Case Study

A 65-year-old man with a history of coronary artery disease, high cholesterol, type 2 diabetes, and hypertension presents with a question about a dietary supplement. He is in good health, exercises regularly, and eats a low-fat, low-salt diet. His most recent laboratory values show that his low-density lipoprotein (LDL) cholesterol is still slightly above goal at 120 mg/dL (goal < 100 mg/dL) and his hemoglobin A_1C is well controlled at 6%. His blood pressure is also well controlled. His medications include simvastatin, metformin, benazepril, and aspirin. He also regularly takes a vitamin B complex supplement and coenzyme Q10. He asks you if taking a garlic supplement could help to bring his LDL cholesterol down to less than 100 mg/dL. What are two rationales for why he might be using a coenzyme Q10 supplement? Are there any supplements that could increase bleeding risk if taken with aspirin?

Dietary Supplements & Herbal Medications: Introduction

The medical use of plants in their natural and unprocessed form undoubtedly began when the first intelligent animals noticed that certain food plants altered particular body functions. While there is a great deal of historical information about the use of plant-based supplements, there is also much unreliable information from poorly designed clinical studies that do not account for randomization errors, confounders, and—most importantly—a placebo effect that can contribute 30–50% of the observed response. Since the literature surrounding dietary supplements is evolving and much of it is not peer-reviewed, it is recommended that reputable evidence-based resources be used to help guide treatment decisions. An unbiased and regularly updated compendium of basic and clinical reports regarding botanicals is Pharmacists Letter/Prescribers Letter Natural Medicines Comprehensive Database (see references). Another evidence-based resource is Natural Standard, which includes an international, multidisciplinary collaborative website, http://www.naturalstandard.com. Unfortunately, the evidence available to these objective and unbiased evaluators is rarely adequate to permit clear conclusions. As a result, all statements regarding positive benefits should be regarded as preliminary and even conclusions regarding safety should be considered tentative at this time.*

For legal purposes, "dietary supplements" are distinguished from "prescription drugs" derived from plants (morphine, digitalis, atropine, etc) by virtue of being available without a prescription and, unlike "over-the-counter medications," are legally considered dietary supplements rather than drugs. This distinction eliminates the need for proof of efficacy and safety prior to marketing and also places the burden of proof on the Food and Drug Administration (FDA) to prove that a supplement is not safe before its use can be restricted or removed from the market. Although manufacturers are prohibited from marketing unsafe or ineffective products, the FDA has met significant challenges from the supplement industry largely due to the strong lobbying effort by supplement manufacturers and the variability in interpretation of the Dietary Supplement Health and Education Act (DSHEA). DSHEA defines dietary supplements as vitamins, minerals, herbs or other botanicals, amino acids or dietary supplements used to supplement the diet by increasing dietary intake, or concentrates, metabolites, constituents, extracts, or any combination of these ingredients. For the purposes of this chapter, plant-based substances and synthetic purified chemicals will be referred to as dietary supplements. Among the purified chemicals, glucosamine, coenzyme Q10, and melatonin are of significant pharmacologic interest.

This chapter provides some historical perspective and describes the evidence provided by randomized, double-blind, placebo-controlled trials of several of the most commonly used agents in this class. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9.

*The industry marketing these materials is replacing the terms "herbal medication" and "botanical medication" with the term "dietary supplement" in order to avoid legal liability and governmental regulation. For the purposes of this chapter they are identical.

Historical & Regulatory Factors

Under the DSHEA, dietary supplements are not considered over-the-counter drugs in the USA but rather food supplements. Although dietary supplements are regulated as food, consumers may use them in the same fashion as drugs and even use them in place of drugs or in combination with drugs.

In 1994, the United States Congress, influenced by growing "consumerism" as well as strong manufacturer lobbying efforts, passed the DSHEA. DSHEA required the establishment of Good Manufacturing Practice (GMP) standards for the supplement industry; however, it was not until 2007 that the FDA issued a final rule on the proposed GMP standards. This 13-year delay allowed supplement manufacturers to self-regulate the manufacturing process and resulted in many instances of adulteration, misbranding, and contamination. Therefore, much of the criticism regarding the dietary supplement industry involves a lack of product purity and variations in potency. Under the new GMP standards, large dietary supplement manufacturers had until June 2008 to comply with the GMP rule and smaller manufacturers until 2009 or later.

Because of the problems that resulted from self-regulation, another law, the Dietary Supplement and Non-Prescription Drug Consumer Protection Act, was approved in 2006. This law requires manufacturers, packers, or distributors of supplements to submit reports of serious adverse events to the FDA. Serious adverse events are defined as death, a life-threatening event, hospitalization, a persistent or significant disability or incapacity, congenital anomaly or birth defect, or an adverse event that requires medical or surgical intervention to prevent such outcomes based on reasonable medical judgment. If this requirement were enforced, and consumers cooperated, these reports would make it possible to identify trends in adverse effects and would help to alert the public to safety issues.

Clinical Aspects of the Use of Botanicals

Many United States consumers have embraced the use of dietary supplements as a "natural" approach to their health care. Unfortunately, misconceptions regarding safety and efficacy of the agents are common, and the fact that a substance can be called "natural" does not of course guarantee its safety. In fact, these products may be inherently inert, toxic, or may have been adulterated, misbranded, or contaminated either intentionally or unintentionally in a variety of ways.

Adverse effects have been documented for a variety of dietary supplements; however, under-reporting of adverse effects is likely since consumers do not routinely report, and do not know how to report, an adverse effect if they suspect that the event was caused by consumption of a supplement. Furthermore, chemical analysis is rarely performed on the products involved, including those products that are described in the literature as being linked to an adverse event. This leads to confusion about whether the primary ingredient or an adulterant caused the adverse effect. In some cases, the chemical constituents of the herb can clearly lead to toxicity. Some of the herbs that should be used cautiously or not at all are listed in Table 64–1.

