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Almost two years ago, this magazine ran an article entitled

"Supplements Target Ketogenesis and Metabolic Flexibility for Sports and Health."1 (June 2016) Last month there was a review of the state of caloric restriction / fasting and ketogenic diets today. However, many readers have little interest in either caloric restriction or ketogenic diets as lifestyle choices. Both of these approaches are difficult to follow even if being utilized for specific health purposes. Nevertheless, their basic principles have application to general health and to athletics. The foremost impediment to taking advantage of these approaches was laid out in the 2016 article.

A major problem in achieving keto-adaptation by diet alone is that most individuals who have been raised on Western-style diets can take six months or more to make the shift and this shift becomes ever more difficult as we age. Studies examining the role of carbohydrates in the metabolism with roughly 30 year old males in good physical condition have revealed, for instance, that even transitioning from a high glycemic index diet to a low glycemic index diet while maintaining the same ratio of carbohydrate, fat and protein can take more than four weeks. Shifting to fatty acid metabolism for energy can be difficult.

For most of us, the issue is whether a moderate change in diet accompanied by a judicious utilization of special foods and dietary supplements can achieve the goals usually associated with caloric restriction, fasting and ketogenic diets. Fortunately, the answer for the preponderance of readers is "yes." Both for anti-aging purposes and for athletics, metabolic flexibility likely can be achieved through approaches within the reach of almost everyone. The goal is not to be ketogenic all the time, but to be able to metabolize ketones and free fatty acids routinely and easily. For a nice introduction to the distinction, readers might visit the blog entitled "Ketogenesis, Measuring Ketones, and Burning Fat vs Being in Ketosis."2

The Diet

Previously in these pages, it was noted that consuming too little protein presents issues, but, likewise, too much protein in the diet, meaning above roughly 30 percent of calories, defeats a major goal of caloric restriction, which is to not just reduce circulating insulin, but also to avoid elevating insulin-like growth factor-1 (IGF-1). Although those not trained in nutrition seldom realize this, protein sources can be used for gluconeogenesis, which is to say, to produce glucose from, non-carbohydrate sources. It is not just consuming too little fat and too much carbohydrate or too much of these two together with too little protein that defeat the aims of an anti-aging diet.

The recent Prospective Urban Rural Epidemiology (PURE) study followed 135,335 adults in eighteen countries for over seven years with respect to morbidity and mortality in terms of cardiovascular disease, strokes and non-cardiovascular disease mortality as correlated with the effects of nutrients.3 In an interview, Dr. Mashid Dehghan, the lead author, reported that Participants were categorized into quintiles of nutrient intake (carbohydrate, fats, and protein) based on percentage of energy provided by nutrients. We assessed the associations between consumption of carbohydrate, total fat, and each type of fat with cardiovascular disease and total mortality.

As noted by the researchers, their results flatly contradict decades of nutritional advice: High carbohydrate intake was associated with higher risk of total mortality, whereas total fat and individual types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke. Global dietary guidelines should be reconsidered in light of these findings.

In the PURE study, those who consumed at least 35 percent of their calories from fat were 23 percent less likely to die than those who consumed only 10 percent or less as fat. According to PURE findings, the higher the fat intake, the less the chance of stroke. Those who consumed 77 percent of their calories as carbohydrates were 28 percent more likely to die than those who consumed less than 46 percent as carbohydrates. The conclusion of the study? "In a nutshell, a healthy diet based on the PURE results would be rich in fruits, beans, seeds, vegetables, and fats, include dollops of whole grains, and be low in refined carbohydrates and sugars."

