e4-04: Non-Botanical Dietary Supplements

The DSHEA legislation of 1994 made it possible for manufacturers to sell dietary supplements directly to the public without the level of FDA approval or oversight that is required of pharmaceuticals. Reports of adulteration and contamination have occurred, but the magnitude of this problem remains unknown. However, information is available on many products that have been independently tested for content and purity. Table e4–3 provides an overview of selected dietary supplements commonly used in the United States today.

Glucosamine and chondroitin have been used in Europe alone and in combination to treat osteoarthritis since the 1980s. While glucosamine and chondroitin use appears to have decreased in the United States, studies from the United Kingdom and Australia report nearly a 20% use of glucosamine. It is an amino-monosaccharide synthesized by chondrocytes that serves as a substrate for the synthesis of cartilage. It is prepared commercially from crustacean shells. In addition to providing structural support, it may also have anti-inflammatory activity. Oral glucosamine is well tolerated and does not elevate serum glucose levels in humans. There is evidence that a dose of 1200 mg once a day of chondroitin is as effective as 400 mg three times daily. There are case reports of an increased international normalized ratio (INR) in patients taking warfarin who ingest glucosamine. There is also a theoretical risk of allergic reactions among patients with shellfish allergy. It is recommended to allow 4–6 months for an adequate therapeutic trial.

Chondroitin is a glycosaminoglycan normally present in the cartilage matrix that helps maintain articular fluid viscosity, inhibits enzymes that break down cartilage, and stimulates cartilage repair. Chondroitin is extracted from bovine tissues, such as the trachea. It is well tolerated and there are no known significant interactions with pharmaceutical medicines, although because of its structural similarity to heparin, some authors have pointed out the theoretical risk of combining chondroitin with warfarin.

After more than 30 years of clinical research, glucosamine and chondroitin remain controversial. Even the most recent trials, reviews, and meta-analyses report mixed results: some report no benefit, while others support their use and even highlight their possible disease-modifying capacity.

For example, a 2016 multicenter, double-blinded, randomized, placebo-controlled trial involving over 600 patients with osteoarthritis of the knee showed that glucosamine and chondroitin supplementation was noninferior to celecoxib. In 2017, a study of 164 patients with knee osteoarthritis concluded there was no benefit from 6 months of glucosamine and chondroitin supplementation for pain or functional status. The 2016 update of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for the management of knee osteoarthritis put glucosamine and chondroitin as “step 1” background maintenance therapy, noting that the highest quality evidence is for the prescription formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. In 2017, a multicenter, randomized, double-blind, placebo-controlled trial of 164 patients did not find any superiority over placebo in the treatment of symptomatic knee osteoarthritis. Two recent systematic reviews and meta-analyses in 2018 that concluded that pain reduction benefit was small to moderate (though still clinically meaningful) for pain reduction in osteoarthritis through oral supplementation with glucosamine or chondroitin. Whether the combination is better than either one alone is unclear.

Whether glucosamine and chondroitin can slow progression of osteoarthritis is also controversial. Previous meta-analyses have come to opposite conclusions about the effect of glucosamine and chondroitin on joint-space narrowing in knee osteoarthritis. A large 2018 meta-analysis and systematic review looking at all pharmacologic options in the treatment of osteoarthritis found that glucosamine sulfate was consistently associated with improvements in pain, physical function, and joint-space narrowing.

In other joints, glucosamine may be effective for reducing symptomatic osteoarthritis of the hand and hip, but additional studies are needed.

Thus, there is mixed evidence of whether glucosamine alone, chondroitin alone, or the two in combination may reduce pain, improve function, and slow progression of osteoarthritis. There are individuals who do appear to respond to these compounds, but it is still unclear as to what characterizes the responders. Despite the lack of clear guidance from existing literature, both glucosamine and chondroitin are well tolerated, safe, and have fewer side effects than NSAIDs; in addition, they may provide a reasonable option for nonopioid treatment.

