Evidence-Based Review of the Most
Commonly Used Herbal Medications
Considering the large number of available HMs, it is beyond the scope of this course to attempt to exhaustively review them all. Ten of the most commonly sold HMs in North America will be reviewed following an evidence-based assessment of several parameters relevant to clinical practice. For each phytomedicine, the following subjects will be presented:
Common name and scientific name
Historical and current us
Evidence-based therapeutic use and effectiveness
Adverse effects and drug interactions
The therapeutic effectiveness of each medication is based on published scientific data regarding in vitro and in vivo studies of the mechanism of action and clinical studies, including randomized clinical trials, clinical studies, and meta-analyses. Accordingly, each herbal product is ranked into one of the following four categories:
8HHVV*** E: Clinically Effective – demonstrated by multiple randomized clinical trials
**E: Clinically Beneficial – demonstrated by several controlled clinical trials, although some studies show conflicting or inconclusive results
*E: Limited effectiveness – demonstrated by controlled clinical trials
No E data: Nonexistent or minimal supporting scientific evaluation
Product safety guidelines follow the same general rules applicable to mainstream drugs, and use during pregnancy, lactation, and childhood should be restricted to compounds tested for teratogenicity, carcinogenicity, and general toxicity. Otherwise, it is not advisable for the patient to be exposed to an untested HM. As a guideline, a product is ranked as:
AEs/DIs : Reported adverse effects and/or drug interactions
No Sdata: Unknown or limited controversial safety data
Common Name and Scientific Name
Saw palmetto (Serenoa repens or Sabal serrulata) is also known as American dwarf palm or cabbage palm. This abundant and scrubby palm is indigenous to Florida and other southeastern states of the U.S.
Historical and Current Use
Saw palmetto berries collected in the autumn were used by southeastern Native Americans in the treatment of urinary disorders and as an antiseptic. Saw palmetto extracts are now used in the treatment of BPH. In several European countries, use of this herb has been approved for the treatment of mild-to-moderate BPH. In Germany and Austria, saw palmetto is the most common form of therapy for BPH and represents more than 90% of all drugs prescribed for the treatment of this disorder [174; 221].
The beneficial effects of standardized liposterolic extracts (phytosterols), which represent 85% to 95% of free fatty acids from saw palmetto berries, in the treatment of BPH are now well established. Both in vitro and in vivo studies revealed that the beta-sitosterol component of the extract correlates with its efficacy in the treatment of BPH [17; 18]. Saw palmetto inhibits 5-alpha-reductase, the enzyme responsible for the transformation of testosterone into dihydrotestosterone (DHT), its tissue-active form [11; 88; 212]. This mechanism of action is similar to the one described for finasteride and dutasteride [32; 159; 227]. 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 .
Other pharmacological mechanisms of action of saw palmetto have been reported in the literature, namely that it competes with DHT and blocks androgen receptor stimulation, although this mechanism does not seem to correlate with its clinical efficacy . In vitro, saw palmetto extracts have alpha-1 adrenoceptor blocking properties like the standard drug tamsulosin, albeit this mechanism does not seem to account for saw palmetto’s therapeutic effects as it is not observed at the lower concentrations, which are equivalent to the doses used in humans . Interestingly, saw palmetto also inhibits cell proliferation and promotes apoptosis (i.e., programmed cell death) of prostate cancer cells, and its anti-inflammatory properties have been linked to its inhibitory actions on cyclooxygenase and lipoxygenase [15; 165; 213]. Together, all of these mechanisms may synergistically contribute to the therapeutic efficacy of saw palmetto extracts.
Use and Effectiveness
The clinical effectiveness of saw palmetto in the treatment of mild-to-moderate BPH has been extensively studied. In 2002, a comprehensive review of clinical studies that assessed the efficacy of saw palmetto versus placebo and saw palmetto versus finasteride was published by Wilt, Ishani, and MacDonald . Results from 21 clinical trials, with a total of more than 3000 patients, were analyzed. Several clinical parameters were evaluated, including urinary symptoms (dysuria, fullness, bladder residual volume), nocturia, urine flow rate, and prostate size (Boyarsky, American Urologic Association Score, and International Prostate Symptom Score). The authors concluded that, “men taking saw palmetto were nearly twice as likely to report improvement in symptoms than men taking placebo” . Also, “when compared to finasteride, saw palmetto provided similar responses in urologic symptoms and flow measures and was associated with a lower rate of impotence” . This review, however, lacks information regarding comparisons between saw palmetto and alpha-1 adrenoceptor antagonists such as tamsulosin.
A large study of more than 2500 patients suffering from mild-to-moderate BPH compared the effectiveness of saw palmetto versus tamsulosin (704 patients), saw palmetto versus finasteride (1098 patients), and two different doses of saw palmetto (160 mg twice a day versus saw palmetto 320 mg once a day) . The study demonstrated a better outcome for patients taking saw palmetto than those taking either of the conventional drugs. Also, unlike the conventional drugs, no negative impact on sexual function was reported by patients treated with saw palmetto. These results further support other well-conducted studies [24; 25; 32; 50; 51; 58; 73; 79]. Interestingly, saw palmetto was less effective than finasteride in reducing prostate volume, although involution of the prostate epithelium and reduction of inflammation was observed [141; 227]. Co-administration of saw palmetto and finasteride did not improve the treatment outcome.
A report by Bent and colleagues that failed to observe saw palmetto efficacy may be attributable to the study being conducted in patients with moderate-to-severe BPH, as opposed to the beneficial effects on patients with a mild-to-moderate condition . In addition to the population cohort difference, the study also failed to conduct an appropriate dose-response study or raise the dose of saw palmetto to adjust for the severity of the medical condition.
In conclusion, evidence demonstrates that saw palmetto is effective in the treatment of mild-to-moderate BPH, is less expensive, and is better tolerated than conventional medications [25; 83]. In addition, it is now well established that saw palmetto does not interfere with the laboratory measurements of prostate specific antigen (PSA), used to assess the progression of prostate cancer [88; 190]. This presents a considerable advantage over 5-alpha-reductase inhibitors finasteride and dutasteride, which are known to mask PSA readings and prevent an accurate assessment of the disease progression and concurrent development of prostate cancer [88; 190]. The efficacy of saw palmetto in the treatment of more severe BPH has not been established.
Saw palmetto has also been used to treat other genitourinary disorders, including chronic prostatitis. However, clinical studies have shown a lack of significant improvement in patients treated with saw palmetto for 1 year, contrasting with the benefits observed in the group treated with finasteride [83; 109].
It has also been advocated that saw palmetto, either alone or in conjunction with other nutraceuticals, may also play an important role in the prevention of BPH, although the results obtained are inconclusive . The effects of chronic saw palmetto administration on the organization of chromatin structure in patients with BPH provides an insight of the molecular effects of saw palmetto potentially relevant to gene expression and tissue differentiation .
Adverse Effects and Drug Interactions
Consistently, all studies revealed the absence of significant side effects. A 2008 meta-analysis of saw palmetto trials found that serious adverse effects (e.g., cancer, sexual dysfunction, hepatoxicity, and respiratory problems) were no more common in treatment groups than in placebo groups . Gastrointestinal symptoms, including nausea or abdominal pain, may occur in less than 2% of patients but seem to decrease when doses are taken with a meal. Because of its antiandrogenic properties, women should not take saw palmetto for treatment of urogenital problems if they take contraceptives, hormone replacement therapy, have breast cancer, or are pregnant . Furthermore, there is no clinical evidence supporting a beneficial effect of saw palmetto in the treatment of urethritis in women. Interactions with anticoagulants are negligible and arise from a single reported case . In clinical trials, 3% of the subjects developed hypertension, compared to 2% treated with finasteride; however, this difference was not statistically significant .
Saw palmetto is widely considered a safe phytomedicine, and no serious toxicological effects are reported in the scientific literature .
Standardized lipophilic extracts of saw palmetto are administered at a dose between 100–400 mg twice daily for the treatment of BPH [159; 174; 227]. A dose of 160 mg twice a day is the most commonly used dosage in clinical trials. Therapeutic benefits are observed within 3 to 4 weeks after the initiation of treatment, which usually lasts for 3 to 6 months.
St. John’s Wort
Common Name and Scientific Name
St. John’s wort (Hypericum perforatum) is also known as amber touch-and-heal, goatweed, and klamath weed.
Historical and Current Use
This perennial, native to Europe, Western Asia, and North Africa, is a resilient weed, widespread in parts of the U.S. and southern Canada. The plant has golden-yellow flowers that bloom in the summer, which are collected and dried. The medicinal use of SJW as a topical anti-inflammatory and for wound healing has been known since ancient Greece. Extracts have been used in folk medicine for the treatment of depression and other mood disorders and also as a diuretic. Today, SJW is used primarily for the treatment of mild-to-moderate depression and is the most commonly prescribed antidepressant in Germany, where it is available as a prescription medication [48; 49].
Several chemicals, including naphtodianthrones (e.g., hypericin and pseudohypericin), phloroglucinols (e.g., hyperforin), flavonoids (e.g., quercetin), and essential oils, are the primary constituents of SJW . Formulations are standardized to concentrations of hypericin, usually 0.3% to 0.4%, which is considered the active ingredient responsible for the antidepressant properties of SJW. Clinical and pharmacological studies, however, have shown that hyperforin concentrations of 2% to 4% correlate closely with antidepressant efficacy [36; 123].
The pharmacological mechanisms of action of SJW extracts relevant to its antidepressant effect are complex. Hypericin inhibits MAO, a mechanism shared with the classical antidepressant phenelzine. This mechanism, however, is not considered clinically significant because it is only observed at concentrations 100 times higher than those used to treat depression . More importantly, 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 .
After a single dose, the half-life of hypericin is 4 to 6 hours, whereas after chronic administration, the half-life of hypericin is 1 to 2 days [85; 111]. These values are comparable to those observed for fluoxetine (1 to 3 days) and the selective serotonin re-uptake inhibitor (SSRI) paroxetine (12 hours) .
Finally, long-term administration of SJW extracts increase the synaptic density of serotonin receptors by 50%, whereas the receptor affinity remains unchanged . The increase in number of serotonin receptors was observed after a minimum 10 to 12 days treatment, a time frame that correlates with the well-known therapeutic delay of standard antidepressant drugs . Together, the increased number of serotonin receptors and the increase in synaptic concentrations of neurotransmitters provide a mechanistic explanation for the antidepressant effects of SJW [71; 85; 150].
SJW extracts also have antibacterial properties, accounting for the antiseptic and wound-healing properties of topical formulations. Hyperforin is effective in inhibiting gram-positive bacteria, including penicillin-resistant and methicillin-resistant Staphylococcus aureus, but it is not effective against gram-negative bacteria. One randomized trial showed the effectiveness of SJW topical application in the treatment of atopic dermatitis
Some in vitro studies have shown that SJW extracts have antiviral properties, namely against influenza virus, and one study has identified a novel protein in SJW that suppresses gene expression in human immunodeficiency virus (HIV) [46; 115]. However, a Phase I clinical trial provided negative results . It is important to emphasize that SJW should not be administered to HIV or acquired immune deficiency syndrome (AIDS) patients because of the pharmacokinetic interactions with antiretroviral protease inhibitors, such as indinavir, saquinavir, and ritonavir, and non-nucleoside reverse transcriptase inhibitors, such as efavirenz, which are metabolized by CYP3A4. Induction of CYP3A4 by SJW drastically reduces drug concentrations in the blood by 50% to 80% with subsequent loss of HIV suppression .
