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Bodybuilding Pharmacology: The Mother of All Fat-Burning Drugs

Bodybuilders?and most other people who want to lose bodyfat?are always looking for substances that will speed up or maximize fat loss.

Bodybuilders’and most other people who want to lose bodyfat’are always looking for substances that will speed up or maximize fat loss. If they can do that with little or no physical activity, so much the better. As I noted in my recent IRONMAN article on the science of bodyfat, however, losing fat is a difficult proposition for many [December ’01]. People who have excess bodyfat tend to have defects in certain aspects of fat metabolism, although many get that way simply by eating too much and living a sedentary lifestyle. The excess calories have no place to go other than be stored as fat.

The current treatment techniques for obesity’or for anyone wanting to lose bodyfat’start with the usual advice to lower calorie intake and increase physical activity to burn more calories. The problem with that age-old advice is it’s easier said than done. As you lose fat, your body fights you by increasing your appetite signals to the brain, thus increasing appetite. Losing fat under such conditions amounts to an exercise in discipline and sheer willpower, as you’re continuously inundated with signals to eat, such as television commercials, the suggestions of other people, and so on. Consequently, you may need help to stay on your diet.

Current drug treatments aimed at the obese and those who have trouble maintaining a calorie-restricted diet include two primary categories. The first are appetite suppressants, which blunt the potent appetite signals to the brain during dieting. The once-popular fen-phen plan consisted of two drugs that suppressed appetite and imparted a sense of fullness so you’d eat less. It proved disastrous for some, as it may have induced pulmonary hypertension, an increase in the blood pressure in the lungs that leads to heart failure. A more current prescription appetite suppressant is sibutramine.

Another pharmacological route to weight loss involves inhibiting lipases, or digestive enzymes that break down and allow you to absorb dietary fats. Orlistat, also known as Xenical, is a prescription lipase inhibitor that, if used according to directions, leads to an inhibition of 30 percent of fat eaten during a meal. Any more than that causes malabsorption side effects like steatorrhea, or fat in the stool, and other gastrointestinal problems. The problem with both of the pharmacological approaches to fat loss is that either they don’t work for many people or people don’t use the drugs properly. As a result, about 90 percent of people who are treated with them regain lost fat within a short time. Clearly, a more foolproof fat-loss drug is needed, and it should also provide a rapid feedback effect; you should be able to see significant fat losses rapidly.

Has such a drug ever existed? In fact, it’s still used today by some bodybuilders. It’s 2,4 dinitrophenol (DNP), and it has achieved an almost mythical status among competitive bodybuilders and others seeking to lose bodyfat rapidly. One well-known professional bodybuilder consulted with me not long ago about the possibility of using DNP for competitive purposes. He had inside information that another very successful top pro regularly used DNP prior to contests to lose every vestige of remaining excess bodyfat.

I had written about DNP in IRONMAN and was familiar with it. While I told the bodybuilder what I knew about it, I also expressed my opinion that DNP was by far the most dangerous drug ever used by bodybuilders and could kill quickly if used improperly. I also told him that even if it didn’t kill him, he would likely feel like crap while using it. That proved to be the case, as the bodybuilder did try using DNP but felt that the considerable loss of energy he experienced was too much of a liability for his upcoming contest preparation. He quit using it after three days.

DNP works by interfering with a cellular process that occurs in the portion of cells called the mitochondria. Mitochondria are cigar-shaped structures located in the cytoplasm, where cellular energy is produced and fat is burned. That’s where DNP enters the picture, since it works by, as the scientists say, ‘uncoupling oxidative phosphorylation.’ That simply means it interferes with the cellular process of ATP synthesis. ATP is the immediate energy currency of the cell, and all energy-producing nutrients, including carbohydrates, are eventually converted into ATP.

Since the cell cannot efficiently synthesize ATP in the presence of an uncoupling substance such as DNP, it must resort to using another readily available energy source to provide calories for the continued production of ATP’fat. The body begins to burn fat the way a fire burns logs.

The use of DNP by bodybuilders is often credited to the late Dan Duchaine, an IRONMAN columnist who had an extensive knowledge of ergogenic aids. While Dan did discuss using DNP for fat-loss purposes, he was hardly the first person to explore its possibilities. The effect of DNP-type drugs was initially observed back in 1885, when scientists noted the thermogenic effects of a coal-tar-derived substance called Martius Yellow that was used to color foods yellow.

