BODYBUILDING PHARMACOLOGY : The New Ephedrine?
by Jerry Brainum
When the Food and Drug Administration banned the sale of ephedrine and mahuang food supplements on April 12, 2004, companies selling those products knew they had a problem. It wasn’t the bogus lawsuits that burgeoned both before and after the ruling but what to do to maintain sales of their various fat-loss products, most of which were based on ephedrine or mahuang, often accompanied by a natural caffeine source, such as kola nut or guarana. The products produced millions in revenue. Unlike many other food supplements, fat-loss products have a huge crossover appeal, not only to bodybuilders and other athletes but also to anyone who wants to drop a few pounds. Considering that at least one-third of all Americans are clinically obese, the market for fat-loss supplements is enormous.
That’s particularly true when you consider what’s available in drug form for those purposes. Most products are molecular descendants of amphetamine, or speed, targeted at promoting fat loss through appetite suppression. The one exception is Xenical, or olestra, which is a fat blocker. None of those drugs works very well. Studies comparing them to the ephedrine-and-caffeine combo have found that the latter produced better results. That, ultimately, led to the demise of ephedrine, since both the drug companies and the FDA had a vested interest in maintaining weight-loss drug sales.
Ephedrine worked better than currently available prescription fat-loss drugs simply because it was far more inclusive than they were. Not only did ephedrine reduce appetite, but it also promoted mechanisms of increased fat oxidation. Ephedrine worked that way because it was chemically similar to catecholamines made in the body, such as epinephrine and norepinephrine, which promote fat mobilization. Ephedrine mimicked many of their actions.
So the problem facing supplement companies following the ephedrine ban was finding a suitable, legal substitute. Several candidates have emerged, such as green tea and hydroxycitrate. The substance most nearly resembling ephedrine that’s still legal—though it may not be for long—is Citrus aurantium, also known as Seville orange and Chinese bitter orange. In herbal form it has various names, depending on the culture in which it’s used. Thus, in China it’s called zhi shi, and the Japanese call it kijitsu, while to Koreans it’s chisil.
Like mahuang, the parent plant from which ephedrine was derived, Citrus aurantium, or CA, has been used for thousands of years, though never for fat-loss purposes. Instead, it’s been used as a condiment and an ingredient in beer and eaten as a rather bitter fruit. The amounts used, however, never approached the concentration of active ingredients in fat-loss supplements.
Analysis of CA shows that the primary active ingredients that promote fat loss are synephrine and octopamine.1 Synephrine bears a close chemical resemblance to ephedrine, while octopamine looks a lot like norepinephrine. Not only are the two substances produced in plants, but they’re also made in the human body, which likely explains why they’re still legal. Neither substance works precisely like ephedrine, despite claims to the contrary.
Synephrine has alpha-adrenergic effects, as did ephedrine, but unlike ephedrine it interacts only with beta-3 adrenergic receptors. Ephedrine interacted with beta-1, beta-2 and beta-3 receptors, with most of the fat-mobilizing effects occurring from its interaction with the beta-2s. The overlap with beta-1 receptors is what led to ephedrine’s side effects, such as excessive cardiovascular stimulation. In reality, that posed a problem only with those who overdosed on ephedrine or had known medical contraindications, such as cardiovascular disease, or CVD.
Octopamine is a selective beta-3 agonist, meaning it interacts exclusively with beta-3 adrenergic receptors. Some ads have implied that this offers distinct advantages. Activating beta-1 and -2 cell receptors unavoidably also increases cardiovascular stress. Beta-3 adrenergic receptors, however, are found only in fat. It sounds good until you realize what type of fat those receptors are found in.
The type of fat that contains beta-3 adrenergic is known as brown adipose tissue, or BAT. It’s loaded with both blood vessels and mitochondria, a portion of cells where fat is directly oxidized, or burned. That explains BAT’s red-brown color. Those attributes also mean that BAT is highly thermogenic, capable of converting fat calories into heat. BAT, in essence, is a built-in radiator. Some scientists previously attributed the ability of some humans to eat whatever they pleased without getting fat to BAT activity.
More research, however, showed that BAT is far more active in babies and animals than it is in adults. In fact, BAT has little or no activity in adults because most adults have little or no BAT. A few scientists still insist that some humans are born with more BAT activity than normal and maintain its heightened activity into adulthood. Others say that those who seem able to eat anything with impunity owe their capacity to something else—for instance, increased activity of the body’s thermogenic proteins, such as uncoupling protein-3, which by the way exists in both brown and white fat.
