Non-Herbal Nutritional Supplements—The Next Wave: A Comprehensive Review of Risks and Benefits for the C-L Psychiatrist

Special Article Non-Herbal Nutritional Supplements—The Next Wave A Comprehensive Review of Risks and Benefits for the C-L Psychiatrist CATHERINE CRONE, M.D. GEOFF GABRIEL, M.D. THOMAS N. WISE, M.D.

The continuing popularity of complementary medicine has led to the frequent appearance of new products in the marketplace. Non-herbal supplements are now a popular choice for patients seeking relief from a variety of medical conditions. As with herbal medicines, there are concerns about the safety of these products in those with physical illness. Clearly, consultation-liaison psychiatrists will encounter patients using non-herbal products or inquiring about them. This article seeks to provide knowledge about the risks and benefits of non-herbal supplements that consultation-liaison psychiatrists are likely to encounter. (Psychosomatics 2001; 42:285–299)

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omplementary-alternative medicine has continued to draw interest from patients and health care providers, forming a multi-billion dollar industry. The desire for “natural” alternatives to prescription drugs has helped to renew interest in herbal medicines. In addition to botanical agents, there has been recent attention to the benefits offered by non-herbal dietary supplements (e.g., DHEA, SAMe). Many of these compounds can be found in the body, where they assist in functions at the cellular and gross structural levels. During aging and medical illness, deficiencies in these compounds may occur. Supplementation is thought to restore the levels to premorbid amounts, thus causing a slowing of the aging process or reversing physical and mental disorders (e.g., arthritis, diabetes, arteriosclerosis, depression). The widespread use of non-herbal supplements among the well, the medically ill, and the elderly makes it likely that the consultation-liaison psychiatrist will encounter patients taking them. Thus, knowledge about risks, benefits, and potential drug–drug interactions is necessary. In this article we seek to cover current information on several of the most commonly chosen nonherbal supplements.

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GLUCOSAMINE SULFATE Osteoarthritis (OA) is the most common form of arthritis and the second leading cause of long-term disability among adults.1 Steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief but cannot stop the deterioration of affected joints. The negative consequences of chronic NSAID use are an added concern. Glucosamine sulfate is an alternative treatment option purported to have a better side effect profile and an ability to halt deterioration in arthritic joints. Mechanism of Action Hyaline cartilage coats articular surfaces, giving joints their shock absorption and weight-bearing capabilities. Received March 7, 2001; accepted April 5, 2001. From the Department of Psychiatry, Inova Fairfax Hospital, Falls Church, VA; the Department of Psychiatry, Georgetown University, Washington, DC; and the Department of Psychiatry, Walter Reed Army Medical Center, Washington, DC. Address reprint requests to Dr. Wise, Department of Psychiatry, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22046. Copyright 䉷 2001 The Academy of Psychosomatic Medicine.

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Nutritional Supplements Proteoglycans (PGs) are important components of hyaline cartilage, consisting of proteins and glycosaminoglycans (GAGs).2 During OA, the PG content of hyaline cartilage is reduced, resulting in loss of shock absorption and excessive strain on bony surfaces.2–4 Over time, the stress induces bony proliferation of joint margins and loss of joint function. Glucosamine, an endogenous aminosaccharide, serves as a building block for PGs and GAGs.2,4 Sulfate, another component of PGs, is thought to enhance the effects of glucosamine. In vitro studies using glucosamine sulfate (GS) show stimulation of PG synthesis, inhibition of PG degradation, and stimulation of cartilage regeneration after experimentally induced damage.4,5 These activities protect cartilage from further deterioration and may reverse existing damage caused by OA. Glucosamine has anti-inflammatory activities as well, although they differ from those of NSAIDs.5,6

has reported a lack of benefit from GS.11 Subjects enrolled in this study were older, heavier, and had longer histories of OA compared with subjects in similar GS trials.11 Although shortcomings exist, clinical studies monitoring patient dropouts and side effect profiles have found GS to be better tolerated than NSAIDs.5,8 In addition, a long-term placebo-controlled trial of patients with knee OA demonstrated significantly less radiographic evidence of joint space narrowing with GS supplementation.12 Results suggest that GS can halt the deterioration of cartilage in affected joints, an activity not seen with NSAIDs or steroids. Findings across GS trials have led the National Center for Complementary and Alternative Medicine (NCCAM) and the National Institute for Arthritis and Musculoskeletal Disease to fund a multimillion-dollar, multicenter study of GS and/or chondroitin sulfate for the treatment of knee OA.13 Adverse Side Effects/Potential Drug–Drug Interactions

