Herbal Supplements

Function

Saw Palmetto

Saw palmetto is indigenous to the southeastern United States. Historically, it was used by Native Americans to treat genitourinary symptoms, relieve inflamed mucous membranes, increase testicular function and increase breast size.[1] The extract is currently a popular supplement for treating benign prostatic hyperplasia (BPH) and those diagnosed with prostate cancer. Saw palmetto has been shown to inhibit 5a-reductase, an enzyme that converts testosterone to dihydrotestosterone.[2] Saw palmetto extracts are approximately 90% fatty acids and are rich in saturated, medium-chain fatty acids, myristate, and laurate. Studies have proposed that fatty acids may be responsible for inhibiting 5a-reductase, but which one(s) is unknown.[2] Saw palmetto also demonstrates a-adrenoceptor, muscarinic, and 1,4-dihydropyridine inhibitory properties.[1]

Garlic

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

Gingko Biloba

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

Echinacea

Echinacea is a native species to eastern and central North America. Historically, Native Americans used Echinacea for treating colds, bronchitis, flu, and respiratory infections.[12] Echinacea is known as an immunostimulant, boosting both innate and specific immunity. It has also demonstrated antiviral, anti-inflammatory, and antimicrobial effects.[12] In the bone marrow of mice, Echinacea extract significantly increased expression of CD80, CD86, and MHCII, upregulated markers of classically activated macrophages (M1), and the production of IL-6 IL-12p70, IL-1beta, nitrous oxide (NO), and TNF-a. Intracellular bactericidal activity and enhanced phagocytosis were also observed.[12] A randomized, double-blind study of 473 patients virologically confirmed with influenza infection showed 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 (PMS), dysmenorrhea, menopausal symptoms, and in particular, hot flashes. It has also seen increased use in women who have breast cancer.[14] Its increased use may, in part, be because of studies from the Women's Health Initiative showing traditional hormone replacement therapy increased the risk of breast cancer and negative cardiovascular consequences.[15] Black cohosh has been shown to have selective estrogen receptor modulator properties, but the specific compounds that impart this effect are as yet undetermined. Triterpene glycosides are one group suggested as the compounds responsible.[14] Cycloartane triterpenoids found in black cohosh induced mitochondrial apoptosis and cell arrest.[14] Actein, also found in black cohosh, showed antiangiogenic effects. A dose of 10 mg/kg of oral actin for seven 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.[14] Black cohosh's efficacy in reducing hot flashes and controlling vasomotor symptoms has been shown in comprehensive studies.[16] 

Ginseng

Ginseng is used commonly 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. These include Panax quinquefolius L (American ginseng), Panax ginseng, and Panax japonicus (Asian ginseng). Ginseng is composed of a diverse amount of active compounds that affect many metabolic pathways. Of those, ginsenosides have been shown to have clinical significance. They 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.[18] In the prevention of fatigue, ginseng was shown to increase recovery of creatinine kinase, decrease IL-6 and increase insulin sensitivity.[18] Ginseng has shown antiproliferative effects in breast cancer.[14] It 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 are known to modulate signaling pathways of metastasis, angiogenesis, inflammation, oxidative stress, and stem/progenitor-like properties in breast cancer cells.[14] For example, ginsenoside Rp 1 induced cycle arrest and apoptosis in cancer cells.[14] Another promising effect ginsenosides had on cancer cells was increasing the sensitivity of those cells to anticancer drugs. By downregulating the RNA level of MDR-1, it increased sensitivity to 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 to varicocele patients improved the number, motility, and shape of spermatozoa 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, angina, atherosclerosis, and high blood pressure. Hawthorn's effects on the heart were first reported in the first century AD and have been well established.[21] WS 1442 and LI 132 extracts have been the most studied compounds of hawthorn and come from the flowers and leaves of the plant. The WS 1442 extract contains oligomeric procyanidins(OPC), which have been shown to act as free radical scavengers.[21] They have also been shown to inhibit human neutrophil elastase which is released from activated leukocytes in previously ischemic myocardium after restoring blood flow.[21] OPCs also increase coronary blood flow, improving endothelium function.[21] WS 1442 extract showed reduced ST-segment elevation on ECG, reduced incidence of ventricular arrhythmias, size of infarction zone, and mortality in pre-treated animals.[21] Long-term administration of WS 1442 was shown to increase myocardial basal vessel blood flow.[22] It prevented alterations of cardiac, renal, and vascular function and structure and deoxycorticosterone acetate (DOCA) 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] Several bioactive compounds have been identified in St. John's Wort that work synergistically to provide its antidepressant and anti-inflammatory attributes.[23] These include phenolic acids, flavonoids (quercetin, isoquercitrin, quercitrin, epigenanin, rutin, hyperoside), hyperforin, and hypericin.[23] These compounds have been shown to affect neurotransmitters like N-methyl-D-aspartic acid (NMDA), g-aminobutyric acid (GABA), and serotonin receptors.[25] 

At a daily dosage of 300 to 1200 mg, St. John's Wort was more efficacious than standard antidepressant therapy in patients with mild-to-moderate depression.[25] St. John's Wort extracts were shown to reduce PGE2 and NO production from macrophages by more than 30% in mice.[26] Hyperforin and hypericin, along with other compounds found 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 multi-drug resistant bacteria, with extracts imparting potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA).[27]

