Throughout human history, plants have been used for medicinal purposes. In the United States, the use of botanicals has increased significantly over the past two decades. Botanical products are used by one of five Americans at an annual total cost of more than $4 billion.
In 1994, the United States Congress unanimously passed the Dietary Supplement and Health Education Act. This legislative act classifies vitamins, minerals, botanicals, and amino acids as nutritional or dietary supplements. Under this law, supplements can be marketed without proof of safety or efficacy as long as no claim is made for their use in the diagnosis, treatment, cure, or prevention of disease. Manufacturers can, however, make "structure and function" claims that a product enhances a normal body function or state such as thinking, mood, or immune function. For example, saw palmetto can be marketed to support urinary tract health but not to treat benign prostatic hyperplasia. In contrast to prescription drugs, which first must be proven safe, the US Food and Drug Administration (FDA) must first prove that a botanical preparation is unsafe before it can order that a product be taken off the market.
In the past, consumers had no guarantee of the quality of the products they purchased. They could not be certain that the plant was accurately identified; that the product was free of microbial, pesticide, and heavy metal contamination; or that all batches contained the same ingredients in the same strengths.
Such lack of consistency prompted the Institute of Medicine to call on the government to implement improved quality-control manufacturing standards for supplements, more accurate labeling requirements, and greater consumer protections. In 2007, the FDA announced that dietary supplement manufacturers must evaluate the identity, purity, strength, and composition of their products and report all serious adverse events. In 2010, the FDA greatly increased inspections of botanical sellers to ensure adherence to good manufacturing practices.
Patients should be advised to follow certain guidelines when considering whether to use botanical medicines (Table E5–1).
Table E5–1.Advice to patients using botanical medicines. |Favorite Table|Download (.pdf) Table E5–1. Advice to patients using botanical medicines.
Discuss use of all therapies with your health care practitioner.
Select formulations that have been studied in clinical trials.
Select formulations that have been independently tested for quality.
Ask your primary care provider, a pharmacist, or a trained herbalist regarding the specific botanicals you are using.
Use botanicals that are standardized to contain a specific quantity of the active ingredients when possible.
Look for a seal of approval from an independent testing agency such as USP (United States Pharmacopeia), NSF International (formerly National Sanitation Foundation), or ConsumerLab.
It should state the common and scientific names of botanical(s).
It should state the concentration or dose of the botanical(s), specify the part of the plant used to make the product (eg, leaf vs. root), provide instructions on dose and frequency.
It should state the name and address of the manufacturer.
It should state the batch or lot number and the expiration date.
Few botanicals have been studied for safety during pregnancy.
Seek advice from your primary care provider before using botanicals during pregnancy.
Discuss with your health care provider the safety profile and interactions that may occur when combining botanicals and when taking herbs plus drugs.
Report any adverse reactions to your state poison control program or the FDA.
Product Formulations & Standardization
Botanical formulations include liquids (extracts, tinctures, infusions, and decoctions) and fresh, dried, and powdered preparations. The potency of botanicals may vary widely depending on which part of the plant is used, where it is cultivated, and what variations there may be in growing conditions and methods of preparation.
To ensure a consistent percentage of the primary active ingredients across batches and brand names, standardized extracts have been developed for certain botanicals. The European scientific community has played a significant role in producing and investigating high-quality standardized extracts that contain consistent quantities of marker compounds (which may or may not be the principal active ingredients). This work has laid the foundation for conducting phase 2 and phase 3 clinical trials. The quality of research in the field is improving, although some botanical medicines have not been evaluated in controlled clinical trials.
Safety of Botanical Medicines
Although the vast majority of medicinal botanicals are safe, a few have significant toxicity, especially when used in doses much higher than those used traditionally. One example is ephedra, an extract of the plant Ephedra sinica (known in Chinese medicine as "ma huang"). This botanical has been banned in the United States due to case reports of severe and fatal reactions, including hypertension, myocardial infarction, and stroke. Ephedra contains ephedrine and pseudoephedrine which are alpha- and beta-receptor agonists that can lead to profound sympathetic nervous system stimulation and consequent increased blood pressure, vasoconstriction, increased myocardial stress, and dysrhythmia. Case reports of ephedra's toxicity occurred when the substance was taken out of the context of its traditional medical system (Chinese medicine) and used in very high doses, often in combination with caffeine for the purpose of selling over-the-counter weight loss supplements. As used in the Chinese medicine system, ephedra is used in a very low dose and in combination with multiple other herbs to treat asthma as well as other conditions and is considered safe. In fact, the vast majority of emergency department visits for adverse effects related to over-the-counter supplements are due to weight-loss and energy-boosting products.
