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 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 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 (OA) since the 1980s. While glucosamine and chondroitin use appears to have decreased in the United States, studies from the United Kingdom and Australia report 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. Besides 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 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. Because of its structural similarity to heparin, their may be a theoretical risk of bleeding when combining chondroitin with anticoagulants.

After over 30 years of clinical research, glucosamine and chondroitin remain controversial with the most recent trials, reviews, and meta-analyses reporting mixed results. The 2016 update of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm for the management of knee OA 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. Systematic reviews and meta-analyses have concluded that pain reduction benefit of oral supplementation with glucosamine or chondroitin was small to moderate (although still clinically meaningful) for pain reduction in OA. Whether the combination is better than either one alone is unclear.

Whether glucosamine and chondroitin can slow progression of OA is also controversial. Meta-analyses have come to opposite conclusions about the effect of glucosamine and chondroitin for knee OA on joint-space narrowing, pain, and physical function. Glucosamine may be effective for reducing symptomatic OA of the hand and hip, but additional studies are needed.

Thus, there is mixed evidence as to whether glucosamine or chondroitin, alone or in combination, reduces pain, improves function, and slows progression of OA. Some individuals appear to respond to these compounds, but it is 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, and 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 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) that were in the fish the Inuit consumed. Multiple mechanisms likely explain the beneficial effects of omega-3 fatty acids for both primary and secondary prevention of CVD, 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 GI symptoms being the most common (nausea, GI upset, halitosis, oily stool). There have been case reports of increased bleeding in patients taking anticoagulant or antiplatelet medications with fish oil; however, controlled studies have not found that fish oil supplement ingestion increases INR in patients taking warfarin 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 RCTs 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. 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 MI, stroke, or death. In a 2019 updated meta-analysis of 127,477 participants, omega-3 supplementation was associated with significantly lower risk of MI (rate ratio [95% CI]: 0.92 [0.86-0.99]), death from CHD (rate ratio [95% CI]: 0.92 [0.86-0.98]), total CHD (rate ratio [95% CI]: 0.95- 0.99]), CVD death (rate ratio [95% CI]: 0.93 [0.88-0.99]), and total CVD (rate ratio [95% CI]: 0.97 [0.94-0.99]). These associations were even stronger with inclusion of the REDUCE-IT trial. Of note, larger doses of omega-3 supplementation were associated with greater effects, with most studies using doses between 1–2 g. The American Heart Association (AHA) does not recommend omega-3 fatty acids for primary prevention of CVD in high-risk patients or in primary prevention of stroke. The AHA states treatment is reasonable for secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD.

2. Hypertriglyceridemia

A meta-analysis of 21 clinical trials has demonstrated the benefit of fish oil in reducing serum triglycerides with 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%. A combination of a statin and fish oil appear to 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. Patients who received this formulation had significant decreases in the risk of ischemic events at 5 years, including cardiovascular death. 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 (HF). The GISSI-HF (Heart Failure) study was a large (n=6975) double-blind RCT investigating the effect of low-dose fish oil supplementation on patients with HF. Results showed that the treatment was well-tolerated and associated with a significant reduction of all-cause mortality and hospitalization due to cardiovascular causes. Four other RCTs have reported that fish oil supplementation in patients with HF increases LV end-diastolic volume, lowers serum BNP, reduces tumor necrosis factor, helps prevent cardiac cachexia, and improves endothelium-dependent vasodilation. A single RCT of 103 patients with nonischemic dilated cardiomyopathy similarly showed increased LV function. A UK study concluded that omega-3 fatty acid supplementation is cost-effective in patients with HF. AHA guidelines indicate that treatment with omega-3 fatty acids is reasonable for the secondary prevention of outcomes in patients with HF.

4. Atrial Fibrillation

Studies of the effects of omega-3 supplementation on atrial fibrillation (chronic, post-coronary artery bypass grafting, postcardioversion) have yielded mixed results. A 2021 systematic review and meta-analysis of 81,210 patients from seven trials found that omega-3 supplementation was associated with an increased risk of atrial fibrillation. The risk appeared to be greater in trials testing doses higher than 1 g/day. The AHA does not recommend omega-3 supplementation for secondary prevention of atrial fibrillation in patients with prior atrial fibrillation or for prevention of atrial fibrillation after cardiac surgery.

5. Hypertension

Three different meta-analyses, the largest of which included 36 RCTs, 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). Another RCT showed fish oil ingestion augmented the blood pressure benefit achieved through weight loss.

6. Other Conditions

Omega-3 supplementation has shown possible benefit in the treatment of rheumatoid arthritis. Results from small RCTs have shown significantly shorter time to remission and less risk of failure of disease-modifying antirheumatic drug therapy in individuals given omega-3 supplementation. A 2021 systematic review suggested there are beneficial effects of omega-3 fatty acids on rheumatoid arthritis disease activity, but longer, well-designed studies are needed.

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

Double-blind RCTs involving pregnant women have found that omega-3 supplementation may be associated with fewer adverse outcomes, including spontaneous preterm delivery and low birth weight. In the KUDOS study, pregnant women received either 600 mg/day of DHA or a placebo beginning at 14.5 weeks' gestation and continued until delivery. Although this study found initial decreases in early preterm birth and improved visual attention in infancy, the7-year follow-up study period found no long-term benefits 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. A 2021 meta-analysis and systematic review found that omega-3 supplementation during pregnancy did not reduce the risk of preterm birth. Although these studies seem to highlight the importance of adequate omega-3 intake in the gestational period, the benefits of supplementation 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 of 304 patients who were deemed at high risk for psychotic disorders found no differences in psychotic conversion after 12 months of omega-3 fatty acid treatment—leading to the conclusion that omega-3 fatty acids do not offer additional benefit when other evidence-based treatments are provided.

