the absorption, metabolism, and elimination of the drug) and pharmacodynamic (mostly involved with herbs and drugs yielding similar effects, additive, or counteracting one another, antagonistic).

Due to the paucity of actual reports of herb-drug interactions, reviews of herb-drug interactions are usually padded with other information, such as reports of simple adverse reactions (not involving interactions). References to what the herbs “may” do when combined with certain drug groups, (e.g., valerian may increase the effects of certain anti-seizure medications or prolong the effects of anesthetic agents) often refer to pharmacology studies rather than actual clinical experience. A standard procedure is to test the herb extract alone and to also test it with drugs that cause the same effect; if the drug effect is increased or prolonged by the herb, it is implied that this additive action can occur clinically. However, the amount of herb used in the pharmacology experiments of this type is often far higher than the amount normally used in clinical practice; the likelihood of herb-drug interactions occurring with usual use of the herb may be minimal. Still, if one wishes to consider possible herb-drug interactions under a variety of scenarios, including excessive use of the herb and use of the herb by individuals who are more sensitive to the possible interaction, then such data must be included in the analysis.

After eliminating published reports alluding to adverse herb reactions (but not interactions) and to pharmacology studies only, one is left with few instances of reported herb-drug interactions. This is likely due to the low dose of any individual herb component usually consumed and the simple absence of significant interaction at any reasonable dose. To help illustrate the low frequency of clinical reports, the following abstract of one such publication will be informative:

Drug-herb interaction among commonly used conventional medicines: a compendium for health care professionals.

Brazier NC, Levine MA.

Center for Evaluation of Medicines and McMaster University, Hamilton, Ontario, Canada.
In: American Journal of Therapeutics 2003; 10(3): 163–169.

The objective of the review was to consolidate the clinical and pharmacologic aspects of drug-herb interactions to develop a compendium of information to provide prescribers with a measure of the risk of interactions, a description of the clinical consequences, and an assessment of the quality (i.e., validity) of evidence. A variety of electronic databases and hand-searched references were used to identify documentation of interactions between herbal products and drugs from the most commonly used therapeutic classes. MEDLINE, Allied and Complementary Medicine Database, CINHAL, HealthSTAR, and EMBASE were searched from 1966 to the present. One hundred sixty-two citations were identified. Only 22 citations met the inclusion criteria. Using a matrix of 165 possible drug-herb interaction pairs (15 therapeutic drug classes by 11 herbal products), we identified 51 (31%) interactions discussed in the literature. Twenty-two of these 51 drug-herb pairs (43%) were supported by randomized clinical trials, case-control studies, cohort studies, case series, or case studies. The remaining interaction pairs reflected theoretic reasoning in the absence of clinical data. Most interactions were pharmacokinetic, with most actually or theoretically affecting the metabolism of the affected product by way of the cytochrome P450 enzymes. In this review, Warfarin was the most common drug and St. John’s Wort was the most common herbal product reported in drug-herb interactions. To create a comprehensive and valid list of herb-drug interactions would require a substantial increase in research activities in this area. Improvements in the quality of methodology used are also necessary.

Hypericin_DiagramPut simply, there were very few well-supported interactions detected: namely 22 that involved more than an individual report, or a simple pharmacology study, or a mere suggestion of potential interaction. Not surprisingly, the main drug of concern is Warfarin, which displays substantial sensitivity to interactions with foods and drugs, and which is very widely used (giving more opportunities to note interactions), while the primary herb involved is St. John’s Wort, one with unique constituents (left: chemical diagram of hypericin, one of the key components) known to affect the drug metabolizing enzymes, such as cytochrome P450, mentioned in the abstract. Use of St. John’s Wort declined dramatically after revelations that it could cause herb-drug interactions along with reports questioning its effectiveness.

In an earlier survey of similar nature, an intensive search of the literature and evaluation of reports of herb-drug interactions yielded the following: “108 cases of suspected interactions were found: 68.5% were classified as ‘unable to be evaluated,’ 13% as ‘well-documented’ and 18.5% as ‘possible’ interactions. Warfarin was the most common drug (18 cases) and St. John’s Wort the most common herb (54 cases) involved.”   Thus, 14 cases were well-documented in this report published about 2 years earlier than the new report which found 22 reasonably supported cases. The same drug and herb emerged as primarily problematic. The rate of well-document herb-drug interactions has been about 4 per year. No doubt, many more instances occurred and were not reported due to their minor nature or uncertainty about the cause. Even so, the numbers should be kept in perspective: the nutriceutical industry estimated (1999) that about 45 million American adults use an herbal supplement at least once per year, and that 21 million adults are regular users of herbal remedies. By 2017, over 30 million adults were regularly using herbal supplements.

St Johns WortAn article published in Pharmacology Research (2017) is titled: “Is the clinical relevance of drug-food and drug-herb interactions limited to grapefruit juice and Saint-John’s Wort?” The title indicates that after many years of examining this subject, grapefruit juice remains the main food that interacts with drugs and St. John’s Wort the main herb. The article states that there should be concern for other foods and herbs, but its title speaks to the limited findings up to this time. In a recent article on herb-drug interaction studies published in the Journal of Alternative and Complementary Medicine (2016), reports from 2000-2014 were obtained and reviewed.