Other cases of botanical medicine toxicity have occurred when the plant is used inappropriately, either in excess as an extract or out of the medicinal context in which it was historically developed. Botanical products have also been adulterated with prescription drugs or contaminated with harmful substances such as pesticides or heavy metals. Prescription drugs such as prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and testosterone have been detected in imported Chinese patent medicines.
Twenty-five percent of patients who take prescription medications also take at least one nonvitamin dietary supplement, creating a theoretical risk for drug-botanical or drug-supplement interactions. This figure increases to 50% in older US adults who take prescription medications. Although most potential interactions are theoretical, insignificant or not harmful, the risk of interaction must be assessed. Resources for busy clinicians to check for interactions between prescription products and supplements or botanical products are the Natural Medicines Comprehensive Database (www.naturaldatabase.com) and Natural Standard (www.naturalstandard.com). A resource for independent third-party testing of purity and safety of particular commercial products is ConsumerLab.com (www.consumerlab.com). In the case of suspected adverse interactions, clinicians should take a detailed history from the patient and, if possible, obtain a sample of the product to facilitate further analysis, if needed. All suspected adverse events should be reported to the FDA's Medwatch Program (http://www.fda.gov/Safety/MedWatch/default.htm), although it is estimated that less than 1% are actually reported.
et al. Cancer patients at risk of herb/food supplement-drug interactions: a systematic review. Phytother Res. 2014 Dec;28(12):1749–55.
et al. Emergency department visits for adverse events related to dietary supplements. N Engl J Med. 2015 Oct 15;373(16):1531–40.
et al. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol. 2013 Mar;75(3):603–18.
Review of the Evidence for Selected Botanical Medicines
Table E5–2 provides an overview of selected botanical medicines.
Table E5–2.Overview of selected botanical medicines. |Favorite Table|Download (.pdf) Table E5–2. Overview of selected botanical medicines.
| ||Leading Indications ||Dosage ||Level of Evidence1 ||Safety2 ||Interaction; Side Effects ||Comments |
|Echinacea (purple coneflower) || |
Treatment of URIs
Prevention of URIs
|500–1000 mg or 2.5–5 mL tincture three times daily || |
|I ||None known: rash, pruritus, nausea ||Avoid in patients with autoimmune disorders; avoid use > 4 weeks |
|Butterbur (Petasites hybridus) || |
|50–100 mg two times daily || |
|I ||Belching, dyspepsia ||Product must be certified pyrrolizidine alkaloid-free |
|Garlic (Allium sativum) || |
Coronary artery disease
|200–400 mg three times daily || |
|I || |
May have antiplatelet activity
|Ginkgo biloba (EGb 761, GBE) || |
|60 mg three times daily || |
|II ||Conflicting evidence about possible anti-platelet effect. ||Avoid crude ginkgo |
|Asian ginseng (Panax ginseng) ||Immune-enhancement, cognitive function ||200–600 mg once daily extract; 1–2 g crude drug ||C: multiple studies but few for any given indication ||I ||Previous reports of toxicity have been attributed to adulterants || |
|St. John's wort (Hypericum perforatum) || |
Depression: mild to moderate
|300 mg three times daily || |
|I ||Significantly induces cytochrome P450, leading to lower serum levels of certain drugs ||Cyclosporine, protease inhibitors, oral contraceptives, alprazolam, warfarin, digoxin levels reduced |
A. St. John's Wort (Hypericum perforatum)
St. John's wort is a perennial plant with a yellow flower native to Europe and naturalized to North America. It is one of the oldest medicinal botanicals of Europe. Most preparations are standardized to hypericin or hyperforin. St. John's wort inhibits serotonin, norepinephrine, and dopamine reuptake in the central nervous system and may modulate autonomic system reactivity. It is very well tolerated. Data from 35 double-blind randomized trials show that drop out and adverse event rates in patients receiving Hypericum extracts were less than for tricyclic antidepressants or selective serotonin reuptake inhibitors. Side effects include gastrointestinal upset, photosensitivity, mild headache, and restlessness. Cases of withdrawal symptoms similar to those that occur with pharmaceutical antidepressants have been described, so gradual tapering of dose is recommended when therapy is terminated. Patients are advised to avoid taking St. John's wort in combination with prescription antidepressants because there have been case reports of the serotonin syndrome. Importantly, St. John's wort also potently induces the cytochrome P450 system (isozyme CYP3A4), which may lower the blood levels of medications that are metabolized by this system (eg, alprazolam, ethinyl estradiol, warfarin, cyclosporine, statins, and indinavir). St John's wort can also lower the serum level of medications by increasing activity of the p-glycoprotein transporter system, thereby increasing drug excretion through the gastrointestinal mucosa.