Finally, in vitro studies have shown that hyperforin and hypericin inhibit tumor cell growth by induction of apoptosis [74; 180]. Although these compounds seem to have high efficacy, their potential clinical usefulness as anticancer agents is, at this point, merely speculative.
Use and Effectiveness
Several clinical trials have assessed the efficacy and safety of SJW preparations in the treatment of depression. A 2005 Cochrane Review extensively analyzed published randomized, double-blind trials comparing SJW with placebo (26 studies) or with standard antidepressants (14 studies) . SJW was demonstrated to be “more effective than placebo and similarly effective as standard antidepressants for treating mild-to-moderate depressive symptoms” . The treatment period lasted from 4 to 12 weeks.
Two large clinical trials, one of which was sponsored by NCCAM, conducted in the U.S. did not support these findings [102; 185]. Both studies were conducted on patients who suffered from moderate-to-severe depression, and many patents presented with a history of drug-resistant depression, which may have affected the outcomes. The Hypericum Depression Trial Study Group has also been criticized because the response rates for both the SJW-treated and the sertraline-treated groups were not different from the placebo-treated group. In another randomized study, conducted in Germany, the effect of SJW (900 mg/day standardized SJW extract) on moderate-to-severe depression was compared with paroxetine (20 mg/day) . The treatment was continued for 6 weeks, and in initial non-responders, after 2 weeks of treatment the doses were increased by 100%. The results indicated that, in the treatment of moderate-to-severe depression, hypericum extract was, “at least as effective as paroxetine” and was better tolerated . A 2008 Cochrane Review of trials examining the treatment of severe depression with hypericum reached similar conclusions as to its efficacy in comparison to placebo and conventional antidepressants. Also, subjects in the SJW groups had a lower drop-out rate, possibly due to fewer side effects .
It is now established in the scientific literature that standardized SJW extracts are effective and safe in the treatment of mild-to-severe depression [64; 115; 128; 134; 174; 230].
Adverse Effects and Drug Interactions
SJW is a well-tolerated and generally safe drug. Mild side effects include gastrointestinal symptoms, mild sedation or tiredness, dizziness, headache, and dry mouth. Incidence of side effects in SJW-treated patients (4% to 12%) is similar to that observed in the placebo-treated group and significantly lower than standard antidepressants [133; 174; 196]. Two rare adverse events may occur after administration of SJW. First, transient photosensitivity may occur when administered in higher doses, and second, the occurrence of a serotonin syndrome when co-administered with SSRIs is possible . The latter results from the synergistic interaction between the drugs raising serotonin to abnormally high levels [54; 125; 126; 182; 219].
Pharmacokinetic interactions with SJW are rare and only occur at higher doses. Induction of cytochrome P450 isoforms, namely CYP3A4 and CYP1A2, by SJW results in a decreased bioavailabilty of drugs metabolized by this liver enzyme. These drugs include the immunosuppressant cyclosporine, the anticoagulant warfarin (bleeding), oral contraceptives (causing breakthrough bleeding), antiretroviral protease inhibitors, and theophylline [94; 128; 137; 174]. A report has also shown a reduction in plasma levels of the HMG-CoA reductase inhibitor simvastatin . Activation of the intestinal P-glycoprotein transporter also accounts for the reduction in plasma concentrations of digoxin .
In conclusion, although SJW has consistently been reported to be a safe drug when administered within its therapeutic range, its potential interactions with other drugs or herbs (e.g., kava) require caution and a thorough investigation during patient interview prior to use.
It is widely accepted in the literature that, when utilized within the normal therapeutic range, SJW is devoid of toxicological properties. In high doses, SJW can elicit photosensitivity. Phototoxicity results from light-induced transformation of hypericin-derived pigments and has been reported in HIV patients receiving high doses of intravenously-administered SJW . To date, only one study of potential teratogenicity during human pregnancy has been conducted, with data collected from the pregnancies of 54 SJW-treated women and 108 women either treated with conventional antidepressants or receiving no pharmacologic treatment. Rates of fetal malformations were similar among the three test groups and similar to rates of malformations in the general population; additionally, premature and live birth rates among the three test groups were similar . Further research in this area is needed, and SJW administration in pregnant patients should therefore be avoided.
Standardized preparations of SJW are usually administered from 500–1800 mg per day [64; 115; 128; 134; 174]. In most studies, 900 mg was administered daily (450 mg twice a day, or 300 mg three times a day).
Common Name and Scientific Name
Ginkgo (Ginkgo biloba), also known as kew tree, ginkyo, or duck-foot tree (because of the characteristic fan-shaped leaves), is a large, resilient and long-living tree cultivated by monks in China, where many individual specimens are documented to be more than 1000 years old. Ginkgo trees, often known as living fossils, are the only survivors of the entire Ginkgoaceae family. Fossils of this tree that date back more than 200 million years have been identified in areas throughout the Northern Hemisphere, including Europe and North America. Ginkgo trees were brought into Japan and other East Asian countries around 1200 C.E., possibly in relation to the spread of Buddhism. In the seventeenth century, they were reintroduced in Europe and, more recently, in North America. Ginkgo is a resilient tree to parasites and diseases and, interestingly, also survived the Hiroshima atomic bombing.
Historical and Current Use
The designation originates from ginkgo, meaning silver apricot, and biloba, which describes the two-lobed shape of the leaf. Historically, leaf extracts have been used in traditional Chinese medicine to treat a variety of disorders, including asthma, allergies, premenstrual syndrome, tinnitus, cognitive impairments resulting from aging and dementia, and vascular diseases including central and peripheral vascular insufficiencies. Standardized leaf extracts are used based on their neuroprotective and vascular regulatory properties in the management of intermittent claudication, age-related memory loss, dementia, and early stages of Alzheimer’s disease [38; 156]. Plum-like fruits of the female tree are not edible and cause contact dermatitis. Ingestion of the seeds causes headache, nausea, diarrhea, and even seizures when ingested in larger amounts [107; 174].
More than 40 chemical components of ginkgo have been isolated, including flavonoids, terpenoids, flavones, catechins, sterols, and organic acids. The two most important and active groups of chemicals are the flavonoids, such as quercetin and kaempferol, and the terpenoids, including ginkgolides A, B, C, J, and M and bilobalide. Ginkgo biloba extracts available in Europe and North America are standardized to 24% flavonoids and 6% terpenoids and have been used in hundreds of in vitro and in vivo studies and numerous clinical trials [156; 174].
The biological properties of ginkgo biloba extract result from the complex interactions among chemical components, and it is therefore difficult to establish a well-defined cause-effect relationship between specific elements and biological effect. Nevertheless, it is now well established that flavonoids have antioxidant and free-radical scavenger properties. They also have a protective effect against apoptosis and beta-amyloid neurotoxicity of Alzheimer’s disease and may play an important role in the prevention of neuronal degeneration in Parkinson’s disease [14; 42].
Terpenoids, particularly ginkgolides, inhibit the platelet activating factor (PAF), and therefore prevent platelet aggregation, have anti-inflammatory properties, and prevent contraction of smooth muscles in the respiratory tract . The vasodilatory properties of standardized ginkgo biloba extract preparations are attributed to the stimulation of endothelium-derived relaxing factor and regulation of nitric oxide release .
Ginkgo biloba extract also stimulates receptor expression and neurotransmitter concentrations in the brain, particularly acetylcholine [5; 99; 100; 226]. This latter mechanism of action is similar to the cognitive enhancer tacrine, used in the treatment of Alzheimer’s disease .
Use and Effectiveness
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 Alzheimer’s disease [108; 122; 156]. 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’s disease, although these findings are not supported by additional studies . Although studies have shown that ginkgo biloba extract improves cognitive functions in older healthy individuals, the findings must be confirmed by larger clinical trials [145; 156].
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 [97; 114].
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’s syndrome [147; 156]. In fact, one clinical trial demonstrated that ginkgo biloba extract is as effective as pentoxifylline, the standard medication for the treatment of intermittent claudication . However, a 2008 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 .
The beneficial effects of ginkgo biloba extract in a variety of medical conditions, such as tinnitus and 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.
Adverse Effects and Drug Interactions
Consistently, ginkgo biloba extract is considered a safe and well-tolerated drug when used at the recommended dose for periods of up to 6 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 . 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 . 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 . Nonetheless, it is advisable to discontinue ginkgo biloba extract administration several days prior to surgery.
Although in vivo studies did not report either embryotoxic or teratogenic effects of ginkgo biloba extract, this phytomedicine should be avoided during pregnancy and breastfeeding [52; 156]. As mentioned, severe contact dermatitis, similar to that caused by poison ivy, can result from direct contact with the pulp of ginkgo fruit of the female tree. Ingestion of ginkgo seeds, but not leaves, in large amounts (50 or more) causes headache, nausea, diarrhea, and even seizures. This condition is known in Japan as gin-nan . Pollen from the male tree can be allergenic for sensitive individuals .
Standardized extracts are administered at a daily dose of 120–240 mg, in two or three equal doses, for periods of 6 months or longer [108; 122; 156].
Safety:No S data
Common Name and Scientific Name
Ginseng is a designation that applies to an HM that is prepared from the root of different plants of the Araliaceae family. Asian ginseng is obtained from Panax ginseng, American or Canadian from P. quinquefolius, and Japanese from P. japonicus. Siberian (Russian) ginseng is obtained from the root of Eleutherococcus senticosus, a plant that, although a member of the same Araleaceae family, is not a member of the Panax genus, and hence, is not considered a true ginseng. High-quality ginseng root is harvested in the autumn from plants that are 5 to 6 years old.
Historical and Current Use
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 [8; 41; 135; 157].
Several chemicals, including polysaccharides (e.g., ginsan and ginsenans) and a variety of saponins known as ginsenosides, are found in ginseng. 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 pharmacological and physiological properties of each compound.
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 [121; 216]. Both in vitro and in vivo models of Parkinson’s 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 .
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 nondiabetic and type 2 diabetic patients [8; 217; 223]. Ginseng also stimulates insulin synthesis and release, an effect possibly caused by the increase in nitric oxide production by ginseng . Preliminary results suggest that ginseng also regulates intestinal absorption of glucose and glycosylation of hemoglobin A1c (HbA1c) . If these results are confirmed, ginseng may become a useful pharmacological tool in the prevention and treatment of type 2 diabetes.
In vitro studies show that ginsenosides cause vasodilation and lower blood pressure and that panaxynol, a potent inhibitor of thromboxane A2, prevents platelet aggregation [113; 204]. However, further scientific evidence of the antihypertensive effects of ginseng is required prior to considering its potential benefits in cardiovascular diseases.
The immunostimulatory and antiproliferative properties of ginseng have also been reported in the scientific literature, but further studies are required . 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.
Use and Effectiveness
A Cochrane Review has concluded that the beneficial effects of ginseng preparations were “not established beyond reasonable doubt” . 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 [41; 157]. A modest improvement in cognitive performance has also been reported [41; 157].
Adverse Effects and Drug Interactions
Ginseng preparations are generally well tolerated when administered within the recommended dosage, and the available animal and human studies suggest that it is safe. As a result of its hypoglycemic properties, it should be used cautiously in patients with type 2 diabetes concurrently treated with oral hypoglycemic drugs.
Anticoagulant properties may also account for a few reports of epistaxis and vaginal bleeding. In contrast, a randomized, controlled clinical trial has shown that ginseng increases the risk of blood clotting in patients treated with warfarin. This pharmacokinetic interaction occurs only after long-term administration of ginseng and results from the induction of hepatic CYP450 isoforms responsible for warfarin metabolism .
