Study Points

Herbal Medications: An Evidence-Based Review

Course #98394 - $50 • 10 Hours/Credits

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  1. What percentage of adults in the United States used complementary/alternative medicine (CAM) in 2012?

    PREVALENCE OF HERBAL MEDICATION USE

    The desire to maintain and promote individual health has contributed to the prevalent use of natural health products, including herbal medications. In 2012, more than 3 out of 10 adults (33.2%) in the United States used complementary medicine approaches and 17.7% used natural products other than vitamin and mineral supplements [1]. In Canada, an estimated 18% of the population takes natural products other than vitamin and mineral supplements [4].

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  2. Which of the following statements regarding CAM and herbal medication (HM) use is TRUE?

    PREVALENCE OF HERBAL MEDICATION USE

    The desire to maintain and promote individual health has contributed to the prevalent use of natural health products, including herbal medications. In 2012, more than 3 out of 10 adults (33.2%) in the United States used complementary medicine approaches and 17.7% used natural products other than vitamin and mineral supplements [1]. In Canada, an estimated 18% of the population takes natural products other than vitamin and mineral supplements [4].

    Data from the National Center for Health Statistics (NCHS) indicate that supplement use among U.S. adults 20 years of age and older increased from 48.4% to 56.1% during the period 2007–2008 and 2017–2018, with use more common among women (63.8%) than men (50.8%) [5,6,7,8]. Nonvitamin, nonmineral natural products are the most commonly used category of CAM (17.7%), followed by deep breathing (10.9%), yoga, tai chi, and qi gong (10.1%), chiropractic care (8.4%), meditation (8.0%), and massage therapy (6.9%). The NCHS also found that approximately 12% of children 17 years of age or younger use some form of CAM [5]. Considering the aging of the "baby-boom" generation and increased incidence of chronic health issues, it is likely that the use of CAM, and HMs in particular, will continue to increase in this group. In 2017–2018, dietary supplement use increased with age, both overall and in both sexes, and was highest among women 60 years of age and older (80.2%). The most common types of dietary supplements used were multivitamin-mineral supplements, followed by vitamin D and omega-3 fatty acid supplements [8].

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  3. The prevalent use of HMs is particularly relevant to healthcare practice because

    PREVALENCE OF HERBAL MEDICATION USE

    The prevalent use of herbal medications is particularly relevant to medical practice for three main reasons. First, it is commonly and erroneously assumed by patients that by being natural the compound is intrinsically beneficial and devoid of adverse effects. Second, patients often neglect to report to their physicians and other healthcare providers that they are taking HMs, as they think that it is not relevant. Third, pharmacologic interactions between compounds, regardless of whether they are from herbal or conventional origin, may alter therapeutic efficacies and cause negative interactions or serious adverse effects.

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  4. Which of the following statements regarding the differences between HMs and conventional medications is TRUE?

    HISTORICAL OVERVIEW OF HERBAL MEDICATIONS IN NORTH AMERICA

    Chemical compounds extracted from plants, animals, or micro-organisms, either in raw or purified form, have been used to treat disease for centuries and even millennia. Many of these substances are essential therapeutic tools and widely used in conventional medicine. Aspirin, digitalis, reserpine, morphine, most antibiotics, and anticancer drugs, to name but a few, are perfect examples of the long historical transition between natural medications and mainstream or conventional Western medications. The introduction of new and more effective conventional medications, such as statins, a class of drugs that inhibit 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and effectively lower hyperlipidemia, and the antimalarial drug artemisinin, are pertinent examples of identification, extraction, and pharmaceutical application of natural compounds [14,15]. In fact, it has been estimated that approximately 25% to 50% of marketed drugs are derived from natural sources [16]. One review found that almost 50% of the new small-molecule drugs introduced between 1981 and 2002 were natural products or their chemical derivatives [15]. Consequently, the difference between NHPs/HMs and conventional Western medications is not solely or primarily based on the origin of the compound (i.e., natural versus synthetic) but rather on the process of scientific evaluation of the pharmacologic and biologic properties, toxicologic profile, and therapeutic efficacy of a particular compound prior to its approval for marketing. In Western countries, the process of approval of new conventional drugs is tightly regulated. It falls under the jurisdiction of the U.S. Food and Drug Administration (FDA) in the United States; in Canada, it is regulated by Health Canada.

