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Indian Journal of Pharmacology
Medknow Publications on behalf of Indian Pharmacological Society
ISSN: 0253-7613 EISSN: 1998-3751
Vol. 39, Num. 3, 2007, pp. 129-139

Indian Journal of Pharmacology, Vol. 39, No. 3, May-June, 2007, pp. 129-139

Educational Forum

Herb-drug interactions: A review and study based on assessment of clinical case reports in literature

Gohil KJ, Patel JA

Department of Pharmacology, Institute of Pharmacy, Nirma University of Science and Technology, Ahmedabad

Correspondence Address:Department of Pharmacology, Institute of Pharmacy, Nirma University of Science and Technology, Ahmedabad
jagrutiap@gmail.com

Date of Submission: 10-Jul-2006
Date of Decision: 16-Feb-2007
Date of Acceptance: 10-Jun-2007

Code Number: ph07033

Abstract

Objective : To conduct a systematic review of literature on interactions between conventional drugs and various herbs.
Materials and Methods : We carried out a literature survey to assess published herb-drug interaction information in clinical case reports and case series to check the report reliabilities.
Results : From 133 cases of suspected interactions, 67% cases were classified as possible interactions, 27% cases were unable to be evaluated and only 6% of the cases were well-documented. St. John's wort was the most common herb involved (37 cases) in drug interactions. Warfarin was the most common drug (34 cases) interacting with various herbs.
Conclusion : Herb-drug interactions are a stark reality today. Hence, proper reporting of cases, careful vigilance, evidence-based appraisal and constantly updated reviews of such herb-drug interactions are very important to promote systematic research.

Keywords: Case series, clinical assessment, clinical case reports, herb-drug interactions

Introduction

Millions of people today use herbal therapies along with prescription and nonprescription medications. Although considered natural, many of these herbal therapies can interact with other medications, causing either potentially dangerous side effects and / or reduced benefits from the medications. Currently, there is very little information published on herb-drug interactions whilst the use of herbs is progressively growing across the world.

The size of the worldwide market of herbal medicines is estimated to be around US $80 billion to US $100 billion and this market is expected to reach US $2500 billion by the year 2010. [1],[2] In the West, the demand for herbal drugs has reached a new high in recent years. Since 1999, the global market for herbal supplements exceeded US $ 15 billion, with a US $ 7 billion market in Europe, US $ 2.4 billion in Japan, US $ 2.7 in the rest of Asia and US $ 3 billion in North America. [3] The results of a nationwide survey indicated a marked increase in the number of individuals using alternative therapies between 1990 and 1997 estimating total out-of-pocket expenditures for alternative therapies at $27 billion. [4]

India is very rich in natural resources and the knowledge of traditional medicine and the use of plants as a source of medicine is an innate and very important component of the healthcare system. The Indian system of medicine has identified 1,500 medicinal plants of which 500 are commonly used. [2] It is estimated that there are over 7800 medicinal drug-manufacturing units in India, which are estimated to consume about 2000 tons of herbs annually. [5] According to a recent estimate of the World Health Organization (WHO), 70-80% of the world population especially in developing countries, relies on traditional medicine, mostly plant drugs for their primary healthcare needs. [2],[6]

As the use of herbs is getting popular, interactions between herbs and allopathic drugs need to be addressed and reviewed properly. Certain herbal supplements can cause potentially dangerous side effects when taken with prescription drugs. The use of alternative therapy is mostly not supervised by physicians or alternative therapy practitioners resulting in increased harm to patients, especially if they are using herbal and prescription medicines that have latent interactions. These interactions can go unnoticed until a patient is hurt or a serious life-threatening event has occurred.

Despite the urgent need for information, very little is known about herb-drug interactions unfortunately as experimental data in this field is limited and case reports and case series are rare. [7],[8]

Objective

The aim of our present study was to conduct a review of literature on interactions between conventional drugs and various herbs based on descriptions of the clinical consequences, case series and case reports. In addition, we also wanted to assess the quality of the data generated for the study of herb-drug interactions.

Materials and Methods

A literature survey was carried out to compile information about herb-drug interactions. As per the guidelines for the use of electronic and internet media, [9],[10] a high quality and reliable medical information from the internet was retrieved only from the Health-on-Net (HON) conduct-certified and accredited websites like Entrez PubMed [Medline], CAM-PubMed, Allied and complementary medicine database, Natural medicine comprehensive database, Embase and Cochrane library. The databases were searched from 1986-2006 using the search terms "herb-drug interactions, side effects, herb toxicities, adverse drug reactions, herbal medicine, herbal medicinal, prescriptions, case reports, case series, clinical trials and clinical assessments". Non-English language citations were excluded. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which were in the form of case reports and limited clinical observations. The nature of the findings and probability of interactions were then abstracted and compiled in a final report [Table 1 in pdf]. The probability of interactions was evaluated on a 10 point scoring scale reported earlier, [8] where each of the case reports received one point for inclusion of any of the following ten evaluating parameters:
  • Adequate patient history.
  • Concurrent diseases, conditions.
  • Documentation of concomitant medications.
  • Adequate description of interactions.
  • Exclusion of obvious alternative explanations.
  • Complete chronology.
  • Reasonable time sequence of drug administration to adverse event.
  • Adequate description of adverse event.
  • Cessation of event on stopping the drug.
  • Recurrence of event with a re-challenge.

