Herbal medicine is one of the modalities frequently relied upon in functional medicine because herbs can be powerful and effective drivers of physiologic and biochemical change. Nearly 25% of American adults report taking a prescription medication with a dietary supplement (5). Among the concerns of dietary and herbal supplements are drug interactions with polypharmacy. Understanding the pharmacokinetics and pharmacodynamics of herbs and medications is essential to gauge the safety profile of therapeutic recommendations. This article will discuss potential drug interactions associated with well-known and frequently administered herbal supplements.
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What is an Herb-Drug Interaction?
An herb-drug interaction is a pharmacological modification in the body caused by an herbal substance to another medication that is being coadministered. Concomitant use of herbs and drugs can result in beneficial or undesirable effects. The active ingredients in herbs can dramatically alter the properties of a medication, holding the potential to significantly increase or decrease the drug's activity, cause adverse side effects, or even therapeutic failure. (1, 4)
Well-designed clinical studies evaluating the interactions between herbal supplements and prescription medications are limited and sometimes inconclusive. Most herb-drug interactions are inferred from in vivo research, animal studies, and observational data. Therefore, understanding interactions between herbs and drugs is rarely absolute and requires practitioners to understand the complex workings of herbal mechanisms of actions and targets in the body. (2, 3)
Various factors can further contribute to the issue's complexity, including the concentration of active herbal compounds, part of the plant (e.g., root, leaf, fruit) being administered, and manufacturing of the herbal supplement. (3)
Pharmacokinetic vs. Pharmacodynamic Interactions
Herbs are capable of altering the pharmacokinetics and pharmacodynamics of a drug.
Most commonly, herb-drug interactions manifest as pharmacokinetic interactions. Pharmacokinetics is the science of how the body absorbs, distributes, metabolizes, and eliminates a drug. The risk of a pharmacokinetic interaction exists when an herbal supplement shares the same one of these mechanisms as a coadministered drug. Competition between the herb and the drug for a shared pharmacokinetic mechanism can increase or decrease the drug's concentration in circulation. Competition and modification of the cytochrome (CYP) family of detoxification enzymes is responsible for most herb-drug interactions. (3, 5)
Pharmacodynamics is the branch of pharmacology concerned with the effects of a drug on the body. Pharmacodynamic interactions are less common but equally important as pharmacokinetic interactions. A pharmacodynamic interaction occurs when an herb directly changes the mechanism of action of a drug without changing its concentration. It may do this, for example, by stimulating or blocking a drug's target receptor. (5)
Common Herbal Supplement-Drug Interactions
This article will summarize the herb-drug interactions of seven commonly used herbal dietary supplements. This list is not comprehensive; the herbs discussed may have more interactions than those listed, and herbs not discussed may have drug interactions. Discussing a specific herb's capacity to cause interactions with a knowledgeable healthcare professional is always advised before starting a new supplement. Online interaction checkers are available to help make informed decisions about the safety of herbal supplements.
St. John's Wort
St. John's Wort (Hypericum perforatum) is an herb with many actions and is indicated for various health conditions, including depression, menopause, and skin conditions. It is a potent inducer of cytochrome P450 enzymes and intestinal P-glycoprotein, which can lead to clinically significant reductions in coadministered medications, including cyclosporine, tacrolimus, warfarin, protease inhibitors, irinotecan, theophylline, digoxin, venlafaxine, and oral contraceptives. (5)
Additionally, St. John's Wort effectively treats depression by acting as a serotonin reuptake inhibitor, reducing serotonin uptake at neuronal synapses and effectively increasing serotonin in circulation. Because of these serotonergic properties, taking St. John's Wort with antidepressants (i.e., SSRIs, SNRIs, TCAs, MAOIs) can lead to serotonin syndrome, a potentially life-threatening drug reaction. (6)
Grapefruit
Grapefruit has the opposite effect on the cytochrome P450 enzymes; it can inhibit their enzymatic activity, which slows the metabolism of coadministered drugs and increases their concentrations. Serious adverse events related to grapefruit drug interactions have been reported with amiodarone, verapamil, statin medications, tacrolimus, colchicine, and oral contraceptives. (7)
Goldenseal
Goldenseal (Hydrastis canadensis) inhibits CYP2D6 and CYP3A4, two enzymes responsible for the metabolism of more than 50% of pharmaceutical agents. Inhibition of these enzymes can cause increased concentrations of medications and toxicity-associated side effects. For example, irregular heart rhythm has been documented using goldenseal and antipsychotic medications pimozide and thioridazine. (5, 8)
Ginseng
The different species of ginseng, American ginseng (Panax quinquefolius) and Asian ginseng (Panax ginseng), have slightly different profiles of their active constituents. Because of this, ginseng's drug-herb interaction profile is dependent on the species of the herb being used.