St. John's wort has been studied in thousands of patients for the treatment of depression. Most of the more than 60 randomized controlled clinical trials, systematic reviews, and meta-analyses, including a 2008 Cochrane review, have shown that St. John's wort is more effective than placebo, is as effective as prescription antidepressants for the treatment of mild to moderate depression, and has fewer side effects than pharmaceutical antidepressants. A 2015 meta-analysis of 66 studies involving more than 15,000 patients found St. John's wort as effective for the treatment of depression as other drug classes (ie, tricyclic, selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, norepinephrine reuptake inhibitor, and noradrenergic and specific serotonergic antidepressants), with significantly fewer dropouts due to side effects. In addition, in a randomized controlled trial involving 154 patients, St. John's wort performed better than citalopram in preventing relapse and recurrence of depression. Preliminary evidence suggests it is effective for depression with atypical features as well, but large trials are lacking. An economic evaluation of St. John's wort showed substantial cost savings compared to venlafaxine ($359.66 per patient) and sertraline ($202.56 per patient) as well as gained quality of life years (0.08-0.12 QALYs over 72 weeks).
et al. Better tolerability of St. John's wort extract WS 5570 compared to treatment with SSRIs: a reanalysis of data from controlled clinical trials in acute major depression. Int Clin Psychopharmacol. 2010 Jul;25(4):204–13.
et al. Efficacy and acceptability of pharmacologic treatments for depressive disorders in primary care: a systematic review and network meta-analysis. Ann Fam Med. 2015 Jan–Feb;13(1):69–79.
et al. St John's wort use in Australian general practice patients with depressive symptoms: their characteristics and use of other health services. BMC Complement Altern Med. 2014 Jun 26;14:204.
et al. An update on the ability of St. John's wort to affect the metabolism of other drugs. Expert Opin Drug Metab Toxicol. 2012 Jun;8(6):691–708.
J. St. John's wort for the treatment of psychiatric disorders. Psychiatr Clin North Am. 2013 Mar;36(1):65–72.
et al. Duration of response after treatment of mild to moderate depression with Hypericum
extract STW 3-VI, citalopram
and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine. 2011 Jun 15;18(8–9):739–42.
et al. Economic evaluation of St. John's wort (Hypericum perforatum
) for the treatment of mild to moderate depression. J Affect Disord. 2013 Jun;148(2–3):228–34.
Garlic is one of the most popular medicinal herbs in Europe and the United States. It has been used since antiquity for the treatment of cardiovascular and infectious diseases. Several mechanisms for garlic's beneficial effects on cardiovascular disease have been proposed: decreased platelet aggregation and adhesion, increased fibrinolysis, antioxidant activity, blood pressure lowering, and decreased low-density lipoprotein (LDL) cholesterol synthesis.
Garlic is approved by the German Federal Health Agency Commission E and the European Scientific Cooperative on Phytotherapy for the treatment of hyperlipidemia and atherosclerosis. Garlic is available in many different formulations (dried, powdered, oils). The most frequently studied form is dehydrated garlic powder extract. Many products are standardized to a certain percentage of allicin, the ingredient historically believed responsible for both its odor and much of its therapeutic benefit, although it is likely that the many other sulfur-containing moieties and other compounds in garlic contribute to the therapeutic effects.