The observant reader who takes the time to look at the PURE study's findings will quickly realize that the traditional reliance on "markers" such as blood LDL-cholesterol levels—markers long used to argue against the inclusion saturated fats any large amount of fats in general in the diet as well to promote carbohydrate consumption— does not correspond well with the actual endpoints of morbidity and mortality. This does not mean that the PURE diet needs to be ketogenic. To quote from the TotalHealth 2016 article, As admitted by Ben Greenfield, a serious triathlete who was tested with regard to the ergogenic benefits of a ketogenic diet, "after the study at University of Connecticut, I personally quit messing around with ketosis and returned to what I considered to be a more sane macronutrient intake of 50-60% fat, 20- 30% protein, 10-30% carbohydrate."4

As a practical matter, a more normal diet with supplements might look like this:
The diet should not be high in simple sugars, fructose or refined carbohydrates. For non-athletes and those looking primarily to increase metabolic flexibility, the diet should resemble a modified Sears Diet, meaning approximately 20 - 30 percent protein, 30 - 40 percent carbohydrate and 30 - 40 percent fat. For athletes and individuals who seriously want to initiate and maintain a fat-adapted diet, Ben Greenfield's suggestion is more in order: "50-60% fat, 20-30% protein, 10-30% carbohydrate."

Those who want to achieve most of the benefits of a ketogenic diet without undergoing the grueling restrictions normally involved (limitations not just on carbohydrate intake, which are extreme, but also on protein intake) should consider the fact that ketone bodies supply 2–6 percent of the body's energy requirements after an overnight fast (no eating at bedtime) with the higher figure reflecting a longer period without eating. After three days of fasting, 30–40 percent of energy needs are met by endogenously produced ketones. Such facts, again, lead to at least two possibilities aside from caloric restricted and ketogenic diets. First, will consuming exogenous ketones as esters or salts provide the same benefits as special diets? Second, is there a role for dietary supplements in delivering these benefits?

Ketones (Acetoacetate and β-hydroxybutyrate) Esters and Salts?

The new kid on the block in anti-aging and sports supplements is oral ketones, including a ketone ester (D-beta-hydroxybutyrate and D 1,3-butanediol) sports drink and ketone salts, typically beta-hydroxybutyrate bound to calcium, magnesium, potassium or sodium. A limited body of research indicates that such supplements may improve very long-duration endurance performance, but relatively little is known about their impact on short-duration and high-intensity workouts. Likewise, it is unclear that supplementation with ketones delivers the same benefits as adaptation to a ketogenic diet.

As one can learn from a variety of sources, "ketone bodies are three water-soluble molecules that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation and prolonged intense exercise… These ketone bodies are readily picked up by the extra-hepatic [outside the liver] tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids."5

In the liver, metabolism of fatty acids for energy, as opposed to ketone bodies, works in conjunction with a normal pattern of activity in the mitochondria, including the citric acid cycle. Ketone bodies are formed when there is not enough glucose from either carbohydrates, including glycogen, or the breakdown of protein to fuel the cycle. Technically, the supply of oxaloacetate is exhausted, at which point the liver produces and exports ketone bodies to tissues that can metabolize ketones fully. In starvation and under very low carbohydrate intake accompanied by restrained protein intake, ketone bodies supply up to 50 percent of the energy requirements for most body tissues and up to 70 percent of the energy required by the brain. The blog mentioned above provides a nice diagram of the cellular steps involved in ketone formation. The author also helpfully points out:

As I have written about eight hundred times in other posts, you do not need to be generating high levels of ketones to be metabolizing fat. The body does not operate in a binary system where the two choices are:

(1) Maintain deep ketosis …or…
(2) Become obese

Just because you're not in ketosis doesn't mean you're somehow not metabolizing fat so that the only other possible destination for it is to be stored.6

Ketone esters and salts can be ingested in an attempt to mimic a ketogenic state and work by elevating blood ketone levels to force the burning fat as fuel while interfering with certain other glycogen-related metabolic pathways. Whether supplements are the equivalent of a ketogenic diet in terms of benefits has been tested in humans only to a limited extent. In animal trials, they are not entirely equivalent and this appears also to be the case in humans. Let's start first with the animal experiments. The positive finding is that a 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague– Dawley rats caused a rapid and sustained elevation of beta-hydroxybutyrate and a reduction of blood glucose.7 No doubt, this represented a shift in the energy source to make use of the ingested ketones.

However, in a comparative trial of a ketogenic diet, ketone supplementation and control diet examining both control and chronic stress conditions, results differed with the intervention. Chronic experiments showed that under control conditions, only the ketogenic diet resulted in pronounced metabolic alterations and improved performance in the novel object recognition test and only the ketogenic diet prevented stress-induced deficits at the end of the trial and improved certain other aspects of performance. The advantage was to the ketogenic diet rather than supplementation in the areas of blood glucose, insulin and overall fat metabolism.8 Ketone supplements in animal models do indeed provide benefits, but not at the level of diet-induced endogenous production.