An important risk factor in the use of dietary supplements is the lack of adequate testing for drug interactions. Since botanicals may contain hundreds of active and inactive ingredients, it is very difficult and costly to study potential drug interactions when they are combined with other medications. This may present serious risks to patients.

Botanical Substances

Echinacea (Echinacea Purpurea)

Chemistry

The three most widely used species of Echinacea are Echinacea purpurea, E pallida, and E angustifolia. The chemical constituents include flavonoids, lipophilic constituents (eg, alkamides, polyacetylenes), water-soluble polysaccharides, and water-soluble caffeoyl conjugates (eg, echinacoside, chicoric acid, caffeic acid). Within any marketed echinacea formulation, the relative amounts of these components are dependent upon the species used, the method of manufacture, and the plant parts used. E purpurea has been the most widely studied in clinical trials. Although the active constituents of echinacea are not completely known, chicoric acid from E purpurea and echinacoside from E pallida and E angustifolia, as well as alkamides and polysaccharides, are most often noted as having immune-modulating properties. Most commercial formulations, however, are not standardized for any particular constituent.

Pharmacologic Effects

Immune Modulation

The effect of echinacea on the immune system is controversial. In vivo human studies using commercially marketed formulations of E purpurea have shown increased phagocytosis, total circulating white blood cells, monocytes, neutrophils, and natural killer cells but not immunostimulation. In vitro, E purpurea juice increased production of interleukins-1, -6, and -10, and tumor necrosis factor- by human macrophages. Enhanced natural killer cell activity and antibody-dependent cellular toxicity was also observed with E purpurea extract in cell lines from both healthy and immunocompromised patients. Studies using the isolated purified polysaccharides from E purpurea have also shown cytokine activation. Polysaccharides by themselves, however, are unlikely to accurately reproduce the activity of the entire extract.

Anti-Inflammatory Effects

Certain echinacea constituents have demonstrated anti-inflammatory properties in vitro. Inhibition of cyclooxygenase, 5-lipoxygenase, and hyaluronidase may be involved. In animals, application of E purpurea prior to application of a topical irritant reduced both paw and ear edema. Despite these laboratory findings, randomized, controlled clinical trials involving echinacea for wound healing have not been performed in humans.

Antibacterial, Antifungal, Antiviral, and Antioxidant Effects

Some in vitro studies have reported weak antibacterial, antifungal, antiviral, and antioxidant activity with echinacea constituents. The applicability of these findings to clinical trials is discussed below.

Clinical Trials

Echinacea is most often used to enhance immune function in individuals who have colds and other respiratory tract infections.

Two recent reviews have assessed the efficacy of echinacea for this primary indication. A review by the Cochrane Collaboration involved 16 randomized trials with 22 comparisons. Trials were included if they involved monopreparations of echinacea for cold treatment or prevention. Prevention trials involving rhinovirus inoculation versus natural cold development were excluded. Overall, the review concluded that there was some evidence of efficacy for the aerial (above ground) parts of E purpurea plants in the early treatment of colds but that efficacy for prevention and for other species of echinacea was not clearly shown. Among the placebo-controlled comparisons for cold treatment, echinacea was superior in nine trials, showed a positive trend in one trial, and was insignificant in six trials.

A separate meta-analysis involving 14 randomized, placebo-controlled trials of echinacea for cold treatment or prevention was published in Lancet. In this review, echinacea decreased the odds of developing clear signs and symptoms of a cold by 58% and decreased symptom duration by 1.25 days. This review, however, was confounded by the inclusion of four clinical trials involving multi-ingredient echinacea preparations, as well as three studies using rhinovirus inoculation versus natural cold development.

Echinacea has been used investigationally to enhance hematologic recovery following chemotherapy. It has also been used as an adjunct in the treatment of urinary tract and vaginal fungal infections. These indications require further research before they can be accepted in clinical practice. E purpurea is ineffective in treating recurrent genital herpes.

Adverse Effects

Flu-like symptoms (eg, fever, shivering, headache, vomiting) have been reported following the intravenous use of echinacea extracts. Adverse effects with oral commercial formulations are minimal and most often include unpleasant taste, gastrointestinal upset, or rash. In one large clinical trial, pediatric patients using an oral echinacea product were significantly more likely to develop a rash (~5%) than those taking placebo.

Drug Interactions & Precautions

Until the role of echinacea in immune modulation is better defined, this agent should be avoided in patients with immune deficiency disorders (eg, AIDS, cancer), autoimmune disorders (eg, multiple sclerosis, rheumatoid arthritis), and patients with tuberculosis. While there are no reported drug interactions for echinacea, some preparations have a high alcohol content and should not be used with medications known to cause a disulfiram-like reaction. In theory, echinacea should also be avoided in persons taking immunosuppressant medications (eg, organ transplant recipients).

Dosage

The dosing can be provided only for E purpurea preparations due to inadequate data for the other two plant species of echinacea. E purpurea freshly pressed juice is given at a dosage of 6–9 mL/d in divided doses two to five times daily. Echinacea is generally taken within the first 24 hours of cold symptoms. It should not be used as a preventative agent or for longer than 10–14 days.

Garlic (Allium Sativum)

Chemistry

The pharmacologic activity of garlic involves a variety of organosulfur compounds. Dried and powdered formulations contain many of the organosulfur compounds found in raw garlic and will likely be standardized to allicin or alliin content. Allicin is responsible for the characteristic odor of garlic, and alliin is its chemical precursor. Dried powdered formulations are often enteric-coated to protect the enzyme allinase (the enzyme that converts alliin to allicin) from degradation by stomach acid. Aged garlic extract has also been studied in clinical trials, but to a lesser degree than dried, powdered garlic. Aged garlic extract contains no alliin or allicin and is odor-free. Its primary constituents are water-soluble organosulfur compounds, and packages may carry a standardization to the compound S-allylcysteine.