Preparation/Pharmacokinetics Glucosamine sulfate is commonly sold as 500milligram capsules, often combined with chondroitin sulfate. Typical daily doses are 500 mg three times a day.5 Once it is taken, about 90% is absorbed in the small intestine before entering the systemic circulation. A large proportion undergoes first-pass metabolism, yielding an oral bioavailability of 26%.4,6 The remainder is bound to plasma proteins or used for other biosynthetic processes.4 Glucosamine is mainly distributed to hyaline cartilage, with smaller amounts found in the liver and kidneys.6 Elimination is achieved through urine, feces, and exhaled carbon dioxide.4 Indications/Clinical Studies Clinical benefits suggest a role for GS in the treatment of osteoarthritis, but flaws in study design have hampered interpretation of results.2,5–10 Nonetheless, therapeutic effects have been similar to those seen with NSAIDs. Onset of action is much slower for GS, but improvements do not plateau as rapidly.7,8 McAlindon et al. performed a recent systematic review of nearly forty trials using GS or chondroitin sulfate for the treatment of osteoarthritis.10 Fifteen trials met inclusion criteria; all were randomized, doubleblind, placebo-controlled, and at least 4 weeks in duration. Meta-analysis showed moderate to large effects on OA symptoms, but evidence of size effects and publication bias were also found.10 Interestingly, only one published trial 286

Adverse side effects are primarily nausea, diarrhea, heartburn, and epigastric pain.6 Less common are drowsiness, headache, insomnia, edema, skin reactions, and tachycardia.6 Concerns have been raised for those with shellfish allergies because GS supplements may be derived from shellfish exoskeletons.14 However, there are no reports directly linking adverse events to shellfish allergies. A woman developed an immediate hypersensitivity reaction to GS, later confirmed by intradermal testing.15 Glucosamine sulfate–induced insulin resistance is another concern. Increased insulin levels have developed in rats and nondiabetic humans given GS.14,16 Reports of poorer glucose control in diabetic patients using GS have also appeared.14 Because of these findings, diabetic patients should be watched for reduced effectiveness of their hypoglycemic drug regimens when GS is taken concurrently. CHONDROITIN SULFATE Chondroitin sulfate (CS) is a primary glycosaminoglycan present in articular cartilage, tendon, bone, corneas, and heart valves.5 Like glucosamine sulfate, CS is a part of hyaline cartilage, which protects joints during weightbearing activities. When OA is present, the integrity of cartilage is compromised such that articular joints are prone to damage. Chondroitin sulfate is believed to protect cartilage from ongoing deterioration and subsequent loss of function. Psychosomatics 42:4, July-August 2001

Crone et al. Mechanism of Action Maintenance of joint function is dependent upon cartilage formation outpacing cartilage degradation. Osteoarthritis reverses this balance by causing inflammation at joint areas.2 Chondroitin sulfate inhibits the proteolytic enzymes that destroy cartilage and also acts as a building block for additional proteoglycans.3,17 The combined actions protect affected joints from excessive loss of hyaline cartilage. Preparation/Pharmacokinetics Chondroitin supplements are derived from bovine cartilage, shark cartilage, or synthetic sources.5,14 Oral dosing usually calls for 600 to 1,200 mg/day. Topical and intramuscular forms are manufactured, but the latter form is not sold in the United States.14 Because CS is a large molecule, intact absorption into the intestinal mucosa has been questioned. Later studies showed that 8% to 18% is absorbed whole, the remainder undergoing hydrolysis into smaller components.4 Chondroitin sulfate is concentrated in liver, kidneys, articular cartilage, and synovial fluid, with a portion being excreted in the urine.4

OA showed significantly less radiographic evidence of cartilage degeneration on CS compared with placebo.19,20 Adverse Side Effects/Drug–Drug Interactions Gastrointestinal side effects are most common and include epigastric pain, constipation, nausea, and diarrhea. Eyelid edema, lower limb edema, alopecia, and extrasystoles have also been reported.14 Because chondroitin sulfate is a minor component of danaparoid, a heparinoid mixture, concerns exist about potential anticoagulant effects.14 No reports of hematologic changes have been published, but there is still potential risk of drug–drug interactions between CS and anticoagulant or antiplatelet agents. CHROMIUM Chromium, a trace element, has gained attention as a possible enhancing agents for both athletic performance and overall life span. An essential micronutrient, chromium serves a function in glucose metabolism. Multiple claims have been made regarding the positive effects of chromium on lean body mass, stamina, addictive behaviors, sleep hygiene, and mood.21–23

Indications/Clinical Studies

Mechanism of Action

Leeb et al. recently reviewed 16 trials using CS supplementation for hip and knee OA; 7 were included in a meta-analysis.17 All studies were randomized, doubleblind, placebo-controlled, and parallel in design. Chondroitin sulfate was given to subjects for at least 3 months, in doses up to 1,600 mg/day. Pooled results showed at least a 50% improvement in outcome measures when compared with placebo.17 The use of NSAIDs and other analgesics was significantly lower in the CS group.17 Although publication bias could not be ruled out, Leeb and colleagues felt that the results were strong enough to support clear benefits from CS.17 McAlindon and co-workers were less certain about the positive results in their meta-analysis of glucosamine sulfate and CS studies.10 Individual clinical trials highlight the benefits derived from CS. A well-controlled study compared CS and diclofenac sodium in the treatment of knee OA.18 Reductions in pain and acetaminophen use, along with improvements in functional ability, were slower with CS supplementation. However, by the end of the trial, overall benefits were greater with CS.18 Recent studies also suggest that CS offers chondroprotective effects. Patients with knee or hand