This probability scale, though not validated, served only as a guide to assess whether the reports of herb-drug interactions contained reliable information or not. The sum total of all these parameters was calculated and referred to as report reliability scores as per the criteria mentioned below. This report reliability score was further validated by a third party, i.e ., two independent raters unaware of the study protocol.

a. A score of 0-3 suggested that the case contains insufficient information (unable to be evaluated).

b. A score of 4-7 implied some evidence for an interaction (possible) and

c. A score of 8-10 indicated a well-documented report with reliable evidence for interaction (likely).

Results

The search of all listed sources produced 133 cases of suspected interactions. All interactions were tabulated and categorized by herb, drug, other medications, signs or symptoms of interaction, mechanism and report reliability scores [Table 1 in pdf]. 67% of the cases (89/133) were classified as possible interactions, 27% (36/133) were considered to contain insufficient information to evaluate the probability of an interaction (Unable to be evaluated) and 6% (08/133) as well-documented (likely) interactions. St. John's wort was the herb most commonly implicated in interactions with various drugs (37 cases) namely digoxin (13 cases), clopidogrel (06 cases), indinavir (08 cases), irinotecan (05 cases), antipsychotics (04 cases) and tacrolimus (01 case). Other herbs most commonly implicated in herb-drug interactions were ginkgo biloba (27 cases), kava-kava (08 cases), ginger (06 cases) and Panax ginseng (05 cases). The anticoagulant drug, warfarin was found to be the most common drug interacting with various herbs (34 cases) of which 22 cases were classified as 'unable to be evaluated' interactions, 10 cases were 'possible' interactions and 2 cases were classified as 'well-documented' or 'likely' interactions.

Discussion

The results of our search point towards the fact that herb-drug interactions certainly do occur and are much more common than we would like to believe, contrary to the popular belief that Nature is always safe. In many cases, mechanisms and causality are uncertain or unpredictable; in addition, inadequate information and under-reporting make it very difficult to determine whether herb-drug interactions have occurred or not. In the past, very few case reports related to herb-drug interactions were reported and many reactions could only be explained theoretically. Recently, however, there are several reported cases of possible herb-drug interactions with the increased use of herbal medications. [11],[12],[13],[14]

An earlier survey of literature for reports of herb-drug interactions presented 108 cases of suspected interactions out of which 68.5% were reported as unable to be evaluated, 18.5% as possible and 13% as well documented cases. [8] In this study, 133 new cases of suspected herb-drug interactions were identified of which 27% cases (36/133) were unable to be evaluated, 67% cases (89/133) were described as possible and only 06% cases (08/133) emerged as well documented interactions.

In the present study, St. John's Wort was the most common herb implicated in various drug interactions and warfarin was the most common drug interacting with various herbs. [8],[15],[16],[17],[18] A previous study reported 85 interaction cases of St. John's Wort of which 54 cases were with the drug cyclosporin. Other drug categories mentioned were oral contraceptives (12 cases), antidepressants (09 cases), warfarin (07 cases) and one case each with theophylline, phenprocoumon and loperamide interacting with St. John's Wort. [8] The present study identified 37 cases of interactions for St. John's Wort with digoxin (13 cases), clopidogrel (06 cases), indinavir (08 cases), irinotecan (05), antipsychotics (03), tacrolimus (01 case) and with an anesthetic (01 case). This makes St. John's Wort a somewhat risky proposition when combined with drugs in the categories mentioned above.