But getting back to CA, if the main ingredients in the supplement work primarily by activating beta-3 receptors, it wouldn’t be an effective fat burner for most people. In addition, the two primary active ingredients in CA—synephrine and octopamine—inhibit the production of cyclic AMP.2 Cyclic AMP, produced from the body’s ATP, is the first chemical in the metabolic cascade that results in fat oxidation. A substance that inhibits cyclic AMP could be expected to decrease fat oxidation.
Another frequently mentioned advantage of CA over ephedrine is the lack of apparent cardiovascular symptoms, such as fast heartbeat or the shakiness that some ephedrine users experienced. They were related to the activation of beta-1 receptors by ephedrine, which doesn’t occur with CA. Unfortunately, another cardiovascular side effect often attributed to ephedrine is shared with CA—hypertension, or elevated blood pressure.
Catecholamines, such as epinephrine and norepinephrine, promote vasoconstriction, or a tightening of arterial blood vessels that results in elevation of blood pressure. Since ephedrine was similar in structure to catecholamines, it also led to a slight increase in blood pressure, which didn’t pose a problem for most people. Synephrine and octopamine are structurally similar to catecholamines, and they can also increase blood pressure.
What about the evidence that CA does stimulate fat loss? Unlike the evidence for ephedrine, it’s thus far sparse.3 Animal studies do show significant fat loss with CA, but animals such as rats, hamsters and dogs have far more active beta-3 receptors than humans. Those studies also show that octopamine is far more potent than synephrine in promoting fat loss but far less potent than norepinephrine. Octopamine worked well for rats, hamsters and dogs but produced no fat-mobilizing effect whatever in humans and guinea pigs. Synephrine does promote fat loss in humans but only when used at levels high enough to also significantly increase blood pressure.
CA shares a property with grapefruit juice that doesn’t exist with ephedrine: It contains at least two substances that inhibit the cytochrome P450 enzyme system in the liver. That particular system metabolizes more than 25 percent of available drugs, and inhibiting it could lead to dangerously high concentrations of drugs in the body. CA is even more potent than grapefruit juice in that regard.
Case studies of CA’s side effects are starting to appear in medical journals. Like the cases that involved ephedrine, however, they show little or no direct cause-and-effect relationship to use of CA. One case involved a 52-year-old woman who experienced unremitted tachycardia (rapid heartbeat) after taking 500 milligrams of a CA supplement containing 6 percent synephrine, or 30 milligrams.4 She’d been taking thyroid medication for 10 years, however, and the doctors reporting her case suspected an interaction between thyroid hormone and CA. That makes sense considering that natural catecholamines produced in the body can result in a similar effect when used with thyroid medication.
Another case involved a 55-year-old woman who had used a supplement containing CA.5 She had a heart attack, which her examining physicians attributed to the CA. She had no apparent cardiovascular risk factors, such as elevated blood cholesterol or lipids, high blood pressure and so on. On the other hand, she was a heavy smoker, and smoking can independently lead to a heart attack. Again, no true cause and effect to indict CA.
Even if CA proved to be less “dangerous” than ephedrine, it still wouldn’t compare in effectiveness to ephedrine. That’s mainly because CA interacts with beta-3 receptors, not the beta-2 receptors that are the main player in human fat loss. Even worse, CA has the same potential for causing an increase in blood pressure that was linked to ephedrine, and it inhibits the liver’s vital drug-detoxifying system.
Food-supplement purveyors will have to come up with something better than CA if they want to keep their Mercedes.
1. Fugh-Berman, A., et al. (2004). Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: Current status of clinical and basic research. Exp Biol Med. 229:698-704.
2. Airriess, C.N. (1997). Selective inhibition of adenyl cyclase by octopamine via a cloned A2A-adrenoceptor. Br J Pharmacol. 122:191-98.
3. Bent, S., et al. (2004). Safety and efficacy of Citrus aurantium for weight loss. Am J Cardiol. 94:1359-1361.
4. Firenzuoli, F., et al. (2005). Adverse reaction to an adrenergic herbal extract (Citrus aurantium). Phytomedicine. In press.
5 Nykamp, D.L., et al. (2004). Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacotherp. 38:812-16.