Interactions between ginseng and MAO inhibitors have also been reported and may cause headaches, insomnia, nervousness, and mood disorders. Pharmacokinetic (e.g., CYP450 induction) and pharmacodynamic potentiation of antihypertensive drugs have also been reported, and it should not be administered to hypertensive patients .
A few case reports describe the occurrence of diarrhea, unstable mood, skin rash, or itching after long-term administration. Ginseng has also been associated with loss of menstrual periods and vaginal bleeding in menopausal women. Therefore, ginseng should not be administered to patients with hormone-sensitive conditions, such as breast or uterine cancer and endometriosis. In men, it may be associated with estrogen-like effects, such as reduced libido and gynecomastia .
At normal doses, ginseng is reported in the literature as being safe. Nevertheless, ginseng should be avoided during pregnancy and breastfeeding [64; 157]. A case of reversible masculinization of a newborn girl when a mother allegedly took Eleutherococcus senticosus (Siberian ginseng) during pregnancy has been reported . In fact, it resulted from the adulteration of the original product and substitution of Periploca sepium, a vine of the milkweed family, for ginseng. Periploca sepium has been used in traditional Chinese medicine for its stimulatory and libido enhancing effects. Accordingly, it must be emphasized that the mentioned report has been erroneously used as published evidence of ginseng toxicity [9; 10; 218]. Pediatric safety concerns regarding ginseng treatment for upper respiratory tract infections were addressed in a 2008 Canadian trial involving 75 subjects (3 to 12 years of age) given standard doses, low doses, or placebo. The treatments were well tolerated, considered safe, and warrant additional research for use on these and other types of pediatric infections .
Purified ginseng extracts are generally standardized to 4% or 7% ginsenoside contents. Usually, 100–200 mg of standardized 4% extract is administered orally once or twice daily, for as many as 12 weeks. In traditional Chinese medicine, 0.5–2 g/day of dried ginseng root, equivalent to 200–600 mg of standardized extract, is commonly used. Long-term administration of ginseng should not exceed 1 g/day of the dry root form or 400 mg/day in the extract form. It is administered daily for 2 to 3 weeks, then discontinued for 1 to 2 weeks. This treatment schedule may be repeated for several months [64; 157].
Common Name and Scientific Name
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.
Historical and Current Use
Echinacea was used by Native Americans for a wide variety of conditions, including chewing the roots for toothaches and gingivitis, root and leaf infusion for stomach pain, colds, and infections, and topically as a disinfectant and for wound healing. The use of echinacea was quickly adopted by early European settlers, and shortly thereafter, it became widely used by European herbalists and physicians.
In Germany, it has been commonly used in mainstream medicine for almost a century. The German Commission E has approved the use of echinacea for the amelioration of common-cold symptoms, upper respiratory infections, and urinary tract infections, as well as topical administration for treatment of superficial wounds . The scientific literature generally supports a beneficial effect of echinacea extracts in the treatment of cold symptoms, but evidence of its efficacy in the prevention of colds is still limited . Echinacea is the most widely sold HM in the United States and is the third most popular natural product overall (surpassed only by fish oil and glucosamine) .
Preparations from different portions (e.g., root or leaves) of the echinacea plants (e.g., E. angustifolia, E. purpurea, E. pallida) are collected during the blooming season. The products are usually dried, and several chemical components, namely caffeic acid derivatives (e.g., echinacosides and cichoric acid derivatives), flavonoids (e.g., quercetin), alkylamides, and polysaccharides, are identified upon alcoholic extraction . Laboratory analysis of echinacea extracts with high-pressure liquid chromatography provides the chemical fingerprint of different echinacea species. In fact, in E. purpurea, no echinacosides are detected, whereas they are abundant in E. angustifolia and E. pallida. On the other hand, the amount of cichoric acid present in E. purpurea is forty- to sixtyfold higher than that present in E. angustifolia and E. pallida, respectively . The relative concentration of various chemicals within the same species also varies in different plant parts. Echinacoside concentrations are higher in the root, whereas cichoric acid concentrations are higher in the flower of all echinacea species than in other plant parts.
Due to its complex chemical makeup, the precise pharmacological and therapeutic properties of each compound remain to be determined. Naturally occurring phenols, such as the caffeic acid derivatives, are potent antioxidants due to the presence of hydroxyl groups on aromatic rings that scavenge tissue-damaging free radicals . In vitro experiments revealed that alkylamides from echinacea inhibit cyclooxygenase and 5-lypoxygenase, accounting for its anti-inflammatory properties .
The immunostimulatory properties of echinacea have been demonstrated both in vitro and in vivo. Nonspecific effects, such as macrophage proliferation, stimulation of interleukin-1, tumor necrosis factor, and interferon stimulation, as well as specific effects, such as increase in numbers of T lymphocytes and natural killer cells, have been reported in several studies . Because the total immunostimulatory effect of echinacea in humans remains to be established, the German Commission E discourages the use of echinacea in patients with autoimmune diseases.
Many preparations are standardized to 4% to 5% echonacosides, while others also report the concentration of cichoric acid. A detailed study conducted by investigators from the University of Colorado Health Sciences Center analyzed 59 samples of echinacea-only preparations purchased from 11 retail outlets in the Denver area . Ten percent of the samples did not contain measurable amounts of echinacea, and the species content only agreed with the label in 52% of the cases. Twenty-one preparations claimed to be standardized, but only nine met the composition reported on the label. Although the efficacy of echinacea in the treatment of some medical conditions has been reasonably established, the lack of species identification and standardization, as well as product contamination/adulteration, should be thoroughly investigated prior to being administered. The poor quality of many available products certainly contributes to, or may account for, the conflicting results and significant number of negative reports published in the scientific journals.
Use and Effectiveness
The therapeutic effectiveness of echinacea preparations in prevention and treatment of the common cold has been extensively studied. Several extensive reviews and meta-analysis studies have been published, and some have provided conflicting or inconclusive results.
Caruso and Gwaltney evaluated the therapeutic effectiveness of echinacea in the treatment of the common cold based on 9 placebo-controlled clinical trials, and they concluded that, “the possible therapeutic effectiveness of echinacea in the treatment of colds has not been established” .
A Cochrane Review also evaluated the effects of echinacea on naturally-acquired colds . Sixteen of the 58 published trials met their inclusion criteria. In the treatment of colds, echinacea was effective in most clinical trials (9) and beneficial or marginally better than the placebo group in one trial. In the remaining 6 clinical trials, no difference was observed between groups . Interestingly, the authors also commented on the pervasive issue of lack of standardization, the variability in bioactive composition of echinacea preparations, and the likelihood that they may contribute to, or account for, the lack of consistency in treatment outcomes.
Three randomized, double-blind, and placebo-controlled trials assessed the effectiveness of echinacea on the avoidance of and severity of colds. Consistently, they all revealed that subjects preventively treated with standardized echinacea extracts acquired fewer colds (22%, 58%, and 49%) than the placebo group (33%, 82%, 56%) [192; 210; 211]. However, due to the small number of subjects studied in each trial, the decreases were not statistically significant. A meta-analysis evaluated these three clinical trials, and due to the common methodology used, the results of almost 400 subjects were combined . The meta-analysis suggests that the risk of developing a cold was 55% higher in the placebo than in the echinacea-treated group, a statistically significant difference .
In vitro and in vivo studies and in some cases preliminary clinical evidence as well, support other possible therapeutic applications of echinacea preparations (e.g., immunostimulant, anti-infective, wound-healing). However, due to the limited data, the actual therapeutic outcome is inconclusive.
Adverse Effects and Drug Interactions
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 . 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%) . One case of anaphylaxis has been reported in a patient with a history of atopic reactions . 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 .
Both in vitro and in vivo studies suggest that, even when administered at doses several-fold higher than the ones normally used, echinacea is devoid of toxicity. Analysis of 112 pregnant women who were exposed to echinacea preparations during the first trimester of pregnancy showed no difference in fetal health when compared to the nonechinacea-exposed group . Although other studies seem to confirm safety, echinacea preparations should be avoided during the first trimester due to lack of definitive evidence.
For treatment of cold symptoms and upper respiratory infections, an initial 300–1000 mg titrated dose of powdered herb in capsules or its equivalent (tincture or juice) is administered for 5 to 7 days [41; 64; 154; 174]. Preparations containing 15% pressed herb are used topically as disinfectants.
Common Name and Scientific Name
Kava (Piper methysticum), a member of the pepper family, is a widely cultivated shrub indigenous to the South Pacific islands. It is also known as kava-kava, kawa, or ava pepper.
Historical and Current Use
A drink prepared from the root of the kava plant has been used traditionally in the South Pacific for ceremonial, social, and medicinal purposes for several centuries, if not millennia. It is used for its mild relaxing and calming properties, culturally comparable to alcohol use in Western societies. Following the European trend, the use of kava for the treatment of anxiety has become popular in the U.S. In some countries, including Germany, it has been commonly prescribed to treat anxiety, stress, and insomnia, although very serious concerns regarding potential hepatotoxicity have lead to warnings and bans in North America.
The lipid-soluble extract of kava is rich in kava pyrones, including kavain, dihydrokavain, and methysticum . Kava pyrones block voltage-dependent sodium channels, a mechanism responsible for the local anesthetic properties of kava drinks, which causes numbness and tingling of the mouth. Kava also contains antioxidant flavonoids and alkaloids. It has been reported that kava has a direct effect on limbic structures, particularly the amygdala. It does not bind to the GABAA receptors, unlike benzodiazepines, which target the GABAA receptors abundantly distributed in the cerebral cortex. This may account for the difference in anxiolytic properties of kava, which, unlike benzodiazepines, does not cause sedation .
At higher doses, kava lactones also have muscle-relaxant and anticonvulsant properties, which are possibly related to the stimulation of the glycine receptor . Kavain has dose-dependent antiplatelet aggregation and anti-inflammatory properties .
Use and Effectiveness
The clinical effectiveness of kava has been widely studied, and clinical studies strongly support its efficacy in the treatment of moderate and mild cases of anxiety. One meta-analysis included data from 11 double-blind, controlled clinical trials, and the authors concluded that kava, when compared to placebo, is effective in the symptomatic treatment of anxiety . A standardized preparation of kava (LI 150) was as effective as the anxiolytic drugs buspirone and opipramol . An extensive literature review also confirmed the clinical effectiveness of kava preparations in the treatment of anxiety .
Several clinical studies, including one published by Holm and colleagues, assessed the effect of kava on memory and compared it with both the anxiolytic oxazepam and placebo . They concluded that kava, unlike oxazepam, does not impair cognitive performance and memory. In fact, an improvement in memory was observed in the kava-treated group, but these interesting results wait for confirmation .
Adverse Effects and Drug Interactions
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. Neurotoxicity, pulmonary hypertension, and choreoathetosis have also been reported in chronic heavy drinkers in the Australian Aboriginal population . A few rare cases of kava-induced Parkinson-like extrapyramidal disorders have been reported, as well as the aggravation of existing Parkinson’s disease in one patient . There are some reports, however, 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 . In August 2002, Health Canada issued a stop-sale order for all products containing kava .
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’s 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 [26; 158]. As a precautionary measure, kava should not be administered during pregnancy and lactation due to the lack of safety studies. Kava administration should be discontinued at least 24 hours prior to surgery because of possible potentiation of the sedative effect of anesthetics .