    In the United States, herbal medications are considered dietary supplements and are regulated by the Dietary Supplement Health and Education Act (DSHEA) of 1994 [3]. Under this legislation, some claims, including structure and function, may be made by the manufacturer without requiring proof of safety and efficacy needed for conventional FDA-regulated medications. The product may be advertised as beneficial to maintaining or improving health of a particular organ or system, and the DSHEA states that the manufacturer is responsible for the safety of herbal products [3]. It is, however, the responsibility of the FDA to prove that an herbal compound is unsafe before a product is removed from the market [17]. This has been the case regarding the sale of dietary supplements, including HMs, containing ephedrine alkaloids (e.g., ephedra), which were prohibited in the United States by the FDA in April 2004 [18].

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  5. Which of the following contributes to the inaccurate and biased perceptions of the use of HMs?

    MEDICAL AND PATIENT PERCEPTIONS AND MISCONCEPTIONS ABOUT THE USE OF HERBAL MEDICATIONS

    The pharmacology, therapeutic properties, and toxicologic potential of herbal medications are often the object of inaccurate and biased assessment. Numerous factors contribute to this situation. In some cases, healthcare providers may have limited formal training in the area, which can result in a limited appreciation of the beneficial properties of some phytochemicals and of their potential health risks, including pharmacologic interactions with conventional medications [20]. A survey of community pharmacists in Texas showed that in spite of the fact that 70% of new patients use CAM, pharmacists rarely ask patients about CAM use. This is a particularly troublesome occurrence considering the role played by the pharmacist in assessing potential interactions with conventional drugs [21].

    A 2010 United Kingdom-based Drug and Therapeutics Bulletin (DTB) survey of 164 healthcare professionals, consisting mostly of hospital physicians and general practitioners, found that while a majority of physician participants (75.3%) considered HMs to be helpful in some circumstances, 72% indicated that the general public had misplaced faith in HMs and 86% felt the general public was poorly informed about HMs [22].

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  6. An estimated 40% to 70% of patients neglect to report HM use to healthcare providers. According to a review of the literature, the major reason for this failure to disclose CAM use is

    DISCLOSURE AND CLINICAL NEED TO IDENTIFY THE USE OF HERBAL MEDICATIONS

    As noted, an estimated 40% to 70% of patients fail to report the use of HMs to their physicians and other healthcare providers [5,11,13]. Some patients assume that reporting CAM use is not relevant because they are not mainstream medical products or procedures. In one literature review, the major reason for patients' failure to disclose the use of CAM was their concern of a negative reaction by the practitioner [11]. In the same study, lack of interest or assumed lack of knowledge by the medical practitioner were also reported among the main reasons for nondisclosure. This is supported by the 2010 DTB survey, which indicated physicians felt that their personal knowledge about HMs was "quite" or "very" poor (36.2% and 10.4%, respectively), and 89% conceded that their knowledge of herbal medications was "much poorer" than their knowledge of prescription drugs [22].

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  7. The concentration of active ingredients in HMs is affected by

    CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

    In North America, regulation of HMs is not as strict as that applied to conventional medications. In fact, good manufacturing practices applicable to food manufacturing are some of the only regulations in place to assure standards and quality control of dietary supplements [25]. The concentration of active ingredients in HMs, however, is affected by numerous factors, including [11,26,27,28]:

    • The correct identification of the botanical source

    • The presence of contaminants or substitution of the intended source or other plants of lower cost with potential toxicologic consequences

    • Growing conditions, including temperature, geography and time of harvest, and possible contamination with micro-organisms, heavy metals, pesticides, or prescription drugs

    • Collection of the appropriate plant part (e.g., leaves versus root)

    • Preparation of specimens (e.g., drying, grinding)

    • Laboratory processing (e.g., solvent used for extraction of active ingredients)

    • Storage

    • Formulation of the final product (e.g., liquid versus solid pill)

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  8. Which of the following statements regarding pharmacokinetics is TRUE?

    CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

    Pharmacokinetics is the study of the effects exerted on drugs by the body, namely the processes of drug absorption, distribution, biotransformation, and ultimate elimination of drugs and their metabolites. All drugs ingested for nutritional, therapeutic, preventive, or diagnostic purposes, regardless of being of natural or synthetic origin, undergo processes of absorption and eventual distribution throughout body tissues and systems prior to reaching their molecular target. Drug distribution does not occur homogeneously throughout the body. Effective availability and concentration of a drug in different organs and tissues is influenced not only by the chemical properties of the drug (e.g., molecular size, electrical charge, ability to bind to plasma proteins, affinity for transporters that will carry the drugs across cell membranes) but also by the anatomic and histologic properties of the tissues themselves (e.g., degree of vascularization and type of capillaries present, including the tightly sealed blood-brain barrier).