Research suggests that trivalent chromium (III) influences carbohydrate and lipid metabolism in mammals by interacting with insulin and promoting carbohydrate uptake.24,25 Evidence for its role in human metabolism comes from the discovery that the addition of chromium (III) to total parenteral nutrition reverses the signs and symptoms of impaired glucose tolerance.26,27 In the potentiation of insulin activity, chromium (III) may depend upon chromodulin, a low molecular chromium binding substance.28,29 Studies show that by potentiating insulin, chromodulin may play a vital role in the physiological processes of the adipose cell.30 Furthermore, studies of diabetic patients show a relationship between reduced plasma chromium (III) levels and higher glucose levels.31,32

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Preparations/Pharmacokinetics The estimated safe and adequate daily dietary intake (ESADDI) for chromium has been set at 50–200 lg/day.33 Trivalent (III) and hexavalent (VI) forms of chromium are the most common, with chromium (III) the most stable. Chromium (VI) is a strong oxidizing agent that is highly 287

Nutritional Supplements toxic to tissues and is used mainly in industry. Commercial supplements do not contain chromium (VI); rather, they are made up of chromium (III). After oral ingestion, the majority of chromium (III) is absorbed in the small intestine. Unexpectedly, increased chromium intake actually tends to cause decreased intestinal absorption of this compound.34–36 There are currently three forms of chromium (III) commercially available: chromium nicotine, chromium picolinate, and yeast chromium. Chromium picolinate is highly lipophilic, and the picolinic acid has been shown to increase the bioavailability of chromium (III). Nevertheless, estimates suggest that less than 3% of ingested chromium picolinate is actually absorbed. Indications/Clinical Studies Evidence supporting improvements in glucose tolerance among non–insulin-dependent patients has been inconsistent. Studies have noted beneficial effects of chromium (III) supplementation on HbA1c, total cholesterol, fasting glucose, and high-density lipoprotein (HDL) levels.32,37 Lee and Reasner failed to find benefits for glucose control in their study of non–insulin-dependent diabetic patients, although there was a significant decline in triglyceride levels.38 Interest has grown in the possibility that chromium (III) supplements may improve body composition, muscle strength, and athletic performance. An early trial used a cohort of athletes given 200 lg/day of chromium (III) over a 6-week period.21 The treatment group eventually lost an average of 3.4 kg of fat and gained an average of 2.6 kg of lean body weight, while those on placebo lost an average of 1.0 kg of fat and gained 1.8 kg of lean body weight.21 Although this study has been widely quoted as evidence proving a fat-burning ability for chromium (III), there are clear problems with the study design and measurement techniques. Later studies have failed to demonstrate changes in lean body mass, percentage of body fat, muscle size, or strength with chromium (III) supplementation.39–41 Adverse Side Effects/ Drug–Drug Interactions There is definite knowledge that chromium (VI) exposure causes dermatological conditions, renal failure, lung carcinoma, gastroenteritis, pancreatitis, hepatitis, and coagulopathies.42,43 Skin conditions such as dermatitis and generalized exanthematous pustulosis have also been seen 288

with chromium (III) picolinate.44,45 This observation suggests that those with an undiagnosed sensitivity or specific allergy to chromium (in leathers, cement, and drywall) may be at risk for body-wide dermatitis with chromium (III) supplementation. The use of chromium (III) has also been associated with renal failure. In one case, a 33-year old woman suffered nephrotoxicity and hepatotoxicity following daily ingestion of 1,200–2,400 lg of chromium (III) picolinate over a period of 4 to 5 months.46 In a second case, a 49year-old woman developed chronic active interstitial nephritis in the context of using 600 lg/day of chromium (III) picolinate for 6 weeks.47 Because this patient was taking other medicines with known nephrotoxic effects, a drug–drug interaction could not be ruled out. Notably, both cases involved the daily use of chromium (III) above the established ESADDI. On a different note, Huszonek reported a case of a 35-year-old man who experienced episodic cognitive and perceptual changes during daily use of 200 lg of chromium (III).48 The delirium may have been caused by chromium (III) or by other substances present in the supplement. COENZYME Q 10 Coenzyme Q10, or ubiquinone, is a cofactor for mitochondrial oxidative phosphorylation and an antioxidant agent within various cellular membranes.49,50 There has been considerable interest in the role of coenzyme Q10 as a treatment for cardiac disease and neurodegenerative disorders. Added attention comes from the possibility that coenzyme Q10 improves exercise tolerance.51 Mechanism of Action The particular structure of coenzyme Q10 allows it to be highly mobile in the inner phospholipid bilayer of the cellular membrane.52 Coenzyme Q10 is widely distributed across tissues, but is concentrated in the cells of organs with higher metabolic rates, such as kidneys, pancreas, heart, and liver.53 During oxidative phosphorylation, coenzyme Q10 acts to accept electrons from complex I (NADH-CoQ oxidoreductase) and complex II (succinate-CoQ oxidoreductase) of the electron transport chain.49 This follows the oxidation of NADH, FADH2, and succinate.54 Thus, coenzyme Q10 is reduced prior to transferring an electron to complex III.49 Coenzyme Q10 also reforms the reduced form of vitamin E, an important cellular antioxidant.49 Psychosomatics 42:4, July-August 2001