Preclinical studies of American ginseng show low potential for drug interactions. Studies have shown no effect of American ginseng on HIV antiviral medications indinavir and zidovudine, but suggest slightly decreased efficacy of the anticoagulant warfarin. (5)
Asian ginseng appears to be more likely to decrease the effectiveness of medications because of its ability to induce CYP3A4. The use of Asian ginseng should be cautioned with the following medications: calcium channel blockers, chemotherapy agents, HIV antivirals, and statin medications. (5, 8)
Garlic
Garlic (Allium sativum) extract is an herbal dietary supplement promoted for its antimicrobial, antihypertensive, and cholesterol-lowering effects. Although almost 200 drug interactions are reported with garlic, most are reported as minor, and it is likely safe to take concurrently with precautionary dosing modifications and close monitoring. Garlic has been shown to decrease concentrations of drugs transported by P-glycoprotein, so special attention to interactions should be placed when combining garlic supplements with medications like colchicine, digoxin, verapamil, and quinidine. (5, 8)
There are rare reports of increased risk of bleeding associated with garlic. Given this, patients on blood thinning and anticoagulant agents like aspirin and warfarin should be monitored for easy bruising and increased bleeding. (8, 9)
Kava Kava
Kava kava (Piper methysticum) appears safe to take with some medications but unsafe with others. Kava root is an herbal sedative, muscle relaxant, and analgesic. Concurrent use with other nervous system depressants, like alcohol or benzodiazepines, should be avoided to decrease the risk of excessive central nervous system and motor reflex depression. (8)
In multiple human studies, kava has not affected CYP1A2, CYP2D6, CYP3A4, or P-glycoprotein; kava is safe to take with medications metabolized by these enzymes (5).
One study has shown its ability to inhibit CYP2E1, an enzyme involved in metabolizing several anesthetic agents and acetaminophen. Therefore, patients should be advised to stop taking kava at least five days before procedures requiring anesthesia. (5)
In vitro studies suggest kava's potential to inhibit CYP2C9 and CYP2C19, both involved in metabolizing nonsteroidal anti-inflammatory drugs; angiotensin receptor blockers (for high blood pressure and heart failure); glipizide, glyburide, and rosiglitazone (for type 2 diabetes); valproic acid and phenytoin (anticonvulsants); warfarin (anticoagulant); proton pump inhibitors (for heartburn); and clopidogrel (antiplatelet blood thinner). Patients taking these medications, or others metabolized by CYP2C9 and CYP2C19, with kava should be monitored for adverse events and changes to monitoring lab results, such as glucose, HbA1c, or INR. (5)
Ginkgo
Drug interactions with ginkgo (Ginkgo biloba) are very unlikely, except for warfarin. Plant constituents called terpenoids act within the cardiovascular system to improve blood flow by dilatating blood vessels and inhibiting platelet aggregation. Although most evidence does not indicate an increased risk of bleeding when ginkgo is administered alone, there is potential to increase bleeding when coadministered with warfarin. Patients on warfarin should therefore refrain from supplementing with ginkgo or have their INR closely administered when starting to supplement with the herb. (5)
Functional Medicine Labs to Help Treat Herb-Drug Interactions
Cessation of herbal therapy is often required in the treatment of herb-drug interactions. Modifying herbal and pharmacologic dosing may also be an option depending on the severity of the interaction and the effects it causes. Often, herb-drug interactions can be diagnosed by patient-reported symptoms. Still, labs may be beneficial to definitively identify and quantify effects in the body so that dosage modifications can be appropriately recommended.
Liver Function
Drug-induced hepatitis can occur as a side effect of some medications, amplified when multiple supplements and medications are coadministered due to an increased burden on liver detoxification pathways. Liver inflammation can be identified by elevated liver function enzymes AST, ALT, and GGT.
Detox Genomics
Patients may be at higher risk for heightened severity of adverse effects due to pharmacokinetic herb-drug interactions if they have a genetic predisposition for altered function of the enzymes involved in the metabolism of drugs. Genetic profiling can identify genetic variations to determine risk and patient abilities to tolerate various supplements and medications.
INR
Often, pharmacologic medications require close monitoring with lab work to measure drug concentration or confirm their desired effect on the body. An example is the prothrombin time (PT) and international normalized ratio (INR) to measure clotting times in people taking warfarin. PT and INR may need to be measured more frequently if patients take herbal supplements that can influence warfarin's anticoagulant actions.
Summary
Understanding herb-drug interactions is complex due to the various effects herbs and medications can have on the body. The risk of interaction and severity of adverse events increases with the number of coadministered herbal supplements and medications. Taking a medication does not definitively exclude using herbal supplements in a health protocol. However, understanding the pharmacologic mechanisms of all agents is important for polypharmacy risk stratification. Functional medicine doctors are trained to understand the biochemistry and safety of herbal medicine to create safe and effective integrative treatment plans that include botanical and conventional medicinal modalities to achieve desired health outcomes.
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