Supplements that do not neatly fit into other supplement categories are called specialty supplements in the industry. Included in the list of the 20 most popular supplements are five supplements that fall into this category: omega-3 oils, fiber, probiotics, glucosamine and chondroitin, and coenzyme Q10. In this chapter we review these five supplements and include a discussion of their function in the body, the reasons people use them and if these reasons are supported by clinical studies, and their safety. You may notice that, in this chapter, an emphasis is placed on discussing the evidence behind the use of omega-3 oils as dietary supplements.
This is done because of the controversy over some of the health claims associated with these products. As with most dietary supplements, there is evidence for and against the claims made about
them. We will try to present an objective look at the evidence on either side. Keep in mind that our discussion of any of the following supplements is not exhaustive, and there is a lot more to say and more research to review than can be included in this book. Nevertheless, it is hoped that just enough information is presented to spark even more interest into the fascinating research behind specialty supplements.
Omega-3 Fatty Acids
Essential fatty acids (EFAs) are a group of nutritionally essential polyunsaturated fatty acids required for proper growth, maintenance, and function of the body. EFAs include both omega-3 and omega-6 fatty acids. The terms omega-3 and omega-6 designate their structures and refer to the position of the double bond relative to the terminal, or “omega,” carbon.
Omega-3s and omega-6s are precursors to a group of hormone-like lipid compounds called eicosanoids; these include prostaglandins, thromboxanes, and leukotrienes. Eicosanoids play critical roles in regulating many complex physiological processes such as immunity and inflammation, algesia, cell division and growth, blood clotting, labor and delivery, secretion of digestive juices and hormones, and movement of substances like calcium into and out of cells.
As omega-3 fatty acid supplements are the focus of this chapter, we will forego discussion of omega-6 fatty acids, which are rarely consumed as a dietary supplement. Dietary sources of omega-3 fatty acids include flax seeds, walnuts, and fatty fish. Omega-3s from plant sources is in the form of alpha- linolenic acid (ALA). Fatty fish provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The fatty acids EPA and DHA are by far the most commonly supplemented omega-3s.
Fish oil is the most plentiful source of EPA and DHA, and the majority of omega-3 products are sourced from various abundant species of fish, sardines and anchovies being the most common. Fish oil supplements often contain small amounts of vitamin E to improve stability and shelf life. Some omega-3 products do not contain oil from fish but are sourced from other marine animals including krill and marine algae. The source and processing of the oils can lead to different forms of fatty acids in the finished product. For example, the majority of fish oil supplements provide EPA and DHA in the form of triglycerides. Krill and some algae on the other hand provide EPA and DHA in the form of phospholipids. This difference impacts both digestibility and absorption.
Fish oil and oil derived from krill and some algae involve different digestion processes according to the differences in their chemical form. The digestive lipolytic enzymes pancreatic phospholipase A2 and lipase are involved in the digestion of phospholipids and triglycerides respectively. These two enzymes differ both in nature and activity.
Each enzyme reacts in very specific ways with its substrate. Fish oils are somewhat resistant, at least in vitro, to digestion by lipases because their structure partly obstructs the site where the enzyme acts on them (Bottino 1957), whereas phospholipase A2, which is required to digest phospholipids, is not influenced by the structure of the fatty acids because it acts at a different site that is not obstructed. This facilitates the digestion of phospholipids compared to that of triglycerides.
Phospholipids also affect the oil’s solubility. Krill oil, for example, is naturally emulsified by its phospholipid content. Emulsification improves digestion and absorption of EPA and DHA because of the increased solubility of the krill fatty acids compared to fatty acids in triglyceride form (Garaiova et al. 2007; Schuchardt et al. 2011). The emulsified and more water soluble state of krill oil increases its exposure to digestive enzymes and thus diminishes gastric clearance time (Raatz et al. 2009). This can also have a significant impact on “fishy burp back” that some fish oil users experience, which causes many to stop taking it. The increased solubility of phospholipid oils allows it to mix with stomach contents leaving less to float at the top as a layer of oil thus reducing fishy burp back and improving compliance.
Rationale for Supplementation
Achieving Nutritionally Adequate Levels of EPA and DHA
EFA deficiency manifests in a variety of bodily systems and tissues. Symptoms include scaly skin rashes, alopecia, brittle nails, infertility, neurological dysfunction, altered immunity, and decreased growth in children and infants (Smit, Muskiet, and Rudy Boersma 2004). Though outright deficiency is not common in developed countries, an inadequate intake is common and can contribute to a number of chronic health problems. It has been estimated that as many as 96,000 deaths per year in the United States can be attributed to inadequate intake of EPA and DHA (Danaei et al. 2009). Epidemiological data suggests that the average American consumes less than 100 mg/day of EPA and DHA (USDA 2012). This level is well below the published recommendations of 250 to 500 mg/day of combined EPA and DHA (USDA 2010).
Some suggest increasing plant based sources of omega-3s, which provide ALA, will provide adequate EPA and DHA. This strategy however is often ineffective. Technically speaking, EPA is a nonessential n-3 fatty acid as long as ALA is consumed in the diet. In humans however, there is tremendous interindividual variability in the ability to enzymatically convert ALA into EPA and DHA (see Figure 3.1). Research indicates that conversion of ALA to EPA and DHA may be as low as 0.3 and 0.01 percent respectively (Hussein 2005). These conversion rates generally do not provide optimal levels of EPA and DHA, thus putting these fatty acids in the category of conditionally essential nutrients. Adequate intake of EPA and DHA can be accomplished by consuming fatty fish at least twice weekly and taking marine sourced omega-3 dietary supplements.
Improving the Ratio of Omega-6 and Omega-3 Fatty Acids in the Diet
Both omega-3 and omega-6 fatty acids are precursors to eicosanoids; however, those derived from omega-3s and omega-6s lead to different subgroups of eicosanoids with sometimes opposing physiological effects. Generally speaking, eicosanoids derived from omega-6 fatty acids are proinflammatory, while eicosanoids derived from omega-3 fatty acids are anti-inflammatory (see Figure 3.2). It is believed that the ratio of omega-3 derived eicosanoids and omega-6 derived eicosanoids can impact systemic levels of inflammation (Patterson et al. 2012).