Crone et al. Preparations/Pharmacokinetics

Adverse Side Effects/Drug–Drug Interactions

Coenzyme Q10 is produced by fermentation of beets with different strains of yeast, and it is sold as tablets, chewable wafers, softgels, and intra-oral spray.55 UbiQGel is a formulation that has FDA approval for the treatment of mitochondrial disorders. Slowly absorbed from the gastrointestinal tract, coenzyme Q10 requires the presence of postprandial lipids for optimal absorption. With a half-life of approximately 35 hours, coenzyme Q10 is eliminated mainly via the biliary tract.56

Doses of up to 200 mg/day in human trials have produced infrequent side effects, mainly nausea, emesis, epigastric pain, and headaches. Studies reviewed did not report the development of psychiatric symptoms, although coenzyme Q10 is lipophilic and crosses the blood–brain barrier. Infrequently, supplementation with higher than 300 mg/day of coenzyme Q10 has been linked to mild elevations in liver transaminases unaccompanied by serious hepatotoxicity.53 There are also cases noting an interaction between coenzyme Q10 and warfarin, which is thought to relate to the former having procoagulant effects.69 Because of this possibility, careful monitoring of the international normalized ratio (INR) is recommended.69

Indications/Clinical Studies Observations have noted that coenzyme Q10 levels are reduced in the myocytes of those with congestive heart failure, and there is a negative correlation between coenzyme Q10 levels and the severity of congestive heart failure.57,58 Controlled and open-label studies involving coenzyme Q10 supplementation for congestive heart failure have discovered gains in ejection fraction, functional status, hospitalization rates, and long-term survival.59 Positive results have not been seen in all studies, however. A randomized, double-blind, controlled trial failed to demonstrate significant changes in ejection fraction, peak oxygen consumption, or exercise duration.60 Permanetter and colleagues also did not find benefits in exercise tolerance or other functional parameters among patients with idiopathic cardiomyopathy given coenzyme Q10.61 Some have questioned whether coenzyme Q10 therapy might lower cortical lactate levels in patients with Huntington’s disease.62 Increased lactate levels in the cerebral cortex and basal ganglia of Huntington’s patients may act as a marker for impaired energy metabolism, which contributes to neuronal degeneration and ultimate cell death.63,64 In one group of patients, coenzyme Q10 produced significant reductions in cortical lactate concentrations.65 Modulation of lactate levels was notably reversed when coenzyme Q10 was stopped. Studies have shown that complex I activity is reduced in the substantia nigra and platelets of patients with Parkinson’s disease.66 Also, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) is thought to cause neurotoxic effects on the dopaminergic neurons of the substantia nigra via inhibition of complex I activity.67 Laboratory rats exposed to MPTP and given coenzyme Q10 experienced attenuation in the loss of striatal dopamine.68 No trials have been published yet involving humans with Parkinson’s disease. Psychosomatics 42:4, July-August 2001

DHEA Dehydroepiandrosterone (DHEA) is an androgenic hormone synthesized primarily in the adrenal glands. Both DHEA and its sulfate ester (DHEA-S) are precursors in the endogenous production of estrogens and testosterone.70 Conversion of DHEA and DHEA-S into testosterone explains much of the popularity of these supplements for increasing muscle size. Mechanism of Action Pregnenolone is the precursor for DHEA, glucocorticoids, mineralocorticoids, and androgens. Dehydroepiandrosterone sulfotransferase (DHEAST), present in the adrenal glands, liver, and small intestine, converts DHEA into DHEA-S.71 The adrenal secretion of both DHEA and DHEA-S is stimulated by adrenal corticotropin-releasing hormone (ACTH).72 Interestingly, there is no feedback control for their secretion at the hypothalamopituitary axis. Research has pointed to a role for DHEA and DHEA-S under various stress situations. Although results are mixed, the levels of DHEA and DHEA-S appear to be elevated when the body is stressed by exercise and reduced when the body is stressed by different disease states.73 Studies have also reported that DHEA and DHEA-S produced in mammalian brain tissue might act locally to antagonize GABA(A) receptors and modulate NMDA receptors.74,75 If DHEA comes from peripheral locations, it crosses the blood–brain barrier and is converted into DHEA-S.76 Preparations/Pharmacokinetics Synthetic DHEA is available as an oral formulation or an intra-oral spray. Independent analysis of commercial 289

Nutritional Supplements DHEA preparations found that the actual amount of DHEA differed sharply from the labeled amount.77 In humans, the levels of DHEA and DHEA-S are both age- and genderdependent, with levels initially being high in the fetus and falling after birth.78 As the adrenal zona reticularis undergoes hyperplasia, levels gradually climb to a second peak in the second and third decade of life.79 Significant declines occur during the period of adrenopause, appearing in the fifth and sixth decades. For males, levels of DHEA-S remain higher from adolescence onwards; females consistently have about 60% of the circulating levels present in males.79,80 Although DHEA-S is more abundant than DHEA, the latter appears to be more biologically active.70

creases muscle mass by raising testosterone levels. Various studies have used doses from 50 to 1,600 mg/day, achieving mixed results after analysis of body fat and muscle mass.96–98 In general, DHEA does not appear to influence total body weight. Enhancement of immunity has also created interest in DHEA supplements, as aging entails decreases in immune function.99 Preliminary research has shown partial reversal of immune dysfunction and a protective effect against various pathogenic organisms.100–102 Among elderly males, DHEA may raise the levels of B cells, monocytes, and T-cell receptors.103 Although DHEA levels are depressed in advanced stages of AIDS, there is a lack of controlled trials employing DHEA supplements for this population.

