Continuing Education Activity

Herbal products, botanical products, or phytomedicines are derived from plants or botanicals and are used to maintain health or treat diseases. Herbal supplements are products specifically used for internal use. A large number of prescription drugs and over-the-counter medications originate from plant derivatives. They differ from herbal supplements because they use Food and Drug Administration–regulated purified ingredients. However, the Food and Drug Administration does not regulate the manufacture of herbal supplements. Therefore, preparations may contain a portion of the plant or the whole plant and may vary in consistency. Herbal supplements are often sold in solid forms, such as capsules, pills, tablets, and lozenges, but are also available in liquid or powder forms.

This activity focuses on the commonly used herbal supplements in the United States and reviews the treatment of conditions using these medications, highlighting the role of the interprofessional team in treating patients using these medications. This activity about herbal supplements is designed to provide evidence-based insights to enhance patient care and outcomes and emphasize strategies to safely incorporate herbal supplements into treatment plans while minimizing the risk of adverse drug reactions. Healthcare professionals gain knowledge of various herbal supplements' adverse effects and efficacy, enabling them to offer informed, individualized care while navigating the complexities of herbal medicine and ensuring safe and effective patient management.

Objectives:

• Identify the Food and Drug Administration regulations involving herbal supplements.

• Assess the potential for inconsistency in herbal dosing.

• Evaluate the risks, benefits, and potential interactions of the common herbal supplements.

• Implement effective interprofessional team strategies to promote a culture of safety regarding herbal supplements.

Introduction

Herbal products, botanical products, or phytomedicines are derived from plants or botanicals to maintain health or treat diseases. Herbal supplements are products specifically used for internal use. A large number of prescription drugs and over-the-counter medications originate from plant derivatives. These medications differ from herbal supplements as they use Food and Drug Administration (FDA)-regulated, purified ingredients. However, the FDA does not regulate the manufacture of herbal supplements. Therefore, preparations may contain a portion of the plant or the whole plant and vary in consistency. These supplements are most commonly sold in solid forms, such as capsules, pills, tablets, and lozenges, but are also available in liquid or powder forms.

This activity focuses on the following herbal supplements commonly utilized in the United States:

• Saw palmetto
• Garlic
• Ginkgo biloba
• Echinacea
• Black cohosh
• Ginseng
• Hawthorn
• St. John's wort
• Goldenseal
• Feverfew
• Capsaicin

Function

Saw Palmetto

Saw palmetto is indigenous to the southeastern United States. Historically, this plant was used by Native Americans to treat genitourinary symptoms, relieve inflamed mucous membranes, increase testicular function, and increase breast size. Today, saw palmetto is a popular supplement for treating benign prostatic hyperplasia and is frequently used by individuals with prostate cancer. Saw palmetto has been shown to inhibit 5α-reductase, an enzyme that converts testosterone to dihydrotestosterone. Saw palmetto extracts are approximately 90% fatty acids and are rich in saturated, medium-chain fatty acids, such as myristate and laurate. Although studies suggest that these fatty acids may play a role in inhibiting 5α-reductase, the specific fatty acid(s) responsible remain unknown. Saw palmetto also exhibits α-adrenoceptor, muscarinic, and 1,4-dihydropyridine inhibitory properties.[1][2]

Garlic

Garlic (Allium sativum) is among the most researched herbal supplements and is the second most used complementary therapy.[3] In the United States, garlic has primarily been used to reduce hypercholesterolemia and hypertension. Studies have shown that garlic has hepatoprotective, neuroprotective, and antioxidant properties. In several studies, S-allyl cysteine, a compound found in garlic, demonstrated neuroprotective and cardioprotective properties by inhibiting cellβ damage in the heart, neurons, and endothelium.[4] S-allyl cysteine has also been shown to destabilize amyloid-β fibrils found in Alzheimer disease.[5] S-allyl cysteine inhibits free radical production, neuronal damage, and lipid peroxidation in rats with brain ischemia. In severely hypertensive patients, garlic has been shown to reduce blood pressure and cardiovascular events. S-propyl-L-cysteine, a structural analog of S-allyl cysteine, has been shown to reverse gastric cancer in mice.[6] Allicin is a compound in garlic produced when it is chopped or crushed. A daily dose of 0.5 to 1.5 g of allicin significantly reduced HbA1c levels in patients with type 2 diabetes within 12 weeks.[7][8]