Interest in fish oil began more than 40 years ago, when it was learned that the Inuit population of Greenland had low rates of coronary heart disease (CHD), despite consuming a high saturated fat diet. It was believed that protection might be conferred by the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the fish that the Inuit consumed. Multiple mechanisms likely explain the beneficial effects of omega-3 fatty acids for both primary and secondary prevention of cardiac disease, including reductions in triglyceride levels, inflammation, blood pressure, blood clotting, arrhythmias, and atherosclerotic plaque formation, and improvements in arterial and endothelial function. Fish oil supplements have few side effects, with gastrointestinal symptoms being the most common (nausea, gastrointestinal upset, halitosis, oily stool). There have been case reports of increased bleeding in patients taking anticoagulant or antiplatelet medications with fish oil; however, controlled research examining the effect of fish oil supplement ingestion on the INR in patients taking warfarin has not demonstrated this risk until total EPA and DHA dose exceeds 3 g/day. Fish oil supplements are widely available over the counter and should be dosed based on their content of EPA and DHA.

1. Coronary Heart Disease

Historically, evidence from multiple large-scale observational studies and randomized controlled trials suggested that intake of fish, particularly fatty fish such as herring, anchovy, mackerel, and salmon, or ingestion of fish oil supplements containing the omega-3 fatty acids EPA and DHA, had benefit in primary and secondary prevention of CHD. One of the most impressive secondary prevention studies was the 1999 GISSI-Prevenzione study, which showed a large reduction in sudden cardiac death, total cardiovascular mortality, and overall mortality. However, more recent studies have suggested that may not be the case. Omega-3 fatty acid supplementation did not have any significant association with fatal or nonfatal CHD or vascular events in a 2018 meta-analysis. The ASCEND study (with over 15,000 patients with diabetes randomized to receive either 1 g of omega-3 fatty acid or olive oil) found no significant differences between the groups in the risk of serious vascular events, including nonfatal myocardial infarction, stroke, or death. The American Heart Association (AHA) has recommended the following regarding treatment with omega-3 fatty acids: no treatment in primary prevention for patients with diabetes or who have high risk of cardiovascular disease or in primary prevention of stroke; treatment is reasonable for secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD.

2. Hypertriglyceridemia

Many clinical trials have demonstrated the benefit of fish oil in reducing serum triglycerides, and a meta-analysis of 21 trials concluded the same. Most analyses also agree there is a linear dose-response relationship. Beneficial effects can be attained at doses as low as 2 g/day of omega-3 fatty acids. A dose of 4 g/day can lower triglyceride levels by 25–40%. There are trials that also examine the combination of a statin and fish oil, which show added benefit on lipid profiles. A prescription formulation of fish oil is FDA approved for use in patients with hypertriglyceridemia. The 2019 REDUCE-IT trial examined over 8000 patients with hypertriglyceridemia on a statin who were randomly assigned to receive 2 g twice daily of a purified EPA. This study found that patients who received this formulation had significant decreases in the risk of ischemic events, including cardiovascular death, at 5 years. The 2020 STRENGTH trial of over 13,000 patients with high cardiovascular risk and hypertriglyceridemia examined a different formulation of 4 g of EPA and DHA but found no reductions in major adverse cardiovascular events.

3. Heart Failure

There are clinical and epidemiologic studies that have indicated that fish oil is beneficial for patients with heart failure. The GISSI-HF (Heart Failure) study was a very large (n = 6975) randomized, double-blind, placebo-controlled trial investigating the effect of low-dose fish oil supplementation on patients with heart failure. Results showed that the treatment was well tolerated, and there was a significant reduction of all-cause mortality and hospitalization due to cardiovascular causes in the experimental group. Four other randomized, controlled clinical trials have reported that fish oil supplementation in heart failure patients increases left ventricular end-diastolic volume, lowers serum B-type natriuretic peptide (BNP), reduces tumor necrosis factor (TNF), helps prevent cardiac cachexia, and improves endothelium-dependent vasodilation. A single randomized controlled trial of 103 patients with nonischemic dilated cardiomyopathy similarly showed increased left ventricular function. A UK study concluded that omega-3 fatty acid supplementation is cost-effective in patients with heart failure. The AHA guidelines indicate that treatment with omega-3 fatty acids is reasonable for the secondary prevention of outcomes in patients with heart failure.