Indications/Clinical Studies Adverse Side Effects/Drug–Drug Interactions Much interest has focused on the possible effects of DHEA on the cardiovascular system.81,82 There seems to be a relationship between low levels of DHEA-S and increased angiographically defined atherosclerosis in males, which is not seen in females.83 In fact, an earlier study using a community-based cohort of postmenopausal females failed to note cardioprotective effects for DHEA-S.84 The variance in response may be related to gender-specific conversion of DHEA that depends on the baseline hormonal environment.84 For postmenopausal women, DHEA may be selectively converted to testosterone, increasing the risk of cardiovascular disease, whereas males derive cardioprotective effects from the conversion of DHEA into estrogens. Levels of DHEA-S have been analyzed in men and women with rheumatoid arthritis, but results are inconsistent.85 Nonetheless, most studies have reported a decrease in DHEA-S levels for this group. A review on the use of DHEA in systemic lupus erythematosus (SLE) indicates that DHEA may help to lower corticosteroid doses needed in SLE treatment.86 Additionally, one study involving patients with mild to moderate SLE treated with DHEA and steroids revealed a reduction in active disease.87 Studies to date exploring a role for DHEA supplementation in cognition have been unsupportive.88–90 However, the use of DHEA in psychiatric disorders is still promising. Reduced DHEA levels have been reported in unmedicated schizophrenic patients and depressed children.91–93 Clinical studies have indicated potential benefits from DHEA in the treatment of dysthymia and major depression.94,95 DHEA is a precursor of anabolic steroids, and advocates therefore claim that DHEA supplementation in290

Among studies reviewed, DHEA used in varying amounts for differing periods of time did not report irreversible organ toxicity. A few studies using larger doses of DHEA found elevations in transaminases and lactate dehydrogenase, but no notable hepatotoxicity.97,104 Caution is needed because of the knowledge that increased DHEA and DHEA-S levels are associated with elevated androgens and estrogens. In females, there is a theoretical risk of weight gain, voice changes, hirsutism, menstrual irregularities, and headaches. For males, estrogens could cause gynecomastia, while increased testosterone levels could lead to prostatic hypertrophy. There is further concern about the possible effects of DHEA supplementation on hormonesensitive tumors, including prostate cancer.105 Although DHEA levels appear to be positively correlated with breast cancer survival, the safety of DHEA supplements in hormone-sensitive tumors has not been established. Lastly, recent findings suggest that DHEA-S may inhibit cytochrome P450 3A4 enzymes.106 Because of this, care is necessary when DHEA use is combined with calcium channel blockers, sildenafil, antibiotics, and other medicines metabolized through this pathway. GAMMA-HYDROXYBUTYRATE Despite a government ban, gamma-hydroxybutyric acid (GHB) and its related compounds, gamma butyrolactone (GBL) and 1,4-butanediol (BD) are often used as recreational drugs. Their widespread use poses a significant public health threat.107,108 Although GHB affects varied neurotransmitter systems, its actions as a central nervous Psychosomatics 42:4, July-August 2001

Crone et al. system (CNS) depressant are the primary draw for recreational users. Mechanism of Action A metabolite of gamma-aminobutyric acid (GABA), GHB is a four-carbon short-chain fatty acid. Both GBL and BD are precursors in the production of GHB. Naturally found in brain tissues and peripheral tissues, GHB possesses high-affinity receptor sites in the hippocampus and the frontoparietal and entorhinal cortices in rat brain.109,110 GHB does not bind to GABA(A) receptors, but may have partial agonist effects at GABA(B) receptors.111 Administration of GHB causes decreased dopamine secretion in the CNS. The phenomenon is followed by increased dopamine release in the nigrostriatal neurons.112 Prior to this increase, there is marked elevation in the secretion of endogenous opioids.113 Both increases in opioid and dopamine may contribute to a reinforcing capability for GHB. In addition to these changes, GHB may inhibit release of serotonin.114 On a separate note, GHB is known to promote slow-wave sleep, a state during which growth hormone is increased.115 This fact has been utilized in the argument that GHB promotes an increase in muscle mass through anabolic effects. Preparations/Pharmacokinetics After the FDA banned GHB in 1991, GBL and BD became popular substitutes, sold in various oral forms under names such as “Blue Nitro,” “SomatoPro,” “Weight Belt Cleaner,” and “GH Revitalizer.”107 Following rapid absorption in the gastrointestinal tract, GHB readily crosses the blood–brain barrier.108 The majority is converted by oxidation into carbon dioxide and is excreted as expired air.116 Approximately 5% of GHB is eliminated in the urine. There are no active metabolites produced from GHB, and peak plasma concentrations are reached in about 30 to 60 minutes after ingestion.114 Both GBL and BD are used primarily as industrial solvents; GBL is rapidly converted into GHB in the human body.117 Butanediol is converted into gammahydroxybutyraldehyde by alcohol dehydrogenase, then into GHB by aldehyde dehydrogenase.118,119 Since these compounds are not detected in routine urine or blood drug screens, mass spectrometry or gas chromatography is needed to identify them. Psychosomatics 42:4, July-August 2001