Garlic is well tolerated and apparently safe for long-term use. In addition to the well-known breath and body odor, common side effects include gastrointestinal upset, nausea, and flatulence.
There is inconsistent information about the effects of garlic on cytochrome P450 3A4 (CYP3A4) isoenzymes. Some garlic preparations containing allicin appear to induce activity of CYP3A4. This was demonstrated in one small trial that showed a significant reduction in saquinavir levels, a CYP3A4 substrate. Because garlic has some antiplatelet activation activity, there is a theoretical risk of increased bleeding, especially if taken with aspirin, anticoagulants, or NSAIDs. However, a 2006 study of 48 patients taking warfarin randomized to aged garlic extract or placebo for 12 weeks did not report any increased bleeding in those taking garlic. In addition, a 2008 study showed no effect of garlic on warfarin pharmacokinetics in healthy volunteers. The effect of garlic on bleeding risks in patients taking the new (or novel) anticoagulants is unknown. No changes in platelet function were noted in healthy volunteers after ingesting raw garlic and garlic oil, but nevertheless some clinicians recommend stopping garlic 1–2 weeks prior to undergoing elective surgery.
Consistent with prior studies, two meta-analyses from 2015 showed garlic has the capacity to lower blood pressure in hypertensive patients. A previous double-blind, placebo-controlled randomized trial showed that an aged garlic extract worked synergistically with antihypertensive treatment to lower systolic blood pressure by 10 mm Hg and diastolic blood pressure by 4 mm Hg in hypertensive patients. This extract was very well tolerated by patients. A 2012 Cochrane review based on two trials also reported blood pressure benefit from garlic but due to statistical concerns concluded that its true impact of on lowering blood pressure was difficult to determine. In 2013, a 12-week randomized double-blinded placebo-controlled trial of 79 patients showed a mean systolic blood pressure reduction of 11.8 mm Hg.
An interesting study attesting to its vascular effects looked at garlic's effect in patients with the hepatopulmonary syndrome. In this study, 41 patients were randomized to either garlic supplement or placebo and monitored for 18 months. Baseline PaO2 increased and A-a gradient decreased significantly in the experimental group, two-thirds of them experienced resolution of their hepatopulmonary syndrome, and their mortality was dramatically reduced.
There is conflicting evidence of the effect of garlic on serum lipids. For example, one meta-analysis of 29 trials published in 2009 concluded that garlic significantly lowered total cholesterol and triglycerides but had no effect on LDL or high-density lipoprotein (HDL) cholesterol, whereas another meta-analysis of 13 trials published the same year concluded that garlic had no effect on any lipid measures. The largest meta-analysis to date concludes that it produces a modest but significant benefit for lowering total and LDL cholesterol. One possible explanation for these inconsistent results is the lack of standardization of garlic preparations. Among powdered preparations, the allicin content of brands used in trials varies as much as 230-fold.
Prior to 2013 there were a few small and medium-sized studies showing reduced progression of atherosclerotic plaque and attenuation of age-related loss of vascular elasticity with garlic use; however, methodologic concerns have been raised with these studies (eg, accuracy of ultrasound measurement of plaque). A randomized controlled trial of 65 firefighters (chosen because of higher cardiovascular risk in this occupational group) showed that aged garlic extract and coenzyme supplementation significantly benefitted vascular elasticity and endothelial function and reduced progression of coronary artery atherosclerosis.
Numerous observational studies have suggested that regular consumption of garlic might reduce the risk of developing certain malignancies, but conclusions from the few prospective trials are unclear. A 2014 meta-analysis concluded that there appears to be an association with garlic intake and reduction in gastric cancer but further studies are needed. Another 2015 meta-analysis of case-control studies concluded high allium vegetable consumption likely decreases gastric cancer risk. However, two meta-analyses from 2014 did not find a decreased risk of colorectal cancer with garlic intake.
