Should You Take Herbal Dietary Supplements?

A botanical, by definition, is a plant or part of a plant valued for its medicinal or therapeutic properties. Products made from botanicals are called herbal products, botanical products, phytomedicines, or nutraceuticals. These may include teas in addition to other product forms. Most herbal products differ from other dietary supplements in that they do not usually contain essential nutrients but contain, instead, phytochemicals believed to have some beneficial drug-like effect on the body or some unique antioxidant property. In addition, most herbal products sold as dietary supplements are known for their “traditional use.” The traditional use of a product refers to the presence and use of a botanical within cultural medicine systems. Examples include traditional Chinese Medicine and Ayurvedic Medicine. Traditional use can refer to a historic use no longer in practice or to those used medicinally even today.

With herbal products, benefits can be claimed for any known area of health. This is due to the tremendous variety of phytochemicals they contain. This variety of chemicals also poses risks, in that oftentimes the chemicals in herbal products interact with each other. Some may act synergistically together, while others may counteract each other. Some benefits may be additive for a specific effect whereas others may be entirely unrelated to one another. I tell people taking a herbal product for a specific benefit is like trying to calm a headache by opening up a medicine cabinet full of over the counter medicines, and taking one pill from each bottle because you know one of them contains an aspirin.

This chapter reviews five of the most popular consumer herbal products in the market today. The benefits they offer range from preventing urinary tract infections (UTIs) to supporting heart health and several things in-between. I should mention that the five herbal supplements we discuss in this chapter constitute a very small selection of the large herbal product category. There is a far greater variety of herbal products on the market than any other dietary supplement category.

Green Tea

Background

According to legend, the first cup of tea was brewed by a Chinese emperor some 4,000 years ago. Since then, green tea has had a place in traditional Chinese medicine as a remedy for many things including headaches, body aches and pains, digestion, depression, immunity, low energy, and aging.

All teas (i.e., green, black, and oolong) are derived from the same plant, Camellia sinensis. C. sinensis is a member of the Theaceae family. The difference between the types of teas is in how the leaves are prepared. Green tea, unlike black and oolong, is not fermented, so the active constituents remain unoxidized. Not only are green tea leaves not fermented they are steamed, which inactivates the enzymes responsible for oxidation, thus preserving the active compounds in their original form.

Tea is one of the most widely consumed beverages in the world, second only

to water. A great deal of research has been done to understand the chemical composition and health effects of green tea. About 30 to 40 percent of the compounds in an extract of green tea leaves are polyphenols. One class of polyphenol, in particular called flavanols, play an important role in the health benefits of green tea. These flavanols are comprised mostly of compounds called catechins namely, epigallocatechin-3-gallate (EGCG), epi-gallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC). EGCG is present in the highest concentration and is perhaps the most potent.

Because of the long history of traditional use (i.e., millennia), green tea has been recommended for many ailments from cavities to cancer and everything in between. The most researched properties of green tea center on its antioxidant activity, its ability to promote weight loss, and its anticancer properties. Most recently, green tea has been examined for its prebiotic properties as well.

Green tea’s antioxidant potential is directly related to the combination of aromatic rings and hydroxyl groups of the polyphenols it contains. The structure of these molecules enables the binding and neutralization of free radicals by the hydroxyl groups. The oxygen radical absorbance capacity assay is commonly utilized to measure the antioxidant capacity of plant-based antioxidants. Units are expressed as trolox equivalents, and green tea provides ~1,300 μmol of trolox equivalents per gram of dried tea leaves (Forester 2011).

Green tea’s connection to weight loss stems from its caffeine content as well as its interaction with an enzyme called catechol-O-methyltransferase (COMT). COMT deactivates catecholamines such as dopamine, epinephrine, and norepinephrine. Green tea polyphenols are a substrate for this enzyme and can reduce its activity leading to increased serum levels of catecholamines in the body (Dulloo et al. 2000; Lu, Meng, and Yang 2003). Both norepinephrine and epinephrine are lipolytic, meaning they stimulate the breakdown and release of stored fat from fat cells. As a COMT inhibitor, green tea polyphenols have the potential to increase the level and duration of activity of these lipolytic catecholamines.

The mechanistic role of green tea in cancer metabolism is multifaceted. EGCG and ECG are potent antioxidants and may protect cells from DNA damage caused by reactive oxygen species. Green tea polyphenols stimulate detoxification systems; they can induce phase I and phase II metabolic enzymes that increase the degradation of carcinogens; they inhibit biochemical markers of tumor initiation and promotion, including lowering the rate of cell replication and thus the growth and development of neoplasms; and they prevent mutagenicity and genotoxicity (Brown 1999).

Rationale for Supplementation

Most consumers of green tea supplements take them because they believe that there are overall health benefits to taking it. This makes sense considering the beneficial properties of polyphenols discussed previously. Besides general wellness, many consumers take green tea or products with green tea ingredients for specific purposes, particularly, weight loss and cancer. More recently, polyphenols such as those found in green tea have been studied for their ability to enhance beneficial gut flora (Cardona et al. 2013; Dueñas et al. 2015).