Thanks to recently published clinical trials, in the area of human athletic performance there now is evidence as to the limitations of ketone supplements. In one study, ten healthy adult males with similar athletic abilities and body mass indices fasted and then consumed either beta-hydroxybutyrate ketone salts or a matched placebo in a randomized order followed by a cycling time trial. Power output on the day participants consumed ketone salts was seven percent lower than on the day they consumed the placebo. As observed by study co-author Jonathan Little, assistant professor in University of British Columbia's (UBC) Okanagan's School of Health and Exercise Sciences, "Elevated blood ketones seem to inhibit the body's use of glycogen, the stored form of glucose, and favours burning fat instead."9,10 A previous study utilizing ketone esters (573 mg/kg athlete body weight) in conjunction with carbohydrate consumption had positive findings of better performance in cycling to exhaustion trials.11

The authors of both studies seem to agree that the ingestion of ketones leads to nutritional ketosis that alters the hierarchy of fuel substrate usage during exercise and it is clear that as the intensity of exercise increases, the demand for carbohydrate as an energy source increases. The ketone salt trial tested shorter and higher intensity training versus the longer period tested in the ketone ester trial, hence these were not entirely apple-to-apple trials. In addition, the ketone ester trial tested roughly 30 grams of ketone ester taken in conjunction with carbohydrate leading to significant benefit versus carbohydrate alone. However, bicycle ergometer time trial performance was only approximately two percent greater using the ketone ester plus carbohydrate versus carbohydrate alone "representing a modest increase in physical capacity in these highly trained athletes, despite significant changes in muscular metabolism." This finding, once again, indicates the difficulty of fully substituting ketones for glycogen-dependent aspects of muscle performance.

The latest studies continue the trend from above. Ingested ketones, for instance, as esters, impaired performance in elite cyclists in ˜31 kilometer laboratory-based time trials on a cycling ergometer programmed to simulate the 2017 World Road Cycling Championships course.12 Achieving overall fat / keto adaptation via dietary means is more successful. Nevertheless, aside from the difficulty in following such diets, keto adaptation to a low carbohydrate, high fat diet requires time. Three weeks clearly is not sufficient even in highly trained athletes such as elite endurance walkers.13 Ten weeks in trained athletes appears to be on the margin, improving feelings of wellbeing, but not performance.14 At least insofar as attested in published trials, a full 12 weeks or more of adaptation is required even in the relatively young (20 subjects, 33 ± 11 years) and vigorous to achieve superior endurance results in comparison to a high carbohydrate diet.15

The above findings lead this author to the observation that although ketone ester-induced ketosis may increase metabolic flexibility during exercise by reducing glycolysis and increasing muscle fat oxidation, the benefits during shorter time periods and/or higher VO2/max demands are either not great or actually negative. Metabolic flexibility in the ester trial, such as it was, required the coingestion of carbohydrate. Without the co-ingestion of carbohydrate, as demonstrated in the other ketone trials (both salt and ester), there was a significant inhibition of the ability to access glycogen stores for energy upon demand.

Metabolic Fitness Supplements

Before looking at individual supplements, it is important

to understand that nutrients that aid metabolic fitness generally fulfill a number of requirements, among them the following:

  • It is helpful to support fat metabolism directly such as through improved transport of fatty acids into the mitochondria for oxidation.
  • Insulin sensitivity must be improved and maintained and insulin levels kept low.
  • The release of fatty acids from fat cells likely is less important than is dis-inhibiting fatty acid metabolism. The first is accomplished with caffeine, yet often with a downside such as increased cortisol levels, hence alternatives to caffeine and other similar stimulants are needed.
  • Inclusion of substances that actively promote fatty acid oxidation is important to help kick-start the body's ability to metabolize fats.
  • Excessive gluconeogenesis by the liver (creation of glucose from glycogen in response to the release of glucagon) should be inhibited to promote fatty acid oxidation as the alternative.
  • With diets that are heavy in alcohol and fat, potential "reverse" effects must be prevented.