One well-designed study of 146 people showed a greater than 50% reduction in the number of upper respiratory infections experienced in the group taking supplemental garlic and, among those in whom upper respiratory infections developed, only one-third as many days of illness. Another randomized, double-blind, placebo-controlled study of cold and flu episodes in 120 people over 3 months showed 58% fewer work days missed, 21% fewer symptoms and improved NK and gamma-delta T-cell function for the experimental group ingesting an aged garlic extract daily. A 2014 Cochrane Review looking at garlic for the common cold believed there was insufficient evidence supporting its use.
In chronic viral hepatitis, a randomized, double-blind, placebo-controlled trial of 88 patients looked at the use of garlic oil in addition to pharmacologic therapy and showed significant reductions in alanine transaminase (ALT) levels. Similarly, an aqueous garlic extract was effective and well tolerated for treating yeast stomatitis caused by denture wear in a randomized clinical trial of 40 elders.
et al. Consumption of garlic and risk of colorectal cancer: an updated meta-analysis of prospective studies. World J Gastroenterol. 2014 Nov 7;20(41):15413–22.
et al. Meta-analysis: does garlic intake reduce risk of gastric cancer? Nutr Cancer. 2015;67(1):1–11.
et al. Beneficial effects of aged garlic extract and coenzyme Q10 on vascular elasticity and endothelial function: the FAITH randomized clinical trial. Nutrition. 2013 Jan;29(1):71–5.
et al. Efficacy and tolerability of diphenyl-dimethyl-dicarboxylate plus garlic oil in patients with chronic hepatitis. Int J Clin Pharmacol Ther. 2012 Nov;50(11):778–86.
et al. Garlic for the common cold. Cochrane Database Syst Rev. 2014 Nov 11;11:CD006206.
et al. Supplementation with aged garlic extract improves both NK and γδ-T cell function and reduces the severity of cold and flu symptoms: a randomized, double-blind, placebo-controlled nutrition intervention. Clin Nutr. 2012 Jun;31(3):337–44.
et al. Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial. Eur J Clin Nutr. 2013 Jan;67(1):64–70.
et al. Effect of garlic on serum lipids: an updated meta-analysis. Nutr Rev. 2013 May;71(5):282–99.
et al. Major dietary factors and prostate cancer risk: a prospective multicenter case-control study. Nutr Cancer. 2011;63(1):21–7.
et al. Garlic for the prevention of cardiovascular morbidity and mortality in hypertensive patients. Cochrane Database Syst Rev. 2012 Aug 15;8:CD007653.
et al. Allium vegetable intake and gastric cancer: a case-control study and meta-analysis. Mol Nutr Food Res. 2015 Jan;59(1):171–9.
et al. Aged garlic extract and coenzyme Q10 have favorable effect on inflammatory markers and coronary atherosclerosis progression: A randomized clinical trial. J Cardiovasc Dis Res. 2012 Jul;3(3):185–90.
et al. Allium vegetables and garlic supplements do not reduce risk of colorectal cancer, based on meta-analysis of prospective studies. Clin Gastroenterol Hepatol. 2014 Dec;12(12):1991–2001.
The dried leaf of the ginkgo tree has been used medicinally for thousands of years. Multiple pharmacologically active compounds have been isolated from ginkgo. Flavonoids have antioxidant and free radical scavenging ability and terpene lactones have platelet-activating factor antagonist activity. In addition, ginkgo extracts increase the production of nitric oxide and activate certain central neurotransmitters, including the cholinergic system, which may contribute to their beneficial effects on memory and cognition. EGb 761, the formulation that has been studied most extensively, is standardized to contain 24% flavonoid glycosides and 6% terpene lactones.
In general, ginkgo is well tolerated in healthy adults at recommended doses for up to 6 months. Allergic skin reactions, gastrointestinal disturbances, and headaches occur in less than 2% of patients. There are theoretical concerns about a risk of increased bleeding because antiplatelet activating factor activity has been demonstrated in vitro. Nearly 20 cases of increased bleeding in patients taking ginkgo have been reported, but establishing a causal relationship is challenging because many of these patients had other risk factors including age and medications such as aspirin, NSAIDs, or warfarin. Of note, no excess bleeding complications have been reported in clinical trials and differences in coagulation, platelet function, or pharmacokinetics have not been reported in healthy volunteers taking warfarin nor in men taking ticlopidine. Ginkgo should still be used cautiously in patients with bleeding disorders or who are taking aspirin, NSAIDs, warfarin or other anticoagulants, or other botanicals that may increase the risk of bleeding.