An increase in the consumption of processed foods and omega-6 rich vegetable oils over the last few decades has increased the omega-6 to omega-3 ratio (~15:1) in the American diet as well as many other developed countries (Blasbalg et al. 2011). The optimum ratio is believed to be closer to 1.4:1 (Molendi-Coste, Legry, and Leclercq 2011). Increases in the prevalence of chronic inflammatory diseases such as rheumatoid arthritis (RA), obesity, nonalcoholic fatty liver disease, cardiovascular disease, inflammatory bowel disease (IBS), and Alzheimer’s disease has coincided with this perturbation of the omega-6 to omega-3 ratio in Western diets (Patterson et al. 2012). Without a drastic change in dietary habits, omega-3 supplementation is required to bring the omega-6 to omega-3 ratio back down to a level that may reduce the incidence and prevalence of chronic inflammatory diseases.
Finally, there is evidence that postpartum depression (PPD) may be associated with the dietary ratio of omega-6 and omega-3s. PPD is a serious condition affecting the emotional state and maternal behaviors of the mother. PPD can increase the risk of psychopathologies and developmental problems in the child.
Some research has shown that the prevalence of PPD more than doubles in women with a dietary omega-6 to omega-3 ratio greater than 9:1 (da Rocha and Gilberto 2012).
Achieving Tissue Levels of EPA and DHA Associated with Reduced Cardiovascular Risk
Perhaps the strongest evidence for the value of supplementation with omega-3s is for cardiovascular health. Mechanistically, it has been demonstrated that EPA and DHA could contribute to preventing cardiovascular disease through several mechanisms. DiNicolantonio and colleagues have provided a list of many mechanisms by which EPA and DHA could be affecting cardiovascular health (see Table 3.1) (DiNicolantonio et al. 2014).
The aforementioned mechanisms by which EP and DHA may reduce cardiovascular risk are associated with and dependent upon the amount of EPA and DHA in tissues and cells. It is thought (and data supports) the notion that a certain level of EPA and DHA in tissues and cells is required before protective effects are seen (Harris and von Schacky 2004). The level of EPA and DHA in tissues and cells can be expressed as a percentage derived by use of the Omega- 3 Index (O3I). The O3I is a measure of the combined percentage of EPA and DHA in the total fatty acids in red blood cell membranes. The O3I is directly related to dietary intake of EPA and DHA (Flock et al. 2013). Data presented in Table 3.2 suggests that a desirable target value for the O3I is ≥8 percent and an undesirable level of ≤4 percent (see Table 3.2) (Harris 2015).
The data from Table 3.2 illustrates the importance of adequate omega-3 fatty acids in the diet. As of this writing, the O3I has not been officially recognized by the American Heart Association or other authoritative bodies, such as the American Medical Association, as an official predictor of cardiovascular risk. It is very likely this will change in the near future in the light of currently available and newly published evidence of its predictive value.
Pro-Resolving Lipid Mediators
Pro-resolving lipid mediators are molecules enzymatically derived from EPA, DHA, and the omega-6 fatty acid AA. Increasing the intake of EPA and DHA may lead to active resolution of inflammation by way of pro-resolving lipid mediators (Mas et al. 2012). I will generalize the various pro-resolving lipid mediators derived from EPA, DHA, and AA simply as “resolvins” for the sake of simplicity; nevertheless, it should be noted that there are at least four recognized classes of these lipid mediators, namely lipoxins from AA, resolvins and protectins from EPA and DHA, and maresins, a novel pro-resolving mediator derived from DHA that is released from macrophages.
It was believed until recently that the resolution of inflammation was a passive process. It was thought that the dissipation of inflammatory cytokines would eventually decrease the inflammatory activity until it had resolved, much like a fire is left to “burn itself out.” More recently it has come to light that the resolution of inflammation is an active process involving locally produced bioactive compounds that actively resolve inflammation, much like a fire extinguisher quenches a fire (Serhan et al. 2014). EPA and DHA are the precursors to these resolvins. It may be that the levels of resolvins are dependent on the tissue levels of its precursors EPA and DHA, which are known to be influenced by dietary intake. This topic is the focus of recent research and initial results indicate that supplementation with EPA and DHA is a viable approach to increasing resolvin levels (Mas et al. 2012). Currently, much is being learned about these and other pro-resolving mediators. For the time being however, for those that wish to act proactively to support healthy and appropriate inflammatory activity supplementing with EPA and DHA is a logical option.
Other Potential Health Benefits of Supplementing with Omega-3 Fatty Acids
Mood and Cognitive Function. Evidence from animal and human studies show that omega-3 deficiency leads to impaired neuronal function of serotoninergic and dopaminergic pathways in the brain (Patrick and Ames 2015). In addition, several epidemiological studies have demonstrated an inverse relationship between fatty fish consumption and depressive disorders. Over a decade ago an inverse association between fish consumption and prevalence of major depression across nine countries was reported (Hibbeln 1998). Since then, several epidemiological studies on oily fish consumption and depression demonstrated a significant inverse correlation between oily fish consumption and prevalence and incidence of depression and bipolar disorder, setting a threshold of vulnerability of about 650 mg/day. Meta-analyses have concluded that n-3 PUFA supplements may be beneficial in treating unipolar and bipolar depressive disorders (Lin 2007). At least one meta-analysis however did not come to the same conclusion (Appleton et al. 2006).
There has been considerable interest in the effects of omega-3 supplementation on attention deficit hyperactivity disorder (ADHD) in children. ADHD is estimated to effect as many as 10 percent of school age children. Accumulating evidence from epidemiological, biochemical, and intervention studies suggests that a diet inadequate in the omega-3 fatty acids EPA and DHA may have a detrimental effect on children’s behavior and cognitive development (Schuchardt et al. 2010) (Ryan et al. 2010). Data is also available showing reduced levels of EPA and DHA in children exhibiting ADHD. Randomized controlled trials and meta-analysis, however, have shown mixed results: some show significant improvements in cognitive performance and behavior, while others fail to show meaningful benefits (Bloch and Ahmad 2011; Gillies et al. 2012).
Eye Health. There is some evidence that people who consume fish oil from dietary fish at least twice a week have a reduced risk of developing age-related macular degeneration (AMD). Most epidemiological studies show an inverse relationship between dietary intake of EPA and DHA and prevalence of AMD. Both an increase in dietary intake and frequency of dietary intake resulted in a lowered risk of AMD progression (Liu et al. 2011).
Asthma. Inflammatory eicosanoids derived from omega-6 fatty acids are believed to play a role in the pathology of asthma. Supplementation with omega-3 fatty acids can reduce the production of inflammatory eicosanoids and, in turn, reduce the inflammatory potential of tissues. Clinical trials have been conducted to explore the benefits of omega-3 supplementation on the etiology of asthma. A meta-analysis and systematic review failed to show consistent benefit in subjects with asthma following fish oil supplementation (Thien, Woods, and Abramson 2002). Some clinical trials however, show that taking fish oil supplements improves peak flow and reduces medication use and cough in children with asthma (Broughton et al. 1997).