Pharmacologic Effects

Cardiovascular Effects

In vitro, allicin and related compounds inhibit HMG-CoA reductase, which is involved in cholesterol biosynthesis (see Chapter 35), and exhibit antioxidant properties. Several clinical trials have investigated the lipid-lowering potential of garlic. Of the two most recent meta-analyses, the first involved 13 randomized, double-blind, placebo-controlled trials and found a small but significant reduction in total cholesterol of 5.8%. This effect, however, became insignificant when dietary controls were in place. The second review involved 45 randomized, controlled trials. Compared with placebo, garlic significantly lowered total cholesterol at 4–6 weeks by 7.2 mg/dL and at 8–12 weeks by 17.1 mg/dL. Results of a study by the National Center of Complementary and Alternative Medicine (NCCAM) evaluating three different sources of garlic (fresh, powdered, and aged garlic extract) in adults with moderately elevated cholesterol contradicted the findings of these prior reviews and found no effect of any formulation of garlic versus placebo on LDL cholesterol. Cumulatively, these data indicate that garlic is unlikely to be effective in reducing cholesterol to a clinically significant extent. Clinical trials report antiplatelet effects (possibly through inhibition of thromboxane synthesis or stimulation of nitric oxide synthesis) following garlic ingestion. A majority of human studies also suggest enhancement of fibrinolytic activity. These effects in combination with antioxidant effects (eg, increased resistance to low-density lipoprotein oxidation) and reductions in total cholesterol might be beneficial in patients with atherosclerosis. A randomized, controlled trial among persons with advanced coronary artery disease who consumed dried powdered garlic for 4 years showed significant reductions in secondary markers (plaque accumulation in the carotid and femoral arteries) as compared with placebo, but primary endpoints (death, stroke, myocardial infarction) were not assessed.

Garlic constituents may affect blood vessel elasticity and blood pressure. A variety of mechanisms have been proposed. A cross-sectional observational study in individuals aged 50–80 years of age chronically consuming garlic powder (averaging 460 mg/d) for 2 years or more showed significant reductions in parameters of aortic stiffness as compared with age- and sex-matched controls. However, a separate review of 30 randomized controlled trials, measuring garlic's effect on blood pressure outcomes, showed that the observed reductions were infrequent and unlikely to be clinically meaningful.

Endocrine Effects

The effect of garlic on glucose homeostasis does not appear to be significant in persons with diabetes. Certain organosulfur constituents in garlic, however, have demonstrated hypoglycemic effects in nondiabetic animal models.

Antimicrobial Effects

Allicin has been reported to have in vitro activity against some gram-positive and gram-negative bacteria as well as fungi (Candida albicans), protozoa (Entamoeba histolytica), and certain viruses. The primary mechanism involves the inhibition of thiol-containing enzymes needed by these microbes. The antimicrobial effect of garlic has not been extensively studied in clinical trials. Given the availability of safe and effective prescription antimicrobials, the usefulness of garlic in this area appears limited.

Antineoplastic Effects

In rodent studies, garlic inhibits procarcinogens for colon, esophageal, lung, breast, and stomach cancer, possibly by detoxification of carcinogens and reduced carcinogen activation. Several epidemiologic case-control studies demonstrate a reduced incidence of stomach, esophageal, and colorectal cancers in persons with high dietary garlic consumption.

Adverse Effects

Following oral ingestion, adverse effects may include nausea (6%), hypotension (1.3%), allergy (1.1%), and bleeding (rare). Breath and body odor have been reported with an incidence of 20–40% at recommended doses using enteric-coated powdered garlic formulations. Contact dermatitis may occur with the handling of raw garlic.

Drug Interactions & Precautions

Because of reported antiplatelet effects, patients using anticlotting medications (eg, warfarin, aspirin, ibuprofen) should use garlic cautiously. Additional monitoring of blood pressure and signs and symptoms of bleeding is warranted. Garlic may reduce the bioavailability of saquinavir, an antiviral protease inhibitor, but it does not appear to affect the bioavailability of ritonavir.

Dosage

Dried, powdered garlic products should be standardized to contain 1.3% alliin (the allicin precursor) or have an allicin-generating potential of 0.6%. Enteric-coated formulations are recommended to minimize degradation of the active substances. A daily dose of 600–900 mg/d of powdered garlic is most common. This is equivalent to one clove of raw garlic (2–4 g) per day.

Ginkgo (Ginkgo Biloba)

Chemistry

Ginkgo biloba extract is prepared from the leaves of the ginkgo tree. The most common formulation is prepared by concentrating 50 parts of the crude leaf to prepare one part of extract. The active constituents in ginkgo are flavone glycosides and terpenoids (ie, ginkgolides A, B, C, J, and bilobalide).

Pharmacologic Effects

Cardiovascular Effects

In animal models and some human studies, ginkgo has been shown to increase blood flow, reduce blood viscosity, and promote vasodilation, thus enhancing tissue perfusion. Enhancement of endogenous nitric oxide (see Chapter 19) and antagonism of platelet-activating factor may be involved.

Ginkgo biloba has been studied for its effects on mild to moderate occlusive peripheral arterial disease. Randomized studies involving 120–160 mg of a standardized ginkgo leaf extract (EGb761) for up to 6 months have generally reported significant improvements in pain-free walking distance as compared with placebo. Efficacy may be comparable to pentoxifylline (see Chapter 20) for this indication. (It should be noted that physical conditioning is as effective as pentoxifylline in improving walking distance.)

