Pharmaceutical Phenotype Enhancement: Clenbuterol

First ‘The Man’ marginalized ephedra. Then we saw the realization of a second supplement ban—one which will effectively deprive the mainstream bodybuilding community of its most-preferred anti-catabolic ancillary: the pro-hormone or pro-steroid. So just how the hell is a dieter supposed to preserve lean body mass these days while languishing on laughably low calories? Well, aside from investing in our beloved LeptiGen and shipping out for real gear, it seems like a lot of would-be-chiseled chaps are taking a new interest in the age-old diet drug Clenbuterol (1-(4-Amino-3,5-dichlorophenyl)-2-tert-butyl-aminoethanol), a sympathomimetic beta2 adrenergic agonist most commonly used in veterinary therapeutics and livestock doping. But is this recent, glaringly rekindled curiosity in clen leading would-be and first-time users to the right drug? Or for that matter, is clen a safe drug? So, without further ado, I think it’s time M&M gave ephedra’s “wonder-cuz’” its full-on, discerning attention.

Clen in Context: Basic Pharmacology

I throw around the word sympathomimetic a lot to compensate for my chronically low self-esteem. In the forums, in my sleep, during sex—it’s just such a dazzlingly erudite sounding word. And using it makes me feel special. And while you yourself may not feel the inclination to use it colloquially any time soon, if phrases like “nutrient partitioning” or “fat loss while preserving muscle” pique your interest, you should care about how this class of compounds works and what those workings result in.

Chances are you wouldn’t be reading this article if you didn’t, so quickly: sympathomimetics (take “sympath” from ‘sympathetic nervous system,’ throw an ‘o’ on there, and add ‘mimetic’ [i.e. ‘to mimic’] and you’re in business) are a class of drugs that affect the sympathetic nervous system (SNS), either by prompting central catecholamine (NE/NA and E/A) release or by peripherally mimicking the effects of those same endogenous hormone/neurotransmitters. Most of a sympathomimetic’s pharmalogical interplay occurs via interaction with beta andrenoreceptors. Ephedrine is a sympathomimetic, norephedrine is a sympathomimetic, H.E.A.T. is a sympathomimetic, and boy is clenbuterol ever a sympathomimetic. There are also many others.

With clenbuterol specifically, what we see is both forms of sympathomimetic activity. Clen synthetic mimics some of norepinephrine’s and epinephrine’s effects in specific outreaches of the SNS, and centrally exerts these effects in skeletal muscle, adipose tissue, and in an often-overlooked third area: the brain. Yes, that’s right: clenbuterol crosses the blood brain barrier, and is able to readily activate certain central adrenoreceptors (1).

Virtually all of this peripheral mimicking occurs at the beta2 adrenergic receptor, which is the reason clenbuterol is characterized as a beta2 specific agonist. When it interacts with these receptors in muscle, clenbuterol is able to catalyze Cyclic Adenosine Monophosphate (cAMP) production, a second-messenger signal transducer which regulates rates of glycogen decomposition, protein synthesis, and lipolysis (among many other things). What distinguishes clenbuterol prominently from ephedrine is its specificity, potency, and duration of effect.

Ephedrine, whether you already knew it or not, has very little direct activity in muscle or fat. Rather, it stimulates central sympathetic nerve terminals, thereby inciting an indiscriminate release of NE/NA (and to a lesser extent, epinephrine/adrenalin), which then relays across the entirety of the SNS. This makes ephedrine a primarily indirect and non-specific sympathomimetic, as it effectively delivers a mild ‘catecholamine carpet-bombing’ to all your various beta receptors (beta1, beta2, atypical beta3, and putative, atypical beta4). It is also this mechanism that gives ephedrine its long-term pharmacological viability: although not very set-point friendly, it will nonetheless continue to indirectly agonize adrenergic receptors along your SNS, even after months of continual use.

Clenbuterol is somewhat of a different beast. As mentioned earlier, it is able to prompt a small degree of catecholamine release from central adrenoceptors, as well as interact directly with the beta2 receptor in a dose-dependent manner with a potency that far exceeds the resultant effects of ephedrine administration.