As with conventional medicines, herbal medicines interact with drugs in two general ways: pharmacokinetically and pharmacodynamically. [14] Pharmacokinetic interactions result in alterations of the drug's or natural medicine's absorption, distribution, metabolism or elimination. These interactions affect drug action by quantitative alterations, either increasing or decreasing the amount of drug available to have an effect. The interfering drug may act as an inducer, inhibitor and / or substrate of the cytochrome P450 enzyme that is responsible for the metabolism of the respective drugs. This is the most important mechanism for interactions between herbal therapies and antiretroviral drugs. [19] St. John wort, widely prescribed for various psychopathologic conditions involving depression and anxiety [20] is reported to lower serum concentrations of cyclosporine, [8],[21],[22],[23],[24],[25],[26],[27] theophyllin, [28] warfarin, [29],[30] oral contraceptives, [30] digoxin, [31],[32],[33] indinavir [34] and clopidogrel [35] by inducing CYP450 (CYP 3A4, CYP 2C9 and CYP1A2). [8],[36],[37],[38],[39] On the other hand, the same herb has also been reported to inhibit the CYP 3A4 isoform. [40] Another mechanism stated for St. John's wort, responsible for affecting clearance of many drugs is that it increases expression of duodenal P-glycoprotein (PgP), an ATP-dependent drug efflux transporter known to pump drugs out of the cell and thus decrease the intracellular concentration of drugs. [8],[41],[42],[43] Caution is warranted when using St. John's wort with several medications like barbiturates, carbamazepine, dextromethorphan, fenfluramine, fexofenadine, narcotics, nortriptyline, phenytoin, photosensitizing drugs, reserpine and simvastatin during pregnancy and lactation for the risk of potential interactions. [44]

Pharmacodynamic interactions affect a drug's action in a qualitative way, either through enhancing effects (synergistic or additive actions) or antagonizing effects. The interactions reported in this category include those of St. John's wort with various antidepressants namely paroxetine, sertraline, nefazodone, venlafaxine, clonazepam and interactions of haloperidol [45],[46],[47],[48],[49] with loperamide [50] and kava-kava with alprazolam. [51] Cases of serotonin syndrome (serotonin-amplifying effect) with St. John's wort have also been studied. [52]
Ginkgo biloba, the secondmost common herb involved in drug interactions is reported to have potent drug interactions with fluoxetine, buspirone, insulin, monoamine oxidase inhibitors (MAOIs) and with drugs metabolized by cytochrome P450 3A4, P450 3A5, P450 1A2 and P450 2D6 enzymes. Hence, Ginkgo biloba should be used with caution during pregnancy and lactation. [53] This antioxidant herb is mainly promoted for use in improving cognitive function (brain booster) and blood flow. [20],[54] It is reported to inhibit platelet aggregation activity resulting in spontaneous bleeding when used simultaneously with aspirin, [20],[54] acetaminophen, [20],[54],[55] trazodone, [56] ibuprofen [57] and warfarin. [53],[54],[58] Twenty-seven cases of ginkgo interactions were noted with acetaminophen, ibuprofen, nifedipine and sodium valproate in the present study, extending the list in a previous study where the herb was reported to interact with trazodone, warfarin, aspirin and thiazide diuretics. [8] CYP2C9 is the CYP- 450 isoenzyme responsible for the metabolism of the more potent warfarin enantiomer, (S)-warfarin. Recently, a study conducted to ascertain the influence of Ginkgo biloba on CYP2C9 , stated that Ginkgo biloba extract inhibits human liver microsomal CYP2C9 enzyme in vitro but not in vivo . [59]

Kava kava is shown to have additive effects with central nervous system depressants and caution is advised with regards to its simultaneous use with benzodiazepines, barbiturates, antipsychotics and alcohol. [20],[51] In addition, patients with Parkinson's disease are also discouraged from using kava products. [20],[60] In this report, eight new cases of kava-kava were listed with various drugs including levodopa, [60] caffeine, [118] hydrochlorthiazide, [119] amino acid complex, [119] promethazine and biperiden. [120]

Millions of people regularly take blood-thinning medications such as warfarin and over-the-counter drugs like aspirin and similar medications. These medications are very commonly prescribed for patients with high risk of blood clotting such as those with artificial heart valves, deep vein thrombosis or arterial fibrillation. The risk grows many fold when such patients take herbs possessing antiplatelet or anticoagulant activities and fail to report the use of herbs to their doctors. There are reports of potential herb-drug interactions with analgesic drugs, particularly aspirin, which have the potential to interact with herbal supplements that are known to possess antiplatelet activity as well as those containing coumarin components, thus enhancing the risk of bleeding. [61,62] In the present study, warfarin was found to interact with at least 19 types of different herbs with a total of 34 cases of interactions adding to the list of 18 interactions previously reported. [8] There is a reasonable documentation of interactions between coumarin anticoagulants like warfarin with various herbs, [63] apart from St John's Wort, ginkgo biloba, [20],[55],[65] panax ginseng, [20],[64],[65] coenzyme-Q, [65] siberian ginseng, [66] danshen, [67],[68],[69] dong quai, [70],[71],[72] garlic, [73] devil's claw, [74] birch, [75] boldo, fenugreek, [76] green tea, [65],[78] quilinggao, a Chinese herbal product, [79] Chinese herbal tea ( Lycium barbarum ), [80] saw palmetto, [81],[82] papain, [121] cranberry juice [127],[128],[129],[130] and chamomile. [131] Taking much needed precautions such as regular monitoring of weekly prothrombin time (PT test) and International normalized ratio (INR) can prove to be helpful in avoiding risk due to these interactions.

