Herbal Supplements;Evidence/Safety/Drug interactions

From Journal for Nurse Practitioners

Herbal Supplements: Talking With Your Patients

Joyce K. Anastasi, PhD, DrNP, FAAN, Lac; Michelle Chang, MS, Lac; Bernadette Capili, DNSc, NP-C

Authors and Disclosures
Posted: 02/01/2011; Journal for Nurse Practitioners. 2011;7(1):29-35. © 2011 Elsevier Science, Inc.


Abstract and Introduction
Abstract
The popularity and prevalence of herbal products and dietary supplements in the US has grown steadily. Patients are increasingly using them to prevent disease, complement conventional therapies, and promote well being and health. Nurse practitioners play a critical role in discussion, communication, and education of herbal supplement use. This article provides a review of commonly used herbal supplements regarding recent evidence for efficacy, possible drug interactions, and safety considerations.

Introduction
Approximately 38 million US adults use herbal and dietary supplements.[1] In 2009, Americans spent $5.03 billion on herbs and other botanical supplements, and their sales are steadily growing.[2] From Sam's Club to natural food retailer Whole Foods Market, even convenience stores sell herbal supplements such as ginkgo and echinacea alongside aspirin. Patients are regularly using herbal products to self-treat medical conditions, complement conventional therapies, and maintain their overall health and well-being. Most patients receive their information about herbs and supplements from their friends, family, and the Internet but rarely from their healthcare provider.[3]

Since the US Dietary Supplement Health and Education Act (DSHEA) became law in 1994, vitamins, minerals, and herbal supplements are presumed to be safe and freely available. However, the FDA does not regulate dietary supplements, and there are no pre-market safety or efficacy studies required. If a dietary supplement has safety issues once it is on the market, the FDA can take action against the manufacturer by issuing a warning or removing the product. In 2007, the FDA issued its final current "good manufacturing practices" (GMPs) regulations to maintain that dietary supplements are processed consistently and meet quality standards. While improvements have been made in the oversight of supplements, issues of quality and safety continue. In 2010, the US Government Accountability Office (GAO) released a report finding trace levels of lead and other contaminants (within levels accepted by the FDA and EPA) and examples of deceptive or suspect marketing claims.[4]

Despite increasingly common usage, only one-third of patients tell their physician about their use of supplements.[1] Physicians do not commonly ask patients about their complementary and alternative medicine (CAM) use, and patients may feel uncomfortable discussing it. But concomitant use of herbal supplements with prescription drugs or over-the-counter (OTC) medications can put patients at risk for a variety of serious drug interactions. Herbs and drugs often interact when they use the same transport or metabolic protein, commonly cytochrome P450 (CYP) enzymes, glucuronosyltransferases (UGT), and P-glycoprotein (Pgp), resulting in induction or inhibition activity.[5] However, many factors, including the dose, schedule, and route of administration, can affect the potential drug-botanical interaction. If the botanical and drug are administered at different times, it is less likely that a clinically relevant interaction will occur.[5]

Garlic (Allium Sativum)
Purported uses: hyperlipidemia, hypertension, atherosclerosis, cardiovascular disease (CVD), cancer prevention

Evidence to date: The active sulfur compounds alliin, allicin, and ajoene may inhibit platelet aggregation, reduce plaque formation, increase fibrinolysis, and modestly reduce blood pressure. The exact effects of garlic on CVD and cerebrovascular events are unclear. Randomized controlled trials (RCTs) on hyperlipidemia conducted in the early 1990s suggested garlic powder tablets lowered lipid levels, but trials since then have not reported any statistically significant effects on plasma lipid concentration with similar dosages and in similar populations.[6] A meta-analysis suggested antihypertensive effects, but further research is needed to clarify its effects on CVD.[7] Population-based studies have shown increased dietary garlic consumption may be associated with a decreased risk of developing stomach and colorectal cancer, but supplements do not seem to offer the same benefit.[8]

Adverse effects/safety considerations: Prolonged bleeding time, gastrointestinal (GI) complaints, breath and body odor. Discontinue use at least 7 days before surgery.

