25:8
A Review of Herb-Drug Interactions: Documented and Theoretical
Jason E. Lambrecht, Pharm.D.
Fellow, Outcomes Research, Instructor of Pharmacy Practice,
Creighton University School of Pharmacy
and Allied Health Professions, Omaha, NE

William Hamilton, Pharm.D.
Associate Professor, Creighton University School of Pharmacy and
Allied Health Professions, Omaha, NE

Aviqdor Rabinovich, Pharm.D. (cand.)
Creighton University School of Pharmacy and Allied Health Professions,
Omaha, NE


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Herbal remedies have reached their highest usage since the FDA’s decision to categorize them as food supplements in 1990.1 Estimates of annual herbal medicine sales have skyrocketed to between $2 and $3 billion. In 1997, a survey suggested that nearly 60 million Americans use herbal medicines.1 Estimates suggest that one fourth of this population or 15 million people use vitamins or herbal medicines together with prescription medications. As a result, many patients are at risk for having an herb-drug interaction. Complicating things are estimates suggesting that 47%–72% of patients fail to report herbal medicine use to health care professionals.2 This may result 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. Currently, there is very little information published on herb-drug interactions. This challenges healthcare professionals to discern appropriate action during patient visits or counseling sessions. Healthcare professionals must continue to educate themselves and patients about herb-drug interactions in order to provide the best possible patient care, and guard patients from choosing inappropriate and unsafe herbal medicines in relation to their current medical conditions and prescription medications. The purpose of this article is to enhance healthcare professional knowledge about known and potential herb-drug interactions by providing a review of documented and potential herb-drug interactions, as well as discussing counseling and monitoring issues concerning the use of herbal and prescription medications.

The herbal medicines that were selected for review either had an existing report of an interaction or were believed to be used commonly by patients. Resources used to obtain information included MEDLINE, Drugs and Pharmacology, tertiary and peer reviewed journal articles. Search terms included herbal, medicine, medicinal, prescriptions, drug, and medications.

Pharmacokinetic and Pharmacodynamic Interactions

As with conventional medicines, herbal medicines interact with drugs in two general ways: pharmacokinetically and pharmacodynamically. Pharmacokinetic interactions result in alterations of drug or natural medicine 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. Pharmacodynamic interactions cause alterations in the way a drug or natural medicine affects a tissue or organ system. These interactions affect drug action in a qualitative way, either through enhancing effects (synergistic or additive actions) or antagonizing effects. Multiple examples of both categories of interactions are discussed below.

Documented Herb-Drug Interactions

In the past, very few case reports related to herb-drug interactions were reported, and many of the reactions could only be explained theoretically. Recently, however, there have been several reported cases of possible herb-drug interactions. For clinicians, case reports provide more relevance than theoretical, in vitro, or animal data, allowing them to examine the components of the interaction and their relevance in terms of its onset, severity, and outcome. Recognizing that case reports have limitations (which may or may not be attributed to the reported events), limited generalizability is important.

Additionally, it is important to note that one or two reports may not warrant an absolute contraindication to combination herbal and prescription therapies. Below is
a discussion of documented case reports involving herbal and prescription medication interactions. A summary of these reports is provided in TABLE 1.


Table 1
Interactions Based on Case Reports

Drug
Herb Mechanism of Action Description of Interaction Counseling and Monitoring
Alprazolam22 Kava Synergistic gamma-aminobutyric acid (GABA) receptor site action Increases sedation, leading to coma Tell patients to avoid using alprazolam and kava together since they may have a similar mechanism of action and may result in increased sedation.

Aspirin15


Ginkgo Ginkgolide B may inhibit platelet-activating factor Increases inhibition of platelet aggregation Tell patients to monitor for increased bruising, petechia, purpura, and bleeding, and to have their PT and INR values monitored during initial therapy until stabilized, then monitor routinely thereafter while continuing the ginkgo. If the ginkgo is stopped, no additional monitoring is needed. If any increased bruising, petechia, purpura, or bleeding should occur the patient should discontinue the ginkgo and contact their physician.
Digoxin24