Rheumatoid Arthritis. RA is a disease characterized by significant inflammation of the joints. The ability of omega-3 fatty acids to reduce inflammatory eicosanoids makes it a logical candidate for reducing the symptoms of RA. Many studies on the effects of omega-3 fatty acids as an adjunct treatment for RA have been conducted, including a trial using krill oil. According to one placebo-controlled trial, krill oil significantly improved measures of pain, stiffness, joint function as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).
Krill oil also reduced the use of rescue medicines and reduced the systemic inflammatory marker CRP levels compared to placebo (Deutsch 2007). Reviews of these RA intervention trials have concluded that there is some benefit derived from supplementing with omega-3s, characterized by a reduction in pain, stiffness, and pain upon examination (Fortin et al. 1995). Two meta-analysis of RA clinical trials agree with the aforementioned reviews. In these analyses, supplementation significantly decreased the number of painful and tender joints on physical examination (Fortin et al. 1995; Goldberg and Katz 2007). Taken together, there is good evidence that supplementation with omega-3s improves symptoms of RA.
Pregnancy. In a review of fifteen randomized controlled trials with over 8,454 pregnant women, supplementation with omega-3 long-chain polyunsaturated fatty acids was associated with 26 percent lower risk of early preterm birth and moderately increased birth weight compared with placebo (Imhoff-Kunsch et al. 2012).
Omega-3 supplementation during pregnancy substantially increases fetal DHA concentration at birth. Two randomized controlled trials have shown that DHA supplementation during pregnancy also significantly improves infant neurocognitive development. One striking study was able to show that supplementation with omega-3s during pregnancy and lactation increases a child’s IQ at 4 years of age (Helland et al. 2003). It should be mentioned however that when the children are left to consume a typical diet without omega-3 supplementation, the differences in IQ disappear by age seven (Helland et al. 2008).
The previous list is only a small sample of conditions that have been investigated for beneficial effects of omega-3 fatty acids. To examine them all is beyond the scope of this work. The preceding does however represent the more common potential health benefits for which people chose to supplement with omega-3 fatty acids.
Because most omega-3 supplements are taken in the form of fish oil, the potential for these products to contain ocean contaminants such as methylmercury, Polychlorinated biphenyls (PCBs), and dioxins has been noted. Several independent laboratory analyses in the United States have found most commercially available omega-3 supplements to be free of methylmercury, PCBs, and dioxins (Melanson et al. 2005). The absence of methylmercury in fish oil supplements can be explained by the fact that mercury accumulates in the muscle rather than the fat of the fish. It should be noted that fish body oils contain lower levels of PCBs and other fat-soluble contaminants than fish liver oils. Additionally, fish oils that have been more highly refined and deodorized by a process called molecular distillation also contain very low levels of PCBs.
An evidence report or technology assessment conducted by Tufts University reviewed 148 studies to evaluate adverse events not including fishy aftertaste- from the use of omega-3 fatty acid supplements (typically fish oils) (Wang and Chung 2004). The report included about 10,000 subjects who had taken omega- 3 supplements in various forms and dosages ranging from 0.3 to 8 g/day for at least 1 week to more than 7 years. Half of all studies reviewed reported no adverse events. Less than 7 percent of subjects reported side effects, and those that were reported were minor, mainly gastrointestinal in nature (such as diarrhea) and were associated with higher doses of oil. Although bleeding is a theoretical concern, this was not borne out by the evidence. All adverse events related to consumption of fish-oil or ALA supplements consist mainly of stomach upset and can be managed by reducing the dose or discontinuing the supplement.
Fiber is generally considered to include all nondigestible vegetable matter in the diet. This includes polysaccharides, lignin, oligosaccharides, and resistant starches (Jones, Lineback, and Levine 2006). Fiber is made up of components of plant cell walls. Fresh fruits, vegetables, whole grains, nuts, and legumes are our primary source of dietary fiber. Fibers are classified as water soluble and water insoluble. Most fibrous foods are not exclusively soluble or insoluble. Soluble fiber, such as fruit pectin, can be fermented in the colon, and insoluble fibers, such as wheat bran, may only be fermented to a limited extent. Fermentation is the process of being broken down or metabolized by glut flora. Soluble fiber that specifically enhances the growth of beneficial bacteria in the digestive tract is known as prebiotic fiber. Prebiotic fibers include the oligosaccharides and resistant starches such as inulin and high-amylose maize, respectively. A short list of food sources of dietary fiber appears in Table 3.3.
Fiber supplements contain fiber isolated and extracted from foods and vegetable matter. Generally they are in the form of powders that can be added to liquids and drunk. Unlike foods, fiber supplements generally do not have both soluble and insoluble characteristics. This stems from the fact that they are isolated substances rather than a mix of different food stuffs. Fiber supplements can be classified according to their characteristics:
Soluble Fiber Supplements:
Fiber supplements, as described by McRorie, can be categorized into three classes based on the following characteristics: solubility, degree and rate of fermentation, viscosity, and gel formation (McRorie 2015a, 2015b).
Viscous or gel-forming, readily fermented fiber: These fibers dissolve in water and form a viscous gel. They increase viscosity of stomach contents to slow nutrient absorption and through this means may improve glycemic control. These fibers may also lower elevated serum cholesterol when combined with a low fat low cholesterol diet. They are readily fermented, which increases short chain fatty acid production as well as gas. Fermentation results in loss of gel and waterholding capacity, and thus, they have no significant laxative effect or retained gel to attenuate diarrhea. Examples include A-glucans from oatmeal and barley, and raw guar gum.
Viscous or gel-forming, nonfermented fiber: These fibers readily dissolve in water and form a viscous gel. They increase viscosity of stomach contents to slow nutrient absorption and through this means may improve glycemic control. These fibers may also lower elevated serum cholesterol when combined with a low fat low cholesterol diet. These fibers are not fermented by gut bacteria; therefore, they do not cause gas production or short chain fatty acid production. Because this type of fiber is not fermented, it remains gelled throughout the large intestine providing the unique benefit of reducing both constipation and diarrhea. An example is psyllium from psyllium husk.
Nonviscous, readily fermented: These fibers dissolve in water but do not increase viscosity of stomach contents; so they do not provide any gel- dependent benefits such as slowed nutrient absorption. They are rapidly and completely fermented in the small and large intestines. Once fermented, the fiber is no longer present in the stool. They can cause rapid gas formation and increased flatulence in large doses. Short chain fatty acid production is increased, and perhaps most importantly, the numbers of beneficial bacteria in the gut is also increased. They produce no laxative effect at normal doses and have no short-term benefits for constipation or diarrhea. Examples include the prebiotic fibers such as inulin, short chain fructo- oligosaccharides (SCFOS), and resistant starches.