The evidence for the efficacy of green tea extract in weight loss is mixed. A recent double blind study showed that EGCG at a daily dose of ~860 mg for 12 weeks produced significant weight loss, reduced waist circumference, and improved cholesterol profile without side effects in women with central obesity (Chen et al. 2015). This is in contrast to a review of 15 different placebo- controlled studies involving 1,945 subjects that was unable to demonstrate a consistent statistically significant effect on weight loss after 12 to 13 weeks of green tea supplementation (Jurgens et al. 2012). Looking closely at the data, however, reveals that in studies that failed to show statistical significance, there are individuals who did have clinically relevant results. This could have happened due to at least three reasons. First, green tea extracts differ in the levels of not only polyphenols but also caffeine. Green tea affects weight loss in part because of its caffeine content. Caffeine is able to increase levels of catecholamines such as norepinephrine in the body, which is synergistic with green tea’s ability to inhibit COMT. 

If the studies in question used green tea extracts that differed in their polyphenol and caffeine content, this could affect the results. Second, there appears to be some genetic variability in the activity on COMT (Inoue-Choi et al. 2010; Miller et al. 2012). Because the mechanism of green tea involves COMT, any variation in its activity from subject to subject could explain why some individuals experienced meaningful weight loss and others did not. Finally, there is the issue of absorption. There is evidence that tea catechins such as EGCG are very poorly absorbed, perhaps less than 2 percent of what is ingested (Warden et al. 2001). Factors such as taking it on an empty stomach or with a meal affect absorption; with absorption increasing when taken on an empty stomach. At the same time, fish oil has been shown to increase the bioavailability of EGCG in mice (Giunta et al. 2010). This too could have affected the outcome in many studies that looked at green tea supplementation and weight loss.

In addition to weight loss, people sometimes look to green tea extract for its anticancer properties. As discussed previously, green tea polyphenols such as EGCG and ECG show mechanistic involvement in many processes relating to cancer growth and development. In animal studies, green tea polyphenols have also been shown to inhibit tumor cell proliferation and induce apoptosis of cancer cells (Lambert and Yang 2003). In addition, tea polyphenols may protect against skin damage caused by UV radiation. Furthermore, green tea has been shown to stimulate detoxification systems, specifically selective induction or modification of glutathione S-transferase and quinone reductase, that may help protect against tumor development (National Cancer Institute 2010; Steele et al. 2000).

In vitro animal and epidemiological studies are very promising showing anticancer effects against many types of cancer. Human clinical trials, however, have not shown the same efficacy. In a double-blind placebo-controlled study, involving men with high-grade prostatic intraepithelial neoplasia, which is thought to be a precursor of prostate cancer, 1 in 30 subjects had detectable prostate cancer following one year of supplementation compared to 9 in 30 men in the placebo group (Bettuzzi et al. 2006). This is contrasted by two uncontrolled studies that were unable to show significant activity against cancer in patients with existing prostate carcinoma (Choan et al. 2005; Jatoi et al. 2003). At best, the evidence supporting the use of green tea extract for cancer prevention is inconclusive.

The broadest benefits of green tea extract could come from its ability to interact with microbial populations in the gut. Interest in the microbiome has grown precipitously within the last decade. The microbiome consists of all the genes of living organisms that live on the surface of the body. The gastrointestinal tract presents a large surface area with favorable conditions for microbes, particularly bacteria. The large majority of bacteria found in the gut play an important role in human health. There are no transporters for polyphenols to be absorbed from the gut. They must cross the gut barrier through passive diffusion, and it is known that only a very small percentage (<2 percent) of the polyphenols are absorbed intact. Unabsorbed polyphenols travel through the gastrointestinal tracts and end up in the large bowel where they are metabolized by bacteria. In fact, many of the beneficial effects attributed to polyphenols may be due to phenolic metabolites produced by gut bacteria that are more bioavailable (Dueñas et al. 2015). Additionally, beneficial gut bacteria increase in number after green tea consumption (Jin et al. 2012).

Safety

Consumption of green tea is considered safe as attested by the thousands of years of its use. Green tea extracts, however, present the body with much higher doses of polyphenols and other substances than can be achieved by drinking tea. There have been reports of cases of elevated liver enzymes following green tea extract supplementation. It is unknown, however, if these events were caused by the green tea or by the presence of impurities or adulterants in some commercial products. Green extract supplements can be considered safe when taken as directed. As always, it is good to consult your physician or health care provider before taking any nutraceutical-type product.

Garlic

Background

Garlic is a fragrant culinary herb from the genus and species Allium sativum which has been traditionally used worldwide for centuries. Garlic is made up of more than 200 chemicals including the sulfur compounds (allicin, alliin, and agoene); volatile oils; enzymes (allinase, peroxidase, and miracynase); carbohydrates (sucrose and glucose); minerals; amino acids such as cysteine, glutamine, isoleucine, and methionine; bioflavonoids such as quercetin and cyanidin; and vitamins A, C, E, B1, B2, niacin, and beta-carotene.

The beneficial properties of garlic are most commonly tied to their organosulfur compounds. Whole garlic bulbs contain alliin (S-allylcysteine (SAC) sulfoxide), gamma-glutamyl-S-allylcysteine (GSAC), S-methylcysteine sulfoxide (methiin), S-trans-1-propenylcysteine sulfoxide, and S-2- carboxypropylglutathione and SAC. Cutting, crushing, or grinding garlic releases the enzyme alliinase, which very quickly converts alliin to allicin. Allicin is responsible for the pungent odor and taste of garlic. Allicin is easily transformed into oil-soluble polysulfides, namely, diallyl disulfide, diallyl sulfide, diallyl trisulfide (DATS), and diallyl tetrasulfide. Because of allicin’s instability, it is unlikely that it is responsible for the biological activity of garlic. An active component of garlic, Ajoene (4, 5, 9-trithiadodeca-1, 6, 11-triene-9- oxide) is generated via allicin S-thiolation and 2-propenesulfenic acid addition. Other active compounds, SAC and S-allylmercaptocysteine (SAMC) are water- soluble compounds formed during aqueous garlic extraction.