St. John’s Wort Induces P-glycoprotein in the gut, reducing absorption Decreases digoxin drug levels Tell patients to monitor for any differences in exercise tolerance, shortness of breath, heart rate, palpitations, or other cardiac related adverse effects that may be attributed to the combination. Patients should have serum digoxin levels monitored until stabilized and routinely thereafter while continuing on the St. John’s wort. If the St. John’s wort is stopped, regular monitoring of digoxin levels and signs and symptoms should occur until the level is stabilized, then monitor routinely thereafter. If at any time, the patient experiences symptoms that may be related to the combination, the patient should discontinue using the St. John’s wort and contact their physician.
Indinavir25
St. John’s Wort Components may induce drug metabolism
Decreases indinavir drug levels
Tell patients to avoid using indinavir and St. John’s wort together.
Levodopa23 Kava Unknown together

Increases dyskinesias Tell patients to avoid using kava and levodopa together.
Phenelzine19,20

Ginseng Inhibits cyclic AMP phosphodiesterase activity Increases psychoactive stimulation Tell patients to avoid using phenelzine and ginkgo together.
Warfarin8,9,10,12,13,18 Danshen Components may inhibit platelet aggregation
Increases prothrombin and international normalized ratio values Tell patients to monitor for increased bruising, petechia, purpura and bleeding and have PT and INR values monitored during initial therapy until stabilized then routinely thereafter while continuing on the herbal medicine or if the herbal medicine is stopped. If the patient experiences any increased bruising, petechia, purpura and bleeding, the patient should discontinue using the herbal medicine and contact their physician.



Dong quai Unknown Increases prothrombin and international normalized ratio values

Garlic Components may inhibit platelet aggregation Increases international normalized ratio values



Ginkgo Ginkgolide B may inhibit platelet-activating factor Increases international normalized ratio values

Ginseng Unknown Decreases international normalized ratio values Tell patients to have their INR values monitored during initial therapy until stabilized, then monitored therapy until stabilized, then monitored routinely thereafter while continuing on the ginseng. If the ginseng is stopped, regular monitoring of INR values should occur until the value is stabilized, then routine monitoring should occur thereafter.