Gingko Biloba

Ginkgo biloba is commonly used to improve memory and cognition in older patients with impaired cerebral circulation. Mitochondrial dysfunction has been proposed as the leading cause of cognitive decline. The 2 main components in Gingko biloba leaves are flavonoids and terpene trilactones. Together, these compounds enhance and protect mitochondrial function and scavenge reactive molecules such as hydroxyl and peroxyl radicals, nitric oxide, and superoxide ions. Gingko biloba can significantly improve cognitive function in patients with dementia and is also effective as adjunctive therapy for chronic schizophrenia patients.[9][10] New research has shown a positive effect for Alzheimer patients supplemented with Gingko biloba. Specifically, Gingko biloba has been shown to improve endocrine homeostasis, regulate hormone sensitivity, maintain endothelial microvascular integrity, and proteolyze tau proteins.[11] However, in healthy individuals, Gingko biloba is ineffective in improving concentration, memory, or executive function.

Echinacea

Echinacea is a native species to eastern and central North America. Historically, Native Americans used Echinacea for colds, bronchitis, flu, and respiratory infections.[12] Echinacea is known as an immunostimulant, boosting both innate and specific immunity. Echinacea exhibits antiviral, antiinflammatory, and antimicrobial effects. In the bone marrow of mice, Echinacea extract significantly increased the expression of CD80, CD86, and major histocompatibility complex (MHC) class II, upregulated markers of classically activated macrophages (M1). Echinacea also increased the production of nitrous oxide (NO), tumor necrosis factor-α, and interleukins 6, 12p70, and 1β. Intracellular bactericidal activity and enhanced phagocytosis were also observed. A randomized, double-blind study involving 473 patients virologically confirmed with influenza infection showed that Echinacea was as effective as oseltamivir with fewer adverse events and reduced risk.[13]

Black Cohosh

Black cohosh (Actaea racemosa) is commonly used to treat premenstrual syndrome, dysmenorrhea, menopausal symptoms, and, in particular, vasomotor symptoms (hot flushes). The supplement has been increasingly used in women with breast cancer due to findings from the Women's Health Initiative, which indicated that traditional hormone replacement therapy increases the risk of breast cancer and has negative cardiovascular consequences. Black cohosh has been shown to have selective estrogen receptor modulator properties, but the specific compounds that impart this effect are undetermined. Triterpene glycosides are a group of compounds suggested as potential contributors. Cycloartane triterpenoids found in black cohosh induced mitochondrial apoptosis and cell arrest.[14][15] Actein, also found in black cohosh, showed antiangiogenic effects. A dose of 10 mg/kg of oral actein for 7 days inhibited blood vessel formation. The same dose given orally for 28 days decreased breast tumor size and metastasis to the lungs and liver in mice. Comprehensive studies have confirmed black cohosh's efficacy in managing vasomotor symptoms.[16] 

Ginseng

Ginseng is commonly used to boost energy, enhance physical and mental performance, treat erectile dysfunction, and strengthen the immune response. Ginseng is a generic term that represents several species in the genus Panax, including Panax quinquefolius L (American ginseng), Panax ginseng, and Panax japonicus (Asian ginseng). Ginseng contains a variety of active compounds that affect many metabolic pathways; the ginsenosides have been shown to have clinical significance. Ginsenosides are found in the plant's roots but have also been reported to be abundant in the berries.[17] Ginsenosides have been shown to activate macrophages and natural killer cells primarily responsible for innate immunity. They also regulate immunocytes and cytokines, which affect cell-mediated and humoral immunity. In the prevention of fatigue, ginseng was shown to increase recovery of creatinine kinase, decrease interleukin 6 levels, and increase insulin sensitivity.[18] Ginseng has demonstrated antiproliferative effects in breast cancer.[14] Ginseng has also been shown to effectively treat chronic kidney disease, non–small cell lung cancer, acute respiratory distress syndrome, and septic acute lung injury.[19] 