Insoluble fiber has fewer variable characteristics. There is essentially only one class of insoluble fiber:
Insoluble, poorly fermented: These fibers do not dissolve in water (no water-holding capacity). They are poorly fermented and thus have little impact on gut flora. They can exert a laxative effect by mechanical irritation or stimulation of gut mucosa if particles are sufficiently large and coarse. Small smooth fiber particles (e.g., wheat bran flour or bread) have no significant laxative effect. Insoluble fiber does not gel or alter viscosity and thus does not provide other (gel-dependent) fiber health benefits such as reduced cholesterol and glycemic control. Examples include wheat bran, skins of fruits and tubers, and leafy green vegetables.
Rationale for Supplementation
Large Bowel Function
Constipation and diarrhea are two common large bowel dysfunctions that can be improved with fiber supplementation. The functional benefits of fiber, with the exception of prebiotics, are due to the fiber’s physical effects in the small and large intestine. Insoluble fibers such as wheat bran exert a laxative effect by increasing stool weight and mechanical irritation or stimulation of gut mucosa if particles are sufficiently large and coarse. Decreased transit time through the digestive tract and particularly the large bowel may decrease the incidence of large bowel disorders such as constipation, diverticulitis, and large bowel cancers. Fibers such as psyllium are gel forming and can “normalize” stool by absorbing excess water in the large bowel, reducing the frequency of bowel movements.
The majority of clinical benefits provided by dietary fiber, whether it is from whole foods or supplements, are due to the viscous properties of select fibers. The viscosity of certain fibers slows the digestion of foods by preventing bulk absorption of nutrients across the intestinal lumen. This can have a significant effect on glycemic control as well as cholesterol levels. Both of these are related to one’s risk of cardiovascular disease.
Glucose obtained from the carbohydrates in a meal is normally rapidly absorbed in the most proximal end of the small intestine. This rapid absorption results in a correspondingly rapid rise in blood glucose levels. Even in healthy individuals, this rapid rise in blood glucose levels produces a spike in insulin levels. High insulin causes a rapid decline in blood glucose that transiently falls below baseline levels, causing temporary hypoglycemia. Viscous gel-forming fiber can dramatically reduce this rollercoaster in blood glucose levels. By forming a gel, glucose is trapped within the viscous bolus and absorption is dramatically slowed. With the addition of a gel-forming fiber, absorption of glucose takes place along the entire length of the small intestine, reducing peak glucose and insulin levels and suppressing appetite.
Regular intake of a viscous gel-forming fiber supplement can also have significant benefits for long-term management of blood sugar levels. An eight- week, placebo-controlled clinical study evaluated psyllium for improved blood sugar control in 49 patients already being treated for type 2 diabetes (Ziai et al. 2005). After 8 weeks of taking 5 g of psyllium twice a day, fasting blood glucose was significantly decreased compared to the placebo group. Hemoglobin A1c and measure of long-term blood glucose levels also showed a significant decrease versus placebo. Interestingly, the improvements seen with psyllium supplementation were additive to the effects of the oral medications these subjects were already taking to control blood sugar levels.
It has been demonstrated that a 1 percent reduction in serum levels of LDL- cholesterol corresponds to a 1 to 2 percent reduction in occurrence of CHD events, making LDL-cholesterol a good biomarker for assessment of CHD risk (Kendall, Esfahani, and Jenkins 2010). Supplementing with fiber can have a significant effect on cholesterol levels.
Viscous gel-forming fibers have significant hypocholesterolemic effects, whereas nonviscous fibers do not. Two gel-forming fibers, Guar gum and psyllium, have been heavily studied for their effects on cholesterol. Anderson et al. have provided information on the net impact of soluble viscous fibers on cholesterol (change with fiber treatment minus change with placebo treatment) (Anderson et al. 2009). A review of over 40 clinical trials on guar gum indicated that intakes ranging from 9 to 30 g/day, divided into at least three servings per day, were associated with a weighted mean reduction of 10.6 percent for LDL-cholesterol values. For pectin, consumption of 12 to 24 g/day in divided doses was associated with a 13 percent reduction in LDL-cholesterol. Barley beta-glucan intake of 5 g/day in divided doses was associated with an 11.1 percent reduction in LDL-cholesterol values. Although less data is available for hydroxypropyl methylcellulose, trials indicate that 5 g/day in divided doses decreases LDL-cholesterol values by 8.5 percent.
Some fibers are able to selectively increase the populations of good bacteria in the digestive tract. We call these fibers prebiotics. Prebiotics are not classified in the same manner as “bulk” fibers. Prebiotics are classified simply by their ability to selectively increase good microflora. The current official definition of a prebiotic is “A dietary prebiotic is a selectively fermented ingredient that results in specific changes in the composition and activity of the GI microbiota thus conferring benefit(s) upon host health” (Gibson et al. 2010).
The concept of prebiotics is rather new in terms of the history of discoveries about human health (Gibson and Roberfroid 1995). Nevertheless, the number of studies published on prebiotics has increased from one in 1995 to over 340 in 2014. The growth in our understanding has increased dramatically just in the last 10 years; for example, the number of published studies has increased by a factor of six since 2005. Out of this research has come a range of potential health areas that are or may be impacted by the use of prebiotics. Table 3.4 lists some of these health areas being studied with prebiotics (Roberfroid et al. 2010).
Because fiber is a natural component of foods that we consume every day, there has never really been any suspicion that it might be unsafe. Rather, fibers are evaluated in terms of “intestinal acceptability” (Coussement 1999). Intestinal acceptability of fiber is determined mainly by two criteria: (1) The osmotic effect, which leads to an increased draw of water into the colon. Smaller molecules exert a higher osmotic pressure and bring more water into the colon. (2) The fermentability of the fiber, which leads to the buildup of fermentation products, mainly short-chain fatty acids and gases. Slowly fermenting compounds appear to be easier to tolerate than their fast fermenting analogs. This would explain why inulin is easier to tolerate than oligofructose.
The intake of fermentable fibers is self-limiting because of flatulence or gas. For nonfermentable fibers it is loose stools or diarrhea. Dietary fibers are considered nontoxic and are considered safe in food as dietary supplements. Synthetic fibers, although less common, must demonstrate their safety by applying for generally recognized as safe (GRAS) status with the Food and Drug Administration (FDA). GRAS is the label given to food components and ingredients approved for human consumption by the FDA. A synthetic or semisynthetic fiber intended to be used as a dietary supplement would also have to apply for and receive approval as a “new dietary ingredient” (NDI) from the FDA.