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  9. Herb-drug interactions

    CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

    The complex composition of HMs can, in principle, become the source of various interactions. Multiple chemical compounds can interact either synergistically (i.e., increase the activity of one or more of its chemical constituents) or antagonistically (i.e., decrease the activity of one or more of its components). Furthermore, herbal remedies may include complex mixtures of several herbs, thereby significantly increasing the number of active compounds in the preparation. This makes it particularly difficult to ascertain which of the chemicals is pharmacologically responsible for a particular biologic event. The co-administration of HMs and conventional drugs further increases the possibility of interactions, which can be manifested during experimental conditions or clinically.

    Herb-drug interactions apparently occur less frequently and are less serious than drug-drug interactions. This is due to the weaker potency of the herbal medications; however, interactions and adverse events may also be under-reported and relevant information may not be collected [35,36].

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  10. Adverse effects caused by HMs

    CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

    As discussed, the pharmacologic properties of HMs and their interactions with prescription drugs can cause adverse effects, also known as adverse drug reactions, and have the potential to cause toxicologic effects. The reporting of adverse effects is the most important tool in post-marketing drug surveillance and accounts for 60% of the data used for adverse effects assessment [54,55]. In the United States, the FDA has the FDA Adverse Event Reporting System (FAERS). Adverse event reporting for dietary supplements, including HMs, should be directed to FDA's MedWatch. The equivalent agency in Canada is the Canada Vigilance Adverse Reaction Online Database. Reports should be made to MedEffect Canada. An adverse events reporting system, Natural MedWatch, has also been established by the Therapeutic Research Faculty, an independent publisher of evidence-based recommendations for pharmaceuticals (Resources).

    In both the United States and Canada, adverse effects can also be reported to the manufacturer. In turn, the manufacturer should submit all the collected information to the regulatory agencies. The efficiency of this latter process, however, has been the subject of lengthy debate.

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  11. Toxicologic effects of HMs can result from

    CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

    Systematic analysis of the evidence-based toxicologic properties of HMs is scarce. Toxicologic effects of HMs can result from:

    • Administration of a high dose of an HM and consequent abnormal exacerbation of the intended therapeutic effect or occurrence of a toxic effect unrelated to the original therapeutic effect

    • Adulteration of the product either by contamination with other plants or with prescription medications illegally included in the product

    • Interactions with conventional drugs or other HMs

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  12. In the United States,

    HERBAL MEDICATIONS: REGULATORY ASPECTS

    If approved, human studies of the investigational new drug (IND) can be initiated. At the institutional level, interdisciplinary review boards are responsible for assuring the ethical and scientific integrity of the clinical trials.

    Clinical studies are conducted in four stages or phases (I, II, III, and IV). Phase I is aimed at establishing drug safety, dosage, and pharmacokinetic properties of the drug (e.g., half-life, metabolism). These are open or nonblind studies, in which both investigators and healthy subjects (25 to 100) know what is being administered. Results of human studies are compared with animal studies.

    The goal of Phase II is to study the effect of the drug on volunteer patients (100 to 200) with the disease for which the drug was developed. Subjects will either receive the drug, a placebo (negative control), or the standard drug (positive control) used in the treatment of the disease. Further toxicologic studies in animals will continue to assess chronic toxic potential.

    Finally, in Phase III, double-blind or cross-over studies are conducted to further evaluate the efficacy of the drug in larger groups of thousands of patients. When Phase III is finished and if the results meet the goals initially established, a new drug application (NDA) will be submitted to the FDA or its congener in another country. After several years of preclinical research, four to six years of clinical trials, and as many as three years after the NDA has been submitted, the FDA may then approve marketing of the drug. At that point, Phase IV is initiated and a mechanism of post-marketing surveillance, including reporting of adverse effects, will be in place.

    Compared with this elaborate process of approval, the mechanisms required for the marketing of HMs are extremely simple. To start, in many Western countries, including the United States and Canada, herbal medications are not legally considered drugs, but rather as dietary supplements and natural health products, respectively. Consequently, HMs are not legally required to undergo extensive preclinical investigation, and clinical trial evaluations are not required prior to the marketing of the herbal product. Rather, approval is based on traditional usage.

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  13. All of the following are measures that contribute to an evidence-based approach to HMs, EXCEPT:

    SCIENTIFIC EVALUATION OF HERBAL MEDICATIONS

    The number of scientific studies aimed at unraveling the mechanism of action of HMs has undergone a remarkable growth in recent decades. Development of new legislation, availability of research funds to study the pharmacologic mechanisms of action and therapeutic efficacy of HMs, drug standardization, and implementation of clinical trials to assess HMs have played a central role in the development of an evidence-based approach to phytotherapeutics. The NCCIH in the United States and the NNHPD in Canada are pivotal in establishing advisory panels, coordinating scientific resources and expertise, and funding quality research on HMs [64,66]. The American Society for Pharmacology and Experimental Therapeutics has long supported the increase in the National Institutes of Health's NCCIH budget for peer-reviewed research on botanical medications, particularly aimed at studying mechanisms of action and interactions with prescription drugs [67].