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 (HF, statin-induced myopathy), increased endothelial production of prostacyclin (hypertension), and improved mitochondrial function (migraine, HF, mitochondrial myopathies). CoQ10 is well-tolerated, with rare minor GI 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 RCT in 25 people on warfarin showed no effect of CoQ10 administration.

1. Heart Failure

The Q-SYMBIO trial provides the strongest evidence to support the use of CoQ10 for HF. This prospective, multicenter, adequately powered RCT enrolled) evaluated aCoQ10 supplementation (100 mg 3 times daily) over 2 years in 420 patients with moderate to severe HF. The study found CoQ10 treatment was safe, improved symptoms, and reduced major adverse cardiac events in patients with HF. Meta-analyses and reviews have found that CoQ10 improves EF and New York Heart Association (NYHA) clinical status.

2. Hypertension

Four RCTs and multiple other trials have evaluated the efficacy of CoQ10 for hypertension. An updated 2016 Cochrane review, which included only two studies in its meta-analysis, 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 contributes to the pathogenesis of statin-induced myopathy. A meta-analysis of 12 RCTs with a total of 575 enrolled participants 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). The authors concluded that CoQ10 supplementation may be a complementary approach to manage statin-induced myopathy. Other 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

A 2021 systematic review and meta-analysis that included six studies with 371 participants found a significant reduction of migraine frequency and significant reduction in the headache duration by 0.19 hour per month. There was no significant reduction in headache severity during attacks. In a few trials, nausea caused by migraine appeared to be improved with CoQ10. Larger high-quality trials are needed to determine the effect of the CoQ10 in migraines.

5. Neurodegenerative Diseases

CoQ10 has not been proven effective in the treatment of neurodegenerative diseases. A double-blind RCT 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. In the treatment of Parkinson disease, a meta-analysis of eight studies with nearly 900 patients found that CoQ10 was safe and well-tolerated but yielded no benefit to motor symptoms compared with placebo.

6. Reproductive Endocrinology

A double-blind RCT of CoQ10 (200 mg) and vitamin E (400 IU) in 89 patients with polycystic ovarian syndrome (PCOS) found benefit on serum fasting glucose, insulin levels, insulin resistance, and total testosterone levels. CoQ10 supplementation in combination with vitamin E significantly improved sex hormone–binding globulin levels.

CoQ10 supplementation has been used as an adjunct in women of reproductive age with infertility undergoing assisted reproductive technology (ART). A 2020 systematic review and meta-analysis of five RCTs involving 449 women found that oral supplementation of CoQ10 increased clinical pregnancy rates, without differences between women with poor ovarian reserve or PCOS. CoQ10 appears to be safe and well-tolerated, however the dose, frequency, and duration of therapy relative to ART is unclear. Further, larger studies are needed.

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone that is synthesized by the pineal gland from the amino acid tryptophan and 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, raising 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 with long-term use in depressed patients, as one study showed mild exacerbation of depressive symptoms in older adults. 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 not reported more frequently 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 clinical trials of melatonin. Conclusions are mixed but overall suggest efficacy. One meta-analysis of 17 clinical trials involving 284 patients 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 did reveal a reduction in sleep onset latency, which was both clinically and statistically significant. Meta-analyses showed that melatonin decreased sleep latency, increased total sleep time, and decreased the number of awakenings per night. Melatonin has also been shown to reduce challenging daytime behavior and improved sleep parameters.

Melatonin alone was noted to have mild adverse effects on mood but not when used in combination with bright light. An Italian study of long-term care residents with primary insomnia showed improved quality and quantity of sleep and improved quality of life. A large RCT examining the effect of prolonged-release melatonin for insomnia found significant benefit, especially for adults older than 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 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 RCTs and five case series and concluded that "sundowning" and agitated behavior were improved. A 2021 systematic review and meta-analysis found that melatonin improved sleep quality by increasing average hours of night sleep and reducing fragmented sleep in hospitalized patients. It induced sedation and lowered sedative consumptions. It was associated with a lower risk of delirium in surgical patients regardless of the type of surgery and ICU patients regardless of their admitting illness. However, it did not decrease the duration of delirium, the hospital length of stay or all-cause mortality. 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 RCTs concluded that melatonin 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

An RCT that 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 older meta-analyses, of 21 and 8 RCTs, respectively, concluded that melatonin not only reduced many side effects of cancer treatment (fatigue, neurotoxicity, nausea, vomiting, thrombocytopenia) but also increased complete and partial remission rates and reduced 1-year mortality rates. In cachectic patients with advanced cancer, melatonin did not improve appetite or weight. A 2015 RCT 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, of which nine have shown significant benefit compared with placebo. Evidence for a perioperative analgesic benefit is mixed. A 2020 Cochrane review examined 27 RCTs, involving 2319 participants, that assessed melatonin as a treatment for preoperative anxiety, postoperative anxiety, or both. When compared with placebo, melatonin reduced preoperative and postoperative anxiety compared with placebo. There was little or no difference in anxiety when melatonin was compared with benzodiazepines. The authors concluded melatonin may have a similar effect to benzodiazepines in reducing preoperative and postoperative anxiety.