4. Atrial Fibrillation

Studies of the effects of omega-3 supplementation on atrial fibrillation (chronic, post-coronary artery bypass grafting [CABG], post-cardioversion) have generally yielded negative results. A 2013 meta-analysis of studies examining use of fish oil to prevent postoperative atrial fibrillation concluded strongly that there was no benefit. A 2014 study looking at high-dose fish oil in patients with a history of atrial fibrillation not receiving conventional antiarrhythmic therapy did not find reduced atrial fibrillation recurrence. A 2015 study found that preoperative administration of omega-3 fatty acids in patients who were undergoing an isolated CABG for a myocardial infarction within 3 months found a significant relative risk decrease in the incidence of atrial fibrillation postoperatively, but a 2017 trial of post-cardiothoracic surgery patients found no benefit. The AHA has indicated that treatment is not recommended for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation; treatment is not indicated for prevention of atrial fibrillation after cardiac surgery.

5. Hypertension

Three different meta-analyses, the largest of which included 36 randomized trials, and a systematic review concluded that fish oil supplementation, especially at higher doses, significantly lowers blood pressure by a small amount (systolic blood pressure by 3–6 mm Hg and diastolic blood pressure by 2–4 mm Hg). An additional randomized trial showed fish oil ingestion augmented the blood pressure benefit achieved through weight loss.

6. Other Conditions

A 2015 study assessed 140 patients in whom rheumatoid arthritis was diagnosed within the past 12 months who had not been given disease-modifying antirheumatic drugs (DMARDs). Patients were randomized 2:1 to receive high-dose fish oil (5.5 g of EPA+DHA daily) or low-dose fish oil (400 mg EPA+DHA daily) in addition to triple DMARD therapy with methotrexate, hydroxychloroquine, and sulfasalazine. Results showed significantly shorter time to remission and less failure of the DMARD therapy in the high-dose fish oil group. Another 2015 double-blind, randomized, placebo-controlled study of 60 patients with rheumatoid arthritis showed similarly significant symptomatic improvement, both as reported by patients and as assessed by physicians, as well as significantly reduced analgesic use, after 12 weeks of fish oil supplementation. While there are small low-quality trials, a 2018 meta-analysis suggested that there are beneficial effects of omega-3 fatty acids on rheumatoid arthritis disease activity.

A multicenter, double-blind, randomized controlled trial of over 500 patients with dry eye disease found no benefit at 12 months in those randomly assigned to receive 3 g of omega-3 fatty acids compared to those assigned placebo.

The VITAL study group conducted a prospective randomized controlled study of more than 25,000 participants assigned to receive 1 g of omega-3 fatty acids daily versus placebo. At a median follow-up of 5 years, the supplementation did not result in a lower incidence of major cardiovascular events or cancer.

A 2017 prospective, randomized, double-blind, placebo-controlled study with 567 patients found that the high-dose supplementation of fish oil did not result in reductions in arteriovenous fistula failure in patients with end-stage renal disease.

In a 2016 prospective randomized study of over 700 pregnant women, supplementation with 2.4 g of omega-3 fatty acid in the third trimester resulted in a reduction of persistent wheeze or asthma at 5 years in the offspring. A 2017 prospective, randomized, double-blind, placebo-controlled study with 851 pregnant patients found that omega-3 supplementation was associated with fewer adverse outcomes (spontaneous preterm delivery and low birth weight) among smokers, suggesting a protective effect. In the KUDOS study, mothers received either 600 mg/day of DHA or a placebo beginning at 14.5 weeks of gestation and capsules were provided until delivery. This study initially found significant decreases in early preterm birth and improved visual attention in infancy. However, in the 7-year follow-up study period, no consistent long-term benefits were observed into childhood. In a 2019 study, supplementation with 900 mg omega-3 fatty acids from early pregnancy (less than 20 weeks of gestation) did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries. These studies seem to highlight the importance of adequate omega-3 intake in the gestational period, although its benefits still are unclear. Future long-term studies are needed.

Individuals with psychosis, treated with omega-3 fatty acids, have been found to require less antipsychotic medication and have better overall outcomes. The NEURAPRO study, published in 2017, examined this question further among 304 patients with ultrahigh risk for psychotic disorders. There were no differences observed in conversion to psychosis at 12 months—with the conclusion being that omega-3 fatty acids do not offer any additional benefit when other good-quality evidence-based treatments are offered.