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  14. Batch-to-batch variability of HMs is

    SCIENTIFIC EVALUATION OF HERBAL MEDICATIONS

    Standardization of the product and its individual chemical constituents is of major importance, and reliability of practices and procedures by the manufacturer is absolutely crucial. Several reports have analyzed the concentration of active ingredients present in herbal medications and compared the values obtained with those reported on the label by the manufacturer. Batch-to-batch variability has also been reported, and in one particular case of a compound containing ephedrine and methyl ephedrine, concentration of these substances varied by 180% and 1,000%, respectively [68].

    The lack of standardization may also account for negative results obtained in some clinical trials [69]. One study revealed that, in the case of the antidepressant SJW (Hypericum perforatum), the amount of two of its most important chemical constituents, hypericin and pseudohypericin, can vary from 108% to 30% or even to as little as 0.1% of the amount reported on the label when a chemical analysis is conducted in a large number of samples from various manufacturers [70].

    More reassuring results have been reported. The chemical composition of five of the most commonly used HMs was studied, and these results were compared to the information provided in the label by the manufacturer [71]. Results of this study, conducted by the University of California, Los Angeles (UCLA) Center for Human Nutrition, are encouraging and reflect a positive trend in increased quality and standardization of HMs by the manufacturers. For each product, three different samples from each of 12 bottles (6 bottles for each of the two separate batches) were collected. Five of the most commonly used HMs in North America were studied, specifically saw palmetto, SJW, echinacea, ginkgo biloba, and kava. Samples were purchased from 8 to 10 different suppliers nationally available in the United States. A greater consistency of composition was observed for samples purchased over the counter than for those purchased by mail order. A drastic decrease in variability of the marker compound was observed between batches; saw palmetto and SJW were the least variable, and the most variable were ginseng and echinacea [71].

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  15. Saw palmetto

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    The beneficial effects of standardized liposterolic extracts (phytosterols) in the treatment of BPH are now well established. The extracts represent 85% to 95% of free fatty acids from saw palmetto berries. Although the mechanism of action of saw palmetto is not completely understood, both in vitro and in vivo studies have revealed that the beta-sitosterol component of the extract correlates with its efficacy in the treatment of BPH [80,81,82]. Saw palmetto inhibits 5-alpha-reductase, the enzyme responsible for the transformation of testosterone into dihydrotestosterone (DHT), its tissue-active form [82,83]. This mechanism of action is similar to the one described for finasteride and dutasteride [34,82,84]. It should be noted, however, that finasteride only inhibits the type 1 isoform of 5-alpha-reductase responsible for the production of different testosterone metabolites in the tissues, whereas saw palmetto inhibits both type 1 and type 2 isoforms [82,85].

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  16. St. John's wort does NOT inhibit synaptic reuptake of

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    The pharmacologic mechanisms of action of SJW extracts relevant to its antidepressant effect are complex. Hypericin may have a minor role in MAO inhibition, a mechanism shared with the classical antidepressant phenelzine [82]. This mechanism, however, is not considered clinically significant because it is only observed at concentrations 100 times higher than those used to treat depression [33]. Hyperforin is generally agreed to be the active component [82]. Both hypericin and hyperforin inhibit synaptic reuptake of serotonin, which is the same action as fluoxetine and paroxetine, but they also inhibit the reuptake of dopamine and noradrenaline, like other antidepressants including venlafaxine [82,116].

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  17. Clinical trials of ginkgo biloba

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    There is scientific evidence supporting the beneficial use of standardized ginkgo biloba extract, 120–240 mg/day, in the treatment of mild-to-moderate cognitive impairment, such as age-related dementia, multi-infarct dementia, and possibly Alzheimer disease [33,157,158,159]. Some studies show that ginkgo biloba extract is as effective as the acetylcholinesterase inhibitor donepezil (Aricept) in the treatment of patients with early stages of Alzheimer disease, although these findings are not supported by additional studies [160]. One study reported that the combination therapy of gingko biloba extract plus donepezil was more effective than either therapy alone [161]. A 2015 systematic review noted a positive response (defined as improvement in cognitive function and activities of daily living and reduced neuropsychiatric symptoms) to a 240 mg/day dose in study participants with neuropsychiatric symptoms related to a dementia diagnosis but not in individuals thought to have Alzheimer disease [159]. Although studies have shown that ginkgo biloba extract appears to be safe and with no excess side effects compared with placebo, the evidence that it has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent, and whether ginkgo biloba leaf extract is beneficial for the treatment of Alzheimer disease remains controversial. Researchers recommend that the findings be confirmed by larger clinical trials [33,162,163,164,165,166,167,168].