Bacterial colonization of the gut and skin begins at birth and continues throughout life with notable age-specific changes. Bacteria are normal inhabitants of the gastrointestinal tract, where more than 1,000 bacterial species are found. These resident intestinal microflora do not normally have any acute adverse effects, and some of them have been shown to be necessary for maintaining the health and well-being of their host.
The notion of the importance of probiotics is certainly not new. By 1886, Escherich had described the microbiota and early colonization of the infant gastrointestinal tract and suggested their benefit for digestion, whereas Döderlein was probably the first scientist to suggest the beneficial association of vaginal bacteria by production of lactic acid from sugars, thereby preventing or inhibiting the growth of pathogenic bacteria (Goktepe, Juneja, and Ahmedna 2006).
The idea that certain bacteria could be supplemented orally to improve intestinal health was first proposed in 1907 by Eli Metchnikoff, a Russian born Nobel Prize recipient working at the Pasteur Institute (FAO/WHO 2001; Metchnikoff 1907). He observed, “The dependence of the intestinal microbes on the food makes it possible to adopt measures to modify the flora in our bodies and to replace the harmful microbes by useful microbes” (Metchnikoff 1907). In spite of this early understanding of the potential benefits of ingesting beneficial bacteria, the term “probiotic” meaning “for life” was not coined until the mid-1960s, (Lilly and Stillwell 1965). In the intervening century since Metchnikoff’s insightful proposals and more particularly the last two decades, research on probiotics has progressed considerably and significant advances have been made in the identification and characterization of specific probiotic strains and substantiation of health claims relating to their consumption.
A commonly accepted definition of a probiotic is “Live microorganisms which when administered in adequate amounts confer a health benefit on the host” (FAO/WHO 2001). Only a relatively small number of bacterial species meet this definition. Probiotics are primarily bacteria from the lactobacillus, bifidobacterium, and bacillus genera. However, Lactococcus, Streptococcus, and Enterococcus species, as well as some nonpathogenic strains of Escherichia coli and certain yeast strains, may also act as probiotics. A brief list of examples of bacterial probiotics with origins is presented in Table 3.5.
Not all bacteria qualify as probiotics, even if they are not harmful when ingested. To qualify as a probiotic an organism should show some combination of the following characteristics (Dash 2009):
- Be resistant to gastric acidity
- Be resistant to bile acid
- Demonstrate bile salt hydrolase activity
- Adhere to mucus and human epithelial lining of the gut
- Possess antimicrobial activity against potentially pathogenic bacteria
- Possess the ability to reduce pathogen adhesion to surfaces in the
- gastrointestinal tract
- Demonstrate beneficial immune modulating ability.
This list of potential characteristics in not comprehensive. For example, the gut brain axis is now being intensely studied as is the impact of gut bacteria on metabolism and obesity. As our understanding of the microbiome grows, it may soon be that due to complexity, no single list of characteristics will be adequate as inclusion criteria for all potential probiotics.
Rationale for Supplementation
Major probiotic mechanisms of action include fermentation of dietary fiber, enhancement of the epithelial barrier, increased adhesion to intestinal mucosa, concomitant inhibition of pathogen adhesion, competitive exclusion of pathogenic microorganisms, production of antimicrobial substances, and modulation of the immune system (Backhed et al. 2005; Bermudez-Brito et al. 2012).
Fermentation of Dietary Fiber
The cell walls of plant material that we eat contain complex carbohydrate molecules that we cannot digest; we call these carbohydrates dietary fiber. Our ability to digest complex carbohydrates is dependent on the type of enzymes that we produce. We do not produce all the enzymes necessary to break down all the different types of carbohydrates that we eat. Probiotics along with the endogenous bacteria in the digestive tract do however produce numerous enzymes that are able to break down simple as well as very complex carbohydrates in a process called fermentation. Without this help from our gut bacteria, all dietary fiber we eat would pass through the digestive tract much like insoluble fiber. This would dramatically increase the laxative effects of eating nonanimal foods. Probiotics, by their own action and by enhancing the health of the endogenous flora, can aid in reducing digestive upset caused by poor digestion of dietary fiber.
Enhancement of Epithelial Barrier Function
The intestinal epithelium forms the barrier between the outside of the body and the inside, much like your skin forms the barrier on the outside of your body. The integrity of the epithelium is crucial for preventing pathogens from entering the body. Intestinal barrier function relies on several defense mechanisms; antimicrobial peptides and secretory Immunoglobulin A (IgA) form a chemical barrier, while the mucous layer and the epithelial junction adhesion complex (i.e., tight junctions) form a physical barrier. Disruption of any of these layers of defense exposes the cells of the epithelium to bacterial and food antigens and can cause an inflammatory response. If this disruption becomes chronic it can lead to intestinal disorders such as IBS.
Probiotics have been shown to help repair a damaged epithelial barrier in several ways. First, they can suppress the inflammatory response by interacting with immune cells and alter inflammatory cytokine levels. Recently, it has been discovered that some probiotics can prevent inflammation-induced destruction of epithelial cells by preventing apoptosis. Probiotics can also alter gene expression of tight junction proteins, repairing the epithelial junction adhesion complex. Some probiotics may also increase mucin secretion, thereby enhancing the mucosal barrier. Finally, in response to attack by pathogenic bacteria, probiotic strains can also induce the release of antimicrobial proteins from epithelial cells.
Increased Adhesion to Intestinal Mucosa or Inhibition of Pathogen Adhesion
There are a number of ways that probiotics have been shown to protect against the colonization of pathogenic bacteria (Bermudez-Brito et al. 2012). Inhibition of pathogen adhesion, competitive exclusion of pathogenic microorganisms, and production of antimicrobial substances are the primary ways in which probiotics can help protect us from colonization of pathogenic bacteria.
Adhesion of bacteria to mucosal surfaces and epithelial cells is one of the key beneficial features of probiotic action. Adhesion is a prerequisite for intestinal colonization and antagonistic activity against pathogenic bacteria. By this mechanism, endogenous intestinal bacteria as well as some probiotics supplements can provide competitive exclusion of potential pathogenic bacteria.
In part, competitive exclusion of pathogenic bacteria occurs by competitive inhibition of binding sites. Simply put, if you fill all the available binding sites with good bacteria, bad bacteria have nowhere to adhere and are left to continue their journey out of the body. Think of it like musical chairs for bacteria. When the music stops, some probiotics are good at grabbing the only available seats, leaving the bad guys with nowhere to sit. The importance of competitive exclusion becomes obvious when a broad-spectrum antibiotic therapy reduces the number of good bacteria and decreases colonization resistance, which may lead to an overgrowth of opportunistic pathogenic bacteria such as Clostridium difficile (Shanahan 2002).
