Chapter 64: Dietary Supplements & Herbal Medications

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 as a result of unknown or poor-quality natural product formulations, 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, reputable evidence-based resources should be used to evaluate claims and guide treatment decisions. An unbiased and regularly updated compendium of basic and clinical information regarding botanicals is Natural Medicines by Therapeutic Research Center (see References), which includes content review by an international, multidisciplinary, collaborative review committee of experts. The recommendations in this database are limited by the quality of the existing research and the quality of the dietary supplement used at the time of the report. As a result, all statements regarding positive benefits should be regarded as preliminary, and 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 FDA to prove that a supplement is harmful before it can be removed from the market or its use can be restricted. Furthermore, marketed dietary supplements are not tested for dose-response relationships or toxicity, and there is a lack of adequate testing for mutagenicity, carcinogenicity, and teratogenicity. 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). The 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 certain synthetic purified chemicals will be referred to as dietary supplements. Among the purified chemicals, glucosamine, coenzyme Q10, and melatonin are of significant pharmacologic interest. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9.

This chapter provides some historical perspective and describes the evidence provided by randomized, double-blind, placebo-controlled trials, meta-analyses, and systematic reviews involving several of the most commonly used agents in this class. Health care providers should adhere to the principles of “do no harm” but also, because patients are strongly influenced by popular opinion and media reports, be open to therapies that support “integrative health” safely and responsibly. Unproven therapies that are marketed as “alternatives” to conventional medicine should be viewed with caution, but therapies that are supported by evidence-based medicine and have been assessed for benefits and risks when used in combination with conventional medicine can be viewed favorably, especially if a patient expresses an interest in, and a desire to utilize, dual treatment approaches.

Under the DSHEA, dietary supplements are not considered over-the-counter drugs in the USA but rather food supplements used for health maintenance. Legally, dietary supplements are intended to supplement the diet, but 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 US Congress, influenced by growing “consumerism” as well as strong manufacturer lobbying efforts, passed the DSHEA. The 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. For example, a study using DNA barcoding to confirm botanical content evaluated 44 botanicals containing 30 plant species and found product substitutions in 32% of samples (see Newmaster reference). Therefore, much of the criticism regarding the dietary supplement industry involves problems with botanical misidentification, a lack of product purity, and variations in potency and purification, which continue to be problematic even with GMP standards in place. When the new GMP standards are met, dietary supplement manufacturers should be in compliance with this legislation. However, the FDA has limited resources to investigate and oversee compliance with manufacturing standards, particularly since many ingredient suppliers are based overseas. Furthermore, the dietary supplement ingredient supply chain is complex, and federal regulators are not able to inspect all manufacturing facilities in a timely and efficient manner. Finally, the financial incentive to maximize sales ($32 billion in supplement sales in the USA in 2012) is very great, regardless of lack of evidence of product safety or efficacy.

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. These reports are intended to identify trends in adverse effects and would help to alert the public to safety issues.

Many US 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, botanicals may be inherently inert or toxic. If a manufacturer does not follow GMP, this can also result in intentional or unintentional plant species substitutions (eg, misidentification), adulteration with pharmaceuticals, or contamination.

Adverse effects have been documented for a variety of dietary supplements; however, underreporting 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 significant risks to patients.

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, cichoric 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, the purple coneflower, has been the most widely studied in clinical trials. Although the active constituents of echinacea are not completely known, cichoric 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

1. 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 monocytes, neutrophils, and natural killer cells, indicative of general immune modulation. In vitro, a standardized ethanol extract of the aerial (above-ground) parts of E purpurea, known as Echinaforce, inhibited the rise in pro-inflammatory cytokines and interleukins-6 and -8, and also inhibited mucin secretion caused by exposure to rhinovirus type 1A in a 3D tissue model of human airway epithelium. This type of model is intended to mimic what would be seen in vivo. The extract had no effect on cytokine actions.

2. 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 preclinical findings, randomized, controlled clinical trials involving echinacea for wound healing have not been performed in humans.