The results and conclusion (by abstract) was:

The number of herb-drug interaction (HDI) reports has gradually increased since 2000, with a primary focus on neoplasms and diseases of the circulatory system. Most of these [reports] investigated pharmacokinetic reactions, such as cytochrome P450 enzyme metabolism, with fewer reports investigating pharmacodynamics (PD). Most PD interaction studies investigated warfarin, ginkgo leaves, and St. John’s wort. An evaluation of 17 studies revealed a generally positive view of PD effects involving synergism or reduced toxicity and a high average quality score (>3 points on a 0-5 scale). These results demonstrate that most HDI studies so far have examined pharmacokinetic interactions and have been limited to very few conventional drugs and herbal drugs. This suggests that more studies focusing on PD are necessary to understand interactions between commonly used herbal and conventional drugs.

GingkoIn essence, one drug, warfarin and two herbs were the main subjects in mechanistic study during this prolonged period; these studies were instigated by some case reports of interactions. Neither gingko leaves nor St. John’s wort are commonly used Chinese herbs. Overall, the reports on herb-drug interactions were of positive nature: the herbs enhanced rather than detracted from the drug effects. In an article raising concerns about possible herb-drug interactions with HIV antiretroviral therapy (2015), of nine items mentioned (including black pepper, grapefruit juice, and St. John’s wort), only one commonly used Chinese herb was included: ginseng. Since these cautions were based on laboratory studies, ginseng is most likely safe in the majority of cases because of its relative low dosage when used clinically.

SEARCH MECHANISM

If a patient asks you to assure that the herbs you prescribe will not interact or be a problem with a drug regimen being used at the same time, it is not possible to give such assurances. It is reasonable to relay the low incidence of herb-drug interactions and to offer the methods of minimizing herb-drug interactions (e.g., not taking the herbs and drugs at the same time; monitoring for potential interactions by maintaining routine testing, such as blood coagulation tests given to users of Warfarin). However, a practitioner prescribing herbs can also offer to check the most recent literature for reported herb-drug interactions.

Not all suspected cases of herb-drug interactions are published. However, in order for a suspected case to be published, it usually has to be formally written up by a doctor involved in the case, submitted to a journal, and reviewed by other doctors or researchers who are familiar with this subject area. Publication of a suspected case does not mean that the herb-drug interaction definitely occurred, but it does mean that the case was presented in a manner considered consistent with the modern standards for reporting such incidents.

All major medical journals, and many minor medical journals, have several of their articles listed—and often abstracted—in a huge database maintained by the National Center for Biotechnology Information (NCBI) of the National Library of Medicine (NLM), a division of the National Institutes of Health (NIH). The information is posted for easy searching on the internet; the website where one accesses the information is now called PubMed and its search address is:

http://www.ncbi.nlm.nih.gov/pubmed/

This site provides a space into which the user may type the search terms to yield a series of abstract titles, with access to abstracts (or fuller reference information when abstracts are not available). Most abstracts downloaded by this procedure allow for obtaining the original article. The majority of full articles require payment (typically $35), but increasingly there are free access links so that the article is readily consulted. The procedure for checking herb-drug interactions is to type in:

[name of the drug], herb-drug interactions

As an example, one can type in:

Cyclosporin, herb-drug interactions

Upon hitting the return button of the keyboard or clicking on the “search” icon on the screen, the search is rapidly completed. In the example cited here, there are quite a few abstracts of laboratory studies and of subjects not directly related to patient concerns, so a further refinement is used:

Cyclosporin, herb-drug interactions, clinical reports

There are two abstracts (in a 2017 search)—one from 2013 with regard to cranberry juice and the other, from 2000, about St. John’s wort.

In most instances, when checking a drug for interactions, the page will display the following:

No items found.

The small number of reports of specific herb-drug interactions is the reason for getting this as a typical result. If one enters: Warfarin, herb-drug interactions, there will be a large number of abstracts, most of them involving investigation of mechanism of action. Adding the search term clinical report reduces the number to six (as of 2017), those being mainly reviews and proposals; two common supplements, cranberry juice and fish oil are the basis for two of the six reports. One review article (2001) indicates concern for garlic, ginkgo leaf, and salvia (danshen); earlier reports mentioned tang-kuei (danggui). Lack of more recent reports for some of these herbs may suggest that the prior clinical cases were not reproducible interactions. Danshen and danggui are examples of herbs that may have a pharmacodynamic interaction; that is, both Warfarin and these herbs might reduce the speed of spontaneous blood coagulation.