Metabolic Effects

Antioxidant and radical-scavenging properties have been observed for the flavonoid fraction of ginkgo as well as some of the terpene constituents. In vitro, ginkgo has been reported to have superoxide dismutase-like activity and superoxide anion- and hydroxyl radical-scavenging properties. In some studies, it has also demonstrated a protective effect in limiting free radical formation in animal models of ischemic injury and in reducing markers of oxidative stress in patients undergoing coronary artery bypass surgery.

Central Nervous System Effects

In aged animal models, chronic administration of ginkgo for 3–4 weeks led to modifications in central nervous system receptors and neurotransmitters. Receptor densities increased for muscarinic, ₂, and 5-HT_1a receptors and decreased for adrenoceptors. Increased serum levels of acetylcholine and norepinephrine and enhanced synaptosomal reuptake of serotonin have also been reported. Additional effects include reduced corticosterone synthesis and inhibition of amyloid-beta fibril formation.

Ginkgo has been used to treat cerebral insufficiency and dementia of the Alzheimer type. The term cerebral insufficiency, however, includes a variety of manifestations ranging from poor concentration and confusion to anxiety and depression as well as physical complaints such as hearing loss and headache. For this reason, studies evaluating cerebral insufficiency tend to be more inclusive and difficult to assess than trials evaluating dementia. An updated meta-analysis of ginkgo for cognitive impairment or dementia was performed by the Cochrane Collaboration. They reviewed 35 randomized, double-blind, placebo-controlled trials ranging in length from 3 to 52 weeks. Significant improvements in cognition and activities of daily living were observed at 12 but not 24 weeks. Significant improvements in clinical global improvement, however, were observed at 24 but not 12 weeks. The authors concluded that the effects of ginkgo in the treatment of cognitive impairment and dementia were unpredictable and unlikely to be clinically relevant. In the Ginkgo Evaluation of Memory Study, the effects of gingko as a prophylactic agent to prevent progression to dementia was assessed in more than 2500 cognitively intact adults over the age of 75 and almost 500 adults with mild cognitive impairment. No benefit was observed with 6 years of ginkgo treatment. The results of another large study are expected in 2009. To date, there is no known therapy that prevents progression to dementia.

Miscellaneous Effects

Ginkgo has been studied for its effects in allergic and asthmatic bronchoconstriction, short term memory in healthy, non-demented adults, erectile dysfunction, tinnitus and hearing loss, and macular degeneration. In none of these conditions is the evidence sufficient to warrant clinical use at this time.

Adverse Effects

Adverse effects have been reported with a frequency comparable to that of placebo. These include nausea, headache, stomach upset, diarrhea, allergy, anxiety, and insomnia. A few case reports noted bleeding complications in patients using ginkgo. In a few of these cases, the patients were also using either aspirin or warfarin.

Drug Interactions & Precautions

Ginkgo may have antiplatelet properties and should not be used in combination with antiplatelet or anticoagulant medications. One case of an enhanced sedative effect was reported when ginkgo was combined with trazodone. Seizures have been reported as a toxic effect of ginkgo, most likely related to seed contamination in the leaf formulations. Ginkgo seeds are epileptogenic. Ginkgo formulations should be avoided in individuals with preexisting seizure disorders.

Dosage

Ginkgo biloba dried leaf extract is usually standardized to contain 24% flavone glycosides and 6% terpene lactones. The daily dose ranges from 120 to 240 mg of the dried extract in two or three divided doses.

Ginseng

Chemistry

Ginseng may be derived from any of several species of the genus Panax. Of these, crude preparations or extracts of Panax ginseng, the Chinese or Korean variety, and P quinquefolium, the American variety, are most often available to consumers in the United States. The active principles appear to be the triterpenoid saponin glycosides called ginsenosides or panaxosides, of which there are approximately 30 different types. It is recommended that commercial P ginseng formulations be standardized to contain 4–7% ginsenosides.

Other plant materials are commonly sold under the name ginseng but are not from Panax species. These include Siberian ginseng (Eleutherococcus senticosus) and Brazilian ginseng (Pfaffia paniculata). Of these, Siberian ginseng is more widely available in the USA. Siberian ginseng contains eleutherosides but no ginsenosides. Currently, there is no recommended standardization for eleutheroside content in Siberian ginseng products.

Pharmacology

An extensive literature exists on the potential pharmacologic effects of ginsenosides. Unfortunately, the studies differ widely in the species of Panax used, the ginsenosides studied, the degree of purification applied to the extracts, the animal species studied, and the measurements used to evaluate the responses. A remarkable list of reported beneficial pharmacologic effects include modulation of immune function (induced mRNA expression for interleukins-2 and -1, interferon-, and granulocyte-macrophage colony-stimulating factor; activated B and T cells, natural killer cells, and macrophages), increased central levels of acetylcholine, serotonin, norepinephrine, and dopamine in the cerebral cortex; antioxidant activity; anti-inflammatory effects; antistress activity (ie, stimulation of pituitary-adrenocortical system); analgesia (inhibition of substance P); vasoregulatory effects (increased endothelial nitric oxide and inhibition of prostacyclin production); antiplatelet activity; improved glucose homeostasis (increased insulin release, number of insulin receptors, and insulin sensitivity); and anticancer properties (reduced tumor angiogenesis, increased tumor cell apoptosis).