Indications Numerous claims of physiological effects have been made for GHB and its precursors, GBL and BD. Several studies have suggested a role for GHB in the management of alcohol dependence or alcohol withdrawal.120–122 Gallimberti et al. reported on the use of GHB for the suppression of opioid withdrawal.123 A major limitation was the necessity for frequent dosing of GHB because of its short duration of action.123 Findings do not show a clear advantage for using GHB in opioid or alcohol detoxification, compared with more commonly accepted drugs. Because GHB promotes slow-wave sleep and induces REM sleep, it has been employed to treat narcolepsy.124 Interestingly, GHB does seem to increase the length of REM sleep and improve the quality of sleep.125 For anesthesia, GHB can serve as a short-acting general agent with mild analgesic effects. Adverse Side Effects/Drug–Drug Interactions Gamma-hydroxybutyrate produces a number of CNS effects, including nystagmus, ataxia, apnea, sedation, and dizziness. At doses greater than 50 mg/kg, GHB can lead to coma, bradycardia, and death.126 Use can also result in respiratory depression and arrest. A broad range of psychiatric side effects can also appear, such as hallucinations, delusions, agitation, confusion, euphoria, and agitation. Recently, a withdrawal syndrome from GHB has been described, with anxiety, tremor, rebound insomnia, and muscle cramping.127 Overdose can produce seizure-like activity, which has been observed in animal models and isolated case reports. In contrast, in a trial giving GHB for sedation in healthy individuals, no epileptiform activity was observed on EEG.115 Effects on the CNS may be prolonged with GBL, which is more lipophilic in nature than GHB.117 Combined use of GHB and alcohol can produce respiratory and CNS depression. Risk of ataxia, confusion, slurred speech, nystagmus, or aspiration pneumonia occurs when GHB is taken along with benzodiazepines or ketamine, both CNS depressants. Mixing stimulants and GHB can also create worrisome results, including bradycardia, agitation, confusion, and respiratory depression. A potential drug–drug interaction between GHB and HIV-1 protease inhibitors has recently been reported.128 Since protease inhibitors affect the cytochrome P450 system, and the problems thus may have come from inhibition of GHB metabolism. However, conclusions are confounded by 291

Nutritional Supplements 3,4-methylenedioxymethamphetamine (MDMA) having been used in conjunction with the GHB. OMEGA-3 FATTY ACIDS Essential long-chain polyunsaturated fatty acids include omega-3 fatty acids (O3FAs). They are not synthesized in the human body; instead, they come from dietary sources including fatty fish, wild game, and plants.14 Fish oils contain two types of O3FAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Omega-3 fatty acids are used for several clinical purposes and play an important role in a wide range of physiologic processes.14,129,130 Mechanism of Action Arachidonic acid is an omega-6 fatty acid that normally enters the cyclooxygenase and lipooxygenase pathways, where it is transformed into prostaglandins, leukotrienes, and thromboxane. These substances induce inflammatory and thrombotic processes within the body. Omega-3 fatty acids also enter lipooxygenase and cyclooxygenase pathways, causing competitive inhibition of arachidonic acid.131,132 Reductions in the level of arachidonic acid–derived eicosanoids yield both anti-inflammatory and anti-thrombotic effects.131–134 Additional anti-inflammatory actions are derived from alterations in cytokine production.132,134 Omega-3 fatty acids act on cellular membranes to produce a variety of clinical effects. Incorporation into the lipid bilayer raises membrane fluidity. For the vascular system, this restores endothelial reactivity, increases red blood cell deformability, and reduces blood viscosity.14,135 These changes are useful in the treatment of atherosclerosis or hyperlipidemia.135–137 Greater membrane fluidity also benefits neurotransmission by influencing receptor functioning and/or receptor–effector coupling.129,138 Through a separate mechanism, O3FAs dampen intracellular signal transduction.139,140 This is thought to offer mood-stabilizing effects in bipolar disorder.141 Within cardiac cells, O3FAs modify membrane ion channels, prolonging their refractory period.142 Thus, cells become less susceptible to the development of cardiac arrhythmias.132,142,143 In the treatment of hyperlipidemia, O3FAs reduce the synthesis and secretion of very low density lipoproteins (VLDL) and triglycerides.136,137 Changes occur at several levels, including fatty acid synthesis, fatty acid oxidation, and phospholipid formation. All serve to lessen the availability of fatty acids for triglyceride formation.137 The down292