Metabolism of garlic is not well understood. Some studies have focused on compounds measured in expired air; however, this is not a reliable representation of blood levels from oral supplementation. There is some data available, however, regarding the metabolism of SAC in animals and humans. Animal studies have found SAC levels in the blood correlate with administered SAC doses, and urine levels of N-acetyl-S-allylcysteine following oral administration of SAC indicate that SAC can be transformed by N- acetyltransferase (Jandke and Spiteller 1987; Nagae et al. 1994). SAC has also been reported in human blood with ingestion of aged garlic extract (AGE), which has high levels of SAC (Steiner and Li 2001).

Garlic is available in several different forms. The most crude form is the sliced fresh herb, providing ~4 g from one clove. Garlic powder is produced from crushed garlic cloves, and is most commonly provided in 200 to 300 mg dosages with a recommended intake of three times a day. The powder contains alliin and a small amount of oil-soluble sulfur compounds. It does not contain any allicin. Garlic extracts are generated by soaking sliced garlic cloves in an extraction solution for a specified period of time and then concentrating the solution. The most common garlic extract product is the AGE, Kyolic. Kyolic is an ethanol extraction product. The extraction and aging process of this product allows the odorous compounds of the garlic to naturally transform into stable odorless compounds. Kyolic is most commonly sold in dosages of 300 to 800 mg dosages, also recommended to be taken three times daily. This product contains SAC, SAMC, and allyl sulfides.

Rationale for Supplementation

Garlic has been one of the top selling dietary supplements in the United States for many years. In 2000, garlic was ranked third in retail sales in the mass market, generating revenues of greater than $61 million (Blumenthal 2001). Garlic is most commonly used as a supplement for its cardiovascular benefits including lipid-lowering, antihypertensive, antithrombotic effects. The lipid- lowering benefits of garlic are attributed to several mechanisms. Garlic supplementation inhibits cholesterol biosynthesis at the level of beta-hydroxy- beta-methylglutaryl-CoA (HMG-CoA) reductase (Gebhardt 1993; Gebhardt, Beck, and Wagner 1994; Yeh and Yeh 1994; Yeh et al. 1995). Garlic also inhibits cholesterol biosynthesis by enhancing the palmitate-induced inhibition of cholesterol biosynthesis and targeting squalene monooxygenase, the enzyme that catalyzes the downstream pathway in cholesterol synthesis (Gebhardt 1995; Gupta and Porter 2001). Some forms of garlic also contain steroid saponins, which interfere with the absorption of total and low-density lipoprotein (LDL) cholesterol (Matsuura 2001). 

Antihypertensive benefits of garlic are most likely a result of the gamma-glutamylcysteine and fructan content of the herb. Gamma-glutamylcysteine inhibits angiotensin-converting enzyme, which leads to an inhibition of angiotensin II (Lawson 1998; Sendl et al. 1992). Angiotensin II is a hormone responsible for increasing vasoconstriction; therefore, its inhibition results in vasodilation. Fructans inhibit adenosine deaminase, which results in an increase in adenosine, which is responsible for blood vessel dilation (Koch et al. 1992; Lawson 1998). Multiple possible mechanisms are believed responsible for the antithrombotic effects of garlic. Garlic supplementation inhibits platelet aggregation and stimulates fibrinolysis. These benefits have been attributed to allicin and thiosulfinates at low doses and to cycloalliin at high doses (Lawson 1998; Reuter, Koch, and Lawson 1996). Garlic has also been found to inhibit the synthesis of prostaglandins and thromboxanes through the inhibition of lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade (Rahman and Billington 2000; Reuter, Koch, and Lawson 1996). These compounds are associated with platelet aggregation. The Ajoene found in garlic also affects fibrinogen-induced human platelet aggregation and inhibits binding of fibrinogen to adenosine diphosphate-stimulated platelets (Reuter, Koch, and Lawson 1996). 

Several human clinical studies have reported positive benefits of garlic supplementation for cardiovascular health benefits, and a review by the Agency for Healthcare Research and Quality concluded that garlic preparations may have small, positive, short-term effects on lipids and promising antithrombotic effects (Auer et al. 1990; Grunwald et al. 1992; Holzgartner, Schmidt, and Kuhn 1992; Jain et al. 1993; Lau, Lam, and Wang-Cheng 1987; Mader 1990; Steiner and Lin 1994; Steiner et al. 1996; Vorberg and Schneider 1990; Yeh et al. 1995).

Garlic is also supplemented to support immune function. The immunomodulatory benefits of garlic are believed to be attributed to the protein fraction of the herb (Lau, Yamasaki, and Grindley 1991). These fractions have been shown to inhibit activation of nuclear factor kappa B (NF-КB) in T-cells and increase phagocytosis, natural killer (NK) cell activity, antibody titers, and lymphocyte counts (Brosch and Platt 1993; Geng, Rong, and Lau 1997; Kandil et al. 1988; Lawson 1998). A human clinical study providing 2.56 g/day of AGE reported a significant reduction in the severity of cold and flu symptoms as well as improved proliferation of gamma–delta T-cells and NK cells (Nantz et al. 2012).