Drug interactions: Garlic may induce CYP3A4 activity. It decreases the plasma concentration of saquinavir and chlorzoxazone and may interact with chlorpropamide, ritonavir, fluindione, cyclosporine, docetaxel, and paracetamol.[9] Several case reports have suggested that garlic affects platelet functions and blood coagulation, but two clinical trials have found that garlic did not alter the pharmacokinetics or pharmacodynamics of warfarin.[9]

Saw Palmetto (Serenoa Repens)
Purported uses: benign prostatic hyperplasia (BPH)

Evidence to date: Saw palmetto may inhibit 5-alpha-reductase and demonstrate anti-inflammatory activity. The data conflict with some studies suggesting it may improve mild to moderate symptoms of BPH, such as reducing nocturia and improving urinary flow rate,[10, 11] while a recent Cochrane Review suggests it is not more effective than placebo.[12] To firmly establish efficacy, more well-designed RCTs are necessary.

Adverse effects/safety considerations: Current data suggest that saw palmetto is well tolerated by most users and is not associated with serious adverse events. The majority of adverse events are mild, such as GI complaints, and are similar to placebo. It may prolong bleeding time, as there has been one case report of intraoperative hemorrhage, but a recent RCT showed no evidence of serious toxicity.[13]

Drug interactions: There have been no reported herb/drug interactions to date.

Ginkgo (Ginkgo Biloba)
Purported uses: CVD, memory loss, dementia, Alzheimer disease, tinnitus, asthma, bronchitis, intermittent claudication

Evidence to date: The terpenoids, bilobalide and ginkgolide, may improve blood flow through increased release of nitric oxide, and the flavonoids' antioxidant, anti-inflammatory activity appears to be neuroprotective.[14] Most clinical studies have been conducted with a standardized extract of ginkgo, EGb761. Early studies indicated ginkgo may improve cognitive performance in patients with dementia,[15] but more recent studies have shown conflicting evidence. The National Center for Complementary and Alternative Medicine (NCCAM)-funded Gingko Evaluation of Memory (GEM) study, the largest and longest RCT, found no scientific evidence that it decreases the incidence of dementia or Alzheimer's disease in elderly adults and was ineffective in slowing cognitive decline.[16, 17] A secondary analysis of the GEM study reported that ginkgo biloba did not reduce incidence or mortality from CVD. However, it may reduce the risk of peripheral vascular disease and suggests further studies may be useful.[18]

Adverse effects/safety considerations: GI complaints, prolonged bleeding

Drug interactions: Ginkgo may inhibit or induce CYP3A4, -2C9, -2C19. Pharmacokinetic trials have shown it reduces plasma concentrations of alprazolam, omeprazole, ritonavir, and tolbutamide. Case reports indicate it may react with antiepileptics, thiazide diuretics, ibuprofen, risperidone, rofecoxib, trazodone, midazolam, efavirenz, and warfarin. Case reports have also implicated ginkgo with bleeding events, but two clinical trials have shown no effect on international normalized ratio (INR) and platelet aggregation.[9]

Echinacea (Echinacea Purpurea, Echinacea Augustifolia, Echinacea Pallida)
Purported uses: common cold, upper respiratory infections, immunostimulant

Evidence to date: The alkylamides stimulate phagocytosis or macrophage activation, modulate cytokines (such as IL6, IL 8, and TNF alpha), and enhance leukocyte mobility. Clinical studies are mixed; echinacea may be effective for the treatment of colds, but evidence for prevention is lacking. Current evidence suggests it may reduce the incidence and duration of the common cold.[19]

Adverse effects/safety considerations: GI complaints, rash

Drug interactions: Echinacea may modulate the CYP3A4 enzyme system and interact with caffeine and midazolam.[5]

Milk Thistle (Silybum Marianum)
Purported uses: Hepatitis, cirrhosis, hepatotoxicity, diabetes

Evidence to date: The biologically active constituent, silymarin, may have a hepatoprotective effect in the course of liver diseases such as HCV and in hepatoxicity produced by exposure to certain medications, alcohol, and drugs. However, evidence is inconclusive. A large, NCCAM-funded, Phase II study is underway to evaluate the safety and efficacy for treatment of chronic hepatitis C. One RCT showed it reduced hepatotoxicity associated with chemotherapy in children with acute lymphoblastic leukemia.[20] Preclinical data for diabetes and cancer are promising but limited, and more research is recommended.