3. Antibacterial, antifungal, antiviral, and antioxidant effects—In vitro studies have reported some antibacterial, antifungal, antiviral, and antioxidant activity with echinacea constituents. For example, Echinaforce demonstrated virucidal activity (MIC₁₀₀ < 1 mcg/mL) against influenza and herpes simplex viruses and bactericidal activity against Streptococcus pyogenes, Haemophilus influenzae, and Legionella pneumophila in human bronchial cells. In vitro, Echinaforce inactivated both avian influenza virus (H5N1, H7N7) and swine-origin influenza virus (H1N1) at doses consistent with recommended oral consumption. The extract blocked key steps (ie, viral hemagglutination activity and neuraminidase activity in vitro) involved in early virus replication and cellular entry. It was less effective against intracellular virus. Newer in vitro research in human skin fibroblasts also suggests bactericidal activity and inhibition of secretion of inflammatory cytokines produced by Propionibacterium acnes with Echinaforce.

Clinical Trials

Echinacea is most often used to enhance immune function in individuals who have colds and other respiratory tract infections. Two reviews have assessed the efficacy of echinacea for this primary indication. A review by the Cochrane Collaboration involved 24 randomized, double-blind trials with 33 comparisons of echinacea mono-preparations, which are single-ingredient echinacea preparations, and placebo. Trials were included if they involved echinacea for cold treatment or prevention, where the primary efficacy outcome was cold incidence in prevention trials and duration of symptoms in treatment trials. Overall, the review did not find significant evidence of benefit for echinacea (among all species) in treating colds. Preparations made from the aerial parts of E purpurea plants and prepared as alcoholic extracts or pressed juices were discussed as possibly being preferred to other formulations for cold treatment in adults, but still having a weak overall treatment effect. In prevention trials, pooling results suggested a small relative risk reduction of 10–20%, but no statistically significant benefit within individual 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 risk 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

Adverse effects with oral commercial formulations are minimal and most often include unpleasant taste, gastrointestinal upset, or allergic reactions (eg, rash). In one large clinical trial, pediatric patients using an oral echinacea product were significantly more likely to develop a rash than those taking placebo. In a small Norwegian mother and child cohort study, 0.5% of women reported taking any formulation of echinacea during early-stage (conception up to pregnancy week 17) or late-stage pregnancy and had no adverse pregnancy outcomes compared to pregnant women who did not use echinacea. Herbal supplements, and particularly those made from alcoholic extracts, should only be used in pregnancy and lactation after consultation with the primary health care provider.

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) or autoimmune disorders (eg, multiple sclerosis, rheumatoid arthritis). Although there are no well-documented herb-drug interactions for echinacea, in theory, it should also be avoided in persons taking immunosuppressant medications (eg, organ transplant recipients). Co-administration of an echinacea product containing E purpurea and E angustifolia root had no effect on warfarin pharmacodynamics, platelet aggregation, or baseline clotting in healthy subjects. Human studies have shown no effect of varied E purpurea preparations on the pharmacokinetics of lopinavir, ritonavir, etravirine, and darunavir.

Dosage

It is recommended to follow the dosing on the package label, as there may be variations in dose based on the procedure used in product manufacture. Standardized preparations made from the aerial parts of E purpurea (Echinaforce, Echinaguard) as an alcoholic extract or fresh pressed juice may be preferred in adults for common cold treatment if taken within the first 24 hours of cold symptoms. It should not be used on a continuous basis 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 compounds found in raw garlic and will usually 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 (AGE) has also been studied in clinical trials but to a lesser degree than dried, powdered garlic (GP). AGE contains no alliin or allicin and is odor-free. Its primary constituents are water-soluble organosulfur compounds, and packages may carry standardization to the compound S-allylcysteine.