Antimicrobial effects against Helicobacter pylori, the bacteria implicated in some stomach cancers and ulcers, have led some consumers to reach for garlic to support gastric health. Garlic extracts have inhibited H. pylori in vitro, but when taken orally in human clinical studies, garlic has not been able to produce significant benefits for gastric health (Adetumbi and Lau 1983; Cavallito, Buck, and Suter 1944; Sivam 2001; Sivam et al. 1997).

The water-soluble compounds in garlic extracts, SAC and SAMC, have high antioxidant potential (Corzo-Martinez, Corzo, and Villamiel 2007). AGE garlic sources, which are higher in these compounds have a higher antioxidant capacity compared with fresh garlic extracts (Harauma and Moriguchi 2006). Some antioxidant action has also been reported for allicin and thiosulfinates. Garlic supplementation increases the activity of endogenous enzymes including glutathione peroxidase and catalase. It has also been shown to decrease the concentration of lipid peroxides in the blood (Geng and Lau 1997; Han, Liu, and Wang 1992; Ide and Lau 1999; Steiner and Lin 1994).

Safety

Garlic supplementation is safe when consumed at recommended dosages, and long-term use, up to seven years, has not resulted in any serious complications. Moreover, long-term supplementation is generally advised to allow for the cardiovascular benefits of garlic to take effect (Koscielny et al. 1999). The most commonly reported adverse events with garlic supplementation is the odor permeating the breath and skin, with more reports associated with raw garlic than with the cooked form (Blumenthal et al. 1998). Other reported adverse events include changes to the intestinal flora, allergic reactions, postoperative bleeding, spontaneous spinal epidural hematoma, platelet dysfunction, and increased clotting time; however, these events are rare (Brinckmann and Wollschlaeger 2003).

Garlic is contraindicated for use with three prescription drugs. Isoniazid (INH, Nydrazid), Non-Nucleoside Reverse Transcriptase Inhibitors, and saquinavir (Fortovase, Invirase) should be avoided with garlic supplementation (Dhamija, Malhotra, and Pandhi 2006; Piscitelli et al. 2002).

Cranberry

Background

American Cranberry (Vaccinium macrocarpon Ait.) is an evergreen shrub native to North America. It is indigenous to the eastern half of the United States. It can also be found in western Canada and down the western coast through California. Cranberry was used by Native Americans for medicinal purposes.

Today cranberry is cultivated primarily in Wisconsin, Massachusetts, New Jersey, Oregon, and Washington, and throughout Canada. Outside of North America, American Cranberry is cultivated in parts of Europe and Chile. Cranberries can be made into juices and sauces. It can be dried and used in breakfast cereals, snack bars, cheeses, and chocolate and other snack foods.

The health-promoting properties of cranberry are attributed to their high polyphenol content, which serve as a natural plant defense system against microbes. These polyphenols have been shown in vitro to have antibacterial, antiviral, antimutagenic, anticarcinogenic, antitumorigenic, antiangiogenic, anti-inflammatory, and antioxidant properties (Blumberg et al. 2013). Perhaps the most common health benefit attributed to cranberries is protection from UTIs.

The most studied cranberry polyphenol is a group of flavanols called A-type procyanidins (PACs). PACs can be found as A-type or B-type. The difference between A- and B-type PACs is important because their unique structures give them different biological properties. The A-type PACs exhibit significantly greater inhibition of Escherichia coli bacteria in cells that line the urinary tract than the B-type PACs. Adhesion of E. coli to cells lining the urinary tract is believed to be the first step in the development of a UTI. The level of A-type PACs can be used as a measure of quality of cranberry extracts. Other foods, such as apple, grape, and chocolate, contain high amounts of PACs, but only a few (plums, peanuts, avocados, cinnamon) contain A-type PACs, and none of these at the level found in cranberries.

In addition to PACs, cranberries are rich in anthocyanins, phenolic acids, and terpenes. Anthocyanins, which increase as the fruit ripens, are responsible for the deep red color of cranberries. There are many different structural varieties of anthocyanins in cranberries, and this is believed to influence the bioavailability and health effects of cranberries. Cranberry also contains phenolic acids, including hydroxybenzoic and hydroxycinnamic acids, hydroxybenzoic acid being the most abundant. A unique terpene known as ursolic acid is also present in cranberry. Interestingly, ursolic acid is a constituent of many medicinal remedies (Ikeda, Murakami, and Ohigashi 2008). Ursolic acid has strong anti-inflammatory properties. In addition to cranberry, ursolic acid can be found in apple skins, guavas, olives, and several herbs.

Cranberry obviously contains a large number of biologically active compounds including many not included in this discussion (e.g., quercetin). For our purposes, however, we have touched on those most believed to be responsible for cranberry’s unique health-promoting properties.

Unfortunately, you cannot eat cranberries straight off the vine. Many of the phytochemicals we mentioned also give cranberry a very tart and astringent taste. Cranberry is mainly consumed as a juice blended with other sweet fruit juices to mask the astringent taste. The steps involved in the processing of cranberries into juice removes a good deal of the polyphenols and is damaging to many of the beneficial compounds. It is known that meaningful amounts of PACs are actually bound to the skin and that these PACs are made bioavailable in the digestive tract. Creating juice removes the skin and reduces the level of PACs. Some polyphenols are also sensitive to the higher temperatures used to pasteurize the juice and can be destroyed. Finally, oxidation (that occurs during processing) is also a significant reason why cranberry juice does not have the same levels of polyphenols as the raw fruit. Despite the loss of potency during processing, cranberry juice can still provide meaningful levels of polyphenols and the associated health benefits, if consumed regularly.