Adverse effects/safety considerations: GI complaints

Drug interactions: Milk thistle may inhibit CYP3A4 and UGTs. Milk thistle does not seem to affect indinavir in healthy patients or those with HIV.[21]


St. John's Wort (Hypericum Perforatum)
Purported uses: mild to moderate depression, seasonal affective disorder, anxiety

Evidence to date: Hyperforin is the major constituent in St. John's wort (SJW) responsible for its antidepressant activity by selectively inhibiting serotonin, dopamine, and norepinephrine reuptake in the central nervous system. Most studies have shown SJW to be superior to placebo in the treatment of mild to moderate depression, as effective as sertraline or other SSRIs, and have fewer side effects than standard antidepressants.[22, 23]

Adverse effects/safety considerations: Similar to the side effects of SSRIs, it may cause GI upset, rashes, headache, and photosensitivity. If taken concomitantly with SSRIs, it may interact and result in serotonin syndrome.

Drug interactions: SJW's ability to induce the cytochrome P450 system, particularly 3A4, -2C9, -2C19, and/or intestinal P-glycoprotein, reduces plasma concentrations of a variety of drugs, including the immunosuppressants cyclosporine and tacrolimus; antiretrovirals indinavir and nevirapine; antigcoagulants warfarin and phenprocoumon; cardiotonic digoxin; antiarrhythmics ivabradine and talinolol; calcium channel blockers nifedipine and verapamil; statins simvastin and atorvastatin; oxycodone; omeprazole; oral contraceptives; cancer drugs imatinib and irinotecan; benzodiapenes alprazolam, midazolam, and quazepam; and antidepressants buspirone, bupropion, and amitriptyline. It has been to shown to cause serotonin syndrome when combined with SSRIs (paroxetine, sertraline, venlafaxine, nefazodone) and receptor antagonists. It may also interact with fexofenadine, chlorzoxazone, lopinavir, methadone, and theophylline.[24]

Ginseng
There are different species of ginseng, and the following two are the most common:

American Ginseng (Panax Quinquefolium)

Purported uses: diabetes, cancer prevention and treatment, fatigue, immunostimulant, athletic performance, anti-aging

Asian Ginseng or Korean Red Ginseng (Panax Ginseng)

Purported uses: sexual dysfunction, cancer prevention, immunostimulant, stamina, cognitive function, diabetes, HIV/AIDS

Evidence to date: Limited studies have been conducted on ginseng's purported benefits. Its active constituents, ginsenosides, may modulate angiogenesis. American ginseng has been shown to reduce postprandial glucose levels in type 2 diabetes, but more research is needed.[25] A specific, standardized extract may shorten the duration of colds or acute respiratory tract infections when taken preventatively.[26] A recent pilot study suggests benefit in decreasing cancer-related fatigue but warrants more definitive research.[27]

Adverse effects/safety considerations: Possible adverse effects are mild and similar to placebo, including insomnia and GI complaints. Ginseng may have estrogenic actions and should be used cautiously by patients with hormone-sensitive cancers.

Drug interactions: American and Asian ginseng may reduce the effects of warfarin and increase the hypoglycemic effect of insulin and sulfonylureas.[25, 28] There are case reports of panax ginseng interacting with phenelzine.[9]

Black Cohosh (Cimicifuga Racemosa)
Purported uses: menopausal symptoms such as hot flashes, vaginal dryness, mood swings, dysmenorrhea

Evidence to date: Black cohosh may have estrogenic effects, relieve the vasomotor symptoms of menopause, and enhance bone formation. A number of randomized, double-blind, placebo-controlled trials have been conducted, and the evidence does not consistently establish efficacy. Some studies have suggested a benefit,[29, 30] but others have failed to show efficacy in comparison with placebo.[31, 32] Black cohosh in combination with SJW and other multibotanicals may provide benefit in alleviating climacteric complaints than alone.[33]