More than 400 studies over the past 30 years have investigated ginkgo's ability to improve blood flow in a variety of conditions, including memory impairment, dementia, peripheral vascular disease, Raynaud phenomenon, migraine headache, and acute mountain sickness. A standardized form of ginkgo leaf extract (EGb 761) is approved by the German Commission E for the treatment of cognitive impairment and intermittent claudication.
Over the past several decades, there have been conflicting data regarding the effect of Gingko biloba on cognition. Early studies that assessed ginkgo's efficacy on cognitive function in the elderly showed a modest improvement when compared with placebo. The longest of these studies (1 year) showed stabilization of cognitive and functional abilities in 309 demented patients treated with EGb 761 compared with placebo, with no differences in adverse outcomes. A double-blind randomized controlled trial of 118 elders over 85 years of age (when medication adherence was taken into account), a larger (n = 400) 2007 double-blind randomized controlled trial, and a small (n = 60) double-blind randomized controlled trial all concluded that low-dose Ginkgo biloba produced effects equal to low-dose donepezil in patients aged 50–80 years with mild or moderate dementia. A 2009 review found consistent evidence of benefit for specific cognitive functions (eg, long-term verbal and nonverbal memory, selective attention, and some executive processes). In 2010, two meta-analyses were published. A bivariate meta-analysis of six qualifying studies that claimed to fully account for the baseline cognitive changes that would be expected in cohorts of Alzheimer dementia patients concluded that there was a significant benefit of Ginkgo biloba on their symptoms. In 2012, two of three additional large randomized controlled trials showed benefit from ginkgo on cognitive and neuropsychiatric symptoms. Similarly, a meta-analysis of nine trials looking at several types of dementia found significant benefit of Ginkgo biloba for Alzheimer dementia. A 2014 randomized, controlled trial involving 160 patients with mild cognitive impairment who were treated with EGb721 120 mg twice a day orally found a reduction in neuropsychiatric symptoms compared to placebo at 24 weeks. A 2015 meta-analysis reviewed nine trials of 22–26 weeks' duration and concluded that the ginkgo leaf extract EGb 761 dosed at 240 mg orally daily was able to stabilize or slow decline in patients with dementia and cognitive impairment, particularly those with neuropsychiatric symptoms.
On the other hand, one early (2007) systematic review concluded that ginkgo did not have predictable and clinically significant benefits in patients with dementia. A 2009 Cochrane review concluded that use of Ginkgo biloba appears safe, but the evidence that it has clinically significant benefit for people with dementia or cognitive impairment was inconsistent. A well-designed, large NIH-funded study published in 2012 showed that ginkgo (EGb721 120 mg twice a day orally) did not prevent or impede further cognitive decline in dementia in more than 3000 elderly persons with normal or mildly impaired cognitive function who were monitored for a mean of 6 years. A 2013 double-blind placebo-controlled randomized trial of ginkgo for chemotherapy-related cognitive dysfunction in 166 women showed no benefit for the experimental group. In their 2014 Guidelines for Complementary and Alternative Medicine use in Multiple Sclerosis, the American Academy of Neurology lists ginkgo as ineffective for improving cognition in multiple sclerosis.
In summary, there is conflicting data on the effect of Ginkgo biloba on cognition, and further studies are required to elucidate its effectiveness for this indication.
A meta-analysis of six trials examining the use of Ginkgo biloba as adjunctive therapy for chronic schizophrenia concluded that ginkgo significantly improves both total and negative symptoms of chronic schizophrenia. Also relevant to this patient group is a randomized, double-blind, placebo-controlled trial of 157 people that showed a significant reduction in tardive dyskinesia symptoms.