The sources of useful supplements are not generic and this should be kept in mind because different production methods lead to different products with different results. The following discussion reviews key nutrients that fulfill one or more of the above requirements.

Potassium-Magnesium Hydroxycitrate
Very few athletes are aware of the benefits of (–)-hydroxycitric acid (HCA) for sports despite some impressive findings in terms of greater endurance and faster recovery plus reduced inflammation. This is because early trials—there were several large ones—failed to produce benefits for reasons that, in retrospect, are obvious. First, calcium HCA and calcium-containing HCA salts exhibit very poor uptake and poor results in comparative trials.16,17,18 To this should be added the "food effect," meaning the finding that consuming food within 30 minutes of ingesting HCA typically reduces uptake by approximately 60 percent. HCA salts under normal delivery never exhibit more than lackluster bioavailability, hence any reduction of that already modest uptake into the system leads to extremely poor results. A third factor is that even seemingly nearly identical HCA salts (as tested by standard high performance liquid chromatography / HPLC) produced by slightly differing production techniques can exhibit up to 10-fold differences in bioavailability.19 Notably lacking in the research literature is any attempt to determine cellular uptake, an issue separate from bioavailability. Published research simply assumes that all uptake issues can be reduced to bioavailability, meaning blood levels, an assumption proven to be invalid with a number of nutritional substances, such as coenzyme Q10.

One way around these uptake problems with HCA is by means of a special liquid delivery. HCA salts normally are not stable in ready-to-drink formats and break apart to yield what is known as a lactone. The HCA lactone leads to good uptake—bioavailability—but little or no benefits because the molecule exhibits the wrong shape.20 A recently issued US patent describes a method that not only stabilizes HCA salts in liquid, but also dramatically improves their bioavailability and physiologic efficacy.21

Properly produced and delivered HCA can lead to striking improvements in early fat utilization for energy, glycogen sparing and increases in endurance. This is in part because HCA helps to control the muscle's selection of fuels, an experimental finding from twenty years ago.22 More recently, using mice as the model, HCA ingestion for 13 days was found to increase fat oxidation and improve endurance exercise time to fatigue by 43 percent compared to a placebo.23 Chronic HCA ingestion alters fuel selection rather than the simple release of fat from stores as is true of lipolysis per se, i.e., the mechanism for HCA is not the same as with caffeine, capsaicin, etc. Second, the combination of HCA plus L-carnitine improves glycogen status in liver and various muscle tissues versus placebo in exercised-trained rodents. Readers will recall that glycogen-related issues bulk large in the performance failings of ketogenic diets and ketone supplements.

What about HCA ingestion in humans? Similar positive endurance results were found by the same laboratory both with untrained men and women and with trained athletes as found in the animal tests. The following trial was conducted in trained athletes leading to significant improvements in endurance:

Subjects [n = 6] were administered … HCA or placebo as a control (CON) for 5 d, after each time performing cycle ergometer exercise at 60% VO2max for 60min followed by 80% VO2max until exhaustion.24

Under the conditions of the trial, time to exhaustion at 80 percent VO2max went from approximately six minutes to approximately 8.5 minutes, which is a remarkable level of improvement. Lactate levels were lower. In evaluating the results, it must be observed that the earlier animal trials indicated that there is a greater shift in metabolism if the ingestion period lasts longer. But note clearly: the HCA salt used in these trials was a pure synthesized trisodium hydroxycitrate, not the usual HCA available as a dietary supplement.25

Another benefit from HCA is as much as a 100 percent improvement in glycogen repletion in muscle after exercise when a post-workout snack is consumed.26

Mango Leaf Extract and Caffeic Acid Enhance HCA's Ability to Improve Fat Metabolism

An issue that almost always is ignored with HCA is that under conditions of accelerated use of fat for energy, such as during fasting or ketogenic diets, there is a cycle that can undermine the compoundfs effects on fat metabolism by activating inside cells the substance acetyl-CoA carboxylase.27 Two compounds that help to prevent this and actually improve fatty acid oxidation are caffeic acid and mangiferin (a constituent of mango leaf).