Ginsenosides and their metabolites modulate signaling pathways of metastasis, angiogenesis, inflammation, oxidative stress, and stem/progenitor-like properties in breast cancer cells. For example, ginsenoside Rp1 has been shown to induce cell cycle arrest and apoptosis in cancer cells.[14] Another promising effect of ginsenosides on cancer cells is their ability to increase the sensitivity of these cells to anticancer drugs by downregulating the RNA levels of MDR1, which enhances the efficacy of medications such as gemcitabine, cisplatin, paclitaxel, and epirubicin.[14] For erectile dysfunction, ginsenosides have been shown to increase nitric oxide activity in endothelial cells in vitro, relaxing the smooth muscles of the corpus cavernosum.[20][17] A dose of 1.5 g of red ginseng powder daily for 12 weeks administered to patients with varicoceles improved spermatozoa's number, motility, and shape compared to control groups.[18]

Hawthorn

Hawthorn (Crataegus monogyna) is commonly used for heart-related conditions, specifically as a supportive treatment for angina, atherosclerosis, heart failure, and high blood pressure. Hawthorn's cardiac effects were initially described in the 1st century CE and are well established. Hawthorn extracts WS 1442 and LI 132 are the most studied compounds of hawthorn and are derived from the flowers and leaves of the plant. The WS 1442 extract contains oligomeric procyanidins acting as free radical scavengers and inhibitors of human neutrophil elastase released from activated leukocytes in previously ischemic myocardium after restoring blood flow. Oligomeric procyanidins also increase coronary blood flow, improving endothelium function. The WS 1442 extract has shown reduced ST-segment elevation on electrocardiogram, reduced incidence of ventricular arrhythmias, size of infarction zone, and mortality in pretreated animals.[21] Long-term administration of WS 1442 has been shown to increase myocardial basal vessel blood flow and prevent alterations of cardiac, renal, and vascular function and structure and deoxycorticosterone acetate salt–induced hypertension.[22]

St. John's Wort

St. John's wort (Hypericum perforatum) is commonly used to treat mild-to-moderate depression. St. John's wort as a medicinal herb is traceable back to the ancient Greeks, who used it to treat burns, as an astringent to arrest diarrhea, and as a diuretic.[23][24] St. John's wort contains several bioactive compounds, including phenolic acids; flavonoids, such as quercetin, isoquercitrin, quercitrin, epigenin, rutin, and hyperoside; hyperforin; and hypericin, which work synergistically to provide its antidepressant and antiinflammatory effects. These compounds have been shown to affect neurotransmitters such as N-methyl-D-aspartic acid, gamma-aminobutyric acid, and serotonin receptors.[25] 

At a daily dosage of 300 to 1200 mg, St. John's wort is more effective compared to standard antidepressant therapy in patients with mild-to-moderate depression. St. John's wort extracts reduced prostaglandin-E2 and NO production by macrophages by more than 30% in mice.[26] Hyperforin, hypericin, and other compounds in St. John's wort were found to be active against gram-positive and gram-negative bacteria.[24] St. John's wort is active against multidrug-resistant bacteria, with extracts imparting potent antibacterial activity against methicillin-resistant Staphylococcus aureus.[27]

Goldenseal

Goldenseal (Hydrastis canadensis) has long been used for its antiseptic properties and for treating colds, the flu, and inflammation of the nares. Goldenseal is indigenous to eastern North America and southeastern Canada. Native Americans used the roots of goldenseal to treat skin and eye infections and gastrointestinal irritation. The primary compounds that have shown biological activity are beta-hydrastine and berberine.[28] 6-Desmethyl sideroxylon, sideroxylon, and 8-desmethyl sideroxylon were noted to enhance the antimicrobial activity of goldenseal alkaloids (berberine). These compounds, known as flavonoids, inhibit bacterial efflux pumps, allowing berberine to accumulate in bacterial cells.[29] Leaf extracts of goldenseal were shown to have antimicrobial activity against methicillin-resistant Staphylococcus aureus. They reduced alpha-toxin production from Staphylococcus aureus, preventing damage to human skin keratinocytes.[30] Goldenseal extracts also showed antimicrobial activity against multidrug-resistant strains of Mycobacterium species, including M tuberculosis.[31] Berberine has demonstrated antiviral activity against Herpes simplex virus 1 and 2 by modulating host cell activation of the NF-kB and MAPK pathways.[32]