Goldenseal

Goldenseal (Hydrastis canadensis) has long been used for its antiseptic qualities and activity against colds, the flu, and inflammation of the nares. It 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.[28] The primary compounds that have shown biological activity are beta-hydrastine and berberine.[29] 6-desmethyl sideroxylon, sideroxylon, and 8-desmethyl sideroxylon were noted to enhance the antimicrobial activity of goldenseal alkaloids (berberine).[28] These compounds, known as flavonoids, inhibit bacterial efflux pumps, allowing berberine to accumulate in bacterial cells.[28] Leaf extracts of goldenseal were shown to have antimicrobial activity against MRSA.[30] They reduced alpha-toxin production from Staphylococcus aureus, preventing damage to human skin keratinocytes.[30] Goldenseal extracts also showed antimicrobial activity against multiple drug-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 for migraine headaches and menstrual cramps. It is native to Asia Minor but cultivated worldwide. Major active compounds found in feverfew include sesquiterpene lactones, 3b-hydroxy parthenolide, parthenolide, canin, and artecanin.[33] Of these, parthenolide has been shown to have the most biological activity.[33] It is highest in concentration in the leaves and flowers of the plant.[33] Parthenolides have shown efficacy in preventing migraines.[34] Its antimigraine properties include inhibiting serotonin release from platelets, vascular smooth muscle relaxation, and anti-inflammatory effects.[34] Chrysanthenyl acetate, found in feverfew essential oil, was shown to inhibit prostaglandins and have analgesic properties.[35] Parthenolide has demonstrated nephroprotective qualities by inhibiting free radical production from CCL metabolism.[33] Parthenolide has also been shown to inactivate JAKs, consequently blocking STAT3 signaling that leads to the arrest of the growth and migration of cancer cells.[36]

Issues of Concern

A significant concern of herbal supplementation is that many patients use herbal supplements but underreport them to their clinicians. In a Spanish study, 20% of patients reported taking an herbal supplement in addition to prescription drugs.[37] A John Hopkins study revealed that 20% of patients reported using one or more herbal supplements, with 30% of patients reporting using an herbal supplement for the same condition they were using a prescription medication to treat.[38] A Swedish study showed that one-third of patients did not report herbal supplement usage to their physician.[38]

Not knowing if a patient uses herbal supplements may inadvertently complicate treatment. Since 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 side effects.

Clinical Significance

A significant concern of herbal supplements clinically is their interaction with cytochrome p450 enzymes (CYP450). Especially when patients are taking prescription drugs and herbal supplements concurrently. 80% of prescribed medications are metabolized through six CYP enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4).[39] 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 them, increasing the number of toxic compounds produced or releasing reactive oxygen species (ROS), leading to organ damage.[40] Of the supplements covered, 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.[40]

The other possible interaction is when an herbal supplement has a similar mechanism of absorption, distribution, metabolism, or excretion (ADME) to a prescribed drug. In these cases, changing the prescribed drug dosage can safely counteract the negative interaction.[39]

Garlic may act as a blood thinner by inhibiting platelets and negating the effects of anticoagulants.[41] Garlic did not affect blood clotting when compared to aspirin.[42] Garlic has been shown to affect drugs transported by P-gp, specifically decreasing their concentrations. These include colchicine, digoxin, doxorubicin, quinidine, rosuvastatin, tacrolimus, and verapamil.[39]

People with ragweed allergies may be allergic to Echinacea as well. Six months of continuous ingestion of different Echinacea preparations showed no toxic effects.[12] However, there are reports that it may inhibit CYP1A2 and CYP3A.[40]

Black cohosh has been shown to interact with the OATP2B1 enzyme; this may reduce the efficacy of fexofenadine, glyburide, amiodarone, and many statin medications.[39] No clinically significant effects were seen on P-gp and multiple CYP enzymes.[39]

In several human trials, Asian ginseng was shown not to affect CYP2E1, CYP1A2, CYP2D6, or P-gp.[39] In a single trial, American ginseng was shown to reduce the international normalized ratio (INR) by 0.2 when taking warfarin.[43] Ginseng is generally non-toxic, 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. Several studies, however, showed that Gingko did not increase bleeding risk or have a significant effect on hematologic parameters.[39] Gingko may increase INR when combined with warfarin, which may increase the bleeding risk when taking Gingko and warfarin simultaneously.[43]

Goldenseal has been shown to inhibit CYP2D6 and CYP3A4. These two enzymes metabolize 50% of current pharmaceutical agents. It is strongly recommended to avoid taking goldenseal with most prescription and over-the-counter medications.[39]

St. John’s Wort has been shown to induce CYP3A4 and P-gp. It may interact (reduce effectiveness) with irinotecan, protease inhibitors, digoxin, cyclosporine, tacrolimus, warfarin, and oral contraceptives.[39] 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.[39]

Reported possible side effects of hawthorn include nausea, dizziness, vertigo, fatigue, sweating, headache, palpitations, and epistaxis. It is not recommended during pregnancy because it can cause uterine stimulation.[21]

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 done in 2007, this expectation has been transferred over to herbal supplements despite their lack of regulation in the United States. 70% believed the FDA tests herbal supplements, and 60% thought they regulated them.[44] However, this contrasts with other countries like Italy, where herbal supplements (plant food supplements) fall under food law regulation.[45] 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 of the samples contained fillers that had 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, i.e., flowers, roots, or leaves.[12] St. John’s Wort’s different benefits depending on the geographic location it was harvested from, its harvest time, whether fresh or dried plant material underwent processing, etc.[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). It is 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. 

Enhancing Healthcare Team Outcomes

Because patients are generally reluctant to disclose their herbal supplementation, it is crucial to develop a trusting relationship that would allow 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 will optimize therapeutic efficacy and reduce potential adverse effects. [Level 5].

In detecting possible interactions between supplements and drugs, thorough notes should be taken on herbal supplement usage, including initiation and discontinuation.

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 pharmacologic action (pharmacokinetics). This understanding will lead 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 (CME) and/or further research into herbal supplement-prescription drug interactions would increase understanding and benefit the patient-physician relationship.