Addition of herbal medicine to multiple drug therapy holds the potential for herb-drug interactions, [43],[83],[84] although it is also suggested that some of the adverse drug effects and drug interactions reported for herbal products could be caused by impurities as allergens, pollen and spores or batch-to-batch variability. [20] This is because unlike conventional drugs, herbal drug products are not regulated for their purity and potency. [20],[21],[85]

The present study also reports isolated cases of some herbs involved in interactions with various drugs such as ayahusca with fluoxetine, [86] celery with thyroxin, [87] fennel with enalapril, [88] prickly pear with an oral hypoglycemic agent, [89] garlic with saquinavir, [90] ginger with nonsteroidal anti-inflammatory drugs (NSAIDS), [91] licorice with a laxative, [92],[93] soya bean with warfarin, [94] alfalfa with immunosuppresants, [95] shankhapushpi with phenytoin [96] and chamomile with enalapril. [131] In most cases, the mechanism is unknown or just plain additive effects between the herbs and drugs responsible for the respective toxicity.

In an earlier report, concern was raised about herb-drug interactions with anesthesia and it was suggested that herbal therapies be discontinued at least two to three weeks prior to surgeries requiring anesthesia. [97],[98] Grapefruit juice too is reported to interact with number of drugs. Since the first report in 1989 as a result of using the juice as part of placebo preparation in a drug trial, [99],[100],[101],[102] the list has expanded tremendously. At present, grapefruit juice is reported to interact with number of anticancer agents including erlotinib, recently approved by the Canadian health authority as a monotherapy for locally advanced, small cell lung cancer. [103]

A broad concern is raised for a variety of potential interactions based on their pharmacological actions when case reports are not available. Examples are 1) laxative herbs (Aloe, licorice, senna, cascara) with potassium-wasting medications and with the drugs that act on the heart due to the risk of additional loss of potassium, [11],[14],[104],[105] 2) herbs and drugs with similar actions like bitter melon and gymnema with other antidiabetic medications due to the risk of excessive hypoglycemia and 3) herbs like valerian, kava kava, ginger, goldenseal, chamomile with centrally acting agents due to the risk of increased sedation. Also worthy of mention are interactions of caffeine-containing herbs (Guarana, green tea) with other drugs that also affect the central nervous system [11],[14],[104] and of herbs containing a coumarin component (black cohosh, chamomile, bilberry leaf) with warfarin due to the risk of hemorrhage. [14] Recently, reports have emerged that the ayurvedic herbal medicine gugulipid or "guggul" may have unwanted interactions with many prescription medications. [106] The herb is an Ayurvedic medicine taken to help lower cholesterol and stimulate thyroid function. It may interfere with drugs used for treating AIDS and cancer, specifically, gugulipid could interfere with drugs such as azathioprine, various other anticancer agents and cholesterol-lowering statins. The authors suggested that guggulsterone interacts with drugs by binding to a protein called pregnane X receptor (PXR). PXRs induce the body to "turn on" a gene that encodes another protein that breaks down various drugs. Thus, the drug levels in the body are lowered. However, there are no case reports pertaining to interactions of guggul with any medication.

Inadequate reporting makes it very difficult to determine whether a particular herb-drug interaction has occurred. Proper documentation is necessary with all relevant information, clear description of adverse event and careful exploration of alternative explanations along with consideration for a reasonable re-challenge whenever possible.

Although, one or two reports may not warrant an absolute contraindication to combinations of herbal and prescription therapies, precautions do need to be exercised by taking the medical history of patients during counseling sessions to obtain this information. The onus lies on healthcare professionals who can monitor the use of herbal medicines, especially if the patients are taking them with prescription medications. An open-minded approach during patients' visits is to counsel the patients with enough information about signs and symptoms of herb-drug interactions so that they are able to recognize an adverse event if it occurs. It seems only rational that the administration of herb and drug, if taken together, should be at least 1 to 2 hours or several hours apart from each other. It is advisable to avoid using the herb and drug combinations altogether; which are contraindicated or reported frequently for interactions with the specific drug. Despite widespread use, herb-drug interactions are a stark reality today. The number of cases reported for the emerging herb-drug interactions are already on the rise. In fact, the actual number of cases may be higher due to under-reporting There are many plant compounds, which are still unfamiliar and new drugs are produced every day. Unfortunately, the herb-drug interaction remains an unknown area. It is now known that millions of patients take herbal and conventional medicines concomitantly, often without the knowledge of their physicians. Considering our present lack of understanding of herb-drug interactions, proper reporting of such cases, careful vigilance, evidence-based appraisal and constantly updated reviews of such information are very important to promote understanding in this area.[132]

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