Warfarin/Danshen: Danshen (Salvia species) is used for its ability to alleviate menstrual irregularity and relieve bruising. It is also taken for its cardiovascular uses including possible hypotensive, positive inotropic, and vasodilative effects.3-7 Increased pro-thrombin time and international normalized ratios (INR) have been reported when danshen and warfarin were used together. One case involved a 48-year-old housewife with rheumatic heart disease. She was taking warfarin 4 mg daily when she decided to begin taking an herbal medicine that included danshen as one of its main ingredients.8 During this period she was admitted to an emergency room for symptoms unrelated to the interaction. However, during her treatment, physicians noticed that her clotting profile was abnormal. Her prothrombin time (PT) was greater than 60 seconds and international normalized ratio (INR) was 5.62 (average range for anticoagulation is INR = 2.0–3.0, valve replacement INR = 2.5–3.5, patient needed an INR of 2.5–3.5). The physicians could not attribute her abnormal clotting profile to any clinical source and believed that the most likely cause was an interaction between warfarin and danshen. A second report involved a 62-year-old male with a history of rheumatic mitral regurgitation. His daily medications included warfarin 5 mg (stable INR of 3.0), digoxin 0.125 mg, captopril 75 mg, and furosemide 40 mg.9 The patient visited an herbalist and had been advised to take danshen for two weeks to help mend his heart. After two weeks of concomitant use of danshen and other medications, the patient was admitted to an emergency room with an INR of 8.4 and a partial thromboplastin time (PTT) greater than 120 seconds. The physicians attributed the patient’s abnormal INR and increased PTT to a warfarin and danshen interaction.
Warfarin/Dong Quai: Dong quai (Angelic sinensis) has been used to treat menstrual cramping, irregular menses, and menopausal symptoms.4,5 One report suggests that dong quai may increase prothrombin and INR values.10 The report involved a 46-year-old woman who was advised by an herbalist to take dong quai 565–1130 mg daily to help with her perimenopausal symptoms. She had a history of atrial fibrillation and was currently taking warfarin 5 mg, digoxin 0.25 mg and furosemide 20 mg daily. After taking the dong quai and prescription medications for four weeks, she exhibited a greater than two- fold increase in her PT and INR. As a result, the dong quai was stopped. Both her PT and INR returned to normal. As no other cause could be identified, the increased lab values were believed to be related to a warfarin and dong quai interaction.
Warfarin/Garlic: Garlic (Allium sativum) has been used to treat hyperlipidemia and hypertension.4,5,11 Garlic’s hyperlipidemic acions are believed to be linked to allicin associated compounds.11 Several reports have suggested that using garlic and warfarin together may elevate INRs. While not reporting any specific cases, physicians have cited garlic as a cause of elevated prothrombin and INR values in patients previously stabilized on warfarin.12 Garlic alone has been attributed to a spontaneous bleeding episode which occurred in an 87-year-old man.13 The gentleman was not taking any prescription medications at the time and all clinical signs, including intrinsic and extrinsic clotting factors, as well as hepatic function were normal. Clinicians treating the patient believed that the only explanation for the hematoma was the man’s chronic, excessive ingestion of garlic.
Aspirin/Ginkgo and Warfarin/Ginkgo: Ginkgo (Ginkgo biloba) (leaf extract) has been used for vascular insufficiency, stress, and tinnitus.4,5,14 Ginkgo may have neuroprotective and antioxidant effects as well. Ginkgo has also been associated with spontaneous bleeding episodes. One report involved a 70-year-old man who presented with bleeding from the iris into the anterior chamber of the eye one week after beginning a self-prescribed regimen consisting of a ginkgo concentrated extract 40 mg twice daily.15 His medical history included coronary artery bypass surgery three years prior. He was currently taking aspirin 325 mg per day, which he had been prescribed following his bypass surgery. After the spontaneous bleeding episode, he continued to take aspirin but discontinued the ginkgo product. Over a three-month follow-up period, he had no further bleeding episodes and physicians believed that an interaction of the ginkgo product with aspirin was the cause of his ocular hemorrhage. The second spontaneous bleeding episode involved a 78-year-old woman who had been taking warfarin for five years after coronary bypass surgery. She suffered a left parietal hemorrhage after using a ginkgo product for two months.16 The bleeding was attributed to the antiplatelet effects of the ginkgo.
Warfarin/Ginseng and Phenelzine/Ginseng: Ginseng (Panax ginseng) has been commonly used for cognitive function and concentration, endocrine effects, and overall well-being.4,5,17 There have been several reports of ginseng interactions with prescription medications. Decreased INRs have been reported when ginseng and warfarin were used together. For example, a 47-year-old man’s INR declined while taking ginseng and warfarin.18 Once the interaction was discovered, the ginseng was discontinued and his INR returned to its original value after two weeks. No other factors could be identified or associated with the declining INR and the ginseng was the only change in the patient’s regimen. Other reports suggest that ginseng may interact with monoamine oxidase inhibitors causing excessive psychoactive stimulation. One report involved a 64-year-old woman who experienced insomnia, headache, and tremulousness while taking ginseng and phenelzine together.19 A second report involved a 42-year-old woman who had been taking phenelzine for depression.20 After adding ginseng to her therapy, the patient began to have manic-like symptoms, with decreased sleep, irritability, tension headaches, and occasional vague visual hallucinations. The ginseng was stopped and her symptoms resolved with only a few episodes of headache occurring thereafter. Authors could not attribute other medications or supplements (lorazepam 1 mg, triazolam 0.5 mg, or bee pollen) to her manic-like symptoms, and believed them to be associated with the ginseng and phenelzine interaction.
Alprazolam/Kava and Levodopa/Kava: Kava (Piper methysticum) has been used for insomnia and anxiety.4,5,21 Cases have suggested that patients taking benzodiazepines and kava together may be susceptible to increased sedation and somnolence. One report involved a 54-year-old man who was admitted to an emergency room in a semi-comatose state.22 He was lethargic and disoriented. His drug screen was positive for benzodiazepines. After several hours, the patient became more alert and told physicians he had been taking a “natural tranquilizer” called kava for the past three days while taking his other medications (alprazolam, cimetidine and terazosin). He denied overdosing on kava or alprazolam. The physicians believed that the gentleman’s coma was attributed to a kava and alprazolam interaction. Additionally, four cases of involuntary movements were reported when kava and levodopa were taken together.23 After the patients discontinued the kava, the dyskinesia resolved.
Digoxin/St. John’s wort and Indinavir/St. John’s wort: St. John’s wort (Hypericum perforatum) has been widely used for depression.4,5 Recent reports suggest that St. John’s wort may decrease serum digoxin and indinavir levels. In healthy subjects, St. John’s wort decreased the absorption of digoxin by 25% and lowered serum digoxin levels.24 In a separate study, healthy subjects given indinavir and St. John’s wort had a 49%–99% reduction in indinavir serum drug levels.25