Pharmacologic Effects

1. 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. The most recent meta-analysis (Ried et al, 2013) involved 39 randomized, double-blind, placebo-controlled trials with approximately 2300 patients. The investigators studied the effect of garlic mono-preparations on lipid parameters and found a moderate and significant reduction in both total serum cholesterol (–17 ±6 mg/dL) and LDL cholesterol (–9 ±6 mg/dL) when garlic was taken for 2 or more months by patients with elevated baseline cholesterol (>200 mg/dL). Subgroup analysis showed a greater effect on cholesterol reduction when AGE preparations were used than when GP preparations were used. While the benefit of garlic in lowering total cholesterol and LDL cholesterol is clinically relevant, optimal prescription drug therapy is far more efficacious (see Chapter 35).

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 LDL 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 GP for 4 years showed significant reductions in secondary markers (plaque accumulation in the carotid and femoral arteries) as compared with patients on placebo, but primary end points (death, stroke, myocardial infarction) were not assessed. AGE preparations have similarly shown favorable effects in three small (<100 patients) randomized, double-blind, placebo-controlled trials in reducing coronary artery calcification (CAC) progression over 1 year. All trials involved patients with known coronary artery disease (CAD) or who were considered medium to high risk for CAD at baseline.

Garlic constituents may affect blood vessel elasticity and blood pressure. Several mechanisms have been proposed. Twenty placebo-controlled studies using single-ingredient preparations of GP (13 studies), AGE (5 studies), or other preparations (2 studies) were included in a meta-analysis. Significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were present when all trials were considered. Benefits were most pronounced in subjects with baseline hypertension (mean SBP reduction of 8.6 ±2.2 mm Hg and DBP reduction of 6.1 ±1.3 mm Hg), and no significant effect was observed in subjects who had normal or prehypertensive blood pressures (<140/90 mm Hg) at baseline. A Cochrane review on the effect of garlic monotherapy for prevention of cardiovascular morbidity and mortality in hypertensive patients also identified a significant reduction in systolic and diastolic pressure compared with placebo. A separate Cochrane review of the effect of garlic on peripheral occlusive disease found insufficient support for this indication.

2. 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.

3. Antimicrobial effects—The antimicrobial effect of garlic has not been extensively studied in clinical trials. 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. A Cochrane review studying the effect of garlic on cold prevention and treatment found a significant reduction in total number of colds using a garlic supplement (with 180 mg allicin content) once daily for 12 weeks. Limited conclusions can be drawn regarding the effects observed, however, because only one trial met inclusion criteria. Given the availability of safe and effective prescription antimicrobials, the usefulness of garlic in this area appears limited.

4. 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. Current anticancer studies are focused on specific organosulfur garlic compounds in in vivo animal models of cancer and in vitro effects on human cancer cell lines.

Adverse Effects

Following oral ingestion, adverse effects of garlic products 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. A garlic bulb can contain up to 1.8% alliin. Doses of AGE most often range from 600 to 1800 mg/d, but doses up to 7200 mg daily have been safely used in clinical trials for up to 6 months.

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 including ginkgolides A, B, C, and J, and bilobalide.

Pharmacologic Effects

1. 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 effects (see Chapter 19) and antagonism of platelet-activating factor have been observed in animal models.

Ginkgo biloba has been studied for its effects on mild to moderate occlusive peripheral arterial disease. Among 11 randomized, placebo-controlled studies involving 477 participants using standardized ginkgo leaf extract (EGb761) for up to 6 months, a nonsignificant trend toward improvements in pain-free walking distance (increase of 64.5 meters) was observed (P = .06). The authors concluded that the standardized extract lacked benefit for this indication.

The Ginkgo Evaluation of Memory (GEM) study and the recently published GuidAge study evaluated cardiovascular outcomes as well as incidence and mean time to Alzheimer’s dementia associated with the long-term use of ginkgo for 5–6 years in approximately 3000 elderly (age ≥70) adults with normal cognition or mild cognitive impairment. Daily use of 240 mg/d EGb761 did not affect the incidence of hypertension or reduce blood pressure among persons with hypertension or prehypertension. No significant effects in cardiovascular disease mortality, ischemic stroke or events, or hemorrhagic stroke were observed.

2. 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. The flavonoid fraction has also been observed to have antiapoptotic 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.