regulation of esterifying enzymes and the increase in triglyceride uptake also help to lower plasma triglyceride levels.137 Shifts in triglyceride transport result in synthesis of smaller VLDL particles, which are converted into lowdensity lipoproteins (LDL).137 Production of VLDL is hampered by loss of apolipoprotein B to intracellular degradation.137 Further reductions in plasma VLDL levels come from decreased hepatic VLDL secretion along with increased uptake.136,137 Preparations/Pharmacokinetics Clinical studies have used O3FAs in doses of 1–10 g/ day, derived from fish, fish oils, or flaxseed oil.14 Most of the conditions discussed below respond to doses in the lower range, except for bipolar disorder.141 Small amounts of vitamin E are often present in fish oil capsules to prevent oxidation.14 Omega-3 fatty acids are probably metabolized like other fats that are taken up by the intestine and transported to the liver for further disposition. Indications Population studies linking fish intake to a lower incidence of coronary artery disease led researchers to test whether O3FAs could lower triglyceride levels in hyperlipidemia.132 Clinical trials have demonstrated 20% to 50% reductions in triglyceride levels, with ongoing use slowing the progression of atherosclerosis.136,144–149 Omega-3 fatty acids can also lower the incidence of ventricular arrhythmias, a frequent cause of mortality in ischemic heart disease. Trials have enrolled patients with a prior history of myocardial infarction. Although there was no effect on the rate of nonfatal cardiac events, those taking O3FAs had lower rates of ventricular arrhythmia, cardiac mortality, and overall mortality.143,150,151 Omega-3 fatty acids have been used for the treatment of hypertension.152,153 After an extensive review of placebo-controlled trials and a meta-analysis, only mild reductions in blood pressure were found.152 Other studies have examined whether O3FAs might help to manage cyclosporine-induced hypertension.153,154 Cardiac transplant patients started on O3FAs postoperatively developed smaller degrees of cyclosporine-related hypertension compared with those on placebo.153 In another group of cardiac transplant patients, O3FAs produced reductions in mean arterial blood pressure.154 Additionally, O3FAs improved renal blood flow in kidneys exposed to cyclosporine.155 Besides effects on the cardiovascular system, O3FAs may play a role in mental illness. Reduced O3FA levels have Psychosomatics 42:4, July-August 2001

Crone et al. been seen in serious mental illnesses, and animal studies show that O3FA deficiency alters both dopamine and serotonin neurotransmission and receptor density.129,138 A few attempts to treat schizophrenic patients with O3FAs have met with mixed results.130,156 Stoll et al. have tried to determine whether O3FAs produce mood-stabilizing effects in bipolar patients.141 Despite several design flaws, preliminary results of that trial revealed longer periods of remission and improvements on several measures (Clinical Global Impression, Hamilton Rating Scale for Depression, Global Assessment Scale).141 Surprisingly, there was no change in the Young Mania Rating Scale. Some have argued that these results indicate an antidepressant rather than a moodstabilizing effect for O3FAs.157,158 Cases of mania and hypomania appearing in patients taking O3FAs lend support to this idea.157,159 The anti-inflammatory actions of O3FAs have been studied in a number of conditions, including rheumatoid arthritis, inflammatory bowel disease, and asthma. Findings are strongest for rheumatoid arthritis.133,160 Ariza-Ariza et al. noticed improvement in pain, function, and joint swelling in a review of double-blind, placebo-controlled studies.133 In the treatment of inflammatory bowel disease, O3FAs produced positive histologic and clinical changes.134 However, these were not enough to prevent clinical relapses.134 Trials suggesting a role for O3FAs in bronchial asthma are still too limited.161,162 Adverse Side Effects/Drug–Drug Interactions Omega-3 fatty acids from fish oils have been granted the FDA designation “Generally Regarded as Safe.”14 This means that daily ingestion of up to 3 grams of O3FAs is likely safe for humans.14 Problems reported with fish oils mainly involve belching, halitosis, and unpleasant taste.14 Less frequent are reports of nosebleeds.14 High daily doses can cause nausea and vomiting, and non–insulin-dependent diabetics can have blood glucose elevations.14 Increased LDL levels are thought to be offset by lower triglyceride levels.132,163 Omega-3 fatty acids have antiplatelet activity and can alter hematologic/vascular parameters; thus, there is a higher risk of bleeding if O3FAs are combined with antiplatelet or anticoagulant drugs.164 Since O3FAs can lower blood pressure, they may also act synergistically with antihypertensive agents to produce hypotension.152

liver disease. As an antidepressant, SAMe is purported to offer a rapid onset of action and a limited side effect profile. Present in body tissues and fluids, SAMe is synthesized from L-methionine and adenosine triphosphate.165,166 Folate and vitamin B12 are necessary for the formation of SAMe; deficiencies in either yield lower concentrations of SAMe in the central nervous system.14 Mechanism of Action Physiologically, SAMe serves as the principal donor of methyl groups to a variety of molecules, including neurotransmitters, phospholipids, nucleic acids, hormones, and proteins.14,166 Transfer of methyl groups initiates anabolic and catabolic reactions throughout the body.14 After its methyl group is donated, SAMe is converted into adenosine and homocysteine.167 The latter forms additional L-methionine stores or becomes one of the principal cellular antioxidants, cysteine or glutathione.167 The mechanism responsible for the antidepressant actions of SAMe remains unknown. Some researchers believe SAMe produces changes at the cellular membrane level, not entering the target cell.168 This hypothesis is based on the observation that SAMe alters membrane fluidity by raising phosphatidylcholine levels in the lipid bilayer.167 Effects on cell membranes enhance receptor functioning or receptor– effector coupling.167,169 Methylation of monoamines may also produce clinical effects. Baldessarini and others have reported changes in monoamine synthesis, turnover, and reuptake.167–174 Shifts in adrenergic and cholinergic receptor density have also been seen.175 Recent interest has focused on the role of SAMe in polyamine synthesis.176 Noted antidepressant effects may be due to polyamines, which affect intracellular signal transduction.176 Besides antidepressant activity, animal studies have shown that SAMe offers analgesic and anti-inflammatory properties.177 Human chondrocytes treated with SAMe reveal stimulation of proteoglycan synthesis, a benefit in osteoarthritis.177 Chronic liver disease affects methionine metabolism, reducing production of cellular antioxidants.178–180 Antioxidant deficiency leaves hepatic cells more vulnerable to damage from lipid peroxidation.179 Fortunately, the problem can be partly reversed by exogenous SAMe supplementation.178–181