Rationale for Supplementation

Urinary Tract Infections

UTIs are the second most common type of infection. Over 8 million people seek medical care for UTIs each year (Schappert and Rechtsteiner 2008). UTIs are more common in women than men. A woman’s urethra is shorter than a man’s and allows bacteria to more easily reach the bladder. In addition, a woman’s urethral opening is closer to sources of pathogenic bacteria such as the anus. These factors increase a woman’s lifetime risk of getting a UTI to greater than 50 percent. UTIs in men are not as common as in women but can be just as serious when they occur.

UTIs are traditionally treated with antibiotics. The risk of developing antibiotic resistance and damaging the microbiome justify seeking alternative means to treat and prevent UTIs. The most common dietary supplement used for UTIs is cranberry. Most cranberry supplements are powders made by dehydrating the juice.

There are three possible mechanisms by which cranberries help to prevent UTIs (Hisano et al. 2012). First, in vitro studies have shown that cranberry is able to prevent adhesion of pathogenic bacteria to the cells lining the urethra and bladder. E. coli is the primary bacteria responsible for UTIs. The strains of E. coli associated with UTIs have protein tendrils called “fimbriae” on their surface that allow them to bind to cells of the urinary tract. This is believed to be the first step leading to infection. If the bacteria cannot adhere to the cells, they cannot become established and cause infection. Second, in vitro studies show that cranberry is able to alter the morphology of bacteria. Cranberry appears to reduce the number of the fimbriae extending from the surface of the bacteria and thereby reduce their ability to adhere. Again, if the bacteria are unable to bind to cells because of dysfunctional or missing fimbriae they cannot become established and cause infection. Finally, and this is speculation on the author’s part, it is possible that through a prebiotic effect, cranberry polyphenols may improve the number of beneficial bacteria, thereby reducing the number of pathogenic bacteria in the large bowel, lowering the risk of cross contaminating the urethra.

Cranberry has been studied in a number of different groups who are susceptible to recurrent UTIs, among them, women who are pregnant, children, men, and individuals with neurogenic bladder dysfunction (Hisano et al. 2012). In 2008, the Cochrane Database of Systematic Reviews published a review of 10 randomized trials involving 1,049 patients. The review included studies using cranberry juice and cranberry supplement capsules. They concluded that there is some evidence that cranberry juice may decrease the number of symptomatic UTIs over a 12-month period, in particularly, and only, for women with recurrent UTIs (Jepson and Craig 2008). Despite this limited finding by Cochrane Reviews, clearly demonstrating that cranberry is effective at preventing the recurrence of UTIs has been difficult and very inconsistent.

There are a number of reasons why in vivo studies of cranberry and UTIs have not been consistently positive (Blumberg et al. 2013; Hisano et al. 2012). The minimum effective dose of cranberry extract for the prevention of UTIs is not currently known. In addition, the level of active polyphenols in cranberry beverages vary widely even from the same manufacturer. Most studies have used beverages containing 25 percent cranberry juice. Even when the percentage of juice is controlled for, the actual amount of active compounds in the juice is not standardized.

Another possible reason why outcomes from cranberry trials have been inconsistent is the high dropout rates reported. The number of subject dropouts in most studies varied considerably, ranging from 0 to as high as 55 percent. No consistent reason is evident for such high dropout rates, though in pediatric studies, the taste of cranberry juice is often cited as a reason for discontinuation.

Similar to the impact of dropout is noncompliance. Studies done with institutionalized subjects, such as the elderly, have seen a significant reduction in recurrent UTIs (Avorn et al. 1994), while several subsequent studies in the elderly living at home have not been consistently positive. Monitoring compliance is easier when subjects are living in a long-term care facility than in free-living conditions. When dropout rates are high or the level of compliance is unknown, accurate interpretation of the outcome data is significantly more difficult.

When looking at the evidence as a whole, it can be suggested that a daily dose of 240 to 300 mL of cranberry juice cocktail may prevent up to 50 percent of the recurrences of UTIs and can reduce the presence of pathogenic bacteria in the urine. Recommended doses of cranberry extract is 36 mg PACs per day divided into two or three daily doses.

Cardiovascular Health

Beyond urinary tract health, cranberry may provide benefits for cardiovascular health and act as a prebiotic. Several indexes of cardiovascular health may be improved by cranberry supplementation. Cardiovascular risk factors such as dyslipidemia, diabetes, hypertension, inflammation, oxidative stress, endothelial dysfunction, arterial stiffness, and platelet function have been examined with cranberry supplementation.

Cranberry consumption has been shown to lower LDL cholesterol and raise HDL cholesterol in animal models and in some human populations. Human trials showing improvements in blood lipid profiles include subjects with type 2 diabetes, and subjects with low HDL-C, and high triglycerides. Not all human trials, however, have demonstrated cranberry’s ability to significantly improve blood lipids.

Animal studies have demonstrated that cranberry polyphenols lower blood glucose and improve insulin sensitivity in models of type 2 diabetes. Cranberry supplementation in human subjects, however, have yet to show a significant effect on glycemic control in patients with type 2 diabetes.