3. 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, α₂, and 5-HT_1a receptors, and decreased for β adrenoceptors. Increased serum levels of acetylcholine and norepinephrine and enhanced synaptosomal reuptake of serotonin and dopamine have also been reported. Additional possible effects include inhibition of amyloid-beta fibril formation and protective effects of Egb761 on hippocampal neurons against cell death induced by beta-amyloid.

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. A meta-analysis of ginkgo for cognitive impairment or dementia was performed by the Cochrane Collaboration. They reviewed 36 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 assessment 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. However, recent meta-analyses of randomized controlled trials, 22–26 weeks in duration, using EGb761 that limited inclusion criteria to patients with dementia of the Alzheimer type (in eight studies), vascular or mixed dementia type (in six studies), or dementia with neuropsychiatric features (in four studies) showed favorable results. Significant improvements in cognition and activities of daily living were observed for ginkgo compared to placebo. Clinical global assessment of improvement also was significantly improved when EGb761 doses of 240 mg/d were used, but not doses of 120 mg/d. Because of the stricter inclusion criteria used, the overall methodologic quality of the studies was higher than that of the Cochrane review, when determining a benefit in patients with dementia. This suggests that patients with a diagnosis of dementia are more likely to benefit than patients with more mild cognitive impairment. In the GEM and GuidAge studies that included persons with normal or mild cognitive impairment, the effects of ginkgo as a prophylactic agent to prevent progression to dementia were assessed. No benefit was observed with 5–6 years of ginkgo treatment.

4. Miscellaneous effects—Ginkgo has been studied for its effects in schizophrenia, tardive dyskinesia, allergic and asthmatic bronchoconstriction, short-term memory in healthy, nondemented adults, erectile dysfunction, tinnitus and hearing loss, and macular degeneration. Preliminary data from eight randomized, double-blind, placebo-controlled trials suggest that EGb761 can significantly reduce the symptoms of chronic schizophrenia when used in combination with standard treatment (eg, clozapine, haloperidol, olanzapine). These trials were conducted in China, so firm conclusions about benefit in a broader population are lacking. There is insufficient evidence to warrant clinical use for the other conditions listed.

Adverse Effects

Adverse effects of ginkgo 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 some 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. Other single case reports noted virologic failure when ginkgo was combined with efavirenz, sedation when combined with trazodone, priapism when combined with risperidone, and seizure when combined with valproic acid and phenytoin; all warrant further pharmacokinetic studies before firm conclusions can be drawn. Seizures have been reported as a toxic effect of ginkgo, most likely related to seed contamination in the leaf formulations. Uncooked ginkgo seeds are epileptogenic due to the presence of ginkgotoxin. 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 most commonly studied and associated with a benefit in clinical trials of dementia is 240 mg daily of the dried extract in two 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 4–10% 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 may be 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.

Pharmacologic Effects

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, the doses or concentrations involved, and the measurements used to evaluate the responses. Reported beneficial pharmacologic effects include modulation of immune function (induced mRNA expression for interleukins-2 and -1α, interferon-γ, and granulocyte-macrophage colony-stimulating factor; activated B and T cells, natural killer cells, and macrophages). Central nervous system effects included increased proliferating ability of neural progenitors and increased central levels of acetylcholine, serotonin, norepinephrine, and dopamine in the cerebral cortex. Miscellaneous effects included antioxidant activity; anti-inflammatory effects (inhibited tumor necrosis factor-α, interleukin-1β, and vascular and intracellular cell adhesion molecules); antistress activity (ie, stimulated pituitary-adrenocortical system, agonist at glucocorticoid receptor); analgesia (inhibited substance P); vasoregulatory effects (increased endothelial nitric oxide, inhibited prostacyclin production); cardioprotective activity (reduced ventricular remodeling and cardiac hypertrophy in animal models of myocardial ischemia); antiplatelet activity; improved glucose homeostasis (reduced cell death in pancreatic beta cells; increased insulin release, number of insulin receptors, and insulin sensitivity); and anticancer properties (reduced tumor angiogenesis, increased tumor cell apoptosis). Such extensive claims naturally evoke skepticism and require careful replication.