Probiotics also release what are called autogenic regulation factors like lactic acid and hydrogen peroxide. These are antimicrobial substances that make the environment unfavorable for pathogenic bacteria to live. Some of these antimicrobial substances such as bacteriocides act directly to kill pathogenic bacteria.
Modulation of Immune Responses
Approximately 70 percent of the immune system is situated along the intestinal tract as gut-associated lymphoid tissue (GALT). This makes sense considering that the intestinal tract is the primary pathway for outside substances to enter the body. Many human studies have been performed to investigate the effects of probiotic cultures on the immune system. Some studies focused on the intestinal immune system, others on the systemic immunity, including allergies and juvenile asthma. These studies reveal that probiotic bacteria are able to enhance both innate and acquired immunity by increasing natural killer cell activity and phagocytosis, changing cytokine profiles, and increasing levels of immunoglobulins. The two most common species of probiotics Bifidobacterium and Lactobacillus have both been demonstrated in several studies to enhance natural immune function in healthy people as have most other common strains.
The long history of safety has contributed to the acceptance of probiotics as a safe food adjunct. Consequently, many probiotic products and their use in food products and dietary supplements have been granted GRAS status. GRAS status can be achieved when a probiotic has a history of safe use dating before 1958 or have been recognized by experts as safe under the conditions of intended use. For example, B. coagulans GBI-30-SF has had GRAS status since 2007 for general use as a probiotic. B. animalis subsp. lactis BB-12 and S. thermophilus TH-4 have had GRAS status since 2002 for specific use in infant formula.
The assumption of GRAS status however, has been frequently generalized for all probiotic strains being marketed in foods and dietary supplements. There are reported cases of probiotics from the genera Lactobacillus, Leuconostoc, Pediococcus, Enterococcus, and Bifidobacterium that have been isolated from infection sites, leading to the belief that these probiotics can translocate. Bacterial translocation is defined as the passage of viable bacteria (good or pathogenic) from the gastrointestinal tract to sites within the body outside of the gastrointestinal tract. Commensal bacteria and probiotics have been identified in locations such as the mesenteric lymph node complex, liver, spleen, kidney, and bloodstream. The three primary mechanisms allowing bacterial translocation in animal models are: (a) disruption of the microbiota within the digestive tract leading to intestinal bacterial overgrowth, (b) increased permeability of the intestinal mucosal barrier, and (c) deficiencies in host immune defenses (Berg 1999).
Probiotic translocation is difficult to induce in healthy humans, and even if it does occur, detrimental effects are rare. Despite this, probiotics may still induce detrimental effects and various reports have documented health-damaging effects of probiotic translocation in immunocompromised patients. Due to probiotics’ high degree of safety and their morphological confusion with other pathogenic bacteria, they are often overlooked as a potential risk and are least suspected as pathogens. Antibiotic resistance of some probiotic strains, however, has increased the complexity of treating infections in the immunocompromised individual (Liong 2008).
Glucosamine and Chondroitin
Glucosamine and Chondroitin are naturally occurring chemical compounds that are found throughout the body, most notably in the extracellular matrix of the cartilage tissue of joints. The two compounds have clinical support for joint health benefits when used individually, but they are most commonly consumed in combination. The most common form of glucosamine found in dietary supplements is glucosamine sulfate, but glucosamine hydrochloride and n- acetyl glucosamine sources are also available. Glucosamine is most commonly sourced from the shells of shellfish, but it may be synthesized in a laboratory setting as well. Chondroitin is most commonly sourced as chondroitin sulfate. Chondroitin is comprised of repeating subunits of D-glucuronic acid and N- acetyl-D-galactosamine with sulfates attached to either the four- or six-position on the N-acetyl-D-galactosamine. When the sulfate resides in the four-position, the chondroitin is classified as CS A and when it falls in the six-position, it is classified as CS C. Chondroitin is most commonly sourced from bovine or porcine trachea and less commonly from avian sources.
Glucosamine and chondroitin are used by the body as substrates or building blocks in the formation of articular cartilage. Both ingredients have been shown to concentrate in the joint tissues following oral supplementation (Conte et al. 1995; Setnikar, Giacchetti, and Zanolo 1986; Setnikar et al. 1993). Glucosamine is specifically required for and is a rate-limiting step in the production of macromolecules found in articular cartilage, including proteoglycans, glycosaminoglycans, and hyaluronic acid. Glucosamine has also been found to have anti-inflammatory effects in the body (Gouze et al. 2002; Nakamura et al. 2004; Uitterlinden et al. 2006). Chondroitin is combined with proteins in the formation of proteoglycans, which provide structural resistance to compression forces in the joint, a key function of cartilage. The chondroitin compound is also a hydrophilic (water-loving) molecule, which attracts water into the cartilage, causing it to swell, and further supports this compression resistance quality (Bali, Cousse, and Neuzil 2001).
Rationale for Supplementation
Osteoarthritis (OA) affects millions of adults around the world, creating a worldwide public health problem. Symptoms of OA include pain, stiffness and reduced functionality. These effects often reduce quality of life for those individuals suffering from arthritis. Current treatment options include physical activity, hot and cold therapy, maintenance of a healthy weight, assistive devices, rest, and over-the-counter pain relievers or anti-inflammatory medications. In severe cases, joint replacement surgery may be necessary. Glucosamine and chondroitin at 1,500 and 1,200 mg/day, respectively, have been used alone and in combination by individuals with OA or age related declines in joint health and function. This supplement combination has been used for prevention and management of OA for almost 40 years (Vangsness, Spiker, and Erickson 2009).
Relief of joint pain and stiffness is the most common motivation for which consumers look to glucosamine and chondroitin supplementation. Clinical studies have shown that supplementation with glucosamine, chondroitin or the combination of the two can reduce these symptoms of OA over time. Significant improvements in pain, stiffness, and movement in subjects with OA have been demonstrated with glucosamine supplementation (Bruyere et al. 2004; Herrero-Beaumont et al. 2007; Pavelka et al. 2002; Reginster et al. 2001; Thie, Prasad, and Major 2001), chondroitin supplementation (Bourgeois et al. 1998; Bucsi and Poor 1998; Mazieres et al. 2007; Uebelhart et al. 2004), and a combination of the two (Clegg et al. 2006; Das and Hammad 2000; Leffler et al. 1999). The most notable study of this dietary supplement combination is the NIH-sponsored Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (Clegg et al. 2006). This study included ~1,500 OA subjects and included five groups: 1,500 mg/day glucosamine hydrochloride, 1,200 mg/day chondroitin sulfate, the combination of the two, 200 mg/day of CelebrexTM, or placebo. The study ran for 24 weeks. Significant improvements in pain were not found for the supplement groups versus placebo, but when results were controlled for those subjects with moderate to severe baseline pain, supplementation with glucosamine and chondroitin resulted in a significant improvement in pain versus placebo.