Clinical Trials

Ginseng is most often claimed to help improve physical and mental performance or to function as an "adaptogen," an agent that helps the body to return to normal when exposed to stressful or noxious stimuli. Unfortunately, the clinical trials evaluating ginseng for these indications have shown few if any benefits. Some randomized controlled trials evaluating "quality of life" have claimed significant benefits in some subscale measures of quality of life but rarely in overall composite scores using P ginseng. Better results have been observed with P quinquefolium and P ginseng in lowering postprandial glucose indices in subjects with and without diabetes. This was the subject of a recent systematic review in which 15 studies (13 randomized and 2 nonrandomized) were evaluated. Nine of the studies reported significant reductions in blood glucose. Newer randomized, placebo-controlled trials have reported some immunomodulating benefits of P quinquefolium and P ginseng in preventing upper respiratory tract infections. These trials focused on giving ginseng chronically over the course of 4 months and in combination with the flu vaccine as compared with placebo and the flu vaccine in seniors. Significant reductions in cold incidence and duration were claimed. Epidemiologic studies have suggested a reduction in several types of cancer with the use of P ginseng. In summary, the strongest indications for use of P ginseng or P quinquefolium currently relate to its effects in cold prevention and lowering postprandial glucose. The claim of nonspecific cancer prevention requires further study.

Adverse Effects

Vaginal bleeding and mastalgia have been described in case reports. Central nervous system stimulation (eg, insomnia, nervousness) and hypertension have been reported in patients using high doses (more than 3 g/d) of P ginseng. Methylxanthines found in the ginseng plant may contribute to this effect. Vasoregulatory effects of ginseng are unlikely to be clinically significant.

Drug Interactions & Precautions

Irritability, sleeplessness, and manic behavior have been reported in psychiatric patients using ginseng in combination with other medications (phenelzine, lithium, neuroleptics). Ginseng should be used cautiously in patients taking any psychiatric, estrogenic, or hypoglycemic medications. Ginseng has antiplatelet properties and should not be used in combination with warfarin. Cytokine stimulation has been claimed for both P ginseng and P quinquefolium in vitro and in animal models. In a randomized, double-blind, placebo-controlled study, P ginseng significantly increased natural killer cell activity versus placebo with 8 and 12 weeks of use. Immunocompromised individuals, those taking immune stimulants, and those with autoimmune disorders should use ginseng products with caution.

Dosing

One to two grams of the crude P ginseng root or its equivalent is considered standard dosing. Two hundred milligrams of standardized P ginseng extract is equivalent to 1 g of the crude root. Ginsana has been used as a standardized extract in some clinical trials and is available in the USA.

Milk Thistle (Silybum Marianum)

Chemistry

The fruit and seeds of the milk thistle plant contain a lipophilic mixture of flavonolignans known as silymarin. Silymarin comprises 2–3% of the dried herb and is composed of three primary isomers, silybin (also known as silybinin or silibinin), silychristin (silichristin), and silydianin (silidianin). Silybin is the most prevalent and potent of the three isomers and accounts for about 50% of the silymarin complex. Products should be standardized to contain 70–80% silymarin.

Pharmacologic Effects

Liver Disease

In animal models, milk thistle purportedly limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo studies demonstrate that silymarin reduces lipid peroxidation, scavenges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry.

Milk thistle appears to have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase activity and reduces leukotriene formation. Inhibition of leukocyte migration has been observed in vivo and may be a factor when acute inflammation is present. Silymarin also inhibits tumor necrosis factor-–mediated activation of nuclear factor kappa B (NF-B), which promotes inflammatory responses. One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme's activity, enhanced protein synthesis and cellular regeneration may occur in diseased but not malignant cells. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the fibrogenic cytokine transforming growth factor-. If confirmed, milk thistle may have a role in the treatment of hepatic fibrosis.

In animal models, silymarin has a dose-dependent stimulatory effect on bile flow that could be beneficial in cases of cholestasis. To date, however, there is insufficient evidence to warrant the use of milk thistle for these indications.

Chemotherapeutic Effects

Preliminary in vitro and animal studies of the effects of silymarin and silybinin have been carried out with several cancer cell lines. In murine models of skin cancer, silybinin and silymarin were said to reduce tumor initiation and promotion. Induction of apoptosis has also been reported using silymarin in a variety of malignant human cell lines (eg, melanoma, prostate, leukemia cells, bladder transitional-cell papilloma cells, and hepatoma cells). Inhibition of cell growth and proliferation by inducing a G₁ cell cycle arrest has also been claimed in cultured human breast and prostate cancer cell lines. The use of milk thistle in the clinical treatment of cancer has not yet been adequately studied but preliminary trials are under way.

Clinical Trials

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. A recent systematic review of 13 randomized trials involving 915 patients with alcoholic liver disease or hepatitis B or C found no significant reductions in all-cause mortality, liver histopathology, or complications of liver disease. A significant reduction in liver-related mortality was claimed using the data from all the surveyed trials, but not when the data were limited to trials of better design and controls. It was concluded that the effects of milk thistle in improving liver function or mortality from liver disease are currently poorly substantiated. Until additional well-designed clinical trials (possibly exploring higher doses) can be performed, a clinical effect can be neither supported nor ruled out.

Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, parenteral silybin is nevertheless marketed and used in Europe as an antidote in Amanita phalloides mushroom poisoning. This use is based on favorable outcomes reported in case-control studies.

Adverse Effects

Milk thistle has rarely been reported to cause adverse effects when used at recommended doses. In clinical trials, the incidence of adverse effects (eg, gastrointestinal upset, dermatologic, headaches) was comparable to that of placebo.

Drug Interactions, Precautions, & Dosing

There are no reported drug-drug interactions or precautions for milk thistle. Recommended dosage is 280–420 mg/d, calculated as silybin, in three divided doses.

ST. John's Wort (Hypericum Perforatum)

Chemistry

St. John's wort, also known as hypericum, contains a variety of constituents that might contribute to its claimed pharmacologic activity in the treatment of depression. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved. Commercial formulations are usually prepared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried.