Ginkgo has also been evaluated for its effect on intermittent claudication. A meta-analysis of 9 randomized, placebo-controlled, double-blinded trials of patients treated with EGb761 showed a modest treatment effect in the increase of pain-free walking distance in favor of ginkgo over placebo. A 2013 Cochrane review of 14 randomized controlled trials concluded that the walking distance benefit given by ginkgo (64.5 meters on treadmill) was of questionable clinical significance. Importantly, a secondary analysis of the large Ginkgo Evaluation of Memory (GEM) Study found significantly fewer events related to peripheral vascular disease (ie, vascular surgery or amputation) in the ginkgo arm.
There is insufficient research to make conclusions regarding the efficacy of ginkgo in treating acute mountain sickness, tinnitus, Raynaud phenomenon, or migraine headache. Two studies with a total of 119 patients showed benefit of ginkgo on age-related macular degeneration; however, a Cochrane review concludes further research is needed. A 2014 randomized, controlled trial of the effect of Ginkgo biloba extract on periodontal disease showed a significant reduction in pathogens in the treated group; this may be an interesting area of further study.
et al. The use of Ginkgo biloba for the prevention of chemotherapy-related cognitive dysfunction in women receiving adjuvant treatment for breast cancer, N00C9. Support Care Cancer. 2013 Apr;21(4):1185–92.
et al; American Academy of Neurology. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 Jul 30;81(5):463–9. Erratum in: Neurology. 2013 Nov 26;81(22):1968.
et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120.
et al. Effects of Ginkgo biloba extract on periodontal pathogens and its clinical efficacy as adjuvant treatment. Chin J Integr Med. 2014 Oct;20(10):729–36.
et al. Efficacy and safety of Ginkgo biloba extract EGb 761 in mild cognitive impairment with neuropsychiatric symptoms: a randomized, placebo-controlled, double-blind, multi-center trial. Int J Geriatr Psychiatry. 2014 Oct;29(10):1087–95.
et al. Ginkgo biloba
extract EGb 761® in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012 Jun;46(6):716–23.
et al; for the GOTADAY Study Group. Efficacy and tolerability of a once daily formulation of Ginkgo biloba
extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial. Pharmacopsychiatry. 2012 Mar;45(2):41–6.
et al. Ginkgo biloba
for intermittent claudication. Cochrane Database Syst Rev. 2013 Jun 6;6:CD006888.
et al. Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimer Dis. 2015;43(2):589–603.
et al; GuidAge Study Group. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol. 2012 Oct;11(10):851–9.
et al. Effects of Ginkgo biloba
in dementia: systematic review and meta-analysis. BMC Geriatr. 2010 Mar 17;10:14.
et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014 Mar 25;82(12):1083–92.
et al. Extract of Ginkgo biloba
treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011 May;72(5):615–21.
The Echinacea genus originated in Eastern North America and these plants were used extensively by Native American people, then later by early US settlers and American Eclectic physicians. They continue to be popular today, especially for use in preventing and treating upper respiratory tract infections. Three species in particular (E purpurea, E angustifolia, and E pallida) are used medicinally. Preparations are made from roots, above-ground parts (stems, leaves, and flowers), or a combination of both. Multiple forms are available over-the-counter, including capsules, fresh pressed juice, tinctures, and teas. Differences in species, growing conditions, plant parts used, and extraction procedures can result in differences in chemical composition and biologic activity. Several active ingredients have been identified, most notably alkamides. Dozens of in vitro, animal, and human studies show that Echinacea stimulates the immune system. Echinacea is very well-tolerated but should not be used by persons with allergy to members of the Asteraceae family (eg, ragweed, daisy, marigold), and there may be an increased incidence of allergic reactions in atopic patients. Some experts consider Echinacea to be contraindicated in patients with autoimmune disease because of the theoretical risk of immune stimulation.
There have been two meta-analyses and two Cochrane reviews examining the dozens of studies using Echinacea preparations for prevention and treatment of upper respiratory tract infections.