In vitro studies have shown that the cranberry polyphenols can inhibit angiotensin-converting enzyme, and thus have the potential to lower blood pressure. Cranberry extract prevented expected increase in blood pressure in hamsters fed a high-fat diet. Multiple trials using human subjects with existing cardiovascular disease and type 2 diabetes, however, failed to show blood pressure-lowering effects using cranberry juice. A study examining the effects of cranberry extract also showed no effect on blood pressure in subjects with untreated hypertension (Blumberg et al. 2013).

It is well established that cranberry polyphenols have antioxidant effects in vitro and in vivo in experimental models, and it seems plausible that these antioxidant properties might play a role in the cardiovascular benefits of cranberry supplementation. There is some evidence that consumption of cranberry juice or cranberry supplements improves blood markers of oxidative stress in healthy subjects and in patients with cardiovascular risk factors. For example, reduced levels of oxidized LDL cholesterol have been seen following cranberry supplementation. Nevertheless, most studies to date have failed to provide evidence for an actual decrease in markers of oxidative damage. In light of this, it is still uncertain what role cranberry’s antioxidant properties might play in cardiovascular health.

Systemic inflammation is considered a risk factor for cardiovascular disease. Cranberry polyphenols are known to have anti-inflammatory properties. In vitro studies show that cranberry extract suppresses the activation of macrophages and T-cells exposed to proinflammatory stimuli. As is often the case with cranberry research, the data is encouraging yet inconsistent. C-reactive protein (CRP) is a serum marker of system inflammation. CRP has been shown to be reduced following cranberry polyphenol supplementation (Zhu et al. 2013). This data is in contrast to similar studies, which were unable to show a significant effect (Blumberg et al. 2013).

Finally, a recent eight-week double-blind placebo-controlled study was done using cranberry juice with a standardized polyphenol content (Novotny et al. 2015). Diet was also controlled. Subjects had not been diagnosed with cardiovascular disease. After eight-weeks, serum triglycerides were lower after consuming cranberry juice daily. Subjects with higher baseline triglyceride levels tended to show a greater improvement. Serum CRP was lower for subjects consuming cranberry than for subjects in the placebo group. Diastolic blood pressure was lower compared with the placebo group. Fasting blood sugar was lower in the cranberry group than in the placebo group and tended to improve more in those subjects with higher faster blood sugar levels at baseline.

Gut Health

Microbes in the digestive tract play a critical role in transforming dietary polyphenols such as those in cranberry into absorbable biologically active compounds (Marchesi et al. 2015). Less than 5 percent of dietary polyphenols that reach the colon go unmetabolized by gut microbes (Clifford 2004). Khoo et al. conducted a randomized, double-blind, cross-over study comparing the effects of consuming a low sugar cranberry juice or placebo on fecal microbes and urine metabolites (Khoo et al. 2010). Levels of the beneficial bacteria bifidobacteria were significantly increased following cranberry juice supplementation for six weeks. This shows that dietary polyphenols such as those from cranberry modulate the human gut microbiota toward a more health- promoting profile by increasing the relative abundance of bifidobacteria.

Safety

Cranberries have been consumed as a food throughout recorded history and are generally recognized being safe as a food or food ingredient. Its safe use in whole form or even as juice does not necessarily imply, however, that highly concentrated cranberry extract is safe in all populations or at high levels of consumption. One possible area of concern is the risk of developing kidney stones. In a study of healthy volunteers consuming cranberry tablets for one week at the manufactures recommended dose, urinary oxalates were found to have increased significantly. While consumption of up to 4 L/day of cranberry juice has been shown to be nontoxic in healthy individuals, people with a history of stone formation may be at increased risk if they consume large amounts of cranberries or cranberry juice (Dugoua et al. 2008). In infants and young children, gastrointestinal distress, including diarrhea, has been reported when they consumed more than 3 L/day of cranberry juice.

Echinacea

Background

Echinacea is a hardy, perennial, medicinal plant belonging to the Aster family indigenous to the United States. Three species of the Echinacea genus, E. purpurea (L.) Moench, E. pallida (Nutt.) Nutt., and E. augustifolia DC, are most commonly used in dietary supplements to provide the health benefits of this plant. The most well-known health benefit for which echinacea is taken is immune support. Although research supports immune benefits from the other Echinacea species also, the E. purpurea species has been shown to have the strongest effect on the immune system (Bodinet, Willigmann, and Beuscher 1993). Echinacea supplements are prepared from the fresh above-ground parts, which are harvested when the plant is flowering, or the fresh or dried root. Echinacea is offered in several different preparations including juice, infusion, tincture, fluid extracts, and powdered extracts. In 1997, echinacea was the top- selling herbal supplement sold in all channels of trade in the United States bringing in $3.6 billion in total sales.

Echinacea plants contain many different constituents including alkamides, caffeic acid, caffeoyl derivatives, cichoric acid, cynarin, dodeca- 2E,4E,8Z,10Z(E)-tetraenoic acid isobutylamides, dodecanoic acid derivatives, echinacoside, glycoconjugates, hydrophilic polysaccharides, N-isobutyldodeca- 2E,4E,8Z,10Z-tetraenamide, pentadeca-(8Z,13Z)-dien-11-yn-2-one, polysaccharide, undeca-2-ene-8,10-diynoic acid isobutylamide, undecanoic acid derivatives, and unsaturated N-alkylamide lipids. The amounts and concentrations of these constituents vary depending upon the species and the part of the echinacea plant used (Blumenthal 2003).