    Clinical trials have assessed the effectiveness of ginkgo biloba extract in the treatment of cerebral insufficiency, which is a syndrome combining mild cognitive impairment, headaches, confusion, poor concentration, fatigue, and dizziness, and is associated with mood disorders. Long-term treatment with ginkgo biloba extract at 120–150 mg/day reduced symptoms and improved short-term memory [169,170].

    Some evidence supports the effectiveness of ginkgo biloba extract in the treatment of peripheral vascular disorders, including intermittent claudication and, to a lesser degree, Raynaud syndrome [33,171]. In fact, one clinical trial demonstrated that ginkgo biloba extract is as effective as pentoxifylline, the standard medication for the treatment of intermittent claudication [172]. Despite its ability to improve circulation, multiple clinical trials failed to show the efficacy of ginkgo biloba extract in the treatment of Raynaud disease compared with conventional therapy or placebo [173,174]. One analysis concluded that while ginkgo biloba treatment did slightly increase treadmill walking time of participants with peripheral artery disease and led to a slight reduction of pain, the therapy produced only modest overall improvements [175].

    The beneficial effects of ginkgo biloba extract in a variety of medical conditions, such as tinnitus, cochlear disorders, and vascular retinopathies (including macular degeneration), have also been reported in the scientific literature, although larger studies are required to confirm the clinical outcome. It is possible that in these conditions, ginkgo biloba extract is the most effective when administered in conjunction with standard therapies.

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  18. In regard to adverse effects and toxicology, ginkgo biloba

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Consistently, ginkgo biloba extract is considered a safe and well-tolerated drug when used at the recommended dose for periods of up to six months. In most clinical studies, the incidence of adverse effects is similar to placebo. Less than 2% of patients develop side effects, namely headache, nausea, or mild gastrointestinal symptoms [51]. Two cases of subarachnoid bleeding have been reported in patients taking ginkgo biloba extract and warfarin, and one case of subarachnoid bleeding and intraocular hemorrhage has also been reported in a patient taking ginkgo biloba extract and acetylsalicylic acid concurrently. A case of postoperative bleeding has also been reported after laparoscopic surgery [176]. In these cases, however, the causal relationship between ginkgo biloba extract and bleeding was not clearly established. Furthermore, bleeding was not reported in any of the clinical trials involving hundreds of thousands of subjects [51]. Nonetheless, it is advisable to discontinue ginkgo biloba extract administration several days prior to surgery [82].

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  19. Which of the following statements regarding ginseng is TRUE?

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    The name Panax is derived from the Greek panacea, meaning cure-all. True to its etymology, the root of the plant has been historically used for a variety of purposes, such as improvement of cognitive and physical performance (i.e., ergogenic effect), cardiovascular diseases (e.g., hypertension), diabetes, cancer, immunomodulation, and menopause. Evidence-based knowledge regarding ginseng's medicinal properties is limited and has generally failed to support historical claims, possibly with the exception of clinical trials assessing the hypoglycemic properties of ginseng [33,178,179,180,181,182].

    Several chemicals, including polysaccharides (e.g., ginsan, ginsenans) and a variety of saponins known as ginsenosides, are found in ginseng [82]. Ginsenosides, the most important bioactive compounds, are complex molecules with a steroidal skeleton and modified side chains. The concentration of different ginsenosides varies among species, age of plant, and season of harvest and contributes to the limited understanding of the pharmacologic and physiologic properties of each compound [82]. Adulterants are commonly found in ginseng preparations due to the high cost of authentic ginseng roots, and the presence of natural methylxanthines also may contribute to some reported physiologic effects [82].