If a report of interaction appears, it is important to check the abstract for details to confirm that there is an actual report of herb-drug interaction rather than merely a concern raised.   Also, once an herb-drug interaction report is found in the first search, a new search should be performed, specifying the herb and the drug in the search box (not just the drug name and general area of herb-drug interactions). For example, if one types in the entry—Warfarin, salvia—there are additional reviews, plus some reports on this specific interaction. One of the recent reviews (2015) that focuses on Chinese herbs expands the list of herbs that may reinforce the anticoagulant action of Warfarin to 44, but the authors caution that the effect is seen in laboratory study but not confirmed clinically:

Many of the interactions of herbs with warfarin are extrapolated from experimental studies; the in vivo effects on humans, however, remain to be found. We also acknowledge that many other herb-warfarin interactions likely go unrecognized by unsuspecting practitioners. As such, we advise that practitioners be cognizant of the entity of herb-warfarin interactions and maintain a high index of suspicion in patients with poor INR control. In view of the documented reports and studies highlighting the risk of over- or under-anticoagulation of the 11 herbs (i.e. danshen, ginkgo, dong quai, American ginseng, safflower, peach kernel, licorice, Asian ginseng, lycium, ginger and notoginseng) with warfarin, we opine that it would only be prudent to exercise caution in cases of concomitant use of these herbs with warfarin.

No individual clinical reports of the interaction of salvia with Warfarin were listed when the PubMed search term clinical report was added. If one tries the entry—cyclosporin, St. John’s Wort—82 references are found, often with passing mention or laboratory studies. Adding the search term clinical report drops the number to 3, only one of them directly involving cyclosporine (from 2000).

There are more sophisticated searches that can be performed by listing more key words to try and capture more references on the first search. However, an easy method of pursuing the subject further is to examine the “similar articles” posted next to each abstract title and use the links for those that may be relevant.

ADVICE TO PATIENTS

Once a search has been conducted, the following can be conveyed to patients:

  1. A search was carried out, and no herb-drug interactions were found; or, if reports found, a search was conducted and a report about potential for herb-drug interactions was found; therefore, the herbs included in that report won’t be included in your formulas (or won’t be included above a certain small level).
  2. Absence of a report in the literature doesn’t guarantee that there is no possibility of an herb-drug interaction. Therefore, we should continue to monitor your overall health and the conditions treated by the drugs, and you should continue all scheduled blood tests that might help confirm that there have been no problems that might be attributed to herb-drug interactions (e.g., weekly blood coagulation tests, daily monitoring of blood sugar or blood pressure). It is advisable, when possible to take herbs and drugs at different times, about an hour apart or more, to minimize chances of interactions.
  3. In China, it is routine practice to combine herbs and drugs to get the best therapy. Therefore, the prescribing of herbs as an adjunct to your drug therapy is consistent with practice there. We are following a standard method, but there is little or no information on the specific details of combining these specific drugs with these specific herbs. Therefore, we will continue the use of an herb formula only so long as it appears to be beneficial to do so, minimizing any risks.
  4. The herb that has been reported most frequently to cause interactions is St. John’s Wort. You are advised not to use that herb while using other drug therapies. The drug that has been most frequently reported to interact with herbs is Warfarin (coumadin). You are advised to maintain weekly blood coagulation tests to assure that the effects of Warfarin remain in the proper range and to change all dietary and herbal regimens gradually. The issues most frequently raised about herb-drug interactions are herbs potentiating an anticoagulant therapy or drug that has antiplatelet activity (e.g., aspirin used for pain) and herbs counteracting immunosuppressive therapy. Therefore, these will be the main focus of adjustment to any herb prescription provided.

While it is not advisable to give firm assurances that there can be no problem, but it is also not advisable to overstate the concerns. A good perspective has been offered in a recent abstract from an article about herb-drug interactions with cardiac drugs:

The prevalence of herb-drug interactions has been exaggerated. Nonetheless, some herbs, including garlic, ginkgo, ginseng, and St. John’s Wort, can have a significant influence on concurrently administered drugs. Herbal medicines may mimic, decrease, or increase the action of prescribed drugs. This can be especially important for drugs with narrow therapeutic windows and in sensitive patient populations such as older adults, the chronically ill, and those with compromised immune systems

The herbs mentioned in this abstract are those suspected of interacting with Warfarin, a drug with a narrow therapeutic window often used by sensitive patient populations. These herbs are often provided in single-herb products where they are at a relatively large dosage, hence the potential for an interaction.

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Our thanks to Subhuti for generously updating this information and allowing us to reprint this article.  He offers a wealth of articles on Chinese herbs and other traditional medicines, through ITM:  http://www.itmonline.org/

Subhuti Dharmananda holds a PhD in Biology from the University of California, and is founder of the Institute for Traditional Medicine and Preventive Health Care, Inc. (ITM).  ITM operates two clinics in Portland, Oregon and engages in a variety of educational and charitable projects related to traditional medicine. Dharmananda has traveled to China several times, between 1977, when travel became possible, and 2001 in the interests of studying traditional Chinese medicine.  He has since written a wealth of professional books and articles, taught extensively, and has served as editor, reviewer, and contributor to several journals on herbal medicine.  ITM is a non-profit 501(c)(3) organization established in 1979, incorporated in 1983, and moved to its current head office in Portland, Oregon in 1988.