More Technical Stuff on Clen’s Workings than You Could Ever Possibly Want to Know: Lipolysis

Nutrient-partitioning junkies, your patience is about to be rewarded. Now that we’ve established some context, it’s time to move on and discuss ‘the goods.’ It’s time to discuss the bad-ass lipolytic and repartitioning effects of clenbuterol in vivo. And it goes a little something like this. Following administration, clenbuterol avoids first-pass metabolism (it’s oral bioavailability ranges between 89-98%) and doses typically reach peak plasma levels roughly two hours after a dosage is ingested. This peak will then stabilize and continue for four additional hours (2). Eventually, roughly 50% of ingested clenbuterol will undergo metabolization into its four primary metabolites; the remaining half will be excreted intact, without metabolic breakdown (3). This biphasic elimination lends clenbuterol a veritable half-life that clocks in at just under thirty six hours.

Once it gets to work clenbuterol, as I already mentioned, binds to cellular beta2 receptors. Intracellularly this will increase cAMP (4), which then binds to regulatory subunits of protein kinase A, causing the release of its catalytic subunit. This process activates the enzyme HSL (hormone sensitive lipase), which hydrolyzes triglycerides, breaking them down into glycerol and fatty acids to allow for beta oxidation.

Now, as you can probably guess, one of the facets to clenbuterol that makes it such a potent lipolytic drug is that it exerts its beta-agonism steadily and continuously. If ephedrine is ‘hit-it-and-quit-it,’ clenbuterol is a friggin’ marathon man when it comes to stimulation. Clen isn’t very cuddly though, so all you high-maintenance bodybuilders are just plum out of luck.

Clenbuterol is undeniably potent at its target receptor. However, clenbuterol cannot be said to own ephedrine (particularly when combined with caffeine) outright for fat loss. Remember, since clen is primarily direct-acting on a cellular level, it can’t prompt the same kind of NE-induced hypophagia (loss of appetite) as ephedrine, which has proved to be an essential pharmacological component in its ability to further weight loss (5). Individuals looking to use clenbuterol for weight loss need to keep this in mind: clenbuterol partitions energy intake, but it will not aide in regulating or helping to decrease it, hence my recommendation that those planning to cut on clen also look into ancillary appetite suppressants.

There is also the prevailing theory in a lot of bodybuilding circles that clenbuterol actually raises metabolic rate by increasing endogenous thermogenesis. So let’s explore the purported calorie-burning properties of clenbuterol. In animals, although clenbuterol increases thermogenesis in mutant rats (genetically obese Zucker rats), multiple studies have demonstrated that in normal rats—even those administered rather hefty dosages of the drug— clenbuterol “did not affect energy intake [or] energy expenditure” (6,7).

In human studies, the direct infusion of the related beta2-specific agonists salbutamol and terbutaline in lean men caused a modest increase in whole body energy expenditure and respiratory exchange ratio—an increase of 0.6 kJ/min in terms EE adjusted for fat-free mass (8). In other words, the guys getting heavy-duty beta2 adrenergic stimulation would have ended up burning about 200 extra kcals over a twenty four hour period. So in other words, thermogenesis was enhanced, but not so much to suggest that clenbuterol has strong calorie-burning properties of its own. Interestingly enough, in the same study the researchers noted that:

during beta2-adrenergic stimulation, the increases in energy expenditure and plasma nonesterified fatty acids and glycerol concentrations were reduced in the obese group. Furthermore, lipid oxidation significantly increased in the normal weight group, but remained similar in the overweight group… [this] data suggests that beta2-adrenoceptor-mediated increases in thermogenesis and lipid utilization are impaired in the obese (8).

In other words, if you’re still in plus-size pants, you’re out of luck: clenbuterol isn’t going to help you lose a whole lot of weight, because your obesity-train-wrecked metabolism just ain’t havin’ that (9). Plus, given the effects of beta adrenergic agonists on heart rate contraction, the use of clenbuterol in significantly overweight individuals may pose significant danger to the user (10,11).

And again, the take home message is the same: when dieting, nutrient-partitioning definitely matters, but in the end it still comes down largely to energy expenditure vs. intake, and clen is a calorie re-distributor, not a burner.