    Ginsenosides Rb1, Rg1, and Rg2 improve cognitive performance, a mechanism likely related to the stimulation of cholinergic activity implicated in the mechanisms of learning and memory [82,183,184]. Both in vitro and in vivo models of Parkinson disease have shown that ginseng extracts have a neuroprotective effect against 1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in rodents [185]. Gintonin, a novel glycolipoprotein, is a ginseng derivative found in the root of Korean ginseng [186]. Gintonin holds lysophosphatidic acid (LPA), a serum phospholipid that stimulates cell proliferation, migration, and survival [186,187,188]. It is thought that gintonin causes significant elevations in levels of intracellular calcium that promote calcium-mediated cellular effects. Research suggests that gintonin has antioxidant and anti-inflammatory effects against different models of neurodegeneration [186,187,189]. In studies of neurodegenerative diseases, such as Alzheimer disease and Parkinson disease, gintonin has demonstrated neuroprotective activity by providing action against apoptosis- and oxidative stress-mediated neurodegeneration [186,187,189]. In vitro and in vivo studies have demonstrated that ginseng polysaccharide GH1 and ginsenosides Rb2 and Re effectively reduce hyperglycemia and liver glycogen in genetically obese mice as well as in patients with and without type 2 diabetes [178,190,191]. Ginseng also stimulates insulin synthesis and release, an effect possibly caused by the increase in nitric oxide production by ginseng [192]. Preliminary results suggest that ginseng also regulates intestinal absorption of glucose and glycosylation of hemoglobin A1c (HbA1c) [179]. A variety of studies (human, animal, cell) have shown that different processed ginseng extracts and specific ginsenosides possess beneficial effects on type 2 diabetes. Most studies of individual ginsenosides have focused on Rb1, Re, or Rg1 as these are the main components of ginseng and easily obtained. However, their large molecule structure results in poor systemic bioavailability. It is thought that these large-molecule ginsenosides may be a form of storage for saponins in ginseng plants rather than the active form in vivo. The smaller molecule ginsenosides (Rg3, Rh1) may be the ingredient that exerts therapeutic effects [193,194,195].

    In vitro studies have shown that ginsenosides cause vasodilation and lower blood pressure and that panaxynol, a potent inhibitor of thromboxane A2, prevents platelet aggregation [196,197]. However, further scientific evidence of the antihypertensive effects of ginseng is required prior to considering its potential benefits in cardiovascular diseases. One double-blind controlled trial found that ginseng significantly improved arterial stiffness and systolic blood pressure but had no noted effect on diastolic blood pressure [198]. Research challenges to understanding the potential benefits of ginseng in cardiovascular disease include understanding and identifying the distinct cardiovascular properties of the different ginsenoside compositions, identifying what likely are multifaceted mechanisms that account for the effects of the distinct compositions, and determining which ginsenosides mediate which cardiovascular properties [199].The immunostimulatory and antiproliferative properties of ginseng have also been reported in the scientific literature, but further studies are required [200]. Ginseng has been studied for use in the treatment of menopause symptoms, due to the steroid-like chemical composition of ginsenosides, but the results were inconclusive.

    A Cochrane Review has concluded that the beneficial effects of ginseng preparations were "not established beyond reasonable doubt" [184]. Other literature reviews, however, have reported that ginseng extracts effectively reduced blood glucose levels in patients with type 2 diabetes, although information regarding dosage and long-term effects is still incomplete [33,179,201]. A modest improvement in cognitive performance has also been reported [33,179]. Ginseng is also being investigated for use in the treatment of chronic fatigue, respiratory tract infections, stroke, dermatologic diseases, and as an adjuvant to chemotherapy in the treatment of non-small-cell lung cancer [202,203,204,205,206,207,208].

    Ginseng preparations are generally well tolerated when administered within the recommended dosage, and the available animal and human studies suggest that it is safe [82]. As a result of its hypoglycemic properties, it should be used cautiously in patients with type 2 diabetes concurrently treated with oral hypoglycemic drugs. Improvements in blood glucose measures and glycemic control with ginseng use have been inconsistently reported [82].

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  20. Echinacea is

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    The designation echinacea applies to several plants of the Asteraceae/Compositae family, including E. angustifolia, E. pallida, and E. purpurea. Echinacea, also known as coneflower, narrow-leafed cone-flower, or black-eyed Susan, is indigenous to North America. It adapts well and thrives in temperate climates, including Europe and Asia, where it has been planted for decorative and medicinal purposes.

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  21. In regard to adverse effects, echinacea

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    In clinical trials, echinacea preparations are generally well tolerated, and the number of patients dropping out of studies is similar to the placebo group. A single study conducted in children 2 to 11 years of age reported the occurrence of an allergic rash [226]. In adults, one review found that the most common adverse effects were nausea and vomiting (<1%), abdominal pain (<1%), and mild drowsiness and headache (<1%) [33]. One case of anaphylaxis has been reported in a patient with a history of atopic reactions [227]. Echinacea should not be administered to individuals with allergies to other plants of the Asteraceae family, including daisies, ragweed, marigolds, and chrysanthemums. It is also recommended to avoid echinacea if currently on immunosuppressants [82].

