To Dope or Not to Dope: Abuse of Clenbuterol as a Diet Drug: An Expert Interview With Drs. Ken McKeever and Hoffman

January 10, 2007

Editor's Note:

Use and abuse. Misuse and overuse. These are topics that we have explored before in our "To Dope or Not to Dope" columns. Previously, we discussed the role of the team physician and why elite athletes may choose to use performance-enhancing drugs. In this column, we talk about the use of performance-enhancing drugs by the everyday weekend warrior.

Clenbuterol has received substantial attention by the lay media as a miracle diet drug with only perfunctory regard to the dangers of its unsupervised use. When used appropriately under the supervision of a physician or veterinarian, clenbuterol can alleviate respiratory distress in horses and may have potential therapeutic benefits in human heart failure. However, off-label unsupervised overuse of the drug can be fraught with dangers and side effects. These interviews deal with the potential abuse of clenbuterol as an unlicensed diet drug, not its legitimate physician-supervised usages.

Charles Kearns, PhD
Editorial Director
Medscape Orthopaedics & Sports Medicine

Part I: Kenneth H. McKeever, PhD

Medscape: Clenbuterol is getting a lot of press these days for misuse by weight lifters and dieters. Could you tell Medscape readers about its legitimate uses in the United States?

Dr. McKeever: Clenbuterol was approved 6 or 7 years ago for use in treating respiratory disease in horses. It's very similar to the bronchodilator albuterol, and is the only beta-2 agonist that has been licensed for use in treating respiratory disease in horses. It is given as a syrup. Horses, like humans, have a full gamut of lung disease -- conditions analogous to asthma, hyperreactive airway disease, and chronic obstructive pulmonary disease.

Unfortunately, the drug has found its way into human sports medicine. There was even a recent issue of a tabloid touting clenbuterol as the new 'skinny pill.' If someone owns horses, it's fairly easy to get a script for clenbuterol from his or her veterinarian.

Medscape: What does clenbuterol do? What are its mechanisms of action that make it appealing to weight lifters and dieters?

Dr. McKeever: Clenbuterol was found to have a repartitioning effect. With the calories you take in, this drug will make it so that those go toward muscle rather than fat. It'll boost the metabolic rate, so you'll burn fat and lay down more muscle. That's what a repartitioning agent does.

Medscape: Burning off fat and adding muscle, sounds like a good thing. What's the risk here?

Dr. McKeever: The risk there is that clenbuterol is also taken up by other tissues in the body. And there are detrimental effects that have been well documented in a number of animal species, including heart failure. There are a number of papers that have shown you can get myocyte cell death or apoptosis in the muscles. In the heart, cell death is not a good thing. Plus, there are other toxicities that can occur.

There have been recent articles on folks in China getting clenbuterol-tainted meat and getting sick. They ate pork from pigs that had been given clenbuterol. There are various cases like this in the scientific literature. There are general systemic toxic effects, but also specific tissues like the heart and skeletal muscle. Some reports show a decrease in testicular function, changes in bone metabolism -- these would make you question whether a young growing animal, or human, would see effects on bone growth and strength. There are a whole host of side effects that are not good.

Acutely, it's a stimulant. You can have a tremendous increase in heart rate, sweating, the shakes, general neurologic and acute cardiovascular effects. There can be a dangerous increase in blood pressure. So, there are dangerous acute effects, and chronic effects when the drug is taken up by the cells, leading to cellular changes that cause cell death.

Medscape: Is this all from animal studies, or does this include studies of toxicity in humans eating tainted meat?

Dr. McKeever: If you go back a couple of decades when clenbuterol was being looked at as a way to put on more muscle mass and less fat in livestock, there were problems. In Europe, clenbuterol was banned because people got sick after eating animals fed clenbuterol. And the producers that were using clenbuterol didn't realize it stayed in the meat for a long time and could be passed on to people who ate it.

Medscape: If clenbuterol ends up in the meat, is it in the same form as it was given in, or is it altered by the animal's metabolic processes?

Dr. McKeever: You know, that's a good question. I'm presuming it's going to be the same. A study out of the University of Pennsylvania looked at clenbuterol in various tissues in horses, and I believe it's in the same or similar form. There are other drugs that, if ingested and excreted, will have been metabolized and will be in a different structure when they're excreted.

Medscape: Is there a potential rebound effect either in animals or people with clenbuterol?

Dr. McKeever: I haven't heard of any rebound effect in horses. With regard to people, I don't know. Unless there are very overt symptoms, horse owners aren't necessarily going to pick up on them.