Coenzyme Q10, also known as ubiquinone or CoQ10, is endogenously produced and found throughout the body. The majority of CoQ10 is in mitochondria where it serves as a critical cofactor in the electron transport chain and thus ATP production. CoQ10 has many other functions including protection and maintenance of cell membrane function and antioxidation. As a therapeutic supplement, its proposed mechanisms of action are repletion in conditions where CoQ10 is depleted (heart failure, statin-induced myopathy), increased endothelial production of prostacyclin (hypertension), and improved mitochondrial function (migraine, heart failure, mitochondrial myopathies). CoQ10 is well tolerated, with rare minor gastrointestinal side effects of nausea, dyspepsia, and heartburn. There are no known significant drug interactions. CoQ10 has a vitamin K-like structure, and it has been theorized that it may therefore antagonize the effect of warfarin, but a double-blind, randomized, placebo-controlled trial in 25 people on warfarin showed no effect of CoQ10 administration.

1. Heart Failure

There are 12 randomized controlled trials examining the effect of CoQ10 on patients with systolic heart failure. Eight of these studies report benefits from CoQ10 and four report no effect. Previous meta-analyses and reviews have shown that CoQ10 improves ejection fraction and New York Heart Association (NYHA) clinical status, but more high-quality studies were needed. Long-term CoQ10 treatment of patients with chronic heart failure is safe and could reduce major adverse cardiovascular events.

2. Hypertension

There are four randomized controlled trials and multiple other trials evaluating the efficacy of CoQ10 for hypertension. The 2009 Cochrane review, including three studies, concluded that CoQ10 lowered systolic blood pressure by 11 mm Hg and diastolic blood pressure by 7 mm Hg but that methodologic limitations of some studies brought into question any definitive conclusion. An updated 2016 Cochrane review included only two studies in its meta-analysis, and it concluded that moderate-quality evidence existed that CoQ10 does not have a clinically significant effect on blood pressure; however, because of the small number of individuals and studies available for analysis, more well-conducted trials are needed.

3. Statin-Induced Myopathy

Statin medications reduce serum CoQ10 levels, and some have postulated that this is part of the pathogenesis of statin-induced myopathy. A 2018 meta-analysis examined whether supplementing with CoQ10 can treat statin-induced myopathy. The analysis examined 12 randomized placebo-controlled trials with a total of 575 enrolled participants and found that CoQ10 supplementation significantly ameliorated muscle pain (P < 0.001), muscle weakness (P = 0.006), muscle cramps (P < 0.001), and muscle fatigue (P < 0.001). They concluded that CoQ10 supplementation may be a complementary approach to manage statin-induced myopathy. Studies have identified methodologic issues (ie, who truly has statin-associated muscle symptoms) as well as pharmacologic issues (ie, which form of CoQ10).

4. Migraine

There have been two randomized controlled trials and four open studies. All of them have shown statistically significant benefit in reduction of migraine frequency on the order of 30–50%. However, in one study, the benefit was lost at 7-month follow-up.

5. Huntington Disease

A 2017 randomized, double-blind, placebo-controlled study of 609 patients with early Huntington disease found that high-dose CoQ10 did not decrease functional decline at 60 months. This study was concluded prematurely.

6. Parkinson Disease

A phase 3 randomized, placebo-controlled, double-blind clinical trial of high-dose CoQ10 in early Parkinson disease did not find any benefit in disease progression, although it was well-tolerated. A 2017 meta-analysis (eight studies with nearly 900 patients) found that CoQ10 was safe and well-tolerated; however, there was no benefit compared to placebo in terms of motor symptoms.

7. Polycystic Ovarian Syndrome

A randomized, placebo-controlled, double-blind clinical trial of CoQ10 (200 mg) and vitamin E (400 international units) in 89 patients with polycystic ovarian syndrome found benefit on serum fasting blood sugar and insulin levels, as well as insulin resistance and total testosterone levels. CoQ10 supplementation in combination with vitamin E significantly improved sex hormone–binding globulin levels.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized by the pineal gland from the amino acid tryptophan that is released into the circulation in a circadian rhythm influenced by environmental light. Serum levels in humans vary 10- to 20-fold over 24 hours from a low of 2–10 pg/mL during daylight hours to a high of 100–200 pg/mL at night. Small physiologic doses of melatonin (0.1–0.5 mg) have been shown to decrease latency time until sleep, increase duration of sleep, and decrease daytime fatigue. Commonly available over-the-counter pharmacologic doses of melatonin (1–10 mg) are thought by many experts to be higher than necessary and raise plasma concentrations to levels 3–60 times greater than normal peak levels. Recommended starting doses of melatonin, therefore, are 0.3–0.5 mg. Melatonin is generally considered safe. Caution is advised, however, with long-term use in depressed patients, and one study showed mild exacerbation of depressive symptoms in elders. There are isolated reports of variable effects of melatonin on the INR in patients taking warfarin, but the validity of this association is unknown. Side effects of fatigue, sleepiness, headache, dizziness, and irritability are no more commonly reported than with placebo.