More than 30 cases of kava-induced hepatotoxicity, ranging from hepatitis and cirrhosis to acute liver failure and death, have been reported in the literature. One study of lipid-extractions of kava led researches to state that rather than being caused by directly toxic mechanisms, reactions to kava likely stemmed from immunologically mediated idiosyncratic mechanisms; therefore, the hepatotoxicity of kava may be similar to benzodiazepines . An Australian trial concluded that water-extracted kavalactones, using dried roots sourced from the island of Vanuatu and prepared in a controlled pharmaceutical manufacturing facility, caused neither an increase in liver enzymes nor hepatotoxic symptoms . Other studies have shown that kava suppresses CYP450 enzymes in the liver, leading to hepatotoxic concentrations of concurrently administered drugs . Although no cases of hepatotoxicity were reported in any of the clinical trials included in a Cochrane Review, it is not recommended for use in the U.S. [64; 169].
Standardized products are available, and the usual recommended daily dose of kavalactones ranges from 120–250 mg/day, divided in 2 to 3 equal doses [158; 174]. In the U.S., most formulations are standardized to 30% or 55%, meaning that a 100 mg tablet contains 30 mg or 55 mg of kavalactones, respectively. Usually, kava use should be limited to 3 months to avoid potential habituation, and patients should be advised of the potential adverse effects on motor coordination and capacity to drive or operate heavy machinery .
Common Name and Scientific Name
Garlic (Allium sativum), also known as allium, is related to chives (Allium schoenoprasum) and onions (Allium cepa), and all belong to the Liliaceae family, which also includes lilies.
Historical and Current Use
The recorded medicinal use of garlic goes back to ancient Egyptian, Greek, and Roman civilizations. It was used for the treatment of a variety of conditions, including heart problems, headaches, intestinal parasites, and tumors, and as a local disinfectant. In the nineteenth century, Louis Pasteur also reported the antimicrobial properties of garlic. It is now used for its effectiveness in reducing cholesterol and for its antithrombotic and antioxidant properties, as well as for its ability to lower blood pressure. Together, these properties have also provided some support for the use of garlic in the prevention of cardiovascular diseases, including atherosclerosis [62; 155; 174]. The benefits of garlic in the treatment of certain cancers, specifically stomach and colorectal, have also been investigated .
The beneficial effects of garlic have been related to its sulfur compounds. More than 20 different sulfur compounds have been identified in garlic. The sulfur compound allinin (S-allyl-l-cysteine sulfoxide) is transformed to allicin (diallyl thiosulfinate) via the enzyme allinase when the bulb is crushed or ground. Allicin is an unstable molecule that is converted into more stable compounds. Other sulfur compounds, such as peptides, steroids, terpenoids, flavonoids, and phenols, derive from allicin metabolism and have been the subject of investigations aimed at identifying their biological role . In vitro and in vivo studies have associated allicin with the antibacterial properties of garlic. Commercially available garlic extracts are standardized to the allicin content. Three water-soluble allicin derivatives, s-allylcysteine (SAC), s-ethylcysteine (SEC), and s-propylcysteine (SPC), are the most effective in reducing in vitro cholesterol synthesis in hepatocytes by 42% to 55% .
Methyl-allyl trisulfide (MATS), a lipid-soluble allicin derivative, inhibits cyclooxygenase activity and prostaglandin synthesis and is responsible for the antithrombotic and antiplatelet aggregation properties of garlic . Another sulfur compound, diallyl trisulfide (DATS), is a potent inhibitor of colon and lung human cancer cell proliferation in cell cultures and is at least partially responsible for the anticancer properties of garlic [98; 176].
The antioxidative properties of garlic are exerted indirectly through the sulfur compound-induced stimulation of protective antioxidant enzymes present in the body, including glutathione-S-transferase, superoxide dismutase, and catalase [7; 62].
Use and Effectiveness
Several clinical trials have reported that garlic lowers total cholesterol levels by 8% to 15% [188; 220]. This effect results from the lowering of the low-density lipoprotein (LDL) and triglycerides, while the high-density lipoprotein (HDL) values remained 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 . In 2001, an extensive meta-analysis of 34 randomized clinical trials including almost 2000 patients confirmed the previous assertions . In conclusion, garlic preparations are moderately effective in lowering LDL and triglycerides and do not change the HDL concentration in the plasma .
The effects of garlic on blood pressure have been studied in several clinical trials. Most studies have shown a small (6%) yet statistically significant effect, although these findings were not replicated by other studies .
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 [155; 167].
Some clinical studies suggest that garlic preparations slow the progression of atherosclerotic plaques . Although encouraging, these results are preliminary and further studies are required.
The anticancer properties of garlic compounds have been reported both in vitro and in vivo, but their clinical effectiveness remains to be established. Epidemiological studies suggest that regular consumption of garlic may be associated with a lower risk of developing gastric and colorectal malignancies . Although the evidence is cautiously positive, well-designed clinical trials are needed before a conclusion can be reached.
Adverse Effects and Drug Interactions
The most common adverse effects reported are bad breath and body odor. Less commonly, dyspepsia and flatulence are also reported. In rare cases, dermatitis and respiratory difficulty can occur in hypersensitive patients . 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 .
Garlic preparations administered within the recommended dosages are safe, although they should not be administered to patients allergic to garlic or to other members of the Liliaceae family, namely chives, onions, leek, or lilies [155; 167]. A dangerous pharmacokinetic interaction between garlic and the protease inhibitor saquinavir has been reported, as it reduces the plasma concentration of the anti-HIV drug by 50% .
Administration of garlic preparations varies greatly according to the preparation used (i.e., fresh, powder, or oil extracts). Standardized preparations to 1.3% allinin or 0.6% allicin are usually administered at 600–900 mg per day. This is considered equivalent to one small clove of fresh garlic .
Common Name and Scientific Name
Valerian (Valeria officinalis), also known as baldrian, is a member of the Valerianaceae family. Other species of the same family that are also used for medicinal purposes include V. wallichi and V. sambucifolia.
Historical and Current Use
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 now 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 [62; 174].
A large number of chemicals, including monoterpenes, sesquiterpenes, valepotriates, amino acids, and alkaloids, have been extracted from valerian. Although no single component has been shown to account for its pharmacological properties, the biologically active valerenic acid has been used as the constituent for standardization. In vivo studies have confirmed the sedative, anxiolytic, and anticonvulsant properties of valerian preparations. Studies have also shown the agonistic effect of valerian and some of its individual compounds on the GABAA receptors and on the 5-HT5a serotonin receptors [57; 164; 206]. Other studies have revealed that valerian extracts inhibit the presynaptic GABA carrier, further contributing to an increased GABAergic inhibitory activity in the brain . Valerenic acid also inhibits GABA transaminase, the enzyme responsible for GABA metabolism . Together, these findings contribute to a better understanding of the molecular mechanisms underlying the sedative and anticonvulsant properties of valerian. More recently, research has identified valerenic acid and its modulation of the GABAA-ergic system as probable cause of the anxiolytic effects, a mechanism similar to benzodiazepines (e.g., diazepam) .
Use and Effectiveness
A systematic review of 9 randomized clinical trials found that results regarding the effectiveness of valerian in the treatment of insomnia were inconclusive . Some benefits were reported within 1 to 2 days, but benefits on sleep were observed only after 4 weeks of treatment. A larger European clinical trial reported that the valerian had minimal or no effect on sleep regulation . Unfortunately, patients were treated for only 2 weeks, a time period considered too short when compared with previous studies, which may account for the negative outcome.
As of 2010, no well-designed trials of valerian in the treatment of anxiety in humans have been published. An investigation of the effect of valerenic acid on rats concluded that valerian use was related to a reduction of anxious behavior .
Adverse Effects and Drug Interactions
In clinical trials, valerian side effects were minor, most commonly headache, stomach upset, or dizziness, and were usually reported as frequently as in the placebo group. Adverse effects on reaction time and alertness were much lower than benzodiazepines. Dependence and withdrawal have not been reported in any of the clinical trials, although a single case report of withdrawal symptoms after discontinuation has been published . As valerian and benzodiazepines similarly target the GABAA receptor, it is possible that the patient may develop physical dependence after lengthy administration. It is therefore advisable to discontinue valerian administration progressively. Valerian potentiates the effects of other sedatives, such as benzodiazepines, barbiturates, alcohol, kava, and chamomile, and should not be co-administered in conjunction with these drugs or phytomedicines .
Valerian is considered safe by the FDA, but administration during pregnancy and breastfeeding is not advised due to the limited availability of safety data.
In clinical trials, for the treatment of insomnia, 900 mg of a standardized solution equivalent or 1.5–3 grams of dried root was administered 30 minutes to 1 hour before bedtime .
Common Name and Scientific Name
Andrographis (Andrographis paniculata) is also known as Justicia paniculata, green chiretta, king of bitters, kan jang, and sambiloto. It is an herb naturally found in Asia, including India, Southeast Asia, and southern China, and it is also cultivated for commercial use in the preparation of traditional HMs. Andrographis is an annual tall herb, up to one meter high, with small white flowers. It thrives in humid climates and shady areas.
Historical and Current Use
The bitter-tasting leaves of andrographis have been used for centuries in traditional Indian and Chinese medicine in the preparation of an infusion used for the treatment of digestive ailments and fever. In Malaysia, andrographis has also been traditionally used for the treatment of hypertension . In northern European countries, andrographis is used for the prevention of upper respiratory tract infections .
Andrographis is rich in diterpenoids and flavonoids. At least 9 diterpinoids, including andrographolide, 14-deoxyandrographolide (DA), and 14-deoxy-11-oxoandrographolide (DDA), have been isolated.
In vitro studies revealed that andrographolide has anti-inflammatory, antiapoptic, and immunomodulatory properties. In vivo studies demonstrated that both DA and DDA effectively lower blood pressure, decrease heart rate, and cause vasodilation . 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 .
Use and Effectiveness
Several clinical trials, including almost 900 subjects, have assessed the effectiveness of andrographis in the treatment and prevention of upper respiratory tract infection. Two meta-analyses concluded that andrographis was significantly more effective than placebo for the treatment of upper respiratory tract infection symptoms [44; 170]. Limited evidence also suggests that andrographis preparations may be effective in the prevention of upper respiratory tract infection . Two clinical studies concluded that andrographis is also effective in the treatment of influenza symptoms, although larger and better-designed studies are needed to confirm the results .
Adverse Effects and Drug Interactions
Andrographis is considered safe and well tolerated. Headache, nausea, vomiting, abdominal discomfort, and nasal congestion are the most commonly reported adverse effects . Although data regarding andrographis interactions with other drugs is still limited, due to andrographis’ hypotensive and hypoglycemic properties, concurrent administration with antihypertensive and hypotensive drugs should be avoided.
In clinical trials, a dose-response dependent toxicity of andrographis has been identified, and fatigue, headache, and lymphadenopathy have been described [30; 31; 75]. Furthermore, three cases of anaphylactic reaction have also been reported .
Three hundred milligrams of standardized preparations of andrographis (4% andrographolides) are taken 4 times a day, for as long as 2 weeks .
English Ivy Leaf
Common Name and Scientific Name
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).
Historical and Current Use
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 .
Ivy leaves are rich in saponins (e.g., hederin and hederacosides) but also contain sterols, flavonol glycosides, and polyalkanes among other chemicals. Saponins stimulate secretion of mucus in the upper respiratory tract and have a mucokinetic and mucolytic effect . They also prevent acetylcholine-induced bronchospasm . Hederacoside C has antifungal and antibacterial properties . Together, these bronchodilatory and antimicrobial properties of ivy leaf extracts provide the pharmacological evidence to support their beneficial effects in the treatment of upper respiratory tract infections.