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. However, the clinical trials evaluating ginseng for these indications have shown few, if any, benefits. Some randomized controlled trials evaluating “quality of life” and “cognition” have claimed significant benefits in some subscale measures of behavior, cognitive function, or 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 systematic review in which 15 studies (13 randomized and 2 nonrandomized) were evaluated. Nine of the studies reported significant reductions in blood glucose. Some randomized, placebo-controlled trials have reported immunomodulating benefits of P quinquefolium and P ginseng in preventing upper respiratory tract infections. Use of ginseng for 2–4 months in healthy seniors may reduce the risk of acquiring the common cold as well as the duration of symptoms. Because of heterogeneity in these trials, however, the findings are insufficient to warrant a recommendation of ginseng for cold prevention. To assess effects on cardiovascular health, a systematic review and meta-analysis of 17 randomized controlled trials involving predominantly P ginseng (12 studies) and P quinquefolium (5 studies) species in persons with and without hypertension was performed. Over a mean time period of 9 weeks, no significant effect was observed of ginseng on SBP, DBP, and mean arterial pressure compared with controls. Finally, two case-control studies and a cohort study suggest a non-organ-specific cancer-preventive effect with long-term administration of P ginseng. Significant benefits in some cancer-related fatigue symptoms have been observed in both a dose-finding study and a multisite, double-blind, randomized trial using P quinquefolium, 2 g daily, versus placebo over a 2-month period. In summary, the strongest support for use of P ginseng or P quinquefolium currently relates to its effects in cold prevention, lowering postprandial glucose, nonspecific cancer prevention, and alleviating cancer-related fatigue.

Adverse Effects

Vaginal bleeding and mastalgia have been described in case reports, suggesting possible estrogenic effects. Central nervous system stimulation (eg, insomnia, nervousness) and hypertension have been reported in patients using high doses (>3 g/d) of P ginseng. Methylxanthines found in the ginseng plant may contribute to this effect. Vasoregulatory effects have not been found 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.

Dosage

A dose of 1–2 g/d of the crude P ginseng root or its equivalent is considered standard dosage. Two hundred milligrams of standardized P ginseng extract are equivalent to 1 g of the crude root. The trademarked preparation 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 50–70% of the silymarin complex. Products should be standardized to contain 70–80% silymarin.

Pharmacologic Effects

1. 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 indicate 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 inhibits nuclear factor kappa B (NF-κB), an inflammatory response mediator. 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 might occur in healthy 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-β. 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.

2. 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, colon, leukemia cells, bladder transitional-cell papilloma cells, cervical 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 in patients undergoing chemotherapy show that it may improve liver function (ie, reduced liver transaminase concentrations in blood). There are insufficient data to support use in patients with cancer. The antioxidant potential of milk thistle should be taken into consideration prior to administration with chemotherapeutic agents that may be affected by antioxidant compounds.

3. Lactation—Historically, milk thistle has been used by herbalists and midwives to induce lactation in pregnant or postpartum women. In female rats, milk thistle increases prolactin production. As such, it is possible that it could have an effect on human breast milk production. Clinical trial data are lacking, however, for this indication, as are safety data on nursing mothers and infants. Until further data become available, milk thistle should not be used for this indication.

Clinical Trials

Oral milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. A 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 with 6 months of use. 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 oral milk thistle in improving liver function or mortality from liver disease are currently poorly substantiated. A recent multicenter, double-blind, placebo-controlled clinical trial in patients with hepatitis C refractory to interferon treatment failed to show a benefit with 24 weeks of milk thistle, 420 mg/d and 700 mg/d, on reduction of serum alanine aminotransferase levels. Milk thistle also had no effect on mean serum hepatitis C virus (HCV) RNA levels at 24 weeks. In contrast, the intravenous use of silybinin succinate has shown some benefit in reducing HCV RNA levels and alanine aminotransferase levels in patients with treatment-resistant hepatitis C infection. Prospective pilot studies have also shown benefits with intravenous silybinin before and after liver transplantation treatment in patients with HCV cirrhosis. Potent antiviral activity was demonstrated with significant reductions in HCV-RNA levels during treatment compared to placebo or nontreated controls when given for at least 14 days before transplantation and 7 days after liver transplantation. HCV-RNA relapsed, however, after silibinin withdrawal. This suggests that formulation and poor oral bioavailability may influence treatment outcomes.

Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, intravenous silybinin is marketed and used in Europe (Legalon SIL) 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. At high doses (>1500 mg), it can have a laxative effect caused by stimulation of bile flow and secretion.

Drug Interactions, Precautions, & Dosage

Milk thistle does not significantly alter the pharmacokinetics of other drugs transported by the P-glycoprotein transporter or metabolized by cytochrome enzymes. In a recent review, the impact of the herb was listed as “posing no risk for drug interactions in humans.” Recommended oral 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

1. 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 β 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.

a. Clinical trials for depression— The most recent systematic review and meta-analysis involved 29 randomized, double-blind, controlled trials (18 compared St. John’s wort with placebo, 5 with tricyclic antidepressants, and 12 with selective serotonin reuptake inhibitors [SSRIs]). Only studies meeting defined classification criteria for major depression were included. 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 major depressive disorder but with fewer side effects. Most trials used 900 mg/d of St. John’s wort for 4–12 weeks. Depression severity was mild to moderate in 19 trials, moderate to severe in 9 trials, and not stated in 1 trial. In a longer but uncontrolled trial, the use of the herb for up to 52 weeks was reported to reduce depression scores in patients with mild to moderate major depression. These data and the mechanism of action data reported above suggest a potential role for St. John’s wort in relieving symptoms of mild to moderate major depression. Due to the short study duration of these clinical trials, efficacy beyond 12 weeks still requires further study.

b. Other mood-related conditions— St. John’s wort has been studied for several other indications related to mood, including premenstrual dysphoric disorder, climacteric complaints, somatoform disorders, and anxiety. For most of these indications, studies are too few in number to draw any firm conclusions regarding efficacy. Evidence for climacteric complaints was the subject of a recent meta-analysis. Six trials were included where two used mono-preparations of St. John’s wort and four used combinations of St. John’s wort and black cohosh, Cimicifuga racemose (note black cohosh warning in Table 64-1). St. John’s wort significantly reduced hot flashes (severity, duration, and frequency) compared to placebo when used for up to 16 weeks. Heterogeneity in these trials limits drawing firm conclusions on efficacy for this indication.

2. 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 some neoplastic cells. Inhibition of protein kinase C and inhibition 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 is related to the hypericin and pseudohypericin constituents in St. John’s wort. Consumers should be instructed to wear sunscreen and eye protection while using this product when exposed to the sun. Rarely, mild gastrointestinal symptoms, fatigue, sedation, restlessness, dizziness, headache, and dry mouth have been observed. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John’s wort. When compared to SSRIs, St. John’s wort appears to be better tolerated when used to support medical treatment of major depression.

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 (see Chapters 16 and 30). The hyperforin constituent of St. John’s wort has been shown to activate the pregnane X receptor (PXR), which ultimately leads to many drug interactions by inducing hepatic CYP enzymes (3A4, 2C9, 1A2) and the P-glycoprotein drug transporter. Another constituent, hypericin, which may not be present in all commercial formulations, does not have any effect on PXR, CYP, or P-glycoprotein. Case reports involving the use of St. John’s wort have suggested the herb resulted in subtherapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV protease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants. Without knowing which constituent is present in a St. John’s wort formulation, indiscriminate combined use with other medicines should be avoided.

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 studied.

SAW PALMETTO (SERENOA REPENS OR SABAL SERRULATA)

Chemistry

The active constituents in saw palmetto berries are not well defined. Phytosterols (eg, β-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 5α-reductase is inhibited by saw palmetto in vitro. Specifically, saw palmetto shows a noncompetitive inhibition of 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 observed in vitro include inhibition of prostatic growth factors, blockade of α₁ 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 5α-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 5α-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. Recent reports suggest that daily saw palmetto, as compared to daily tamsulosin (see Chapter 10), has greater anti-inflammatory activity on infiltrating prostatic cells in men with BPH-related lower urinary tract symptoms at 3 months. The anti-inflammatory effects on infiltrating prostatic cells may serve as a link between hormonal changes and the remodeling process promoted by growth factors. The anti-inflammatory effects of saw palmetto also raise questions as to the value of early initiation of BPH therapy as well as the value of early combination therapy with 5α-reductase inhibitors (see Chapter 40).