Caffeic acid is interesting for a number of reasons. For current purposes, it has been shown to improve the ability to metabolize fats for energy and also to promote the ability of glucose to enter cells, i.e., it is insulin sensitizing. In terms of HCA, caffeic acid helps block the actions of acetyl-CoA carboxylase.28 This means that it helps to block the impact of high alcohol intake and high fat intake or fasting on HCA, thus allowing HCA to perform the function of disinhibiting fatty acid metabolism via β-oxidation as mentioned above.

Mangiferin, the primary active component in mango leaf extract, is even more significant than is caffeic acid. With regard to HCA, mangiferin, like caffeic acid, inhibits acetyl- CoA carboxylase. However, matters do not stop there. In various in vitro and animal trials, mangiferin increased fatty acid oxidation. A major finding is that the compound does the same, and safely, in human beings. Overweight patients with hyperlipidemia (serum triglyceride ≥ 1.70 mmol/L, and total cholesterol ≥ 5.2 mmol/L) were included in a double-blind randomized controlled trial. Participants were randomly allocated to groups, either receiving mangiferin (150 mg/day) or an identical placebo for 12 weeks. As reported in the published study,29

A total of 97 participants completed the trial. Compared with the placebo control, mangiferin supplementation significantly decreased the serum levels of triglycerides and FFAs, and insulin resistance index. Mangiferin supplementation also significantly increased the serum levels of mangiferin, high-density lipoprotein cholesterol, L-carnitine, β-hydroxybutyrate, and acetoacetate, and increased lipoprotein lipase activity.

The increase in β-hydroxybutyrate and acetoacetate as well as lipoprotein lipase activity is a clear indication that mangiferin improves the availability of stored fats and promotes the oxidation of these fats for the production of energy as they became available.

Asparagine, Malate and Aspartates for Energy and Endurance

Some of the best supplements for health and sports have, as it were, slipped under the radar over the years. We tend to be attracted to whatever is "new" to the point of overlooking that these new items often are not actually novel, just older concepts dressed up in new terminology. A good example of this is the great fanfare given to the recent "discoveries" involving nicotinamide riboside. (Caloric Restriction, Fasting and Nicotinamide Riboside TotalHealth Feb 2015)30 Proffered benefits include anti-aging effects, better energy metabolism and endurance.31 Strikingly, both the mechanisms involved and the benefits, upon closer examination, look remarkably similar to the benefits associated with what is known as the malate-aspartate shuttle. The anti-aging benefits, for instance, are similar to those associated with the Chinese herb rock lotus, which activates the enzyme (malate dehydrogenase) linked with this shuttle. (Uncovering the Longevity Secrets of the ROCK LOTUS TotalHealth April 2010)32

For the hard science minded, the malate/aspartate shuttle is a principal mechanism for the movement of reducing equivalents from the cytoplasm to the mitochondria. In other words, this mechanism keeps energy as electrons flowing from the cytoplasm of the cell into the mitochondria and supports the production of adenosine triphosphate (ATP), the basic energy unit of the body. Ketones can play a similar role. As expressed in a recent paper, "cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation... [a ketogenic diet] will increase the NAD+/NADH ratio."33 (NAD exists in oxidized and reduced forms, NAD+ and NADH.) This process is exactly what the recent discoveries regarding nicotinamide riboside are about. The shuttle also is involved in replenishing oxaloacetate, which was mentioned above with regard to ketogenesis and the Krebs/Citric Acid Cycle. Part of the role of oxaloacetate is shown in the diagram.

Now it just so happens that malic and aspartic acid (the "salts" are termed malate and aspartate) are components of this movement of energy. Malate, aspartate and the compound asparagine are known as oxaloacetate precursors. Many athletes use citrulline malate to help promote performance and reduce fatigue thinking that it is the citrulline that is active although, in fact, it is the malate. For instance, in an animal trial a month of supplementation with L-malate increased swimming time endurance by between 26.1 and 28.5 percent.34 The researchers observed the activities of cytosolic and mitochondrial malate dehydrogenase were significantly elevated in the L-malate-treated group compared with the control group.