Medscape: What toxic effects are seen in horses?

Dr. McKeever: Therapeutic doses of clenbuterol given for a moderate length of time -- something well within the scope of what's in the brochure that accompanies the medication -- can not only push a horse towards heart failure, but it also results in other problems. It leads to a decrease in aerobic capacity, a decrease in the time to fatigue, and a shift of muscle fiber profile. When you look at the myocin heavy chain profile on muscle biopsies, you can see a change in the distribution of the different types of muscle fiber. We did research using standard-bred racehorses, which are middle distance runners. Normally, their profiles have a lot of fast-twitch oxidative fibers ('weight lifter' fiber), slow-twitch oxidative fibers (endurance fibers), and a moderate amount of the fast-twitch glycolytic fibers (which have a lot of oxidative capacity). When the horses were on clenbuterol, they shifted more towards a sprinter or weight lifter's profile - where the fast-twitch glycolytic fibers and the fast-twitch oxidative fibers predominate.

In other words, the tissue shifts from looking like it's from an aerobic athlete's muscle profile (as far as the fiber typing), to a profile that looks like it's from a weight lifter. That's over the course of 8 weeks of treatment. As for repartitioning effects, we saw those occurring within 2 weeks. As far as acute effects in the horses -- ie, the nervousness, sweating, elevated pulse rate, increases in blood pressure, muscle tremors -- we saw those as we gave the initial doses and when we wrapped up the dose. It's a very potent drug. The acute effects can be scary, but then the long-term effects look even scarier.

Medscape: But it's not really known whether this happens in humans.

Dr. McKeever: Right.

Medscape: So, really, the main data we have in humans is from people who have eaten tainted meat, is that right?

Dr. McKeever: And the limited therapeutic studies out there in disease populations, plus studies being done in heart failure patients.

Medscape: Heart failure - what can happen there?

Dr. McKeever: It's sort of a paradox. Our research with horses showed that clenbuterol will actually push an animal towards heart failure. You have an individual who has a weakened heart, and clenbuterol will increase the force of contraction and have other systemic effects that may help those individuals in the short term. The question is what happens long term. Are you going to push their heart failure in a downward spiral? That would be my caution. The short-term gains may help that individual to maintain function until some other therapy can help the symptomology related to the heart failure.

Medscape: What about dieters, is it affecting their hearts?

Dr. McKeever: I'd say most likely. It's like any stimulant, you'll have the racing heartbeat, an increase in blood pressure. In the long term, the cardiac muscle is going to take up clenbuterol and there can be the long-term detrimental changes -- at least that's what we've seen in animals. Cell damage and cell death.

Medscape: Would you have an overall message to physicians?

Dr. McKeever: I'd say that if they have patients who are asking about clenbuterol, tell them "no." The long-term and short-term side effects are potentially quite dangerous. There are much safer and more legitimate ways to gain muscle or lose weight.

Part II: Robert J. Hoffman, MD

Medscape: Clenbuterol is getting a lot of press these days as something used by weight lifters and as a diet pill. Yet, it's not approved for human use in the United States. You've treated people with clenbuterol toxicity? Where are they getting the drug from?

Dr. Hoffman: A lot of people get it from Mexico or from the Internet from various parts of the world. Clenbuterol is a beta-2 adrenergic agonist and relaxes smooth muscle. It is most commonly used to treat or prevent an asthma attack. Here in the United States, it is used in horses. In Mexico and Europe, it's approved for use in humans. It's not approved here but is virtually identical to the drugs we do use here in humans. In the United States it is approved for use in animals.

Medscape: Is it similar to abuterol?

Dr. Hoffman: Yes, but with 2 differences. The first is that clenbuterol lasts for a much longer period of time, and the second is that it appears to have some activity at the beta-3 receptor. Of interest, beta-3 receptors are located on fat cells, so clenbuterol may act to stimulate the metabolism of fat cells. Clinically, what farmers or ranchers use clenbuterol for is the same as what bodybuilders illegally use clenbuterol for. Clenbuterol increases the lean weight, so there is more muscle. And it decreases nonlean weight, so there is less fat. Farmers use it to bulk up their beef; bodybuilders use it to be more muscular and lean.

Medscape: What about side effects?

Dr. Hoffman: The side effects of the drug are predictable, and similar to those seen with albuterol: tremor in the hands and shakiness. Users feel anxious, get heart palpitations, nausea. However, clenbuterol is extremely potent. You only need a little bit to get the effects. When bodybuilders take it, the dose that they are taking is much higher than a therapeutic dose and they have to tolerate these adverse side effects -- tremor, palpitations, sweating, nausea, decreased appetite.