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  22. Kava

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    In clinical trials, the side effects of kava preparations were rare and mild, with gastrointestinal discomfort, restlessness, headache, and dizziness reported in about 2% of patients. Kava dermatitis, a yellow discoloration of the skin accompanied by scaly dermatitis, is only observed in chronic heavy kava drinkers and reverses after discontinuation of kava administration. This skin condition resembles pellagra but is resistant to niacin treatment [82]. Neurotoxicity, pulmonary hypertension, and choreoathetosis have also been reported in chronic heavy drinkers in the Australian Aboriginal population [241]. A few rare cases of kava-induced Parkinson-like extrapyramidal disorders have been reported, as well as the aggravation of existing Parkinson disease in one patient and one case in the United States of rhabdomyolysis related to the ingestion of a large amount of kava [51,235]. There are some reports suggesting that kava may cause severe and, in some cases, irreversible liver damage. As a result, the FDA issued an advisory letter to healthcare professionals stating possible health risks [242].

    Kava extracts interact with and potentiate the effects of anxiolytic and depressant drugs, such as benzodiazepines, barbiturates, and alcohol. Due to its antiplatelet properties, kavain-containing preparations should not be administered to patients undergoing anticoagulant therapy, although the clinical relevance of this potential interaction has not been established. Kava preparations should also be avoided in patients with extrapyramidal disorders, including Parkinson disease. Finally, due to the potential hepatotoxicity, kava should not be administered to patients with liver disease or those treated with potentially hepatotoxic medications such as acetaminophen, anabolic steroids, or the anticancer agent methotrexate [33,82,243]. As a precautionary measure, kava should not be administered during pregnancy and lactation due to the lack of safety studies [82]. Kava administration should be discontinued at least 24 hours prior to surgery because of possible potentiation of the sedative effect of anesthetics [244].

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  23. Garlic extracts

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Several clinical trials have reported that garlic lowers total cholesterol levels by 8% to 15% [257,258]. This effect results from the lowering of the low-density lipoprotein (LDL) and triglycerides, while the high-density lipoprotein (HDL) values remain unchanged. A meta-analysis confirmed that, after 10 to 12 weeks, garlic lowers plasma cholesterol, although the benefits (4% to 6%) were less pronounced than previously reported, and this effect was not statistically significant after a six-month period [259]. In 2001, an extensive meta-analysis of 34 randomized clinical trials including almost 2,000 patients confirmed the previous assertions [260]. A meta-analysis of 26 studies found that, overall, garlic is superior to placebo in reducing serum total cholesterol and triglyceride levels [261]. Compared with placebo, serum total cholesterol and triglyceride levels in the garlic group were reduced by 0.28 mmol and 0.13 mmol, respectively. Garlic powder and aged garlic extract were more effective in reducing serum total cholesterol levels; garlic oil was more effective in lowering serum triglyceride levels. Garlic did not lower LDL cholesterol, HDL cholesterol, apolipoprotein B, or the total cholesterol/HDL ratio [261]. Results of a 2018 meta-analysis found that garlic can reduce total cholesterol and LDL levels, but not HDL and total triglyceride levels [262]. In conclusion, garlic preparations are moderately effective in lowering LDL and triglycerides and do not change the HDL concentration in the plasma [33].

    The effects of garlic on blood pressure have been studied in several clinical trials. Some studies have shown a small (6%) yet statistically significant effect, although these findings were not replicated by other studies [33]. Garlic is not recommended for the management of hypertension [82,263].

    Garlic has also been shown to inhibit platelet aggregation, as expected by its inhibitory effects on cyclooxygenase and prostaglandin synthesis. The effective dosages are not well established, and comparison with other antiplatelet aggregation drugs is not yet available. Because several reports have associated garlic with bleeding accidents, administration should be limited to lower dosages and co-administration with drugs that affect hemostasis, including antiplatelet aggregation drugs (e.g., aspirin) or anticoagulants (e.g., warfarin), should be avoided [33,144].

    Some clinical studies suggest that garlic preparations slow the progression of atherosclerotic plaques [264]. Although encouraging, these results are preliminary and further studies are required [82].

    The anticancer properties of garlic compounds have been reported both in vitro and in vivo, but their clinical effectiveness remains to be established [265]. One small trial in mice showed that garlic extract inhibits growth of certain cancer cells, particularly multiple myeloma. Researchers indicated that the reduced proliferation of cancer cells is at least partly mediated by increased endoplasmic reticulum stress [265]. Another small trial with mice indicated that anticancer properties of garlic are more effective when introduced directly to the cancer cells by injection rather than via oral ingestion [266]. Epidemiologic studies suggest that regular consumption of garlic may be associated with a lower risk of developing gastric and colorectal malignancies [267]. A review of 14 studies of the anticancer properties of garlic and onion supports this association [249]. While the results of one systematic review and meta-analysis suggest a significant inverse correlation between the intake of garlic and the risk of gastric cancer, an analysis of health claims provided to the FDA found no credible evidence supporting the use of garlic for prevention of gastric cancer or breast, lung, or endometrial cancers [261,268]. Although the epidemiologic evidence is cautiously positive, well-designed clinical trials are needed before a conclusion can be reached [269].