Another consequence of OA and aging on joint health is the steady breakdown of the cartilage matrix and its components. While the breakdown and rebuilding of cartilage is a natural process that occurs throughout life, during the aging process and OA, the balance between these two processes can shift away from one of cartilage building toward one of cartilage breakdown. Over time, this shift may result in a loss of cartilage thickness and a narrowing of the joint space. Supplementation with glucosamine and chondroitin has been found to support the structural integrity of cartilage and reduce its breakdown over time. In support of this benefit, 1,500 mg of glucosamine sulfate was shown in a clinical trial including 106 subjects with mild to moderate knee OA, to delay the progression of joint space narrowing compared with placebo over a 3-year period (Reginster et al. 2001). Similarly, several studies have shown that over time, supplementation with chondroitin sulfate at 800 mg or more per day results in a reduction in cartilage loss as compared to a placebo (Kahan, Reginster, and Vignon 2006; Michel et al. 2005; Uebelhart et al. 1998; Uebelhart et al. 2004; Wildi et al. 2011).
Given the previously referenced clinical evidence, individuals looking to support their overall joint health as they age may benefit from daily supplementation with 1,500 mg glucosamine and 1,200 mg chondroitin. Such supplementation may help reduce joint discomfort, improve flexibility, support healthy movement, and reduce age-related breakdown in articular cartilage. Furthermore, individuals taking Glucosamine may also be able to avoid or delay the need for knee replacement surgery. In 2007 researchers conducted a 5-year follow-up study of a group of knee OA patients who had participated in a clinical trial providing 1,500 mg of glucosamine sulfate. Results of this study demonstrated that those subjects who had supplemented with glucosamine for at least 12 months were 57 percent less likely to require a total knee replacement versus those subjects who had been taking a placebo (Bruyere et al. 2008).
Glucosamine and Chondroitin are likely safe when taken orally by healthy adults at or below the most commonly recommended dosages of 1,500 and 1,200 mg daily, respectively. DRIs for these compounds have not been determined; therefore, adequate intake levels and tolerable upper limits do not exist for these ingredients. Few studies have been conducted to evaluate the safety of glucosamine or chondroitin at doses that exceed the recommended levels of 1,500 and 1,200 mg/day, respectively. Glucosamine is derived from shrimp, crab, and other shellfish, and consequently should be avoided by individuals with an allergy or sensitivity to shellfish or iodine. Some research has linked glucosamine intake with increased blood sugar levels, while other studies have not found the same result; so individuals with diabetes should consult their physician before considering taking this supplement (Anderson, Nicolosi, and Borzelleca 2005; Biggee et al. 2007; Muniyappa et al. 2006; Scroggie, Albright, and Harris 2003; Tannis, Barban, and Conquer 2004). Chondroitin may increase an individual’s risk for bleeding. Individuals with bleeding disorders should consult their physician before taking chondroitin. As with all dietary supplements, individuals with any diseases or medical conditions should consult their physician before taking any dietary supplements.
Coenzyme Q10 (also known as ubiquinone, ubidecarenone, or CoQ10) is a lipid-soluble vitamin-like compound both synthesized in the body and consumed in the diet. CoQ10 is present in the inner membrane of the mitochondria of every cell of the body. The name ubiquinone refers to the ubiquitous presence of these compounds in living organisms and their chemical structure, which contains a functional group known as a benzoquinone. The structure of CoQ10 consists of a benzoquinone ring and a lipophilic isoprenoid side chain. The length of the side chain varies, but in humans, the side chain is composed of 10 trans-isoprenoid units, thus coenzyme Q “10.”
CoQ10 plays two major roles in the body. In the mitochondria, CoQ10 is a vital coenzyme in the electron transport chain for the synthesis of ATP, the major source of cellular energy. CoQ10 is found at its highest levels in cells with high energy requirements such as heart, brain, liver, and kidney. The second function of CoQ10 is as an antioxidant, particularly in preventing lipid peroxidation. CoQ10 also plays a role in the regeneration of other antioxidants. CoQ10 bears a close relationship with vitamin E allowing it to regenerate in its active, reduced form (alpha-tocopherol). It also serves in the regeneration of the reduced form of vitamin C (ascorbate).
Although CoQ10 is not classified as an essential nutrient, low tissue and serum levels of CoQ10 have been associated with a number of conditions including cardiovascular disease, neuromuscular conditions, hypertension, periodontal disease, asthma, hyperthyroidism, male infertility, and AIDS. CoQ10 deficiency could result from reduced CoQ10 synthesis secondary to other nutritional deficiencies, a genetic or acquired defect in CoQ10 synthesis or utilization, or a conditional deficiency due to increased tissue needs associated with a specific illness. CoQ10 has been used in experimental settings as a treatment for these conditions with varying success. Outcomes suffer from variable serum levels within each subject. This has been attributed in part to the poor bioavailability of common CoQ10 supplements (Bank, Kagan, and Madhavi 2011).
Bioavailability of CoQ10
CoQ10 is a lipid-soluble compound with a high molecular weight (864 Daltons), and this fact can limit absorption. CoQ10 absorption is known to improve in the presence of fat, thus dietary supplements containing powdered CoQ10 formulations that are suspended or emulsified in oil are better absorbed than the powder alone. CoQ10 emulsified in oil will come in the form of a softgel, not a two piece capsule. Many other technologies or systems have been investigated for their ability to enhance absorption. Examples include solubilized formulations in emulsifiers such as soy lecithin, polysorbates, and medium-chain triglycerides. Micronization of raw crystalline CoQ10 powder is often used in these formulations as is micellarization and are often blended with absorption enhancers. CoQ10 can also be complexed with cyclodextrins to form a water-soluble compound. Other formulations include colloidal and nano-beadlet delivery systems (Bank, Kagan, and Madhavi 2011).
Marketers of CoQ10 supplements seek after and rely heavily on the “enhanced absorption” claim on their packaging. Comparative studies looking at bioavailability show that these delivery systems differ, sometimes significantly, in their capacity to improve bioavailability. One must also be aware that most of the studies comparing bioavailability of CoQ10 formulations are conducted or sponsored by companies with a financial interest in the outcome of the study. This does not guarantee that bias is playing a factor in the outcome, but it is always a possibility and is more likely when studies are sponsored by manufactures. Consequently, if there is a quantitative claim about just how much better it is absorbed, take it with a grain of salt, as different absorption technologies and testing methods will return different results.