An early (2006) Cochrane review concluded that (1) the benefits of Echinacea preparations for prevention are inadequately researched; (2) there is some evidence that preparations based on the aerial parts of E purpurea might be effective for the early treatment of colds in adults; however, the Echinacea preparations tested in various clinical trials differed greatly. A later meta-analysis of 14 trials concluded that Echinacea preparations decreased the odds of a patient contracting a cold by 58% and decreased the duration of a cold by 1.4 days. A smaller meta-analysis, that only included the 3 trials involving experimentally induced upper respiratory tract infection, found the likelihood of developing a clinical cold was 55% higher in patients treated with placebo than those treated with Echinacea. One of the studies included in this meta-analysis was a well-designed, 2005 trial that studied three different E angustifolia root preparations for the prevention and treatment of laboratory-induced rhinovirus infections. Four hundred thirty-seven volunteers were randomized to receive either prophylaxis (beginning 7 days before a challenge with rhinovirus) or treatment (beginning at the time of viral challenge), with one of the three different Echinacea preparations. No statistically significant effects were seen on rates of infection or severity of symptoms in patients taking the botanical. The Echinacea used in this trial was well characterized; however, many clinicians point out that the dose used was much lower than that used in routine practice. A 2010 randomized controlled trial used more traditional higher doses; however, it also failed to find benefit of Echinacea for reducing severity or duration of the common cold. Interestingly, additional analysis of this large trial, which was also designed to examine for a placebo effect, showed that the subgroup of patients who believed in the effectiveness of Echinacea and received placebo pills did experience a shorter course of illness, by 2.58 days, compared to those who received no pills. Finally, a 2014 Cochrane review evaluated 12 studies for prevention of colds. With consistent results, none of the trials individually showed a reduction in colds with Echinacea. However, because the authors believed the individual trials underpowered, the data were pooled and, regardless of the Echinacea product used, there was a slight reduction in colds overall in the treatment group versus the placebo group. But the same review did not find a benefit in Echinacea used for treatment of colds.
et al. Placebo effects and the common cold: a randomized controlled trial. Ann Fam Med. 2011 Jul–Aug;9(4):312–22.
et al. Safety and efficacy profile of Echinacea purpurea to prevent common cold episodes: a randomized, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med. 2012;2012:841315.
et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2014;2:CD000530.
et al. Echinacea for preventing and treating the common cold. JAMA. 2015 Feb 10;313(6):618–9.
et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD000530.
et al. Evaluation of Echinacea
for the prevention and treatment of the common cold: a meta-analysis. Lancet Infect Dis. 2007 Jul;7(7):473–80.
et al. Randomised, double blind, placebo-controlled trial of Echinacea
supplementation in air travellers. Evid Based Complement Alternat Med. 2012;2012:417267.
Butterbur (Petasites hybridus) is a perennial plant native to Europe with a history of medicinal use dating back 2000 years to ancient Greece. Its key active constituents are petasin and isopetasin and mechanisms of action are anti-spasmodic effect and anti-inflammatory effect (via inhibition of leukotriene synthesis). Hepatotoxic pyrrolizidine alkaloids are present in the raw unprocessed plant so medicinal preparations must be certified to be free of these compounds before they can be used. Side effects include stomach upset, belching, and fatigue. Caution should be used in patients with allergies to other plant members of the Asteraceae family (see above).
There have been three randomized controlled trials and one open-label study conducted on butterbur for the prevention of migraine including 473 patients in total. All studies were carried out for 12-16 weeks and all showed substantial benefit. Between 45% and 77% of migraine patients in these studies experienced a 50% or greater reduction in the frequency of their migraines. The 75 mg twice daily dose was shown to be superior to 50 twice daily in one study (doses standardized to 15% petasin plus isopetasin). In 2012, the American Academy of Neurology included butterbur in their management guidelines for migraine prevention.
There have been several trials and one systematic review examining the effect of butterbur on allergic rhinitis. Three trials showed superiority to placebo, two trials showed noninferiority to antihistamines (fexofenadine and cetirizine) and one trial was negative, showing no benefit compared to placebo. The review concludes there is "encouraging evidence" for butterbur as a treatment for seasonal allergic rhinitis.
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et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1346–53.
LX. Complementary and alternative medicine for allergic rhinitis. Curr Opin Otolaryngol Head Neck Surg. 2009 Jun;17(3):226–31.