Table 2
Interactions Based on Case Reports

Drug Herb Mechanism of Action Description of Interaction Counseling and Monitoring
Bilberry leaf Anthocyanoside components may decrease excessive platelet aggregation Increases potential for bleeding Tell patients to monitor for increased bruising, petechia, purpura and bleeding.
Antiplatelet and anticoagulants (warfarin, aspirin, heparin, NSAIDs, clopidogrel, eptifibatide, tirofiban, ticlopidine, dipyridamole and COX-2 inhibitors)4,5 Black cohosh Contains coumarin constituents Increases potential for bleeding
Chamomile Contains coumarin constituents Increases potential for bleeding
Fish oil (omega-3 fatty acids)
Docosahexaenoic acid and eicosapentaenoic acid may have antithrombin activity Increases potential for bleeding
Vitamin E Inhibits platelet aggregation and adhesion, interferes with vitamin K-dependent clotting factor Increases potential for bleeding
Ginger
Unknown Increases potential for bleeding
Goldenseal* Unknown - believed to be associated with berberine Decreases potential anticoagulation effect Tell patients to have their prothrombin times monitored while using heparin and constituents goldenseal together.
Potassium wasting medications
(steroids and diuretics)5



Aloe May increase potassium loss in the gastrointestinal tract Increases potential potassium loss Tell patients to monitor for signs and symptoms of hypokalemia (muscle weakness, myalgia, cramps and heart palpitations).


Licorice May increase potassium loss in the gastrointestinal tract Increases potential potassium loss
Immunosuppressants
(cyclosporine, azathioprine and tacrolimus)5 Echinacea Unknown Decreases immunosuppressant effect Tell patients to avoid taking cyclosporine and echinacea together.

Theophylline and xanthine derivatives4,5 Ephedra Ephedrine, a component of ephedra, can cause stimulation Increases stimulatory effects Tell patients to monitor for changes in blood pressure, heart rate, insomnia, nervousness, tremors and headaches.
Green tea Caffeine can cause stimulation
Increases stimulatory effects
Guarana Caffeine can cause stimulation Increases stimulatory effects
Sedatives (benzodiazepines, barbiturates, non-benzodiazepines and alcohol)4,5 Valerian
Valerenic acid inhibits the enzyme responsible for catabolism of gamma-aminobutyric acid (GABA), increasing GABA concentrations and decreasing central nervous system activity Increases sedation effect Tell patients increased sedation may occur if taken together.
Ginger Unknown Increases sedation effect
Goldenseal Unknown Increases sedation effect
Chamomile Unknown Increases sedation effect
MAO inhibitors5 Ephedra Ephedrine can cause stimulation
Increases stimulatory effects
Tell patients to monitor for changes in blood pressure and heart rate, insomnia, nervousness, tremors and headaches.
Phenothiazines4 Ephedra Phenothiazines may block the alpha stimulatory effects of ephedra Hypotension and increases heart rate
Decreases stimulation and energy Tell patients that they may not experience increased energy and to consider avoiding use of ephedra while taking phenothiazines.
Hypoglycemic agents
(glyburide, metformin, insulin)4



Ginseng Panaxosides have reported effects on glycemic control Decreases glucose levels Tell patients to monitor glucose levels routinely.
Antihypertension agents4,5

Ephedra** Ephedrine may oppose the pharmacological effects of beta blockers through unopposed sympathetic stimulation potential for blood pressure increase Tell patients to monitor for changes in blood pressure and heart rate, shortness of breath, and heart palpitations. It may be best to avoid taking herbal medicines that have cardiac cardiac effects along with hypertension medications since little is known about this interaction, which may compromise the cardiac condition
Goldenseal Beberine and hydrastinine components may cause varied cardiac effects Increases or decreases potential for blood pressure increase

Black cohosh

Acteina, an isolated component of black cohosh may have hypotensive effects Increases peripheral vasodilation
Licorice May increase sodium, chloride, and water retention, counteracting the pharmacological effects of antihypertensive medications
Increases potential for blood pressure increase
Cardiac glycosides (digoxin)4,5





Aloe Increases potential for potassium loss which may increase the risk of toxicity Increases risk of toxicity Tell patients to monitor for changes in blood pressure and heart rate, shortness of breath and heart palpitations. It may be best to avoid taking digoxin and aloe, licorice, hawthorn, or goldenseal since little is known about these interactions and they may compromise the patient’s cardiac condition.
Licorice Increases potential for potassium loss which may increase the risk of toxicity Increases risk of toxicity
Hawthorn Varied cardiac effects Increases or decreases cardiac effects
Goldenseal Varied cardiac effects Increases or decreases cardiac effects
Lithium4,5 Green tea Caffeine, if abruptly stopped may increase serum lithium levels Increases lithium levels Tell patients to avoid using lithium and products that contain caffeine concentrations including green tea and guarana.