Clinical Trials

The most recent review involved 32 randomized controlled trials in 5666 men with symptoms consistent with BPH. Seventeen trials compared saw palmetto monotherapy with placebo and found no significant improvement in most urologic symptoms (eg, international prostate symptom scores, peak flow, prostate size).

Adverse Effects

Adverse effects are reported with an incidence of 1–3%. The most common include abdominal pain, nausea, diarrhea, fatigue, headache, decreased libido, and rhinitis. Saw palmetto has been associated with a few rare case reports of pancreatitis, liver damage, and increased bleeding risk, but due to confounding factors, causality remains uncertain. In comparison to tamsulosin and finasteride, saw palmetto was claimed to be less likely to affect sexual function (eg, ejaculation).

Drug Interactions, Precautions, & Dosage

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 dosage of a standardized dried extract (containing 85–95% fatty acids and sterols) is 160 mg orally twice daily. The lack of positive results as noted in the review of randomized controlled studies cited above indicates that the use of saw palmetto in prostate disease cannot be recommended.

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 has been heavily promoted for this reason. It 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

1. Hypertension—In 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 might be related to the antioxidant and vasodilating properties of coenzyme Q10. In three randomized, placebo-controlled trials, coenzyme Q10 was reported to significantly lower systolic and diastolic blood pressure by 11 mm Hg and 7 mm Hg, respectively, compared with no change in the placebo groups. However, an exaggerated treatment effect may have occurred as adequate randomization, blinding, and concealment of allocation have been questioned for these studies. Whether coenzyme Q10 can be used to lower blood pressure remains unclear.

2. Heart failure—Low endogenous coenzyme Q10 levels have been associated with worse heart failure outcomes, but this association is likely because low levels are a marker for more advanced heart failure, rather than a predictor of disease. Despite these findings, coenzyme Q10 is often advocated to improve heart muscle function in patients with heart failure. According to the most recent meta-analysis, coenzyme Q10 was shown to improve ejection fraction by 3.7% when used short term (2–28 weeks). It is unclear whether improvements in ejection fraction are applicable to all patients with heart failure, including those receiving the current standard of care for heart failure management. More research is required to assess the role of coenzyme Q10 in heart failure and its impact on disease severity, particularly with concomitant prescription medications.

3. 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 by reducing proinflammatory markers (including interleukin-6 and C-reactive protein) that contribute to oxidative stress. Double-blind, placebo-controlled trials have suggested 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%).

4. 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. A meta-analysis evaluating the effect of coenzyme Q10 on statin-induced myopathy as measured by muscle pain and plasma creatine kinase activity found that coenzyme Q10 supplementation (30 days to 3 months) did not demonstrate any benefit in reducing myopathy. More information is needed to determine which patients, if any, with statin-related myopathy might benefit from coenzyme Q10 supplementation, 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, has 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/d 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 of the largest and best-designed clinical trials, which compared glucosamine, chondroitin sulfate, the combination, celecoxib, and placebo, found no benefit for glucosamine therapy in mild to moderate disease. Unfortunately the investigators studied the glucosamine hydrochloride formulation, which has been shown to be inferior to the sulfate formulation. The formulation of glucosamine appears to play a critical role with regard to efficacy, and this may be a factor contributing to the variability observed across published studies. Research suggests that use of a crystalline formulation of glucosamine sulfate leads to less pain, functional improvements in knee osteoarthritis, and an improvement in joint space narrowing at 3 years. Currently, national orthopedic and rheumatic societies do not recommend glucosamine for knee osteoarthritis primarily because of formulation variability and study heterogeneity. More research is needed to better define the ideal glucosamine formulation and patient populations that stand to benefit from glucosamine sulfate.