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  24. For patients taking garlic, the highest risk of herb/drug interaction is with

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    The most common adverse effects reported are bad breath and body odor [82]. Less commonly, dyspepsia and flatulence are also reported. In rare cases, dermatitis and respiratory difficulty can occur in hypersensitive patients [51]. The highest risk of herb-drug interaction is between garlic and anticoagulant drugs, such as the vitamin K inhibitor warfarin, and antiplatelet aggregation agents, such as ticlopidine and clopidogrel, and results from the pharmacodynamic potentiation of mechanisms of action [144].

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  25. Valerian use

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Historical documents from ancient Greece, China, and India widely report the use of preparations from valerian root and rhizome in the treatment of insomnia and anxiety. This herb, native to Asia and Europe, is found throughout the world. Topically, it has been used in the treatment of acne and wound healing. It has also been used traditionally for the treatment of a variety of disorders, including digestive problems, flatulence, congestive heart failure, urinary tract disorders, and angina pectoris. For the past 200 years, valerian has been widely used in Europe and North America for its mild sedative properties [37,51].

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  26. Andrographolide, a compound found in Andrographis paniculata, has been shown to

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    In vitro studies revealed that andrographolide has anti-inflammatory, antiapoptotic, and immunomodulatory properties. In vivo studies demonstrated that both DA and DDA effectively lower blood pressure, decrease heart rate, and cause vasodilation [287]. DA and DDA block calcium channels, increase nitric oxide synthesis, and inhibit ß-adrenergic receptors. All of these actions provide the mechanistic explanation for the hypotensive properties of andrographis [287].

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  27. Andrographis paniculata may be taken for as long as

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Usually, 300 mg of standardized preparations of andrographis (4% andrographolides) is taken four times per day, for as long as two weeks [33].

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  28. English ivy leaf (Hedera helix)

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    English ivy (Hedera helix), also known as common ivy, is an evergreen climbing vine. It is native to Europe and Central Asia, grows easily, and is commonly found in humid environments and in forests. It is often used for decorative purposes. It is different from ground ivy (Glechoma hederacea) and American ivy (Parthenocissus quinquefolia). It is particularly important not to confuse it with poison ivy (Rhus toxicodendron).

    The glossy and dark green leaves of common ivy have been traditionally used for the treatment of a wide variety of disorders, including respiratory disease, arthritis, fever, burns, and infections. It is now used as an expectorant and in the treatment of bronchitis and asthma [51].

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  29. Peppermint oil has a demonstrated dose-related

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Peppermint oil is complex and highly variable, with more than 100 components isolated from the oil. Relative concentrations vary depending on climate, cultivar, and geographic location. Peppermint yields 0.1% to 1% of volatile oil composed primarily of menthol (29% to 48%), menthone (20% to 31%), and menthyl acetate (3% to 10%) [82]. Menthol is rapidly absorbed following oral administration, and elimination is mainly via bile [82,307]. Peppermint oil has a demonstrated dose-related antispasmodic effect on gastrointestinal smooth muscle, attributed to calcium channel blockade [82,310,311]. It reduces intragastric pressure, phasic contractility of the proximal stomach, and appetite, with negligible effects on gastric sensitivity, tone, and nutrient tolerance in health [309].

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  30. Chamomile

    EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

    Allergic reactions to chamomile are commonly reported and may be dependent on the route of ingestion. Hypersensitivity reactions include anaphylaxis, dermatitis, gastrointestinal upset, lacrimation, and sneezing. The dried flowering heads may induce vomiting in large amounts. Eye drops containing chamomile have caused allergic conjunctivitis [82]. Chamomile may potentiate the anticoagulant effects of warfarin. No coagulation disorders have been reported, but close monitoring of patients on anticoagulants is advised. In vitro, chamomile has been shown to be bactericidal to some Staphylococcus and Candida species [365]. Chamomile is considered safe by the FDA, but it should be used with caution in individuals who are allergic to ragweed, as cross-allergenicity may occur. Symptoms include abdominal cramping, tongue thickness, tight sensation in the throat, angioedema of the lips or eyes, diffuse pruritus, urticaria, and pharyngeal edema [366,367].

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