Guarana Caffeine, if abruptly stopped may increase serum lithium levels

Increases lithium levels

*Studies indicate heparin only
**Beta blockers




Potential Herb-Drug Interactions
A variety of interactions may be of potential concern based on the pharmacological characteristics of some herbal medicines. Included are the narrow therapeutic index agents, digoxin, theophylline, lithium and warfarin. There are several herbal medicines that have the potential to interact with these and other medications. Although case reports are not available for these interactions at this time, pharmacological actions provide a theoretical basis for potential interactions. TABLE 2 summarizes this discussion.
Narrow Therapeutic Agents: There are several herbal medicines that affect serum potassium levels, most of which have laxative properties (e.g., aloe and licorice).4,5,26 These herbal medicines decrease potassium and may induce digoxin toxicity. Other herbal medicines that may affect digoxin therapy are those that have cardiac effects, such as hawthorn and goldenseal.4,5 In general, herbal medicines with stimulant properties pose a potential problem for patients taking theophylline. Several herbal medicines contain caffeine, including guarana (800 mg of guarana may contain approximately 30 mg of caffeine) and green tea (may contain 1%–4% caffeine depending on the method of preparation), which may have additive central nervous system side effects with theophylline and may also increase serum theopylline levels.4,5 Other herbal medicines, such as ephedra, may also have additive adverse central nervous system side effects if taken with theophylline.4,5 Herbal medicines with diuretic effects are potential problems in patients taking lithium. Products containing caffeine, which have diuretic actions, may alter serum lithium levels. There are reports of increased lithium levels in patients who abruptly stop caffeine consumption.5 Several herbal medicines have been identified as potentially altering bleeding times in patients concurrently taking warfarin. Many of these products have a coumarin component (e.g., black cohosh and chamomile), while others contain different constituents (billberry leaf, fish oil, vitamin E, and ginger) with antiplatelet effects.4,5 When taken with warfarin, these herbal medicines may potentially increase bleeding times and the risk of bleeding.
Other Prescription Medications: Antiplatelet medications may interact with billberry, black cohosh, chamomile, ginger, fish oil, and vitamin E, increasing the risk of bleeding. Goldenseal may decrease the anticoagulant effects of heparin.4,5 Potassium- wasting medications may interact with aloe and licorice, accelerating potassium loss and leading to lower serum potassium levels.5 Immunosuppressants may interact with Echinacea, possibly decreasing or opposing the immunosuppressant’s effect.5 Centrally acting agents used for their sedative properties may interact with valerian, ginger, goldenseal, and chamomile, resulting in increased sedation.4,5 MAO inhibitors may interact with ephedra, causing excessive stimulation.5 Phenothiazines may block the alpha stimulatory effects of ephedrine, resulting in less stimulation.4 Hypoglycemic agents may interact with ginseng, which may cause decreased glucose levels.4 Antihypertensive agents may interact with ephedra, goldenseal, black cohosh, and licorice, causing varied cardiac effects.4,5

Counseling

Healthcare professionals should take an active role in learning which herbal medicines their patients are using to ensure that their patients are receiving correct herbal and prescription medicine information. By taking the time during counseling sessions to obtain this information, healthcare professionals can monitor their patients’ use of herbal medicines, especially if patients are taking them with prescription medications. This is an optimal time to find out if an herb is working or if patients have noticed any changes that could be attributed to the herbal medicine. If patients sense that practioners are judgmental, they may not always be willing to discuss herbal medicine use.27 An open-minded approach during patient visits is essential. The overall goal during counseling sessions is to give the patient enough information about signs and symptoms of herb-drug interactions so they are able to recognize an adverse event if it occurs. TABLE 1 and TABLE 2 provide specific counseling and monitoring information based on whether the interaction is known or potential as well as other factors. This information is not meant to be comprehensive and should only serve as a guide until more research can provide more specific guidelines.

Conclusion

The likelihood that herbs are being combined with prescription and over-the-counter (OTC) products is quite high. Overall, however, herb-drug interactions remain relatively rare when considering the number of people taking herbal products. The fact that a larger number of case reports have not been reported may be a sign that most herbal medications are relatively safe. Absolute contraindications of some combinations (e.g., ginkgo and aspirin) are believed to be inappropriate at this time.


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