The actual idea to use DNP as a fat-loss drug came from observing the effects on World War I French munitions workers, who produced explosives using a mixture of 40 percent DNP and 60 percent TNP. The DNP permeated the factory workers’ skin, leading to rapid fat losses. That effect led to animal studies, which found that DNP potently upgraded cellular respiration, leading to a rapid rise in body temperature.

When the animals’ doses of DNP were increased, they quickly died, as their cells literally cooked from the inside. It was also noted that the animals went immediately into rigor mortis, a stiffening of the body due to loss of ATP in muscular tissues. Since that effect usually occurs four to six hours after death, the researchers realized that all the ATP in the animals’ bodies had been depleted by the high DNP doses.1

Despite the fate of the hapless animals treated with DNP, scientists at Stanford University in Palo Alto, California, saw potential for treating obesity’if they could determine the proper therapeutic dose. So in the early 1930s they began experimenting with DNP in obese people.2 Other researchers combined DNP with thyroid hormone, which controls the metabolic rate of cells.3 Despite the research, determining the dosage of DNP that wouldn’t produce dangerous side effects proved difficult. The drug has a steep dose-response curve, and different people reacted differently to it, with some being able to tolerate higher doses and others showing significant side effects with low doses.

What proved true for all subjects was that DNP unquestionably increased resting metabolic rate by an average of 11 percent for each dosage increase of 0.1 milligram. The studies showed that doses of up to 0.5 grams, or five milligrams per kilogram (2.2 pounds), were well-tolerated by most people. They frequently reported feelings of warmth and increased perspiration while on the drug.4 With a dose of five to 10 milligrams per kilogram of bodyweight, people reported profuse sweating, yet without evidence of elevated body temperature or heart rate. At a 10-milligram dose heart rates did increase, as did breathing rates, and body temperature began to climb into the danger zone.

Based on those Depression-era medical studies, the correct therapeutic dose for DNP was set at three to five milligrams per kilogram of bodyweight. That range led to an increase in resting metabolic rates of 20 to 30 percent within an hour of subjects’ taking DNP. The elevated metabolic rate was maintained for 24 hours, then gradually began to fall. Using DNP daily resulted in an average 40 percent increase in resting metabolic rate that was maintained for at least 10 weeks.

Although none of the subjects using DNP in the early studies attempted to diet in any way, they lost significant weight. One study showed that of 170 people treated with DNP, an average weight loss of 7.8 kilograms (17 pounds), or 0.64 kilograms (1 1/2 pounds) per week, occurred. Since DNP didn’t promote muscle breakdown, the conclusion was that the weight loss consisted of primarily bodyfat.

DNP did, however, promote edema, or water retention, which led to an interesting effect. Some people using DNP failed to lose weight after a certain time despite a continued rise in metabolic rate, but when they got off the drug, they lost weight rapidly. When they stopped using DNP, they lost the retained water’and the fat losses masked by the water retention became apparent.

Despite the notable rise in metabolic rate with DNP use, researchers found few cardiovascular complications. That’s in contrast to thyroid drugs, which are also used to raise the resting metabolic rate. The dose of thyroid drugs needed to accomplish that nearly always leads to some type of heart stimulation, which could lead to complications in people with cardiovascular problems. DNP not only doesn’t overstimulate the cardiovascular system, but it actually lowers elevated blood pressure. Studies show an average fall of 9.4 percent diastolic and 12.6 percent systolic blood pressure readings in 30 people with existing high blood pressure who were given DNP. Diabetics given DNP showed improved glucose tolerance.

The apparent success’and presumed safety’of DNP when taken in established therapeutic doses led to its widespread use as one of the first fat-loss drugs. Unfortunately, many doctors who prescribed it in the early days weren’t familiar with the steep dose-response curve. Another problem was that as its popularity increased, DNP began showing up in various antifat nostrums being peddled without a prescription. By 1934 an estimated 100,000 people had used it.

Today, many bodybuilders believe that DNP isn’t that dangerous and that the side effects associated with it have been exaggerated. The same mind-set existed when DNP use was more common in the ’30s. Several reports at that time show that some unwary DNP users, apparently not familiar with the correct dose range, literally cooked themselves from the inside out as their metabolic rates rose out of control due to excessive DNP. Proponents of DNP noted that those fatalities were remarkably few considering the number of people who had used the drug.