To be honest, we don't really know that there are long-term adverse effects with these higher doses. This is bad because this is a drug with a high abuse potential. I don't think there are any significant long-term adverse effects from this drug.

Medscape: What sort of trouble can come with larger doses?

Dr. Hoffman: Usually if someone takes an overdose of this drug, they are going to be very uncomfortable. But as long as someone is relatively healthy, it's not really going to hurt them. However, you may be at risk for cardiac dysrhythmia. It can drop your blood pressure to a dangerously low level. It can definitely cause severe nausea and vomiting.

Medscape: You've treated cases of clenbuterol toxicity in people; what happened there?

Dr. Hoffman: We've had a few cases, but we haven't published them all. They were all pretty similar. In one, a young woman apparently suspected her boyfriend was using drugs. She found a white powder, dipped her fingertip into it and tasted it. But the quantity that you can get on your fingertip is a huge amount because it is such a potent drug. She got very sick for a long time because clenbuterol lasts so long. We've seen some bodybuilders who have admitted that they have used clenbuterol and didn't expect how powerful the drug can be. Often people don't realize that if someone has recommended that they take 100 mcg as the maximum dose, that really is the maximum you can tolerate. When someone tries to go over that, they don't tolerate the effects and they end up in the ER.

Medscape: It has been reported that clenbuterol can cause sudden cardiac death in horses. Could that happen in humans?

Dr. Hoffman: I suppose any substance that can really increase your heart rate could predispose you to sudden cardiac death, but I don't know. I've never heard of a case of it, but that doesn't mean it's not possible. You wouldn't expect it in someone who is healthy. In horses, you can imagine, the horse who is getting it already has some kind of health problem. So I am not sure if you can compare that to a healthy bodybuilder or healthy young person using clenbuterol.

Medscape: Clenbuterol is used in Europe for the treatment of asthma. In what form?

Dr. Hoffman: It's a pill. Inhalers would be harder to smuggle into North America. It's used in Mexico, too, under the name Brogen.

Medscape: Why hasn't the US Food and Drug Administration (FDA) approved clenbuterol for use in humans?

Dr. Hoffman: I don't know, it probably should be. Clenbuterol is a good, very long-acting drug. The only drug we have that is really long-acting like this is salmeterol, and it's not that great. Clenbuterol could probably replace salmuterol in many of its indications. I don't know why it's not approved. Clenbuterol is a generic drug and not protected by patent. I suspect if somebody had a patent to it and the exclusive rights -- then they might pursue submitting it to the FDA.

Medscape: Body builders who abuse this drug seem to use a 2 weeks on 2 weeks off regimen. Why? Would they get into medical trouble if they didn't cycle like this?

Dr. Hoffman: Probably not. Therapeutically, people such as asthmatics use it long term. In general, bodybuilders tend to cycle the drugs they use and that's probably based on their patterns of steroid use. If somebody stays on steroids too long they get the adverse effects. Usually bodybuilders will cycle steroids for 4 weeks - on for a month and off for a month, or on for 6 weeks off for 6 weeks. It's a general principle they apply to clenbuterol as well. Clenbuterol is not dangerous when used long term (at therapeutic doses) but people definitely develop a type of tolerance to, or tachyphylaxis. Initially when someone starts taking clenbuterol just to take 40 mcg of it, a 40 mcg dose they may barely tolerate it but after a week's use. If you look at the body building sites you'll see they tell people to up the dose. Start with a dose of 50 mcg or thereabouts, and you up it until you can tolerate 100 mcg. After a certain amount of time it is much easier to tolerate that dose; your body has developed tachyphylaxis. For that reason people will usually cycle clenbuterol. Two weeks is a shorter cycle. More people take clenbuterol for a month or even 6 weeks.

Medscape: If it reduces fat and increases muscle mass, dose it increase heart muscle?

Dr. Hoffman: People increase their skeletal muscle mass. Though, there are some cases of cardiomyopathy in larger abnormally enlarged hearts associated with clenbuterol use. So there are cases in which that happens. It would be hard to know, because people who use clenbuterol don't use that drug alone. They use anabolic steroids and other things. It would be very hard to pinpoint it down to just to the clenbuterol use. It wasn't the testosterone or the Winstrol (stanozolol) or whatever else the body builder was using.


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