In addition to formulas designed to enhance the absorption of CoQ10 (ubiquinone), another form of CoQ10 referred to as ubiquin-ol is also sold as a dietary supplement. Ubiquinol is claimed to have superior bioavailability. Ubiquinone is the form synthesized in the body’s cells. It is then converted to ubiquinol. Ubiquinone is the oxidized form of CoQ10, and ubiquinol is the reduced form, and together they form a redox pair. Each can be readily converted into the other in cells, lymph, or the blood when their respective forms are needed. Ingested CoQ10 in the foods we eat is converted to ubiquinone upon cooking. Likewise, ubiquinol ingested as a dietary supplement is converted to ubiquinone in the stomach. Ubiquinol is only slightly more water soluble than ubiquinone. Ubiquinol is considerably more expensive than ubiquinone and the many forms of Ubiquinone (CoQ10) (aside from dry powder) have many years of data demonstrating their effectiveness, so ubiquinone as CoQ10 is generally considered the best option for the majority of consumers.
Rationale for Supplementation
The most common reason people take CoQ10 is for general wellness. CoQ10 is important for the proper functioning of every tissue in the body due to its role in cellular energy production and antioxidant activity. Secondary reasons most often include antiaging and heart health.
Theories explaining the mechanism of aging include the mitochondrial theory of aging. This theory proposes that progressive accumulation of mutations in mitochondrial DNA during our lifetime leads to a decline in mitochondrial function. This is postulated as a key contributing factor to human aging (Wei et al. 2009). CoQ10 levels decline with advancing age, and this decline might play a role in the increase in mitochondrial mutations and declining function of mitochondria. To date, dietary CoQ10 supplementation has not shown direct effects on extending life span in animal studies. Thus, it may be considered that dietary CoQ10 supplementation may not directly extend lifespan; however it may help to prevent life span shortening due to cellular oxidative damage (López-Lluch et al. 2010). One possible exception in which anti-aging effects have been seen is in the beneficial effects of CoQ10 treatment on non–disease- related skin aging (Prahl et al. 2008).
CoQ10 has been investigated as a potential therapy for a large number of health conditions and diseases, especially those that result from reduced mitochondrial function. Currently, CoQ10 is widely promoted as a dietary supplement for supporting cardiovascular health. Myocardial cells contain some of the highest concentrations of CoQ10 in the body (Kumar et al. 2009). The cardiovascular benefits of CoQ10 have been credited to its role in ATP production, its capability of antagonizing oxidation of LDL-cholesterol, its regulation of cell membrane channels, and its ability to reduce the effects of endothelial damage, specifically by improving endothelial function (Mortensen 2003; Sinatra 2009). Consequently, much attention has been directed toward therapies that promote and maintain ATP production.
One aspect of coronary heart failure is ATP consumption exceeding ATP production, resulting in oxidative stress. Patients with heart failure and cardiomyopathy have decreased plasma CoQ10. CoQ10 supplementation can increase left ventricular ejection fraction by as much as 22 to 39 percent in patients with coronary heart failure. Interestingly it also increased ejection fraction by 4 percent in healthy subjects (Langsjoen and Langsjoen 2008; Molyneux et al. 2008). In addition, supplemental CoQ10 increased walking tolerance and decreased distal limb edema in this population. Finally, Molyneux et al. (2008) observed that serum CoQ10 values were an independent predictor of mortality, thereby supporting the strategy of administering CoQ10 to this group.
Effects of CoQ10 Supplementation on Blood Pressure
Studies have shown CoQ10 can lower arterial blood pressure in individuals with hypertension (Wyman, Leonard, and Morledge 2010). The exact mechanism is not known, but one theory suggests it reduces peripheral resistance by increasing peripheral endothelial function (Pepe et al. 2007). Wyman, Leonard, and Morledge (2010) suggested CoQ10 may increase the production of nitric oxide and prostaglandin prostacyclin, both potent vasodilators and inhibitors of platelet aggregation. It should be noted however that in healthy humans and animals CoQ10 has not been shown to possess a direct vasodilating or acute hypotensive effect. This indicates that the hypotensive effect of CoQ10 is likely to be specific to the state of enhanced oxidative stress occurring in hypertensive individuals (Rosenfeldt et al. 2007).
Studies examining the efficacy of CoQ10 as an adjunct to treat essential hypertension are conflicting, in part due to variations in the methods of administering CoQ10 and in part to the study design adopted (Ho, Bellusci, and Wright 2009). Digiesi Cantini and Brodbeck (1990) studied 18 patients with essential hypertension. Patients were randomized to receive either 100 mg/day of CoQl0 or a placebo for 10 weeks. This study ensured the effects were linked specifically to CoQ10 by discontinuing antihypertensive therapy prior to the study. The patients receiving CoQ10 exhibited significant decreases in systolic and diastolic pressures at 3 weeks of treatment, which persisted throughout the subsequent 7 weeks of treatment. After 10 weeks, CoQl0 administration was stopped, resulting in blood pressures increasing to pretreatment levels in 7 to 10 days. A meta-analysis of 12 clinical trials concluded CoQ10 lowered systolic blood pressure by up to 17 mm Hg and diastolic blood pressure by up to 10 mm Hg in patients with essential hypertension without any significant side effects (Rosenfeldt et al. 2007).
Still, not all studies looking at the effects of CoQ10 on blood pressure have demonstrated a clear benefit. A recent 12-week randomized double-blind placebo controlled crossover study by Young et al. (2012) administered CoQ10 or placebo to 30 subjects with the metabolic syndrome (i.e., prediabetes) while maintaining their conventional blood pressure drug regimen. Compared with placebo, CoQ10 was not associated with a statistically significant reduction in blood pressure. These findings concur with one other double-blind, placebo- controlled intervention trial by Mori et al. (2009), who found 8 weeks of CoQ10 administration had no effect on 24-hour ambulatory blood pressure in patients with chronic kidney disease. Interestingly, Young reported that although no significant difference was found for 24-hour measures of blood pressure, daytime “diastolic BP loads” were significantly lower while taking CoQ10 (Young et al. 2012).
CoQ10 supplementation is GRAS. There is a paucity of adverse events reported in short and long term human and animal studies. The most common complaints are stomach upset, but this is associated with three or more g/day. Long term, CoQ10 has been safely used in studies lasting up to 30 months.