Use and Effectiveness
The clinical efficacy of ivy leaf extracts has been the subject of one meta-analysis . Five clinical trials, three of which measured its effect on children, indicated that the treated group showed an improvement in chronic bronchial asthma. In another study not included in the previous review, 1350 children with chronic bronchitis were treated with standardized ivy leaf extracts for 4 weeks. A significant improvement or cure of the following symptoms was observed, when compared to the baseline: cough (92%), expectoration (94%), dyspnea (83%), and respiratory pain (87%) . A postmarketing study of almost 10,000 patients with bronchitis showed that, after a 7-day treatment with ivy leaf extracts, 95% of the patients had improved significantly .
Adverse Effects and Drug Interactions
Ivy leaf extracts are generally considered safe. Mild adverse effects, such as gastrointestinal discomfort, eructation, or nausea, are observed in 0.2% to 2.1% of patients [67; 93]. No drug interactions have been reported. Considering the detergent-like actions of saponins, it has been suggested that ivy leaf extracts should not be ingested at the same time as other drugs, considering the unlikely possibility that ivy leaf extracts may facilitate the absorption of the other drugs. However, this warning is not supported by any evidence and should be considered as speculative.
Ingestion of ivy berries can be toxic, and falcarinol present in cut ivy leafs may cause contact dermatitis, particularly in sensitive individuals . In a bizarre case reported by Gaillard and colleagues ingestion of ivy leaves caused mechanical obstruction and suffocation . Toxicological tests confirmed the cause of death as being suffocation, and no toxin was detected in cardiac blood, femoral blood, or urine of the deceased .
It has been suggested that ivy leaf products should be avoided during pregnancy because the emetine content in ivy leaf may cause uterine contractions . Data on the effects of ivy leaf extracts during lactation are not yet available, and as a result, ingestion of ivy leaf extracts in these cases should be avoided.
Herbal medications have become an important issue in North America for a variety of social, economic, and medical reasons, and the use of HMs continues to increase. It has been estimated that, in 2007, approximately 20% of the U.S. population had used dietary supplements, a 46% increase compared to the 1997 values [208; 240]. Considering that the age group with the highest use (70%) of herbal medications is 18 to 33 years of age, it is expected that the overall consumption will continue to increase in years to come.
In the U.S., the out-of-pocket expenditures for CAM were conservatively estimated to be $34 billion in 2007; this represents about 11% of national healthcare spending . Furthermore, in the United States, the cost of dietary supplements alone in 2007 was estimated at $15 billion (compared with $48 billion spent on prescription drugs in 2007), approximately 40% of the total costs of CAM . Considering the high price of health insurance and changing attitudes towards CAM, the expenditures today are most likely greater.
In addition, more than 50% of patients receiving conventional medical care also use CAM . An estimated 50% to 70% of patients fail to disclose the use of HMs to their healthcare providers, and concern regarding a possible negative reaction or perceived lack of interest by the healthcare provider have been identified as the main reasons for limited disclosure of HMs use [37; 173]. It is commonly believed by the population in general, and by many healthcare providers as well, that due to their natural origin, these products are intrinsically safe and devoid of adverse effects or toxicity, or that the worst possible outcome is lack of therapeutic effectiveness. This has been proven false.
The regulatory framework for the use of HMs in North America was discussed, and the process of approval of conventional medications versus herbal medications was analyzed. A scientific approach to the general pharmacological study of the pharmacokinetic and pharmacodynamic mechanisms underlying the actions of HMs, their therapeutic properties, adverse effects and drug interactions, toxicological profile, and commonly used dosages were presented. Finally, the ten most commonly used HMs were reviewed in detail with an evidence-based approach (Table 1).
In conclusion, it is vital to the provision of optimum health care that healthcare providers have an understanding of the pharmacological properties and therapeutic efficacy of HMs based on evidence-based and updated information. It was the goal of this course to provide the evidence required for healthcare providers to be particularly aware of the need to include current or past use of HMs in the patient’s medical history, discuss relevant information with their patients, to be aware of the possible interactions with conventional medications, and evaluate the potential therapeutic benefits of HMs when appropriate.
A REVIEW OF HERBAL MEDICATIONS (Table 1)
|Common Name||Scientific Name||Typical Modern Uses||Efficacy||Safety|
|Saw palmetto||Serenoa repens or Sabal serrulata||Treatment of benign prostatic hyperplasia (BPH)||**E||S|
|St. John’s wort||Hypericum perforatum||Treatment of mild-to-moderate depression||**E||AEs/DIs|
|Gingko||Gingko biloba||Management of age-related memory loss, dementia, early stages of Alzheimer’s disease||**E||S|
|Treatment of cardiovascular diseases, diabetes, immunomodulation, menopause||*E||No S data|
|Treatment of common-cold symptoms||**E||S|
|Kava||Piper methysticum||Treatment of anxiety, stress, insomnia||***E||AEs/DIs/UnS|
|Garlic||Allium sativum||Prevention and treatment of hyperlipidemia, hypertension, cardiovascular disease||**E||AEs/DIs|
|Valerian||Valeria officinalis||Treatment of insomnia, anxiety||**E||S|
|Andrographis||Andrographis paniculata||Prevention of upper respiratory tract infections||**E||AEs/DIs|
|English ivy leaf||Hedera helix||Treatment of bronchitis and asthma||***E||S|
Source: Compiled by Author Table 1
1. Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Morbidoni L, Lawrence VA. Garlic shows promise for improving some cardiovascular risk factors. Arch Intern Med. 2001;161(6):813-824.
2. Adler AJ, Holub BJ. Effect of garlic and fish-oil supplementation on serum lipid and lipoprotein concentrations in hypercholesterolemic men. Am J Clin Nutr. 1997;65(2):445-450.
3. Agarwal KC. Therapeutic actions of garlic constituents. Med Res Rev. 1996;16(1):111-124.
4. American Society for Pharmacology and Experimental Therapeutics. ASPET Congressional Testimony Supports $37B NIH FY 2011 Budget. Available at http://www.aspet.org/Page.aspx?id=1633. Last accessed April 21, 2010.
5. Amri H, Drieu K, Papadopoulos V. Ex vivo regulation of adrenal cortical cell steroid and protein synthesis, in response to adrenocorticotropic hormone stimulation, by the Ginkgo biloba extract EGb 761 and isolated ginkgolide B. Endocrinology. 1997;138(12):5415-5426.
6. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286(2):208-216.
7. Ariga T, Seki T. Antithrombotic and anticancer effects of garlic-derived sulfur compounds: a review. Biofactors. 2006;26(2):93-103.
8. Attele AS, Zhou YP, Xie JT, et al. Antidiabetic effects of Panax ginseng berry extract and the identification of an active component. Diabetes. 2002;51(6):1851-1858.
9. Awang DVC. Maternal use of ginseng and neonatal androgenization. JAMA. 1991;265(14):1828.
10. Awang DVC. Maternal use of ginseng and neonatal androgenization. JAMA. 1991;266(3):363.
11. Barrett M. The pharmacology of saw palmetto in treatment of benign prostatic hyperplasia. J Am Nutraceut Assoc. 2000;2(3):40-43.
12. Barnes J, Anderson LA, Phillipson JD. St. John’s wort (Hypericum perforatum L.): a review of its chemistry, pharmacology, and clinical properties. J Pharm Pharmacol. 2001;53(5):583-600.
13. Health Canada. Baseline Natural Health Products Survey Among Consumers, March 2005. Drugs and Health Products. Available at http://hc-sc.gc.ca/dhp-mps/pubs/natur/eng_cons_survey_e.html. Last accessed April 19, 2010.
14. Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R. The Ginkgo biloba extract (EGb761) protects hippocampal neurons against cell death induced by beta-amiloid. Eur J Neurosci. 2000;12(6):1882-1890.
15. Bayne CW, Ross M, Donnelly F, Habib FK. The selectivity and specificity of the actions of the lipido-sterolic extract of Serenoa repens (Permixon) on the prostrate. J Urol. 2000;164(3 Pt 1):876-881.
16. Bent S, Kane C, Shinohara K, et al. Saw palmetto for benign prostatic hyperplasia. N Engl J Med. 2006;354(6):557-566.
17. Berges RR, Kassen A, Senge T. Treatment of symptomatic benign prostatic hyperplasia with beta-sitosterol: an 18 month follow-up. BJU Int. 2000;85(7):842-846.
18. Berges RR, Windeler J, Trampisch HJ, Senge T. Randomized, placebo-controlled, double-blind clinical trial of beta-sitosterol in patients with benign prostatic hyperplasia. Beta-sitosterol Study Group. Lancet. 1995;345(8964):1529-1532.
19. Berthold HK, Sudhop T, von Bergmann K. Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism: a randomized controlled trial. JAMA. 1998;279(23):1900-1902.
20. Drug and Therapeutics Bulletin. Results of Drug and Theraputics Bulletin (DTB) Survey on Herbal Medicines. Available at http://dtb.bmj.com/site/about/DTB_survey_on_herbal_medicines.pdf. Last accessed April 21, 2010.
21. Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicines Communications; 2000.
22. Boerner RJ, Sommer H, Berger W, Kuhn U, Schmidt U, Mannel M. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in generalised anxiety disorder—an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine. 2003;10(Suppl 4):38-49.
23. Bogusz MJ, al Tufail M, Hassan H. How natural are “natural herbal remedies”? A Saudi perspective. Adverse Drug React Toxicol Rev. 2002;21(4):219-229.
24. Boyle P, Robertson C, Lowe F, Roehrborn C. Meta-analysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia. Urology. 2000;55(4):533-539.
25. Boyle P, Robertson C, Lowe F, Roehrborn C. Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. BJU Int. 2004;93(6):751-756.
26. Bressler R. Herb-drug interactions: interactions between kava and prescription medications. Geriatrics. 2005;60(9):24-25.
27. Brockmöller J, Reum T, Bauer S, Kerb R, Hübner WD, Roots I. Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry. 1997;30(Suppl 2):94-101.
28. Brown CM, Barner JC, Shah S. Community pharmacists’ actions when patients use complementary and alternative therapies with medications. J Am Pharm Assoc. 2005;45(1):41-47.
29. Budzinski JW, Foster BC, Vandenhoek S, Arnason JT. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures. Phytomedicine. 2000;7(4):273-282.
30. Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements (VAS) to assess the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold: a randomized double blind-placebo study. Phytomedicine. 1999;6(4):217-223.
31. Calabrese C, Berman SH, Babish JG, et al. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res. 2000;14(5):333-338.
32. Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate. 1996;29(4):231-240.
33. Casper HH, Alstad AD, Tacke DB, Johnson LJ, Lloyd WE. Evaluation of vitamin K3 feed additive for prevention of sweet clover disease. J Vet Diagn Invest. 1989;1(2):116-119.
34. Castot A, Larrey D. Hepatitis observed during a treatment with a drug or a tea containing Wild Germander. Evaluation of 26 cases reported to the Regional Centers of Pharmacovigilance [Article in French]. Gastroenterol Clin Biol. 1992;16(12):916-922.
35. U.S. Food and Drug Administration. Consumer Advisory: Kava-Containing Diatary Supplements May Be Associated With Severe Liver Injury. 2002. Available at http://www.fda.gov/Food/ResourcesForYou/Consumers/ucm085482.htm. Last accessed April 19, 2010.
36. Chatterjee SS, Nöldner M, Koch E, Erdelmeier C. Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry. 1998;31(Suppl 1):7-15.
37. Chan JM, Elkin EP, Silva SJ, Broering JM, Latini DM, Carroll PR. Total and specific complementary and alternative medicine use in a large cohort of men with prostate cancer. Urology. 2005;66(6):1223-1228.
38. Christen Y. Ginkgo biloba: from traditional medicine to molecular biology. In: Packer L, Ong CN, Halliwell B (eds). Herbal and Traditional Medicine: Molecular Aspects of Health. New York, NY: Marcel Dekker Publisher; 2004: 145-164.