Pharmacologic Effects

Antidepressant Action

The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical adrenoceptors and up-regulate the expression of serotonin receptors (5-HT₂) in a rodent model.

Other effects observed in vitro include sigma receptor binding using the hypericin fraction and GABA receptor binding using the commercial extract. Interleukin-6 production is also reduced in the presence of the extract.

Clinical Trials for Depression

The most recent systematic review and meta-analysis involved 37 randomized, double-blind, controlled trials (26 compared St. John's wort to placebo, 7 to tricyclic antidepressants, and 7 to selective serotonin reuptake inhibitors [SSRIs]). St. John's wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate depression. Most trials used 900 mg/d (for mild to moderate depression) of St. John's wort for 4–12 weeks.

Efficacy for more severe depression is still in question. A recent randomized, double-blind, three-arm comparison showed equivalence of 20 mg of citalopram and 900 mg of St. John's wort and superiority of both treatments over placebo in reducing symptoms of moderate to severe depression over 6 weeks.

Antiviral and Anticarcinogenic Effects

The hypericin constituent of St. John's wort is photolabile and can be activated by exposure to certain wavelengths of visible or ultraviolet A light. Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given intravenously) and basal and squamous cell carcinoma (given by intralesional injection). In vitro, photoactivated hypericin inhibits a variety of enveloped and nonenveloped viruses as well as the growth of cells in some neoplastic tissues. Inhibition of protein kinase C and of singlet oxygen radical generation have been proposed as possible mechanisms. The latter could inhibit cell growth or cause cell apoptosis. These studies were carried out using the isolated hypericin constituent of St. John's wort; the usual hydroalcoholic extract of St. John's wort has not been studied for these indications and should not be recommended for patients with viral illness or cancer.

Adverse Effects

Photosensitization has been reported, and patients should be instructed to wear sunscreen while using this product. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John's wort.

Drug Interactions & Precautions

Inhibition of reuptake of various amine transmitters has been highlighted as a potential mechanism of action for St. John's wort. Drugs with similar mechanisms (ie, antidepressants, stimulants) should be used cautiously or avoided in patients using St. John's wort due to the risk of serotonin syndrome or MAO crisis (see Chapters 16 and 30). This herb may induce hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein drug transporter. This has led to case reports of subtherapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIVprotease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants.

Dosage

The most common commercial formulation of St. John's wort is the dried hydroalcoholic extract. Products should be standardized to 2–5% hyperforin, although most still bear the older standardized marker of 0.3% hypericin. The recommended dosing for mild to moderate depression is 900 mg of the dried extract per day in three divided doses. Onset of effect may take 2–4 weeks. Long-term benefits beyond 12 weeks have not been sufficiently studied.

Saw Palmetto (Serenoa Repens or Sabal Serrulata)

Chemistry

The active constituents in saw palmetto berries are not well defined. Phytosterols (eg, -sitosterol), aliphatic alcohols, polyprenic compounds, and flavonoids are all present. Marketed preparations are dried lipophilic extracts that are generally standardized to contain 85–95% fatty acids and sterols.

Pharmacologic Effects

Saw palmetto is most often promoted for the treatment of benign prostatic hyperplasia (BPH). Enzymatic conversion of testosterone to dihydrotestosterone (DHT) by 5-reductase is inhibited by saw palmetto in vitro. Specifically, saw palmetto shows a noncompetitive inhibition of both isoforms (I and II) of this enzyme, thereby reducing DHT production. In vitro, saw palmetto also inhibits the binding of DHT to androgen receptors. Additional effects that have been observed in vitro include inhibition of prostatic growth factors, blockade of ₁ adrenoceptors, and inhibition of inflammatory mediators produced by the 5-lipoxygenase pathway.

The clinical pharmacology of saw palmetto in humans is not well defined. One week of treatment in healthy volunteers failed to influence 5-reductase activity, DHT concentration, or testosterone concentration. Six months of treatment in patients with BPH also failed to affect prostate-specific antigen (PSA) levels, a marker that is typically reduced by enzymatic inhibition of 5-reductase. In contrast, other researchers have reported a reduction in epidermal growth factor, DHT levels, and antagonist activity at the nuclear estrogen receptor in the prostate after 3 months of treatment with saw palmetto in patients with BPH.

Clinical Trials

Results of recent meta-analyses and reviews suggested that saw palmetto is significantly more effective than placebo in alleviating urologic symptoms (eg, peak flow, nocturia, international prostate symptom scores) associated with mild to moderate BPH. Saw palmetto, 320 mg/d, was also shown to have comparable efficacy to 5 mg/d of finasteride (a prescription 5-reductase inhibitor) and 0.4 mg/d of tamsulosin (a prescription blocker) in clinical trials lasting 6 months and 1 year, respectively. In marked contrast, a recent well-controlled, double-blind 1-year study showed no significant effect of saw palmetto on symptoms or objective measures in moderate to severe BPH. The efficacy of saw palmetto in BPH beyond 5 years has not been studied.

Adverse Effects

Adverse effects are reported with an incidence of 1–3%. The most common include gastrointestinal upset, hypertension, decreased libido, abdominal pain, impotence, back pain, urinary retention, and headache. In comparison to tamsulosin and finasteride, saw palmetto was claimed to be less likely to affect sexual function (eg, ejaculation).

Drug Interactions, Precautions, & Dosing

No drug-drug interactions have been reported for saw palmetto. Because saw palmetto has no effect on the PSA marker, it will not interfere with prostate cancer screening using this test. Recommended dosing of a standardized dried extract (containing 85–95% fatty acids and sterols) is 160 mg orally twice daily. Patients should be instructed that it may take 4–6 weeks for onset of clinical effects.