Adverse effects/safety considerations: GI discomfort. There have been case reports of possible hepatotoxicity associated, but no serious liver-related diseases were observed or reported in trials.[34]

Drug interactions: It may inhibit CYP2D6 and increase cytotoxicity of doxorubicin and docetaxel.[35]

Green Tea (Camellia Sinensis)
Purported uses: hyperlipidemia, hypertension, atherosclerosis, CVD, cancer prevention and treatment

Evidence to date: Green tea is abundant in polyphenols, such as flavanoids and phenolic acids. Flavanoids, including epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC), are referred to as catechins. These seem to be responsible for many of the proposed benefits of green tea and may confer cardiovascular protection by possibly increasing HDL cholesterol and decreasing LDL cholesterol and triglycerides.[36] One RCT showed a theaflavin-enriched green tea extract lowered LDL and total cholesterol.[37]

Population-based studies examining the association between green tea consumption and mortality have yielded inconsistent results but may have beneficial effects on hypertension and appears to be safe and well tolerated.[38] The possible chemopreventive effects of green tea have shown promise in preclinical studies but remain inconclusive. Results from observational studies on the association between green tea consumption and cancer of the digestive tract, lung, liver, and prostate are insufficient and conflicting.[39]

Adverse effects/safety considerations: Most of the adverse effects result from the caffeine content, such as GI upset, insomnia, and irritability. There have been case reports of liver problems associated with people taking multibotanical supplements with concentrated ethanolic green tea extracts and one case report of acute hepatitis associated with the use of a marketed green tea infusion.[40]

Drug interactions: Evidence is inconclusive, but green tea may inhibit CYP3A4. Green tea may inhibit the therapeutic efficacy of bortezomib and other boronic acid-based proteasome inhibitors.[41]

Valerian (Valerian Officinalis, Valeriana Radix)
Purported uses: insomnia, anxiety, mood disorders

Evidence to date: The active constituents, valepotriates, may have a sedative effect, and valerenic acid may activate gamma-aminobutyric acid (GABA) receptors, which are involved in sleep regulation. Most studies have not reported significant improvement in objective sleep outcomes and evidence for its use in insomnia management is inconclusive. However, a recent meta-analysis concluded that it may be effective for a subjective improvement of insomnia and considered for some patients, given its safety.[42] In regards to efficacy for anxiety, there is insufficient evidence.

Adverse effects/safety considerations: GI complaints, drowsiness

Drug interactions: There is little evidence of herb/drug interactions reported to date. Valerian may effect a modest increase in alprazolam but is unlikely to produce significant effects on CYP3A4 or CYP2D6 metabolic pathways.[43] Animal studies have shown valerian to enhance the sedation time induced by barbiturates.[44] It may have synergistic effects with benzodiazepines and other sedating agents.

Recommendations for Practice
It is important for NPs to be aware of current evidence-based interventions to answer patient questions and concerns honestly, knowledgeably, and safely. Upon assessment, be nonjudgmental and unbiased in attitude about a patient's choice to use supplements. By developing an open rapport, NPs enable patients to feel comfortable sharing information.

Ask your patients if they take any dietary supplements and prompt them for specific amounts and frequency. If you have patients on medication(s) and are uncertain about their interactions with a supplement(s), be sure to do further research or contact your pharmacist. Have patients bring their supplements (bottles, tubes, containers, packaging, etc.) to their visit. Also, make sure to document all information in the patient's record. The following questions should be helpful:

Which herbs/supplements are you taking?
Is the product USP verified or does it follow GMP guidelines?
Why are you taking it?
Who recommended you to take it?
When did you start?
Why did you start?
How often and how much are you taking?
Advise patients to stop taking herbs at least 7 days before any surgery. Avoid taking them altogether if pregnant or nursing. Advise patients to not take herbs and medications together or at the same time. Be alert to possible adverse effects and interactions with lab tests. Check the ingredients carefully for any possible allergens. Advise those patients taking dietary supplements to read and follow the label instructions. Don't exceed recommended dosages or take the herb for longer than recommended. Advise patients to ask any questions, particularly about the best dosage to take.


References
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