It appears the beneficial immune support effects of echinacea are tied to the multiple actions of various active compounds from the echinacea on multiple different components of the immune system. Echinacea has direct virucidal and bactericidal activities (Sharma et al. 2009, 2010). Alkamide-rich extracts of the herb are suggested to have anti-inflammatory benefits resulting in a reduction in 5-lipoxygenase and cyclooxygenase (Muller-Jakic et al. 1994). Echinacea has also been shown to reduce proinflammatory markers induced by pathogens including the secretion of interleukins IL-1, IL-6, and IL-8 and tumor necrosis factor-alpha (TNF-a). Glycoproteins and polysaccharides in the herb have been found to modulate certain immune cell functions including macrophages and NK cells (Bauer et al. 1989). Echinacea may also influence the activity of cytokines, reverse the excessive mucin secretion induced by viruses and modulate gene expression (Altamirano-Dimas et al. 2007; Burns et al. 2010; Hudson 2012; Sharma et al. 2010; Woelkart et al. 2005; Yin et al. 2010). It is believed that echinacea alkamides are absorbed into the blood and exert some of their effects through the endocannabinoid system (Chicca et al. 2009). As specific constituents of the herb may be tied to specific mechanisms, it is important to consider how preparations are prepared and if they are standardized to specific components of the plant when evaluating clinical research and using it to decide which products to purchase.

Echinacea has been used traditionally for centuries. The ethnobotanist M.R. Gilmore claims, “Echinacea seems to have been used as a remedy for more ailments than any other plant” (Gilmore 1911). It was one of the most commonly used medicines of Native Americans of the Great Plains. It is claimed they used it for toothache, mumps, sore throat, snakebite, coughs, burns, and pain relief (Foster 1991). Physicians in the 19th century prescribed echinacea for sepsis, mucous discharge, cancer, typhoid, fever, and skin sores (Felter and Lloyd 1898).

Rationale for Supplementation

Consumers turn to echinacea most often to help prevent and treat upper respiratory infections or colds (Barrett 2003). The common cold is the most common reason for which patients visit their primary care physicians. A large U.S. survey found that more than 70 percent of the population suffers from at least one cold per year (Fendrick 2003). As the common cold is caused by a virus, medical treatment options are limited, leading many patients to look for alternative treatment and prevention methods. A recent Cochrane review of the benefits of echinacea supplementation in preventing and treating the common cold found that the results of almost all of the prevention trials pointed in the direction of small preventive effects. In general, echinacea did not show significant reductions in illness occurrence (Karsch-Volk et al. 2014). The review does state that the great variety of forms of echinacea tested may have affected the ability to draw conclusions. Further, the report claims that some research does indicate that the effects of echinacea is likely due to several components that may have synergistic effects and that echinacea preparations standardized to specific compounds are more likely to produce benefits. Echinacea’s benefits do appear to be most effective if supplementation is started as early as possible after symptoms are first noticed and is continued for 7 to 10 days. Prophylactic use of echinacea to decrease the odds of developing a cold has mixed clinical support (Barrett, Vohmann, and Calabrese 1999; Grimm and Muller 1999; Shah et al. 2007).

Because of its immune supporting properties, consumers also turn to echinacea for help in fighting other infections including UTIs, yeast infections, genital herpes. There is some research supporting oral and topical echinacea for the prevention of yeast infections (Coeugniet and Kuhnast 1986).

Although there is research supporting the use of echinacea for these conditions, dietary supplements are not allowed to be sold for the prevention or treatment of any disease or condition under Dietary Supplement Health and Education Act (DSHEA). Any echinacea products claiming to provide benefits beyond immune support would be in violation of the DSHEA regulations.

Safety

Echinacea supplementation is likely safe when taken orally at recommended dosages for short durations (up to 16 weeks) (Miller 1998). The most common reported adverse events with echinacea use are gastrointestinal upset, rash, and allergic reactions. There are moderate possibilities of interaction of echinacea

with caffeine, cytochrome enzymes in the liver that metabolize many different drugs (e.g., acetaminophen, warfarin, lovastatin), and immunosuppressants (Bossaer and Odle 2012; Gorski et al. 2004; Stimpel et al. 1984; Yale and Glurich 2005).

Ginseng

Background

The term ginseng refers to a fleshy rooted plant belonging to several species of the genus Panax. The two most common species of ginseng are the Asian (Panax ginseng) and American (Panax quinquefolius) varieties. The active compounds used to characterize ginseng are triterpene glycosides called ginsenosides. Different species of ginseng can be distinguished by their ginsenoside content. The most commonly studied ginsenosides are Rb1, Rg1, Rg3, and Rd. Different parts of the plant may also include amino acids, alkaloids, phenols, proteins, polypeptides, and vitamins B1 and B2 (Blumenthal 2003). Standardized ginseng extracts are most commonly in the standardization range of 1 to 7 percent. Standardized doses usually range from 100 to 600 mg/day. Commercially, roots are graded according to source, age, part of the root used, and method of preparation.

Once ingested, ginsenosides are absorbed in the intestines after being metabolized in the stomach and by the bacteria in the digestive tract through a process called deglycosylation and esterification. Ginsenoside metabolism is initiated by the ginsenoside Rd pathway, and results in the production of Compound K (Cpd K). Once absorbed, ginsenosides are shown to enter into the brain rapidly, but their concentrations decline rapidly (Lee et al. 2009; Zhang et al. 2014).