Feverfew

Feverfew (Tanacetum parthenium) is commonly used to treat migraine headaches and menstrual cramps. This plant is native to Asia Minor but cultivated worldwide. Major active compounds found in feverfew include sesquiterpene lactones, 3β-hydroxy parthenolide, parthenolide, canin, and artecanin. Among these, parthenolide has been shown to have the most biological activity, with the highest concentration in the leaves and flowers of the plant. Parthenolides have shown efficacy in preventing migraines. Antimigraine properties include inhibiting platelet-release serotonin, vascular smooth muscle relaxation, and antiinflammatory effects.[33] Chrysanthenyl acetate, found in feverfew essential oil, inhibits prostaglandins and has analgesic properties.[34] Parthenolide has demonstrated nephroprotective qualities by inhibiting free radical production from CCl₄metabolism.[35] Parthenolide has also been shown to inactivate Jak proteins, consequently blocking STAT3 signaling that leads to the arrest of the growth and migration of cancer cells.[36]

Capsaicin 

Capsaicin (Capsicum frutescens, Capsicum annuum), a compound found in chili peppers, has been used for its analgesic properties.[37] Epidermal nerve fibers include non-peptidergic and peptidergic transient receptor potential vanilloid 1 (TRPV1)-positive nociceptors. Partial nerve injury selectively degenerates non-peptidergic afferents, reducing epidermal nerve fiber density and sensitizing the remaining peptidergic afferents through Wallerian degeneration and inflammation. The remaining afferents are responsive to capsaicin, with high concentrations providing analgesia by ablation of afferent terminals within 1 day. Capsaicin also triggers regenerative processes in TRPV1-positive afferents, with regeneration occurring in 24 weeks, at which point neuropathic pain may return. Retreatment with capsaicin can again provide relief.[38] The CDC 2022 opioid guidelines endorse the use of capsaicin patches for treating neuropathic pain.[39][40]

Issues of Concern

A significant concern with herbal supplementation is that many patients use herbal supplements but often fail to report them to their clinicians. In a Spanish study, 20% of patients reported taking an herbal supplement in addition to prescription drugs.[41] A Johns Hopkins study revealed that 20% of patients reported using one or more herbal supplements, with 30% using an herbal supplement for the same condition for which they were taking a prescription medication. A Swedish study showed that one-third of patients did not report herbal supplement usage to their clinician.[42]

This lack of communication can inadvertently complicate treatment. As some herbal supplements are known to inhibit or enhance prescription drugs, not knowing what herbal supplements a patient is taking can lead to either ineffective treatment or toxicity and harmful adverse effects. Healthcare professionals can report misleading advertising for dietary supplements to the Federal Trade Commission. The FDA has dedicated resources for reporting any adverse event associated with dietary supplements. Please see the Center for Food Safety and Applied Nutrition (CFSAN) on Industry and Consumer Assistance or How to Report a Problem with Dietary Supplements.

Clinical Significance

A significant clinical concern with herbal supplements is their interaction with cytochrome p450 enzymes (CYP450), particularly when patients take prescription drugs and herbal supplements concurrently. Approximately 80% of prescribed medications are metabolized through 6 CYP enzymes—CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4.[43] CYP450 enzymes hydroxylate xenobiotics and endobiotics, conjugating them to additional chemical moieties, facilitating elimination from the body. Herbal supplements may inhibit these enzymes, causing increased exposure to toxic compounds or induce the enzymes, increasing the number of toxic compounds produced or releasing organ-damaging reactive oxygen species. Among the supplements discussed, multiple compounds in Gingko biloba, hyperforin in St. John's wort, ginsenosides in ginseng, and diallyl sulfide in garlic induce CYP450 enzymes. Terpenes in black cohosh and Echinacea extract may inhibit CYP450 enzymes.[44]