Clenbuterol and its Interaction(s) With Your Mammoth Guns

If you get one sentence out of this section on clenbuterol and skeletal muscle, please let it be this: clen is never going to get you big, but it is extremely good at keeping you big once you get there. Yes, I know clenbuterol is wicked-anabolic in Dawley-Sprague hyperphagic wombats, but you are a human, and the amount of clenbuterol it would take for you to see a genuine anabolic effect would also put you in a coffin, so let’s just let that one go.

Now, I said clen’s not anabolic, but it certainly does have positive ramifications for protein synthesis, primarily through the beta2s, cAMP, and its ability to mitigate Ca2+-dependent proteolysis in skeletal muscle (12). A critical component to its full effect is its repartitioning properties. As stated earlier, clenbuterol is exceedingly good at liberating fatty acids from adipose tissue. But, more than that, clenbuterol exerts this effect in tandem with large scale, itself-induced skeletal muscular insulin resistance (13).

Now, when you’re a type II diabetic, this isn’t so hot. However, in a healthy bodybuilder using a strong sympathomimetic you basically have the best of all worlds: plenty of free-fatty acids getting released for oxidation in muscle, plenty of insulin-resistant muscle to feast on them, and pretty much all consumed calories getting spared for muscle retention and protein synthesis. Granted, there’s very little good research on human skeletal muscle in the presence of clenbuterol (particularly when it comes to athletes), but reasoned inference and extrapolation certainly paints a pretty convincing picture that clenbuterol is significantly anti-catabolic.

For starters, human research with ephedrine and caffeine has demonstrated that indiscriminate, weaker beta-adrenergic agonism significantly improves protein deposition and preserves lean body mass during periods of caloric restriction (14). Also interesting was the researchers’ discovery that the ephedrine and caffeine mixture wasn’t attenuating skeletal muscular breakdown, but was in fact accelerating protein synthesis. This was proved clinically by 3-methylhistidine examination, an index for skeletal muscle breakdown.

In the sympathomimetic group, an increase in nitrogen balance was demonstrated independent of 3-methylhistidine, which means the ephedrine was actually helping to synthesize lean tissue at a faster rate, and thereby counteracting the increase in diet-induced catabolism (15). See? I wasn’t lying when I said clenbuterol could be anabolic; you just can’t take a high enough dose to get an anabolic degree of protein synthesis augmentation without ending up in the ER long before you could get your shaky ass anywhere near a squat rack.

Nonetheless, because of its pharmacology, clenbuterol is currently recognized in the scientific community as a valid remedial treatment for muscle-wasting conditions (16,17). In rodents, clenbuterol also actively inhibits glucocorticoid-induced muscle atrophy, and one can speculate that it may also exert similar anti-glucocorticoid properties in humans as well (18). Clenbuterol, by virtue of its beta-agonism, may also even be more effective at reducing glucocorticoid activity than that though, as it has been demonstrated that beta-receptor antagonism increases the release of adrenocorticotrophin (ACTH) in humans subjected to stress (19). For those unaware, ACTH is a pituitary hormone that stimulates cortisol secretion, which means there is a possibility that beta-receptor agonism may in fact be able to prompt the opposite: a decrease in ACTH release in response to stress.

All told, clenbuterol is pretty much the bomb and the shiznit as far drugs go for preserving muscle during periods of energy restriction through a number of different pathways. Oh but there are just a few more things…

But I’m Too Sexy To Die… (Side Effects and Precautions Pt. I)

By now it should be clear that clenbuterol is a powerful drug. And with all powerful drugs, there are consequences, ‘cause life just sucks like that. So for those of you about to get all ‘clenbutaholic’ with your research chemicals, here’s a little info I counsel you to take to heart. In fact, speaking of hearts, let’s examine yours in relation to clenbuterol, because there definitely is some cause for concern.

