e4-03: Botanical Medicines

Table e4–2 provides an overview of selected botanical medicines.

St. John's wort is a perennial plant with a yellow flower native to Europe and naturalized to North America. 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. 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 like 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 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 may have fewer side effects than pharmaceutical antidepressants. A 2021 meta-review found a significant reduction of depressive symptoms in major depressive disorder compared to placebo. A 2017 meta-analysis of 27 studies involving more than 3800 patients found St. John's wort to be as effective for the treatment of depression as selective serotonin reuptake inhibitors, with significantly fewer dropouts. Some 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 quality-adjusted life-years [QALYs] over 72 weeks).

Garlic is a popular medicinal herb 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 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 compound historically believed responsible for both its odor and its therapeutic benefit, although it is likely that the many other compounds in garlic contribute to the therapeutic effects. Garlic is well tolerated and generally 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. While these risks have largely been discussed through case reports and findings in animal studies, it is recommended that its consumption be stopped at least 10 days before surgery. The effect of garlic on bleeding risks in patients taking direct-acting oral anticoagulants is unknown.

1. Hypertension

Prior studies have suggested that garlic has the capacity to lower blood pressure in hypertensive patients, but systematic reviews are unable to determine its true impact. In 2018, a 12-week randomized double-blinded placebo-controlled trial of 49 patients showed that an aged garlic extract lowered systolic blood pressure by 10 mm Hg and diastolic blood pressure by 5 mm Hg.

An interesting study attesting to its vascular effects looked at garlic's effect in patients with hepatopulmonary syndrome. In this study, 41 patients were randomized to either garlic supplement or placebo and monitored for 18 months. In the experimental group, baseline PaO₂ increased and A-a gradient decreased significantly, two-thirds of patients experienced resolution of their hepatopulmonary syndrome, and mortality was reduced.

2. Hyperlipidemia

There is conflicting evidence of the effect of garlic on serum lipids. A 2018 meta-analysis concluded that garlic produces a modest but significant benefit for lowering total and LDL cholesterol. Explanations for inconsistent results include the lack of standardization of garlic preparations, as well as how humans metabolize them.

3. Atherosclerosis

There are several small studies showing reduced progression of atherosclerotic plaques with garlic use. The most recent is a 2018 randomized controlled trial of 92 patients with obesity in which arterial stiffness and markers of endothelial function (high-sensitivity C-reactive protein, LDL, plasminogen activator inhibitor 1) were significantly reduced in those taking a garlic extract. In contrast, a small 2016 randomized controlled trial of 26 individuals with type 2 diabetes did not find improvements in endothelial function, vascular inflammation, oxidative stress, or insulin resistance after a 4-week treatment with an aged garlic extract.

4. Cancer

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, given the poor quality of studies, as suggested by a 2018 meta-analysis and systematic review. Another 2018 analysis of two large prospective US cohort studies found no association between high garlic intake and gastric cancer as well as Helicobacter pylori infection. Given the number of in vitro studies that have suggested its antitumor and apoptotic potential, garlic continues to be an HDS of significant interest in the treatment of different cancers.

5. Hepatic Dysfunction

There are small and few studies in this domain. One well-designed study of 75 people showed that daily ingestion of a fermented garlic extract for 12 weeks resulted in improvements in liver biochemical tests (serum GGT and ALT levels in adults) without reported adverse side effects. These findings may have implications for individuals with mild hepatic dysfunction, such as that seen with alcohol liver disease and nonalcoholic fatty liver disease.

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. EGb761, 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. 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 or 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 (EGb761) is approved by the German Commission E for the treatment of cognitive impairment and intermittent claudication.

1. Cognitive Function

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. A 2017 systematic review came to the more cautious conclusion that G biloba is potentially beneficial for the improvement of cognitive function and safe for use in patients with mild cognitive impairment or Alzheimer disease but that more research is warranted due to methodologic quality of some trials. This was supported by another 2018 meta-analysis of randomized controlled trials studying EGb761 in the treatment of dementia; this study found that 22- to 24-week treatment with a standardized 240 mg EGb761 dose may lead to improvements in behavioral and psychological symptoms of dementia, as also further supported by significant decreases in caregiver distress. In addition, another 2018 review found that this standardized extract also may alleviate tinnitus and dizziness that are often seen as concomitant symptoms in patients with dementia. A 2020 updated review noted that while G biloba may be able to improve the cognitive function in patients suffering from mild dementia/cognitive decline when given for more than 24 weeks and appropriate dosage (240 mg/day), there is very little data on the long-term administration.

In summary, there are conflicting data on the effect of G biloba on cognition; however, with the paucity of options in the treatment of mild cognitive decline, ginkgo may be considered an option.

2. Schizophrenia

Prior meta-analyses and reviews of trials examining the use of G biloba as adjunctive therapy for chronic schizophrenia have found that that ginkgo significantly improves both total and negative symptoms of chronic schizophrenia when used as an adjunct to conventional pharmacologic approaches. This still requires further prospective investigation.

3. Claudication

Ginkgo has also been evaluated for its effect on intermittent claudication. Prior meta-analyses of patients treated with EGb761 have shown a modest treatment effect in the increase of pain-free walking distance in favor of ginkgo over placebo, although the clinical significance of these findings is unclear. 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.

4. Other Conditions

There is insufficient research to make conclusions regarding the efficacy of ginkgo in treating acute altitude 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.

The Echinacea genus originated in Eastern North America, and these plants were used extensively by Native American people and 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 (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.

Prior meta-analyses and Cochrane reviews examining studies using Echinacea preparations for prevention and treatment of upper respiratory tract infections have found 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 by decreasing the incidence and duration of the common cold.

A large 2016 prevention trial and a large 2015 meta-analysis of prevention trials both concluded that Echinacea has a clear beneficial effect. The 2016 prevention trial was a double-blinded, randomized, placebo-controlled trial of Echinacea in which 755 healthy people who averaged at least two colds per year were followed for 4 months while taking either an Echinacea purpurea extract three times daily or a placebo. Those in the Echinacea arm experienced 58% (P < 0.0001) fewer days with cold symptoms despite the experimental group reporting having significantly more colds annually at baseline. Those in the experimental group also had significantly fewer cold recurrences and used significantly less over-the-counter pharmaceutical medication to treat cold symptoms. The 2015 meta-analysis of prevention trials included six clinical studies with a total of 2458 participants and found a relative risk of 0.65 (P < 0.0001) for upper respiratory tract infection with Echinacea use as well as a large reduction in risk of complications (including pneumonia).

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. Nonetheless, monitoring of liver enzyme levels should be considered in patients taking butterbur. 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).

1. Migraine

There have been several studies conducted on butterbur for the prevention of migraine. All studies were carried out for 12–16 weeks and all showed substantial benefit. In 2012, the American Academy of Neurology as well as the American Headache Society began including butterbur in their management guidelines for migraine prevention; however, concerns over hepatotoxicity with butterbur resulted in these guidelines being retired. Clinicians are urged to consider not recommending butterbur for migraine prophylaxis until a reliable process of resolving its associated toxicities has been developed.

2. Allergic Rhinitis

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.