39. Caruso TJ, Gwaltney JM Jr. Treatment of the common cold with echinacea: a structured review. Clin Infect Dis. 2005;40(6):807-810.
40. Cheema P, El-Mefty O, Jazieh AR. Intraoperative hemorrhage associated with the use of extract of Saw Palmetto herb: a case report and review of the literature. J Intern Med. 2001;250(2):167-169.
41. Chung AS, Cho KJ, Park JD. Pharmacological and physiological effects of ginseng. In: Packer L, Ong CN, Halliwell B (eds). Herbal and Traditional Medicine: Molecular Aspects of Health. New York, NY: Marcel Dekker Publisher; 2004: 517-536.
42. Christen Y, Maixent JM. What is Ginkgo biloba extract EGb 761? An overview from molecular biology to clinical medicine. Moll Cell Biol. 2002;48(6):601-611.
43. Comhaire F, Mahmoud A. Preventing diseases of the prostate in the elderly using hormones and nutriceuticals. Aging Male. 2004;7(2):155-169.
44. Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 2004;70(4):293-298.
45. Cooper EL. Drug discovery, CAM and natural products. Evid Based Complement Alternat Med. 2004;1(3):215-217.
46. Darbinian-Sarkissian N, Darbinyan A, Otte J, et al. p27(SJ), a novel protein in St. John’s wort, that suppresses expression of HIV-1 genome. Gene Ther. 2006;13(4):288-295.
47. De Berardinis V, Moulis C, Maurice M, et al. Human microsomal epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. Mol Pharmacol. 2000;58(3):542-551.
48. De Smet PA. Herbal medicine in Europe: relaxing regulatory standards. N Engl J Med. 2005;352(12):1176-1178.
49. De Smet PA, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeconomics. 2000;18(1):1-7.
50. Debruyne F, Boyle P, Calais Da Silva F, et al. Evaluation of the clinical benefit of permixon and tamsulosin in severe BPH patients—PERMAL study subset analysis. Eur Urol. 2004;45(6):773-779.
51. Debruyne F, Koch G, Boyle P, et al. Comparison of a phytotherapeutic agent (Permixon) with an alpha-blocker (Tamsulosin) in the treatment of benign prostatic hyperplasia: a 1-year randomized international study. Eur Urol. 2002;41(5):497-506.
52. DeFeudis FV. Ginkgo Biloba Extract (EGb 761): From Chemistry to Clinic. Wiesbaden, Germany: Ullstein Medical; 1998.
53. Délos S, Carsol JL, Ghazarossian E, Raynaud JP, Martin PM. Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblast. J Steroid Biochem Mol Biol. 1995;55(3-4):375-383.
54. Demott K. St. John’s wort tied to serotonin syndrome. Clin Psychiatry News. 1998;26(3):28-29.
55. United States Congress, 103rd Congress. Dietary Supplement Health and Education Act of 1994: Public Law 103-417. October 25, 1994. Available at http://ods.od.nih.gov/about/dshea_wording.aspx. Last accessed April 21, 2010.
56. U.S. Food and Drug Administration. Dietary Supplements: Consumer Information. Available at http://www.fda.gov/Food/DietarySupplements/ConsumerInformation/ucm110417.htm. Last accessed April 19, 2010.
57. Dietz BM, Mahady GB, Pauli GF, Farnsworth NR. Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro. Brain Res Mol Brain Res. 2005;138(2):191-197.
58. Djavan B, Fong YK, Chaudry A, et al. Progression delay in men with mild symptoms of bladder outlet obstruction: a comparative study of phytotherapy and watchful waiting. World J Urol. 2005;23(4):253-256.
59. Donath F, Quispe S, Diefenbach K, Maurer A, Fietze I, Roots I. Critical evaluation of the effect of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry. 2000;33(2):47-53.
60. Draves AH, Walker SE. Determination of hypericin and pseudohypericin in pharmaceutical preparations by liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl. 2000;749(1):57-66.
61. Dreskin SC. A prescription drug packaged in China and sold as an ethnic remedy. JAMA. 2000;283(18):2393.
62. Ebadi MS. Food-drug interactions. In: Ebadi MS. Pharmacodynamic Basis of Herbal Medicine. Boca Raton, FL: CRC Press; 2001: 107-114.
63. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA. 1998;280(18):1569-1575.
64. Ernst E. The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John’s Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern Med. 2002;136(1):42-53.
65. Evans JG, Wilcock G, Birks J. Evidence-based pharmacotherapy of Alzheimer’s disease. Int J Neuropsychopharmacol. 2004;7(3):351-369.
66. Fair WR. Willet F. Whitore, Jr. Lecture: back to the future—the role of complementary medicine in urology. J Urol. 1999;162(2):411-420.
67. Fazio S, Pouso J, Dolinsky D, et al. Tolerance, safety and efficacy of Hedera helix extract in inflammatory bronchial diseases under clinical practice conditions: a prospective, open, multicentre postmarketing study in 9657 patients. Phytomedicine. 2009;16(1):17-24.
68. U.S. Food and Drug Administration. Federal Register proposed rule—68 FR12157, March 13, 2003: current good manufacturing practice in manufacturing, packaging, or holding dietary ingredients and dietary supplements. Federal Register. 2003;68(49):12157-12263.
69. U.S. Food and Drug Administration. Guidance for Industry: Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk; Small Entity Compliance Guide. Available at http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocuments/DietarySupplements/ucm072997.htm. Last accessed April 21, 2010.
70. Fessenden JM, Wittenborn W, Clarke L. Gingko biloba: a case report of herbal medicine and bleeding postoperatively from a laparoscopic cholecystectomy. Am Surg. 2001;67(1):33-35.
71. Field HL, Monti DA, Greeson JM, Kunkel EJ. St. John’s wort. Int J Psychiatry Med. 2000;30(3):203-219.
72. Fleischauer AT, Arab L. Garlic and cancer: a critical review of the epidemiologic literature. J Nutr. 2001;131(3S):1032S-1040S.
73. Fong YK, Milani S, Djavan B. Role of phytotherapy in men with lower urinary tract symptoms. Cur Opin Urol. 2005;15(1):45-48.
74. Fox FE, Niu Z, Tobia A, Rook AH. Photoactivated hypericin is an anti-proliferative agent that induces a high rate of apoptotic death of normal, transformed, and malignant T lymphocytes: implications for the treatment of cutaneous lymphoproliferative and inflammatory disorders. J Invest Dermatol. 1998;111(2):327-332.
75. Gabrielian ES, Shukarian AK, Goukasova GI, et al. A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis. Phytomedicine. 2002;9(7):589-597.
76. Gaillard Y, Blaise P, Darré A, Barbier T, Pépin G. An unusual case of death: suffocation caused by leaves of common ivy (Hedera helix). Detection of hederacoside C, alpha-hederin, and hederagenin by LC-EI/MS-MS. J Anal Toxicol. 2003;27(4):257-262.
77. Gallo M, Sarkar M, Au W, et al. Pregnancy outcomes following gestational exposure to echinacea: a prospective controlled study. Arch Intern Med. 2000;160(20):3141-3143.
78. Garges HP, Varia I, Doraiswamy PM. Cardiac complications and delirium associated with valerian root withdrawal. JAMA. 1998;280(18):1566-1567.
79. Gerber GS. Saw palmetto for the treatment of men with lower urinary tract symptoms. J Urol. 2000;163(5):1408-1412.
80. Gilroy CM, Steiner JF, Byers T, Shapiro H, Georgian W. Echinacea and truth in labeling. Arch Intern Med. 2003;163(6):699-704.
81. Gleitz J, Beile A, Wilkens P, Ameri A, Peters T. Antithrombotic action of the kava pyrone (+)-kavain prepared from Piper methysticum on human platelets. Planta Med. 1997;63(1):27-30.
82. Goepel M, Hecker U, Krege S, Rübben H, Michel MC. Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro. Prostate. 1999;38(3):208-215.
83. Gordon AE, Shaughnessy AF. Saw palmetto for prostate disorders. Am Fam Physician. 2003;67(6):1281-1283.
84. Grabley S, Thiericke R. Bioactive agents from natural sources: trends in discovery and application. Adv Biochem Eng Biotechnol. 1999;64:101-154.
85. Greeson JM, Sanford B, Monti DA. St. John’s wort (Hypericum perforatum): a review of current pharmacological, toxicological, and clinical literature. Psychopharmacology (Berl). 2001;153(4):402-414.
86. Guengerich FP. Cytochrome P450, drugs, and diseases. Mol Interv. 2003;3(4):194-204.
87. Gulick RM, McAuliffe V, Holden-Wiltse J, et al. Phase I studies of hypericin, the active compound in St. John’s wort, as an antiretroviral agent in HIV-infected adults: AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med. 1999;130(6):510-514.
88. Habib FK, Ross M, Ho CK, Lyons V, Chapman K. Serenoa repens (Permixon) inhibits the 5alpha-reductase activity of human prostate cancer cell lines without interfering with PSA expression. Int J Cancer. 2005;114(2):190-194.
89. Hare JT, Elliot DP. Grapefruit juice and potential drug interactions. Consult Pharm. 2003;18(5):466-472.
90. Health Canada. Health Canada Issues a Stop-Sale Order for All Products Containing Kava. 2002. Available at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2002-eng.php. Last accessed April 19, 2010.
91. Health Canada. Natural Health Products Regulations. Canada Gazette. 2003;2. Available at http://www.gazette.gc.ca/archives/p2/2003/2003-06-18/pdf/g2-13713.pdf. Last accessed April 19, 2010.
92. Heck AM, DeWitt BA, Lukes AL. Potential interactions between alternative therapies and warfarin. Am J Health Syst Pharm. 2000;57(13):1221-1230.
93. Hecker M, Runkel F, Voelp A. Treatment of chronic bronchitis with ivy leaf special extract—multicenter post-marketing surveillance study in 1,350 patients [Article in German]. Forsch Komplementarmed Klass Naturheilkd. 2002;9(2):77-84.
94. Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P. St. John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54(4):349-356.
95. Hofmann D, Hecker M, Völp A. Efficacy of dry extract of ivy leaves in children with bronchial asthma: a review of randomized controlled trials. Phytomedicine. 2003;10(2-3):213-220.
96. Holm E, Staedt U, Heep J, et al. The action profile of D,L-kavain: cerebral sites and sleep-wakefulness-rhythm in animals. [Article in German]. Arzneimittelforschung. 1991;41(7):673-683.
97. Hopfenmüller W. Evidence for a therapeutic effect of Ginkgo biloba special extract: meta-analysis of 11 clinical studies in patients with cerebrovascular insufficiency. Arzneimittelforschung. 1994;44(9):1005-1013.
98. Hosono T, Fukao T, Ogihara J, et al. Diallyl trisulfide suppresses the proliferation and induces apoptosis of human colon cancer cells through oxidative modification of beta-tubulin. J Biol Chem. 2005;280(50):41487-41493.
99. Huguet F, Tarrade T. Alpha 2-adrenoceptor changes during cerebral ageing: the effect of Ginkgo biloba extract. J Pharm Pharmacol. 1992;44(1):24-27.
100. Huguet F, Drieu K, Piriou A. Decreased cerebral 5-HT1A receptors during ageing: reversal by Ginkgo biloba extract (EGb 761). J Pharm Pharmacol. 1994;46(4):316-318.
101. Huntley A, Ernst E. Herbal medicines for asthma: a systematic review. Thorax. 2000;55(11):925-929.
102. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287(14):1807-1814.