As pointed out in the TotalHealth article on the rock lotus, the malate dehydrogenase enzyme takes a period of time to be increased in the cell. A number of acute trials of, for instance, aspartates in athletes, compounds that affect the same shuttle mechanism, failed, but this should have been expected due to basic physiology and one wonders why those researchers even bothered. Under conditions of moderate exertion, supplementation with asparagine and aspartate plus L-carnitine increased time to exhaustion by approximately 40 percent.35 In another animal trial, this time with intense exercise and only the two amino acids, the supplemented group showed higher exercise time, lower blood lactate concentration and a decreased the rate of glycogen degradation compared to control leading to the conclusion that "supplementation may increase the contribution of oxidative metabolism in energy production and delay fatigue during exercise performed above the AT [anaerobic threshold]."36

To be sure, there are skeptics regarding magnesium—potassium aspartates for use as ergogenic aids.37 However, the proposed mechanisms of action until recently have been wrong, the time frame for supplementation (acute rather than chronic), the amounts supplemented, etc., typically have been quite wide of the mark. The key mechanism of action involves the shuttle and oxaloacetate. Interestingly, this mechanism also promotes the proper metabolism of that great enemy of athletes, lactic acid. Lactic acid actually can be converted back into an energy source during exercise. As Ben Greenfield explains things in a wonderful post,38 A significant rate limiting step of converting lactic acid into glucose is the conversion of the molecule Nicotinamide Adenine Dinucleotide (NAD) into Nicotinamide Adenine Dinucleotide Hydrogenase (NADH). So what does this have to do with oxaloacetate? In studies, acute oxaloacetate exposure enhances resistance to fatigue by increasing NAD to NADH conversion and allowing lactic acid to get recycled and converted to glucose at a much higher rate.39

Oxaloacetate is notoriously unstable and difficult to supplement orally. A mixture of its precursors (aspartate salts, asparagine and a malate source) plus an activator of the malate dehydrogenase enzyme (rock lotus) supplemented over a period of time (three to four weeks) is a better way to achieve desired benefits. Finally, another benefit of a mixture of malate and aspartate is that the malate-aspartate shuttle plays a role in the regeneration of L-arginine and the production of nitric oxide.40

Move over, NO (nitric oxide) supplements! Altering muscle fuel selection and increasing the anaerobic threshold are the hallmarks of metabolic flexibility in sports. Greater utilization of stored fatty acids for fuel, reduced lactate accumulation and better recycling, enhanced glycogen stores and an elevation of VO2max before the body's limited stores are called upon without an impairment of carbohydrate utilization is an ideal situation. It is not clear that fulfilling this goal demands artificially elevating blood ketone bodies, either through diet or supplements. Instead, maximizing the efficiency of energy pathways that make use of stored fatty acids and the malate-aspartate shuttle would seem to be not just sufficient, but preferred. Chronic HCA ingestion alters muscle fuel selection and improves glycogen stores, especially in conjunction with L-carnitine. Caffeic acid enhances these actions, as does mangiferin from mango leaf in ways that have been demonstrated in humans to augment the metabolism of both fatty acids and carbohydrates leading to elevated energy production. The malate-aspartate shuttle and the enzyme malate dehydrogenase support oxaloacetate recycling and the efficient operation of the citric acid cycle to sustain fatty acid oxidation and the reconversion of lactic acid to glucose for use as fuel by the muscles. Surely a clincher for this approach is that it promises health and anti-aging benefits, not just improvements in athletic performance.


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Dallas Clouatre, PhD

Dallas Clouatre, Ph.D. earned his A.B. from Stanford and his Ph.D. from the University of California at Berkeley. A Fellow of the American College of Nutrition, he is a prominent industry consultant in the US, Europe, and Asia, and is a sought-after speaker and spokesperson. He is the author of numerous books. Recent publications include "Tocotrienols in Vitamin E: Hype or Science?" and "Vitamin E – Natural vs. Synthetic" in Tocotrienols: Vitamin E Beyond Tocopherols (2008), "Grape Seed Extract" in the Encyclopedia Of Dietary Supplements (2005), "Kava Kava: Examining New Reports of Toxicity" in Toxicology Letters (2004) and Anti-Fat Nutrients (4th edition).