Another possible interaction occurs when an herbal supplement shares a mechanism of absorption, distribution, metabolism, or excretion (ADME) similar to a prescribed drug. In such cases, changing the prescribed drug dosage can safely counteract the negative interaction.[43]

Garlic may negate anticoagulant effects or act as a blood thinner by inhibiting platelets.[45] Garlic did not affect blood clotting when compared to aspirin.[46] Garlic has been shown to affect drugs transported by P-glycoprotein (P-gp), specifically decreasing their concentrations, including colchicine, digoxin, doxorubicin, quinidine, rosuvastatin, tacrolimus, and verapamil.[43]

People with ragweed allergies may also be allergic to Echinacea. Six months of continuous ingestion of different Echinacea preparations showed no toxic effects.[12] However, there are reports that Echinacea may inhibit CYP1A2 and CYP3A enzymes.[44]

Black cohosh has been shown to interact with the OATP2B1 enzyme, potentially reducing the efficacy of fexofenadine, glyburide, amiodarone, and many statin medications. No clinically significant effects were observed on P-gp and multiple CYP enzymes.[43]

In several human trials, Asian ginseng did not affect CYP2E1, CYP1A2, CYP2D6, or P-gp.[43] In a single trial, American ginseng was shown to reduce the international normalized ratio (INR) by 0.2 when used with warfarin.[47] Ginseng is generally nontoxic, but high doses (3g daily) have been shown to cause insomnia, nausea, headache, and nervous excitation.[14]

Gingko biloba has been shown to inhibit platelet aggregation. However, several studies showed that Gingko did not increase bleeding risk or affect hematologic parameters.[43] Gingko may increase INR when combined with warfarin, potentially increasing the bleeding risk when used together.[47]

Goldenseal has been shown to inhibit CYP2D6 and CYP3A4, enzymes responsible for metabolizing approximately 50% of pharmaceutical agents. Therefore, it is strongly advised to avoid using goldenseal with most prescription and over-the-counter medications.[43]

St. John's wort has been shown to induce CYP3A4 and P-gp, potentially reducing the effectiveness of medications such as irinotecan, protease inhibitors, digoxin, cyclosporine, tacrolimus, warfarin, and oral contraceptives.[43] Therefore, it should generally be avoided when taking prescription or over-the-counter medications.

Saw palmetto has been shown not to affect CYP1A2, CYP2D6, CYP3A4, or CYP2E1 enzymes.[43]

Reported possible adverse effects of hawthorn include nausea, dizziness, vertigo, fatigue, sweating, headache, palpitations, and epistaxis. Therefore, it is not recommended during pregnancy as it may cause uterine stimulation.[21]

Topical capsaicin may cause localized erythema, pruritus, and a burning sensation and can also lead to a transient increase in systemic blood pressure.[48]

Other Issues

American consumers trust that their prescription drugs are of high quality and are consistent in purity and potency, often without question. According to a study conducted in 2007, this expectation has been transferred over to herbal supplements despite their lack of regulation in the United States. Approximately 70% of consumers believed that the FDA tests herbal supplements, and 60% thought the FDA regulates them.[49] However, this contrasts with other countries, such as Italy, where herbal supplements (plant food supplements) fall under food law regulation.[50] When 20 commercial saw palmetto supplements were compared, the fatty acid and phytosterol quantities varied greatly.[2] Similarly, when 40 Gingko biloba supplements underwent comparison, 6 samples contained fillers with no measurable Gingko biloba DNA.[10]

Preparation is another issue affecting herbal supplements. Herb preparation and the parts used significantly affect its efficacy and attributes. For example, Echinacea’s various effects depend on what part of the plant gets harvested, such as flowers, roots, or leaves.[12] St. John's Wort has different benefits depending on the geographic location from which it was harvested, its harvest time, and whether fresh or dried plant material underwent processing.[24] The antibacterial activity of St. John's Wort was shown to be higher when its collection took place in August compared to July.[24]

One method of alleviating these issues is through certification. In 2007, the FDA established regulations for dietary supplements called current good manufacturing practice (cGMP), a list of nonbinding recommendations in manufacturing, labeling, packing, or holding operations for dietary supplements. Manufacturers can certify their products to verify active components and concentrations of heavy metals and other possible contaminants. Further research is necessary to standardize extraction methods and the preparation of herbal supplements so that their effectiveness is consistent.