103. Itil TM, Eralp E, Ahmed I, Kunitz A, Itil KZ. The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine. Psychopharmacol Bull. 1998;34(3):391-397.
104. Izzo AA, Di Carlo G, Borrelli F, Ernst E. Cardiovascular pharmacotherapy and herbal medicines: the risk of drug interaction. Int J Cardiol. 2005;98(1):1-14.
105. Jacoby D, Mohler ER. Drug treatment in intermittent claudication. Drugs. 2004;64(15):1657-1670.
106. Johnson J, Tanner A. Postmarketting surveillance: curriculum for the clinical pharmacologist. Part I: postmarketing surveillance within the continuum of the drug approval process. J Clin Pharmacol. 1993;33(10):904-911.
107. Kajiyama Y, Fujii K, Takeuchi H, Manabe Y. Ginkgo seed poisoning. Pediatrics. 2002;109(2):325-327.
108. Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry. 2003;36(6):297-303.
109. Kaplan SA, Volpe MA, Te AE. A prospective, 1-year trial using saw palmetto versus finasteride in the treatment of category III prostatitis/chronic pelvic pain syndrome. J Urol. 2004;171(1):284-288.
110. Keane FM, Munn SE, du Vivier AW, Taylor NF, Higgins EM. Analysis of Chinese herbal creams prescribed for dermatological conditions. BMJ. 1999;318(7183):563-564.
111. Kerb R, Brockmöller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin. Antimicrob Agents Chemoter. 1996;40(9):2087-2093.
112. Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr. 2004;44(6):479-488.
113. Kim ND, Kang SY, Schini VB. Ginsenosides evoke endothelium-dependent vascular relaxation of the rat aorta. Gen Pharmacol. 1994;25(6):1071-1077.
114. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J Clin Pharmacol. 1992;34(4):352-358.
115. Klemow KM, Bilbow E, Grasso D. Jones K, McDermott J, Pape E. Medicinal attributes of St. John’s wort (Hypericum perforatum). In: Packer L, Ong CN, Halliwell B (eds). Herbal and Traditional Medicine. Molecular Aspects of Health. New York, NY: Marcel Dekker Publisher; 2004: 757-780.
116. Koch E. Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts. Phytomedicine. 2005;12(1-2):10-16.
117. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4(3):206-220.
118. Koren G, Randor S, Martin S, Danneman D. Maternal ginseng use associated with neonatal androgenization. JAMA. 1990;264(22):2866.
119. Kretzschmar R, Meyer HJ, Teschendorf HJ. Strychnine antagonistic potency of pyrone compounds of the kavaroot (Piper methysticum Forst.). Experientia. 1970;26(3):283-284.
120. Krochmal R, Hardy M, Bowerman S, et al. Phytochemical assays of commercial botanical dietary supplements. Evid Based Complement Alternat Med. 2004;1(3):305-313.
121. Kudo K, Tachikawa H, Kashimoto T, Takahashi E. Properties of ginseng saponin inhibition of catecholamine secretion in bovine adrenal chromaffin cells. Eur J Pharmacol. 1998;341(2-3):139-144.
122. Kurz A, Van Baelen B. Ginkgo biloba compared with cholinesterase inhibitors in the treatment of dementia: a review based on meta-analyses by the cochrane collaboration. Dement Geriatr Cogn Disord. 2004;18(2):217-226.
123. Laakmann G, Schüle C, Baghai T, Kieser M. St. John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(Suppl 1):54-59.
124. Laliberté L, Villeneuve JP. Hepatitis after the use of germander, a herbal remedy. CMAJ. 1996;154(11):1689-1692.
125. Lança AJ. Adrenergic receptor agonists. In: Kalant H, Grant D, Mitchell J (eds). Principles of Medical Pharmacology. Toronto, Canada: Saunders Canada; 2007: 137-155.
126. Lança AJ. Functional and neurochemical organization of the central nervous system. In: Kalant H, Grant D, Mitchell J (eds). Principles of Medical Pharmacology. Toronto, Canada: Saunders Canada; 2007: 187-210.
127. Lash JP, Cardoso LR, Mesler PM, Walczak DA, Pollak R. The effect of garlic on hypercholesterolemia in renal transplant patients. Transplant Proc. 1998;30(1):189-191.
128. Lawvere S, Mahoney MC. St. John’s wort. Am Fam Physician. 2005;72(11):2249-2254.
129. Lewis JH, Ahmed M, Shobassy A, Palese C. Drug-induced liver disease. Curr Opin Gastroenterol. 2006;22(3):223-233.
130. Lewith G, Verhoef M, Koithan M, Zick SM. Developing CAM research capacity for complementary medicine. Evid Based Complement Alternat Med. 2006;3(2):283-289.
131. LexiComp. Available at http://online.lexi.com. Last accessed April 20, 2010.
132. Linde K, Barrett B, Wölkart K, Bauer R, Melchart D. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2006;(1):CD000530.
133. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D. St. John’s wort for depression: an overview and meta-analysis of randomized clinical trials. BMJ. 1996;313(7052):253-258.
134. Linde K, Mulrow CD, Berner M, Egger M. St. John’s wort for depression. Cochrane Database Syst Rev. 2005;(2):CD000448.
135. Liu JP, Zhang M, Wang WY, Grimsgaard S. Chinese herbal medicines for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2004;(3):CD003642.
136. Liu L, Yeh YY. Inhibition of cholesterol biosynthesis by organosulfur compounds derived from garlic. Lipids. 2000;35(2):197-203.
137. Madabushi R, Frank B, Drewelow B, Derendorf H, Butterweck V. Hyperforin in St. John’s wort drug interactions. Eur J Clin Pharmacol. 2006;62(3):225-233.
138. Mansfeld HJ, Höre H, Repges R, Dethlefsen U. Treatment of children with chronic airflow obstruction [Article in German]. TW Pädiatrie. 1997;8:155-157.
139. Mansfeld HJ, Höre H, Repges R, Dethlefsen U. Treatment for bronchial asthma with dry ivy leaf extract [Article in German]. Münchner Medizinesche Wochenschrift. 1998;140:26-30.
140. Markowitz JS, Donovan JL, DeVane CL, et al. Effect of St. John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA. 2003;290(11):1500-1504.
141. Marks LS, Partin AW, Epstein JI, et al. Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia. J Urol. 2000;163(5):1451-1456.
142. McHughes M, Timmermann BN. A review of the use of CAM therapy and the sources of accurate and reliable information. J Manag Care Pharm. 2005;11(8):695-703.
143. Melethil S. Proposed rule: current good manufacturing practice in manufacturing, packing, or holding dietary ingredients and dietary supplements. Life Sci. 2006;78(18):2049-2053.
144. Meredith MJ. Herbal nutriceuticals: a primer for dentists and dental hygienists. J Contemp Dent Pract. 2001;2(2):1-24.
145. Mix JA, Crews WD Jr. A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extracft EGb 761 in a sample of cognitively intact older adults: neuropsychological findings. Hum Psychopharmacol. 2002;17(6):267-277.
146. Federation of State Medical Boards of the United States. Model Guidelines for the Use of Complementary and Alternative Therapies in Medical Practice. 2002. Available at http://www.fsmb.org/pdf/2002_grpol_complementary_alternative_therapies.pdf. Last accessed April 20, 2010.
147. Muir AH, Robb R, McLaren M, Daly F, Belch JJ. The use of ginkgo biloba in Raynaud’s disease: a double-blind placebo-controlled trial. Vasc Med. 2002;7(4):265-267.
148. Müller-Jakic B, Breu W, Pröbstle A, Redl K, Greger H, Bauer R. In vitro inhibition of cyclooxygenase and 5-lypoxygenase by alkamides from Echinacea and Achillea species. Planta Med. 1994;60(1):37-40.
149. Mullins RJ. Echinacea-associated anaphylaxis. Med J Aust. 1998;168(4):170-171.
150. Nathan P. The experimental and clinical pharmacology of St. John’s wort (Hypericum perforatum, L.). Mol Psychiatry. 1999;4(4):333-338.
151. National Institutes of Health. National Center for Complementary and Alternative Medicine. What is Complementary and Alternative Medicine? Available at http://nccam.nih.gov/health/whatiscam. Last accessed April 20, 2010.
152. Natural Health Product Regulation in Canada. Health Canada. About Natural Health Product Regulation in Canada. Available at http://www.hc-sc.gc.ca/dhp-mps/prodnatur/about-apropos/index-eng.php. Last accessed April 20, 2010.
153. Natural Standard Monograph. Natural Standard Database. Andrographis paniculata. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
154. Natural Standard Monograph. Natural Standard Database. Echinacea. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
155. Natural Standard Monograph. Natural Standard Database. Garlic. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
156. Natural Standard Monograph. Natural Standard Database. Ginkgo. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
157. Natural Standard Monograph. Natural Standard Database. Ginseng. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
158. Natural Standard Monograph. Natural Standard Database. Kava. Available at http://www.naturalstandard.com. Last accessed April 20, 2010
159. Natural Standard Monograph. Natural Standard Database. Saw Palmetto. Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
160. Natural Standard Monograph. Natural Standard Database. St. John’s Wort. Available at Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
161. Natural Standard Monograph. Natural Standard Database. Valerian. Available at Available at http://www.naturalstandard.com. Last accessed April 20, 2010.
162. Ng TH, Chan YW, Yu YL, et al. Encephalopathy and neuropathy following ingestion of Chinese herbal broth containing podophyllin. J Neurol Sci. 1991;101(1):107-113.
163. Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristocholia fangchi). N Engl J Med. 2000;342(23):1686-1692.
164. Ortiz JG, Rassi N, Maldonado PM, González-Cabrera S, Ramos I. Commercial valerian interactions with [3H]Flunitrazepam and [3H]MK-801 binding to rat synaptic membranes. Phytother Res. 2006;20(9):794-798.
165. Paubert-Braquet M, Mencia Huerta JM, Cousse H, Braquet P. Effect of the lipidic lipidosterolic extract of Serenoa repens (Permixon) on the ionophore A23187-stimulated production of leukotriene B4 (LTB4) from human polymorphonuclear neutrophils. Prostaglandins Leukot Essent Fatty Acids. 1997;57(3):299-304.
166. Pellati F, Benvenuti S, Melegari M, Lasseigne T. Variability in the composition of anti-oxidant compounds in Echinacea species by HPLC. Phytochem Anal. 2005;16(2):77-85.
167. Philp RB. Herbal-Drug Interactions and Adverse Effects: An Evidence-Based Quick Reference Guide. New York, NY: McGraw-Hill Professional; 2003.
168. Piscitelli SC, Burstein AH, Welden N, Gallicano KD, Falloon J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34(2):234-238.
169. Pittler MH, Ernst E. Kava extract versus placebo for treating anxiety. Cochrane Database Syst Rev. 2003;(1):CD003383.
170. Poolsup N, Suthisisang C, Prathanturarug S, Asawamekin A, Chanchareon U. Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. J Clin Pharm Ther. 2004;29(1):37-45.
171. Ravenna L, Di Silverio F, Russo MA, et al. Effects of the lipidosterolic extract of Serenoa repens (Permixon) on human prostatic cell lines. Prostate. 1996;29(4):219-230.
172. Riedel E, Hänsel R, Ehrke G. Inhibition of gamma-aminobutyric acid catabolism by valerenic acid derivatives [Article in German]. Planta Med. 1982;46(12):219-220.
173. Robinson A, McGrail MR. Disclosure of CAM use to medical practicioners: a review of qualitative and quantitative studies. Complement Ther Med. 2004;12(2-3):90-98.