Purified Nutritional Supplements

Coenzyme Q10

Coenzyme Q10, also known as CoQ, CoQ10, and ubiquinone, is found in the mitochondria of many organs, including the heart, kidney, liver, and skeletal muscle. After ingestion, the reduced form of coenzyme Q10, ubiquinol, predominates in the systemic circulation. Coenzyme Q10 is a potent antioxidant and may have a role in maintaining healthy muscle function, although the clinical significance of this effect is unknown. Reduced serum levels have been reported in Parkinson's disease.

Clinical Uses

Hypertension

In early clinical trials, small but significant reductions in systolic and diastolic blood pressure were reported after 8–10 weeks of coenzyme Q10 supplementation. The exact mechanism is unknown but, if correct, might be related to the antioxidant and vasodilating properties of coenzyme Q10. One meta-analysis of 12 clinical trials found a blood pressure lowering benefit with coenzyme Q10. Although this analysis included open-labeled, uncontrolled trials, with and without concomitant antihypertensive therapy, the results were consistent across all trials. In three well-designed randomized, placebo-controlled trials, coenzyme Q10 was reported to significantly lower systolic blood pressure (17 mm Hg) and diastolic blood pressure (8 mm Hg) as compared with no change in the placebo groups.

Heart Failure

Older studies suggested that coenzyme Q10 was effective as adjunctive therapy in the treatment of heart failure. In particular, improvements in signs and symptoms of heart failure including edema, liver enlargement, resting dyspnea and heart palpitations were claimed. Unfortunately, these observations are outdated since studies enrolled patients not taking angiotensin-converting enzyme inhibitors or blockers, which have been shown to improve morbidity and mortality. In addition, these studies used nonstandard and noninvasive methods to assess heart function. Other research suggests that the supplement does not alter cardiac function (as determined with Swan-Ganz catheter measurements and echocardiography) in cardiomyopathy patients with class I, II, or III New York Heart Association (NYHA) status. One study suggested a small benefit to patients with mild to moderate heart disease (NYHA class II–III) without ischemia. Initiating coenzyme Q10 in the later more severe stages of disease appears to have little to no effect. Furthermore, patients with lower than normal endogenous coenzyme Q10 levels do not display subjective or objective improvements in heart failure assessments when given coenzyme Q10 supplements.

Ischemic Heart Disease

The effects of coenzyme Q10 on coronary artery disease and chronic stable angina are modest but appear promising. A theoretical basis for such benefit could be metabolic protection of the ischemic myocardium. Double-blind, placebo-controlled trials have demonstrated that coenzyme Q10 supplementation improved a number of clinical measures in patients with a history of acute myocardial infarction (AMI). Improvements have been observed in lipoprotein a, high-density lipoprotein cholesterol, exercise tolerance, and time to development of ischemic changes on the electrocardiogram during stress tests. In addition, very small reductions in cardiac deaths and rate of reinfarction in patients with previous AMI have been reported (absolute risk reduction 1.5%).

Prevention of Statin-Induced Myopathy

Statins reduce cholesterol by inhibiting the HMG-CoA reductase enzyme (see Chapter 35). This enzyme is also required for synthesis of coenzyme Q10. Initiating statin therapy has been shown to reduce endogenous coenzyme Q10 levels, which may block steps in muscle cell energy generation, possibly leading to statin-related myopathy. It is unknown whether a reduction in intramuscular coenzyme Q10 levels leads to statin myopathy or if the myopathy causes cellular damage that reduces intramuscular coenzyme Q10 levels. In one small double-blind study, the effect of coenzyme Q10 administration was assessed in patients taking various statins who had developed myopathy. These patients were randomized to receive either coenzyme Q10, 100 mg/d, or vitamin E, 400 IU/d. After 30 days, the patients receiving coenzyme Q10 reported statistically significant reductions in pain as compared with the patients receiving vitamin E. More information is needed to determine which patients with statin-related myopathy might benefit most from coenzyme Q10 especially as it relates to the specific statin, the dose, and the duration of therapy.

Adverse Effects

Coenzyme Q10 is well tolerated, rarely leading to any adverse effects at doses as high as 3000 mg/d. In clinical trials gastrointestinal upset, including diarrhea, nausea, heartburn, and anorexia have been reported with an incidence of less than 1%. Cases of maculopapular rash and thrombocytopenia have very rarely been observed. Other rare adverse effects include irritability, dizziness, and headache.

Drug Interactions

Coenzyme Q10 shares a structural similarity with vitamin K, and an interaction has been observed between coenzyme Q10 and warfarin. Coenzyme Q10 supplements may decrease the effects of warfarin therapy. This combination should be avoided or very carefully monitored.

Dosage

As a dietary supplement, 30 mg of coenzyme Q10 is adequate to replace low endogenous levels. For cardiac effects, typical dosages are 100–600 mg/d given in two or three divided doses. These doses increase endogenous levels to 2–3 mcg/mL (normal for healthy adults, 0.7–1 mcg/mL).

Glucosamine

Glucosamine is found in human tissue, is a substrate for the production of articular cartilage, and serves as a cartilage nutrient. Glucosamine is commercially derived from crabs and other crustaceans. As a dietary supplement, glucosamine is primarily used for pain associated with knee osteoarthritis. Sulfate and hydrochloride forms are available, but recent research has shown the hydrochloride form to be ineffective.

Pharmacologic Effects & Clinical Uses

Endogenous glucosamine is used for the production of glycosaminoglycans and other proteoglycans in articular cartilage. In osteoarthritis, the rate of production of new cartilage is exceeded by the rate of degradation of existing cartilage. Supplementation with glucosamine is thought to increase the supply of the necessary glycosaminoglycan building blocks, leading to better maintenance and strengthening of existing cartilage.