They did, however, note some problematic aspects of DNP use. About 7 percent of users experienced severe skin rashes. DNP also appeared to lower levels of white blood cells needed to fight infections and incipient tumors in the body. In 1935 came the beginning of the end for DNP as an accepted fat-loss treatment, as a number of reports surfaced concerning women using DNP developing cataracts. The Food and Drug Administration took note of those cases and removed DNP from the market in 1938.

While DNP may have been relegated to limbo as a fat-loss drug, it was hardly gone. It continued to be used for various industrial and medical applications. It is still a favored cytotoxic substance for use in in-vitro, or cellular, studies. Scientists like it because it’s such a reliable toxic chemical for destroying cells to access cellular activity. In industry DNP is used in dye manufacture, as a wood preservative and as an insecticide, which has led some to label use of it for bodybuilding purposes ‘the bug spray diet.’ The industrial brand names of DNP include Caswell No. 32, Sulfo Black B, Nitro Kleenup and Maroxol-50.

In the early 1980s DNP reemerged as a fat-loss drug for bodybuilding purposes, sold under the trade name Hexalon. Many top stars of that time used it and nearly all reported getting potent fat-loss and cutting effects. Purveyors of Hexalon warned prospective users that it would make them ‘feel like you had the flu’ and also admonished users not to exceed the suggested dosages, which echoed those prescribed by doctors back in the ’30s. Even so, some bodybuilders still experienced problems with DNP, especially if they used it for longer periods. That isn’t surprising considering the reports that show some people who used the drug long-term in the past died from a relatively small dose of one to four milligrams per kilogram of bodyweight. The established lethal dose of DNP is 14 to 43 milligrams per kilogram of bodyweight’just slightly above the suggested therapeutic dose.

Despite the dangers associated with DNP, the concept of producing fat loss through a cellular-uncoupling mechanism remains intriguing. That’s especially true since the discovery of native cellular-uncoupling proteins. In fact, thyroid drugs produce fat loss by promoting their activity. Cellular-uncoupling proteins work like DNP but in a far more controlled manner. Thyroid drugs bring their own set of problems, such as excessive muscle loss and cardiovascular stimulation.

Another approach involves designing drugs that would activate the uncoupling proteins while keeping the activity specific to fat cells. One idea focuses on beta-adrenergic receptor drugs, particularly those that activate beta-3 adrenergic cell receptors. In animals activating the beta-3 receptors turns on brown adipose tissue (BAT), a thermogenic specialized form of fat that turns fat calories into heat. The effect is thought to be due to an activation of beta-3 receptors, which activate uncoupling proteins. The beta-3 drugs that have been developed thus far work better in animals than humans simply because animals have more BAT and so are more responsive to them.

The ideal fat-loss drug would activate cellular-uncoupling proteins in muscle. You want to keep it specific to muscle because muscle tissue is geared to higher metabolic rates. Exercise alone elevates the metabolic rate in muscle 12 times basal, or resting, rate, so muscle can handle the heightened activity fostered by such a drug with no side effects. If you used it, you’d be a fat-burning, muscle-building machine. DNP doesn’t work’in the sense that it has a high side-effect rate’because it wasn’t specific to muscle. It also affected the brain and nervous system, which are highly dependent on a steady energy level and cannot handle broad fluctuations in metabolic rate the way muscle can.

Absent such an ideal fat-loss drug, what can you do to foster selective activity of the cellular-uncoupling proteins? Eating certain types of fat, such as the omega-3 fatty acids found in fish and flaxseed oils, appears to promote uncoupling activity. Doing aerobics adds to this effect.5 Using thermogenic supplements, such as those containing ephedrine and caffeine, may also help by interacting with beta-3 adrenergic receptors and promoting thyroid hormone activity.

1 Magne, H., et al. (1932). Studies on the action of dinitrophenol 1-2-4. Ann Physiol Physicochem Biol. 8:1-167.
2 Tainter, M.L., et al. (1932). Dinitrophenol in the treatment of obesity: final report. JAMA. 101:322-336.
3 Simkins, S., et al. (1937). Dinitrophenol and desiccated thyroid in the treatment of obesity, a comprehensive clinical and laboratory study. JAMA. 108:2110-2118.
4 Cutting, W.C., et al. (1933). Actions and uses of dinitrophenol: promising metabolic applications. JAMA. 101:193-195.
5 Tonkonogi, M., et al. (2000). Endurance training increases stimulation of uncoupling of skeletal muscle mitochondria in humans by nonesterified acids: an uncoupling-protein mediated effect? Biochem J. 351:805-810.

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