S-ADENOSYL-L-METHIONINE (SAMe)

Preparations/Pharmacokinetics

S-adenosyl-L-methionine (SAMe) has received recent attention as a natural treatment for depression, arthritis, and

Clinical trials have used mainly intravenous and oral forms of SAMe. For depression, oral doses range from 800

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Nutritional Supplements to 1,600 mg/day, and intravenous doses range from 150 to 400 mg/day. Similar doses are used in chronic liver disease, smaller doses for osteoarthritis. Oral bioavailability is low because of significant firstpass effects and rapid metabolism in the liver.14 Peak plasma concentrations develop after 3 to 5 hours, and the half-life is about 100 minutes.14 Metabolites are subsequently excreted in the urine or feces.14 The stability of oral SAMe supplements was recently called into question after raw materials were found to be partially decomposed.182 This possibility has led some proponents to recommend use of an enteric-coated, pharmaceutical-grade pill manufactured in Europe.183,184 Indications As an antidepressant, SAMe has shown therapeutic potential.185–192 Bressa performed a meta-analysis of clinical trials from 1973 to 1992 and concluded that SAMe was comparable to tricyclic antidepressant therapy.169 A later trial enrolled postmenopausal women with DSM-III-R major depression or dysthymia.193 After subjects were randomized to oral SAMe or placebo, those taking SAMe were noted to have significant reductions in their Hamilton Rating Scale for Depression (Ham-D) scores at day 10 and day 30.193 Because SAMe acts rapidly, Fava et al. questioned if it might be used to shorten the onset of standard antidepressant therapy.194 This led to a multicenter, opendesign trial involving nearly 200 subjects with DSM-III-R unipolar depression. Parenteral SAMe was given for 15 days, and patients were rated at baseline, day 7, and day 15. Scores from the Ham-D and Patient Global Impression Severity Scale were significantly reduced, lending support to the idea that SAMe can be used to shorten response times.194 In addition to acting as an antidepressant, SAMe has also been studied for osteoarthritis and chronic liver disease.178–181,195–201 DiPadova reviewed open and controlled trials representing a total of more than 20,000 patients with osteoarthritis.177 Controlled clinical studies showed comparable improvements with SAMe and NSAIDs.177 A separate trial used patients with radiographically confirmed knee osteoarthritis.201 Those who were given SAMe reported significant reductions in pain, which could not be explained by mood changes alone.201 Early studies noticed that exogenous SAMe protected against drug-induced liver dysfunction.180,202 This finding encouraged clinical trials for alcoholic cirrhosis and intrahepatic cholestasis. For one study, patients with alcoholic cirrhosis who were given 294

SAMe had lower mortality rates and less need for liver transplantation.178 Trials for cholestatic liver disease have yielded mixed results, but there have been gains in laboratory and clinical parameters.180,203 Toxicity and Side Effects Generally, SAMe has been well tolerated in clinical trials. Most complaints involve nausea, vomiting, or diarrhea. Anxiety and restlessness have been reported in some patients with depression, and hypomania and mania have been reported in some with bipolar disorder.204,205 Serotonergic syndrome was noted in an elderly woman started on clomipramine and SAMe.206 Exogenous SAMe was found to produce parkinsonian symptoms in rats.207,208 The symptoms were thought to be due to increased monoamine methylation causing depletion of dopamine stores.207,208 Because of this possibility, those with preexisting movement disorders should be monitored closely when taking SAMe. CONCLUSIONS Demand for complementary medicine has continued to fuel a multi-billion dollar annual industry. Beside botanical agents, non-herbal supplements have been important contributors to this trend, partly because of their ready availability to consumers. Proponents claim a broad range of benefits for healthy individuals and those with varied medical illnesses. Although there are publications about the potential risks, benefits, and drug–drug interactions with herbal medicines, information about non-herbal supplements is still lacking. Health care providers need to be aware of these products because patients are likely to use them. Non-herbal supplements have been recommended for a number of conditions, including diabetes, heart disease, arthritis, mood disorders, and obesity. Some are purported to be “anti-aging” products. Clinical studies supporting these claims have shown weaknesses in study design and probable publication bias. Reproducing positive results from earlier trials has also proven difficult. However, there are interesting findings supporting a role for chondroitin sulfate in osteoarthritis, omega-3 fatty acids in hypertriglyceridemia, and SAMe in depression. At the same time, reports of adverse effects, especially with GHB, override possible clinical benefits. Reports also suggest a need for attention to potential interactions of some non-herbal supplements with anticoagulant, antiplatelet, and oral hypoPsychosomatics 42:4, July-August 2001

Crone et al. glycemic agents. Sharing this information with patients can help to avoid unnecessary harm while offering the chance

to strengthen the relationship between patients and their doctors.

References

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