1. Sleep Disorders

A 2005 NIH State-of-the-Science Panel Report concluded that melatonin was effective in the management of chronic insomnia in subsets of the adult population. There have been at least five meta-analyses of the many clinical trials of melatonin. Conclusions are mixed but overall suggest efficacy. One meta-analysis of 17 clinical trials involving 284 subjects concluded that melatonin was effective in reducing the time it took them to fall asleep and increasing the amount of time they remained asleep. The authors concluded that exogenous melatonin was helpful in treating insomnia, particularly in older individuals and those with low nocturnal levels of melatonin.

Another meta-analysis that included only studies on primary sleep disorders (ie, excluding jet lag and shift-work sleep disorder) reported mixed results. Melatonin did cause statistically significant shorter sleep onset latency, but the authors did not believe this had clinical significance. Secondary analysis of a subpopulation with delayed sleep phase syndrome, however, did reveal a reduction in sleep onset latency, which was both clinically and statistically significant. Prior meta-analyses showed that melatonin decreased sleep latency, increased total sleep time, and decreased the number of awakenings per night. It has also been shown to reduce daytime challenging behavior and improved sleep parameters. An interesting study in 189 elderly Dutch residents of 12 group care facilities showed that nightly melatonin (2.5 mg) combined with daytime bright light modestly improved cognitive and noncognitive function. Melatonin alone was noted to have mild adverse effects on mood but not when used in combination with bright light. Similarly, an Italian study of long-term care residents with primary insomnia showed improved quality and quantity of sleep as well as improved quality of life. A large randomized controlled trial examining the effect of prolonged-release melatonin for insomnia found significant benefit, especially for those older than age 55 years. Nevertheless, the 2017 clinical practice guideline of the American Academy of Sleep Medicine does not recommend use of melatonin to treat either sleep onset or sleep maintenance insomnias.

A 2017 systematic review of melatonin for primary adult sleep disorders concluded that melatonin is effective in reducing sleep onset latency in primary insomnia and delayed sleep phase syndrome and regulating sleep-wake patterns in blind patients. A systematic review of melatonin's effect on circadian rhythm disturbances in dementia included four randomized controlled trials and five case series and concluded that “sundowning” and agitated behavior were improved. However, a 2018 study examined the use of melatonin the hospital setting. It found that melatonin given as a nightly dose of 3 mg did not prevent delirium in non–intensive care unit hospitalized patients or improve subjective or objective sleep. In secondary sleep disorders, a meta-analysis of seven studies found that melatonin lowers sleep onset latency and increases total sleep time.

2. Jet Lag

A Cochrane review of 10 randomized placebo-controlled trials examining the efficacy of melatonin for jet lag concluded that it was highly effective for preventing or reducing jet lag. The American Academy of Sleep Medicine has concluded that the evidence for the efficacy of melatonin in jet lag is “quite supportive.”

3. Traumatic Brain Injury

A small randomized controlled study examined the use of 2 mg melatonin in 33 patients with mild to severe traumatic brain injury; over a 4-week period, melatonin significantly improved subjective sleep quality, with associated improvements in anxiety.

4. Cancer

Due to its immunomodulatory and antioxidant activities, melatonin has been used as an adjunctive treatment for patients with cancer. Two 2012 meta-analyses, of 21 and 8 randomized controlled trials, respectively, concluded that melatonin not only reduced many side effects of cancer treatment (fatigue, neurotoxicity, nausea, vomiting, thrombocytopenia) but remarkably also increased complete and partial remission rates and reduced 1-year mortality rates. However, in cachectic patients with advanced cancer, melatonin did not improve appetite or weight. However, a 2015 randomized, placebo-controlled trial of melatonin supplementation in 72 patients with advanced cancer receiving palliative care showed no improvement in fatigue or other quality of life symptoms.

5. Perioperative Use

There are 10 studies examining the use of preoperative melatonin to decrease anxiety, and 9 studies have shown statistically significant benefit compared with placebo. Evidence for a perioperative analgesic benefit is mixed.