174. Rotblatt M, Ziment I. Evidence-Based Herbal Medicine. Philadelphia, PA: Hanley & Belfus; 2002.
175. Ruschitzka F, Meier PJ, Turina M, Lüscher TF, Noll G. Acute heart transplant rejection due to Saint John’s wort. Lancet. 2000;355(9203):548-549.
176. Sakamoto K, Lawson LD, Milner JA. Allyl sulfides from garlic suppress the in vitro proliferation of human A549 lung tumor cells. Nutr Cancer. 1997;29(2):152-156.
177. Sander LC, Sharpless KE, Wise SA. Dietary supplement Standard Reference Materials. Life Sci. 2006;78(18):2044-2048.
178. Santos MS, Ferreira F, Cunha AP, Carvalho AP, Riberio CF, Macedo T. Synaptosomal GABA release as influenced by valerian root extract—involvement of the GABA carrier. Arch Int Pharmacodyn Ther. 1994;327(2):220-231.
179. Schempp CM, Pelz K, Wittmer A, Schöpf E, Simon JC. Antibacterial activity of hyperforin from St. John’s wort, against multiresistant Staphylococcus aureus and gram-positive bacteria. Lancet. 1999;353(9170):2129.
180. Schempp CM, Müller KA, Winghofer B, Schöpf E, Simon JC. St. John’s Wort (Hypericum perforatum L.): a plant with relevance for dermatology [Article in German]. Hautarzt. 2002;53(5):316-321.
181. Schempp CM, Windeck T, Hezel S, Simon JC. Topical treatment of atopic dermatitis with St. John’s wort cream: a randomized, placebo controlled, double blind half-side comparison. Phytomedicine. 2003;10(Suppl 4):31-37.
182. Schulz V. Incidence and clinical relevance of interactions and side-effects of Hypericum preparations [Article in German]. Praxis. 2000;89(50):2131-2140.
183. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy: A Physician’s Guide to Herbal Medicine. 4th ed. New York, NY: Springer; 2001.
184. Schoop R, Klein P, Suter A, Johnston SL. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther. 2006;28(2):174-183.
185. Shelton RC, Keller MB, Gelenberg AJ, et al. Effectiveness of St. John’s wort in major depression: a randomized controlled trial. JAMA. 2001;285(15):1978-1986.
186. Shin JY, Song JY, Yun YS, Yang HO, Rhee DK, Pyo S. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol. 2002;24(3):469-482.
187. Siegel G, Klüssendorf D. The anti-atheroslerotic effect of Allium sativum: statistics re-evaluated. Atherosclerosis. 2000;150(2):437-438.
188. Silagy C, Neil A. Garlic as a lipid lowering agent—a meta-analysis. J R Coll Physicians Lond. 1994;28(1):39-45.
189. Singh YN. Potential for interaction of kava and St. John’s wort with drugs. J Ethnopharmacol. 2005;100(1-2):108-113.
190. Slater MD, Lauer C, Gidley-Baird A, Barden JA. Markers for the development of early prostate cancer. J Pathol. 2003;199(3):368-77.
191. Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med. 1998;339(12):806-811.
192. Sperber SJ, Shah LP, Gilbert RD, Ritchey TW, Monto AS. Echinacea purpurea for prevention of experimental rhinovirus colds. Clin Infect Dis. 2004;38(10):1367-1371.
193. Spillane PK, Fisher DA, Currie BJ. Neurological manifestations of kava intoxication. Med J Australia. 1997;167(3):172-173.
194. Spinas GA, Laffranchi R, Francoys I, David I, Richter C, Reinecke M. The early phase of glucose-stimulated insulin secretion requires nitric oxide. Diabetologia. 1998;41(3):292-299.
195. Srinivasan VS. Challenges and scientific issues in the standardization of botanical and their preparations. United States Pharmacopeia’s dietary supplement verification program: a public health program. Life Sci. 2006;78(18):2039-2043.
196. Stevinson C, Ernst E. Safety of Hypericum in patients with depression: a comparison with conventional antidepressants. CNS Drugs. 1999;11(2):125-132.
197. Stevinson C, Ernst E. Valerian for insomnia: a systematic review of randomized clinical trials. Sleep Med. 2000;1(2):91-99.
198. Stevinson C, Pittler MH, Ernst E. Garlic for treating hypercholesterolemia: a meta-analysis of randomized clinical trials. Ann Intern Med. 2000;133(6):420-429.
199. Stricker BH, Psaty BM. Detection, verification, and quantification of adverse drug reactions. BMJ. 2004;329(7456):44-47.
200. Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St. John’s wort): randomized controlled double-blind non-inferiority trial versus paroxetine. BMJ. 2005;330(7490):503.
201. Tan BKH, Zhang ACY. Andrographis paniculata and the cardiovascular system. In: Packer L, Ong CN, Halliwell B (eds). Herbal and Traditional Medicine. Molecular Aspects of Health. New York, NY: Marcel Dekker Publisher; 2004: 441-456.
202. Tang W, Eisenbrand G. Chinese Drugs of Plant Origin: Chemistry, Pharmacolgy, and Use in Traditional and Modern Medicine. Berlin; New York, NY: Springer-Verlag; 1992.
203. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA. 2003;290(21):2824-2830.
204. Teng CM, Kuo SC, Ko FN, et al. Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng. Biochim Biophys Acta. 1989;990(3):315-320.
205. Teufel-Meyer R, Gleitz J. Effect of long-term administration of Hypericum extracts on the affinity and density of central serotonergic 5-HT1 A and 5-HT2 A receptors. Pharmacopsychiatry. 1997;30(Suppl 2):113-116.
206. Thomas DR. 5-ht5A receptors as a therapeutic target. Pharmacol Ther. 2006;111(3):707-714.
207. Thompson C. Onset of action of antidepressants: results of different analyses. Hum Psychopharmacol. 2002;17(Suppl 1):S27-S32.
208. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by U.S. adults: 1997-2002. Altern Ther Health Med. 2005;11(1):42-49.
209. Tomlinson B, Chan TY, Chan JC, Crichtley JA, But PP. Toxicity of complementary therapies: an eastern perspective. J Clin Pharmacol. 2000;40(5):451-456.
210. Turner RB, Bauer R, Woelkart K, Hulsey TC, Gangemi JD. An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med. 2005;353(4):341-348.
211. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of echinacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother. 2000;44(6):1708-1709.
212. U.S. Pharmacopoeia. Saw Palmetto. Available at http://www.usp.org/USPVerified/dietarySupplements/sawpalmetto.html. Last accessed April 20, 2010.
213. Vacherot F, Azzouz M, Gil-Diez-De-Medina S, et al. Induction of apoptosis and inhibition of cell proliferation by the lipido-sterolic extract of Serenoa repens (LSESr, Permixon) in benign prostatic hyperplasia. Prostate. 2000;45(3):259-266.
214. Van Kampen J, Robertson H, Hagg T, Drobitch R. Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson’s disease. Exp Neurol. 2003;184(1):521-529.
215. Veltri RW, Marks LS, Miller MC, et al. Saw palmetto alters nuclear measurements reflecting DNA content in men with symptomatic BPH: evidence for a possible molecular mechanism. Urology. 2002;60(4):617-622.
216. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng: a systematic review of randomized clinical trials. Eur J Clin Pharmacol. 1999;55(8):567-575.
217. Vuksan V, Sievenpiper JL, Koo VY, et al. American ginseng (Panax quinquefolius L.) reduces postprandial glycemia in nondiabetic subjects and subjects with type 2 diabetes mellitus. Arch Intern Med. 2000;160(7):1009-1013.
218. Waller DP, Martin AM, Farnsworth NR, Awang DV. Lack of androgenicity of Siberian ginseng. JAMA. 1992;267(17):2329.
219. Warsh JJ, Li PP. Antidepressant and mood-stabilizing agents. In: Kalant H, Grant D, Mitchell J (eds). Principles of Medical Pharmacology. Toronto, Canada: Saunders Canada; 2007: 316-333.
220. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol a meta-analysis. Ann Intern Med. 1993;119(7 Pt 1):599-605.
221. Wilt T, Ishani A, Mac Donald R. Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2002;(3):CD001423.
222. Wolsko PM, Solondz DK, Phillips RS, Schachter SC, Eisenberg DM. Lack of herbal supplement characterization in published randomized controlled trials. Am J Med. 2005;118(10):1087-1093.
223. Xie JT, Wu JA, Mehendale S, Aung HH, Yuan CS. Anti-hyperglycemic effect of the polysaccharides fraction from American ginseng berry extract in ob/ob mice. Phytomedicine. 2004;11(2-3):182-187.
224. Yoshitake T, Iizuka R, Yoshitake S, et al. Hypericum perforatum L. (St. John’s wort) preferentially increases extracellular dopamine levels in the rat prefrontral cortex. Br J Pharmacol. 2004;142(3):414-418.
225. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients: a randomized, controlled trial. Ann Intern Med. 2004;141(1):23-27.
226. Zhu L, Gao J, Wang Y, Zhao XN, Zhang ZX. Neuron degeneration induced by verapamil and attenuated by EGb761. J Basic Clin Physiol Pharmacol. 1997;8(4):301-314.
227. Zlotta AR, Teillac P, Raynaud JP, Schulman CC. Evaluation of male sexual function in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) treated with a phytotherapeutic agent (Permixon), Tamsulosin or Finasteride. Eur Urol. 2005;48(2):269-276.
228. Pachter LM. Culture and clinical care: folk illness beliefs and behaviors and their implications for health care delivery. JAMA. 1994;271(9):690-694.
229. Avins AL, Bent S, Staccone S, et al. A detailed safety assessment of a saw palmetto extract. Complement Ther Med. 2008;16(3):147-154.
230. Linde K, Berner MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.
231. Moretti ME, Maxson A, Hanna F, Koren G. Evaluating the safety of St. John’s wort in human pregnancy. Reprod Toxicol. 2009;28(1):96-99.
232. Gardner CD, Taylor-Piliae RE, Kiazand A, Nicholus J, Rigby AJ, Farquhar JW. Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial. J Cardiopulm Rehabil Prev. 2008;28(4):258-265.
233. Vohra S, Johnston BC, Laycock KL, et. al. Safety and tolerability of North American ginseng extract in the treatment of pediatric upper respiratory tract infection: a phase II randomized, controlled trial of 2 dosing schedules. Pediatrics. 2008;122(2):e402-e410.
234. Schulze J, Raasch W, Siegers CP. Toxicity of kava pyrones, drug safety precautions—a case study. Phytomedicine. 2003;10(Suppl 4):68-73.
235. Sarris J, Kavanagh DJ, Byrne G, Bone KM, Adams J, Deed G. The Kava Anxiety Depression Spectrum Study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl). 2009;205:399-407.
236. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos. 2002;30:1153-1157.
237. Murphy K, Kubin ZJ, Shepard JN, Ettinger RH. Valeriana officinalis root extracts have potent anxiolytic effects in laboratory rats. Phytomedicine. 2010;17(8-9):674-678.
238. Brinker F. Herb contraindications and drug interactions. J Altern Complemnt Med. 2002;8(2):215-217.
239. Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Adv Data. 2004;(343):1-19.
240. National Institutes of Health. National Center for Complementary and Alternative Medicine. Statistics on Complementary and Alternative Medicine in the United States: 2007 National Health Interview Survey. Available at http://nccam.nih.gov/news/camstats/. Last accessed April 21, 2010.
Extracted from Course # 9839 • Herbal Medications: An Evidence-Based Review
Release Date: 07/01/2010
Expiration Date: 06/30/2013
PO Box 997571
Sacramento, CA 95899-7571