Adverse Effects

Oral glucosamine sulfate is very well tolerated. In clinical trials, mild diarrhea, abdominal cramping, 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 oral 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

1. Jet lag—Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time, ie, hours of daylight or darkness, 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 of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns, energy, and alertness). These outcomes are also supported by a systematic review that showed melatonin was better than placebo in helping patients fall asleep faster and to sleep better at their destination. When traveling across five or more time zones, jet lag symptoms are reduced when taking melatonin close to the target bedtime (10 PM to midnight) at the new destination. The benefit of melatonin is thought to be greater as more time zones are crossed. In addition, melatonin appears more effective for eastbound travel than for westward travel. Finally, maximizing exposure to daylight on arrival at the new destination can also aid in resetting the internal clock.

2. 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 ramelteon, a prescription hypnotic that is an agonist at melatonin receptors (see Chapter 22).

Clinical studies in patients with primary insomnia have shown that oral melatonin supplementation may alter sleep architecture. Melatonin appears effective in some patients who develop insomnia from β blockers. Subjective and objective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. Specifically, melatonin taken at the desired bedtime, with bedroom lights off, has been shown to improve morning alertness and quality of sleep as compared with placebo. These effects have been observed in both young and older adults (18–80 years of age). Interestingly, baseline endogenous melatonin levels were not predictive of exogenous melatonin efficacy.

3. Pre- and postoperative anxiety in adults—Melatonin given as a premedication has been shown to reduce preoperative anxiety in adults. Melatonin may be as effective as midazolam in reducing anxiety before a surgical procedure (measured 50–100 minutes after administration). The effect of melatonin on postoperative anxiety in adults is mixed, but studies support an overall reduction in anxiety as compared to preoperative anxiety levels.

4. Female reproductive function—The presence of melatonin within the female reproductive system appears widespread in mammals, and research suggests it plays a role in reducing oxidative stress. Melatonin receptors have been identified in ovarian granulosa cell membranes, and significant amounts of melatonin have been detected in follicular fluid. Some studies suggest it can be used as an adjunctive therapy in the treatment of infertility during in vitro fertilization by reducing oxidative stress and thereby improving the quality of oocytes and embryos during ovulation induction and egg retrieval. Melatonin requirements increase during pregnancy, and researchers are evaluating the role of melatonin in preeclampsia and neonatal neurologic morbidity. Importantly, melatonin has been shown to lack teratogenic effects when taken during pregnancy. Melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing.

5. Male reproductive function—Melatonin receptors have been identified on spermatozoa, suggesting melatonin may play a role in sperm function. When melatonin was added to semen samples, sperm motility was increased and early apoptosis was inhibited. These findings suggest that melatonin may be important in male fertility; however, more research is needed.

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. Transient depressive symptoms and dysphoria have been reported rarely. 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, β-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 decrease prothrombin time and may theoretically decrease the effects of warfarin therapy. A dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested according to one in vitro analysis. If combination therapy is desired, careful monitoring is recommended especially if melatonin is being used on a short-term basis. Melatonin may interact with nifedipine, possibly leading to increased blood pressure and heart rate. The exact mechanism is unknown.

Dosage

1. Jet lag—Daily doses of 0.5–5 mg appear to be equally effective for jet lag; however, the 5 mg dose resulted in a faster onset of sleep and better sleep quality than lower doses. The immediate-release formulation is preferred and should be given at the desired sleep time (10 PM–midnight) upon arrival at the new destination and for 1–3 nights after arrival. A dark room environment is important when taking melatonin and when possible, room lights should be turned off. The value of extended-release formulations remains unknown, as evidence suggests the short-acting, high-peak effect of the immediate-release formulation to be more effective. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle.

2. Insomnia—Doses of 0.3–10 mg of the immediate-release formulation given orally once nightly have been used. 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 are effective and may be used but, as noted above, may be inferior to immediate-release formulations. Sustained-release formulations are also more costly.