The exact molecular mechanism by which ginseng imparts its health benefits is not entirely clear. Based on available in vitro and in vivo scientific evidence, it appears that the mechanisms may be linked to effects on the hypothalamus– pituitary–adrenal axis and the hypothalamus-pituitary–testis axis and the combined activities of anti-inflammatory, antioxidant, and immune cell enhancement effects (Kim et al. 2009; Lee, Lee, and Kim 1998; Salvati et al. 1996; Scaglione et al. 1996; World Health Organization 1999). In the nervous system, ginseng appears to induce changes in corticosteroid, monoamine, and interleukin levels in the cortex and hippocampus regions of the brain (Rasheed et al. 2008). The major anti-inflammatory mechanisms are suppression of TNF- a NF-КB, prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX-2) (Kang and Min 2012; Kim et al. 2013). There are also significant mechanisms related to modulation of NK cells and T-cells (Kang and Min 2012). Also, metabolites of ginsenosides such as Compound K and Ginsenoside Rp1 (G-Rp1) have been shown to have antioxidative and anti-inflammatory activities (Li and Zhong 2014; Shen et al. 2011).

Rationale for Supplementation

Ginseng is primarily used as an adaptogen, which is believed to increase resistance to stress and improve well-being. These benefits are attributed to ginseng’s effects on the hypothalamic–pituitary–adrenal axis. This axis controls corticotropin and corticosteroid levels (Nocerino, Amato, and Izzo 2000). Antianxiety, antidepressant, and cognition-enhancing benefits of ginseng were originally recorded thousands of years ago by Shi-Zhen Li in Ben Cao Gang Mu, a premodern herbal book from the days of the Ming Dynasty (Ong et al. 2015). Despite reported traditional use of ginseng for adaptogenic benefits, human clinical research supporting these benefits is lacking. Animal data shows more promise, however (Wei et al. 2007).

Consumers also commonly use ginseng as an ergogenic aid, to improve endurance and athletic performance. Clinical support for ginseng’s ergogenic properties is mixed. While some studies report an improvement in physical performance with ginseng supplementation (Cherdrungsi and Rungroeng 1995; Le Gal, Cathebras, and Struby 1996; Van Schepdael 1993), other clinical studies do not show significant benefits (Engels, Said, and Wirth 1996; Engels and Wirth 1997). A successful study providing 300 mg of ginseng per day for two months reported significant improvements in maximal oxygen uptake, resting heart rate, and leg strength compared with placebo (Cherdrungsi and Rungroeng 1995).

Ginseng supplementation is also commonly taken for cognitive function benefits. Clinical evidence demonstrates benefits of P. ginseng for abstract thinking, attention, mental arithmetic skills, and reaction times in adults (Kennedy et al. 2004; Reay, Kennedy, and Scholey 2005, 2006; Reay, Scholey, and Kennedy 2010; Sorensen and Sonne 1996). Significant benefits of a single 200 mg dose of P. ginseng were found in a clinical study involving 30 healthy young adults. Improvements in the Serial Sevens subtraction task and mental fatigue were also reported using a 10 minute test battery (Reay, Kennedy, and Scholey 2005).

Immune support is another common objective for ginseng supplementation. Clinical evidence supports the use of ginseng for this benefit. Proprietary ginseng extracts have been shown in clinical studies to have immunomodulatory effects in humans and reduce the frequency of influenza and the common cold (McElhaney et al. 2006; Predy et al. 2005; Scaglione et al. 1990; Scaglione et al. 1996). Supplementation with 200 mg/day of the ginseng extract G115 resulted in a significant reduction in frequency of influenza or common cold, as well as increased activity levels of NK cells, the immune system cells responsible for rapid immune responses (Scaglione et al. 1996).

Consumers also look to ginseng to support sexual health. Several human clinical studies support the use of ginseng for erectile dysfunction in men and sexual arousal in women (Amato, Izzo, and Nocerino 2000; Choi, Seong, and Rha 1995; Hong et al. 2002; Jang et al. 2008; Kim et al. 2009; Oh et al. 2010; Salvati et al. 1996). One study showed that 900 mg of Korean red ginseng taken three times daily resulted in a significant improvement in erectile function compared with those given a placebo (Hong et al. 2002). In menopausal women with reduced sexual drive, daily supplementation with 3 g/day of Korean red ginseng resulted in a significant improvement in the Female Sexual Function Index (Oh et al. 2010).

Safety

Ginseng is generally well-tolerated, when taken orally at the recommend dosages for short time periods (up to six months). Potential hormone-like effects of ginseng creates some concern around long-term ginseng supplementation. Intake should be limited to time periods no longer than six months (Cho et al. 2004). Occasionally reported adverse effects included nausea, diarrhea, euphoria, insomnia, headaches, hypertension, hypotension, breast pain, and vaginal bleeding, which were mild and reversible (Kiefer and Pantuso 2003).

There are no known major drug interaction concerns for ginseng, but potential drug interaction risk exists for anticoagulant or antiplatelet drugs, antidiabetes drugs, cytochrome P450 substrates, estrogens, furosemide, immunosuppressants, insulin, and monoamine oxidase inhibitors (Becker et al. 1996; Caron et al. 2002; Gonzalez-Seijo, Ramos, and Lastra 1995; Gurley, Gardner, and Hubbard 2000; Jones and Runikis 1987; Lee et al. 1987, 2003; Mateo-Carrasco et al. 2012; Park et al. 1996; Shin et al. 2000; Smith, Lin, and Zheng 2001; Sotaniemi, Haapakoski, and Rautio 1995). Individuals should be cautious and consult their health care provider regarding these combinations.

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