Hepatotoxicity

According to the American Association for the Study of Liver Diseases (AASLD) practice guidelines, hepatotoxicity due to herbal supplements is a significant concern. Although many herbal supplements are safe, some have been linked to severe liver injuries, including acute liver failure. In 2019, Americans spent over $9.6 billion on herbal products, and the Drug-Induced Liver Injury Network (DILIN) Registry reports that herbal and dietary supplements account for approximately 20% of liver injury cases in adults. Regulation of these products is minimal, requiring manufacturers to ensure safety based on historical use rather than extensive testing. Diagnosing liver injury from herbal supplements is complicated by factors such as ingredient variability, undisclosed additives, and delayed onset of symptoms. This complexity makes causality assessments challenging. Specific genetic factors, including certain human leukocyte antigen (HLA) polymorphisms, significantly influence susceptibility to supplements-related liver damage. For example, the HLA-B*35:01 allele is strongly associated with liver injury caused by green tea extract, particularly in individuals of European descent. Similarly, this HLA allele has been linked to liver toxicity from Polygonum multiflorum in individuals of Asian descent. Compared to drug-induced liver injuries, those caused by herbal supplements may lead to poorer outcomes due to delays in diagnosis and treatment. The widespread use of herbal and dietary supplements, inconsistent safety standards, and potential contamination underscores the importance of increased awareness and caution.[51]

Nephrotoxicity

According to the guidelines for the Kidney Disease: Improving Global Outcomes (KDIGO) 2024, herbal remedies should be approached with caution in patients with chronic kidney disease (CKD) due to their potential nephrotoxicity. Common cases of aristolochic acid nephropathy have been reported, highlighting the risks associated with specific herbal remedies. Similarly, nephrotoxicity due to alkaloid compounds, often found in Chinese herbs, has been documented.[52] However, nephrotoxic effects have also been reported for a wide range of other herbal remedies globally. Herbs such as black cohosh, St. John's wort, yellow oleander, and many others can pose significant risks to kidney health. The guidelines emphasize that patients should disclose all herbal and dietary supplement use to their healthcare providers, who should thoroughly evaluate and monitor for potential adverse effects to prevent the worsening of CKD.[53]

Enhancing Healthcare Team Outcomes

Because patients are generally reluctant to disclose their herbal supplementation, it is crucial to develop a trusting relationship that allows patients to discuss dietary supplement use without reservation. All interprofessional healthcare team members need to be on the same page regarding herbal supplements, share information through open communication between team members, and deliver a consistent message to the patient. This approach optimizes therapeutic efficacy and reduces potential adverse effects.

To detect possible interactions between supplements and drugs, thorough documentation of herbal supplement usage, including initiation and discontinuation, is essential. Clinicians need to understand whether an herbal supplement affects a prescribed drug's clinical effect without affecting its dosage or whether it is affecting the concentration in the blood and, therefore, its pharmacological action (pharmacokinetics). This understanding leads to a more informed decision on whether to change the dosage of a drug or discontinue the supplement(s) in question altogether. Nurses need to include these agents in the patient's medication record. The pharmacist can consult with the clinician to check for interactions, as these are often not benign substances and can alter drug therapy. Providing continuing medical education and further research into herbal supplement-prescription drug interactions increase understanding and benefit the patient-physician relationship.

Nursing, Allied Health, and Interprofessional Team Interventions

All herbal supplements should be documented in the electronic medical records.[54] Potential drug-herb interactions should be checked, and the physician should be notified immediately if significant concerns arise. Patients should be educated about the adverse effects of herbal supplements.

Healthcare professionals can report to the FDA for any adverse event associated with herbal supplements through the Safety Reporting Portal. 

Nursing, Allied Health, and Interprofessional Team Monitoring

Liver function tests should be monitored for patients using hepatotoxic herbal supplements.[51] Renal function and electrolyte levels should be monitored for potential nephrotoxicity in patients with CKD.[53]