Many clinical trials have been conducted on the effects of both oral and intra-articular administration of glucosamine. Early studies reported significant improvements in overall mobility, range of motion, and strength in patients with osteoarthritis. More recent studies have reported mixed results, with both positive and negative outcomes. One meta-analysis found an overall moderate effect in knee osteoarthritis improvement, although study limitations may have overestimated treatment benefits. One of the largest and well-designed clinical trials, which compared glucosamine, chondroitin sulfate, the combination, and placebo, found no benefit for this therapy. Unfortunately the investigators studied the glucosamine hydrochloride formulation. It is possible that glucosamine sulfate would have resulted in different outcomes and that specific subgroups may stand to benefit from glucosamine sulfate. More research is needed to better define the specific patient populations that stand to benefit from glucosamine sulfate.

Adverse Effects

Glucosamine sulfate is very well tolerated. In clinical trials, mild diarrhea and nausea were occasionally reported. Cross allergenicity in people with shellfish allergies is a potential concern; however, this is unlikely if the formulation has been properly manufactured and purified.

Drug Interactions & Precautions

Glucosamine sulfate may increase the International Normalized Ratio (INR) in patients taking warfarin, increasing the risk for bruising and bleeding. The mechanism is not well understood and may be dose-related as increases in INR have occurred when the glucosamine dose was increased. Until more is known, the combination should be avoided or very carefully monitored.

Dosage

The dosage used most often in clinical trials is 500 mg three times daily or 1500 mg once daily. Glucosamine does not have direct analgesic effects, and improvements in function, if any, may not be observed for 1–2 months.

Melatonin

Melatonin, a serotonin derivative produced by the pineal gland and some other tissues (see also Chapter 16), is believed to be responsible for regulating sleep-wake cycles. Release coincides with darkness; it typically begins around 9 PM and lasts until about 4 AM. Melatonin release is suppressed by daylight. Melatonin has also been studied for a number of other functions, including contraception, protection against endogenous oxidants, prevention of aging, treatment of depression, HIV infection, and a variety of cancers. Currently, melatonin is most often used to prevent jet lag and to induce sleep.

Pharmacologic Effects & Clinical Uses

Jet Lag

Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time and the traveler's endogenous circadian clock (internal time). The internal time regulates not only daily sleep rhythms but also body temperature and many metabolic systems. The synchronization of the circadian clock relies on light as the most potent "zeitgeber" (time giver).

Jet lag is especially common among frequent travelers and airplane cabin crews. Typical symptoms of jet lag may include daytime drowsiness, insomnia, frequent awakenings, and gastrointestinal upset. Clinical studies with administration of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns, energy, and alertness). Unfortunately, many of these studies were characterized by inconsistencies in dosing, duration of therapy, and time of drug administration. Although taking melatonin has not been shown to adjust circadian patterns of melatonin release, it may have a role in helping people fall asleep once they arrive at their new destination. In addition to melatonin, maximizing exposure to daylight on arrival at the new destination can aid in resetting the internal clock.

Insomnia

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22).

Clinical studies in patients with sleep disorders have shown that oral melatonin supplementation may alter sleep architecture. Subjective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. However, the significance of these findings is impaired by many study limitations.

Patients older than 65 years of age tend to suffer from sleep maintenance insomnia; melatonin serum levels have been reported to be low in these patients. Elderly patients with sleep maintenance insomnia who received immediate-release and sustained-release melatonin had improved sleep onset time. They did not, however, experience an improvement in sleep maintenance or total sleep time.

Female Reproductive Function

Melatonin receptors have been identified in granulosa cell membranes, and significant amounts of melatonin have been detected in ovarian follicular fluid. Melatonin has been associated with midcycle suppression of luteinizing hormone surge and secretion. This may result in partial inhibition of ovulation. Nightly doses of melatonin (75–300 mg) given with a progestin through days 1–21 of the menstrual cycle resulted in lower mean luteinizing hormone levels. Therefore, melatonin should not be used by women who are pregnant or attempting to conceive. Furthermore, melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing.

Male Reproductive Function

In healthy men, chronic melatonin administration (≥ 6 months) decreased sperm quality, possibly by aromatase inhibition in the testes. Until more is known, melatonin should not be used by couples who are actively trying to conceive.

Adverse Effects

Melatonin appears to be well tolerated and is often used in preference to over-the-counter "sleep-aid" drugs. Although melatonin is associated with few adverse effects, some next-day drowsiness has been reported as well as fatigue, dizziness, headache, and irritability. Melatonin may affect blood pressure as both increases and decreases in blood pressure have been observed. Careful monitoring is recommended, particularly in patients initiating melatonin therapy while taking antihypertensive medications.

Drug Interactions

Melatonin drug interactions have not been formally studied. Various studies, however, suggest that melatonin concentrations are altered by a variety of drugs, including nonsteroidal anti-inflammatory drugs, antidepressants, -adrenoceptor agonists and antagonists, scopolamine, and sodium valproate. The relevance of these effects is unknown. Melatonin is metabolized by CYP450 1A2 and may interact with other drugs that either inhibit or induce the 1A2 isoenzyme, including fluvoxamine. Melatonin may interact with nifedipine, possibly leading to an increased blood pressure and heart rate. The exact mechanism is unknown.

Dosage

Jet Lag

The optimal timing and dose of melatonin have not been established. Current information suggests 5–8 mg of the immediate-release formulation given on the evening of departure and for 1–3 nights after arrival at the new destination. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle.

Insomnia

Doses of 0.3–10 mg of the immediate-release formulation orally given once nightly have been tried. The lowest effective dose should be used first and may be repeated in 30 minutes up to a maximum of 10–20 mg. Sustained-release formulations may be used but currently do not appear to offer any advantages over the immediate-release formulations. Sustained-release formulations are also more costly.

References