For starters, there are more rodent studies under the sun that show clenbuterol use can cause significant cardiac hypertrophy—so many in fact that I’m not even going to bother citing them. Just type “clenbuterol” and “cardiac hypertrophy” into Google if you don’t believe me; no lie, it’s a little unsettling. However, clenbuterol also kills fat cells (adipocyte apoptosis) in rodents too, and it sure doesn’t in humans, so take that animal data for what it’s worth. Unfortunately though, things don’t look too much better when we move up the evolutionary chain and start looking at hearts in good-ole’ human beings either.

For example in 1998, the internal medicine outpatient clinic at the University of Alabama Birmingham received a walk-in from a previously healthy 26-year-old bodybuilder complaining of significant chest pains. The man, who had a history of moderate anabolic steroid use but who had not used any steroid preparations in the weeks leading up to his visit, revealed that he had continuously been using clenbuterol for nearly a month [Loki’s note: idiot]. During check-up, the man turned out to be completely fit and healthy with the only exception being a significant amount of left ventricle (heart) hypertrophy and cardiac dyskinesias (meaning distortion of muscle [in this case smooth muscle] activity)(20).

In fact, between 1988 and 1998, eight cases of medically-diagnosed cardiac hypertrophy have been reported in drug-using bodybuilders within the United States (21,22). We can assume many more went overlooked or unreported. Still, because of the steroid outlier (which could also be a potential factor in the pathology—or perhaps even the outright cause), the medical community has been unable to isolate clenbuterol’s true role in contributing to these instances of myocardial infarcation (20). Still, the researchers who have examined this phenomenon arrived at a conclusion that should give most clen user’s pause of thought. Namely that:

We suspect there may have been a synergistic role between the anabolicsteroid and clenbuterol. Hypothetically, the anabolic steroid may have caused cardiac hypertrophy, coronary artery spasm, or thrombosis. The clenbuterolmay have precipitated ischemia by producing intermittent tachycardia. Alternately, clenbuterol may have contributed primarily to the cardiac hypertrophy…(20)

Furthermore, clenbuterol ingestion (particularly excessive ingestion) has also been documented to cause tachycardia (sudden, rapid racing of the heart)(20,23,24), hypokalemia (23), hypophosphatemia (23), potassium depletion (24), taurine depletion (25), headaches (24), tremors (24), and vertigo (24). Now, it should be noted that the more severe of the aforementioned conditions have only been demonstrated in instances of clenbuterol overdose and are thus not directly applicable to carefully monitored doses within the 20-100mcg range. Nonetheless, clenbuterol is definitively a “big kid sympathomimetic,” and not a drug that lends itself to immoderation, recklessness, or just outright stupidity.

And for now, I’m afraid that’s just going to have to do it for Part I of our comprehensive look at Clenbuterol. Next issue we’ll get into receptor down-regulation, clenbuterol, the brain, and neuroprotection (for all my Chemically Correct homies), cycling, stacking recommendations, and potential novel uses for clenbuterol in the treatment of injuries and various diseases and conditions.


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4. Tsuji T, Kato T, Kimata M, Miura T, Serizawa I, Inagaki N, Nagai H. Differential effects of beta2-adrenoceptor desensitization on the IgE-dependent release of chemical mediators from cultured human mast cells. Biol Pharm Bull. 2004 Oct;27(10):1549-54.

5. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. Int J Obes Relat Metab Disord 1993 Feb;17 Suppl 1:S41-3

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7. Rothwell NJ, Stock MJ. Effect of a selective beta 2-adrenergic agonist (clenbuterol) on energy balance and body composition in normal and protein deficient rats. Biosci Rep. 1987 Dec;7(12):933-40.

8. S. L. H. Schiffelers, W. H. M. Saris, F. Boomsma and M. A. van Baak Beta1- and Beta2-Adrenoceptor-Mediated Thermogenesis and Lipid Utilization in Obese and Lean Men. The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2191-2199

9. Jung RT, Shetty PS, James WP, Barrand MA, Callingham BA. Reduced thermogenesis in obesity. Nature. 1979 May 24;279(5711):322-3.

10. Abramson MJ, Walters J, Walters EH. Adverse effects of beta-agonists: are they clinically relevant? Am J Respir Med. 2003;2(4):287-97.

11. O de Divitiis, S Fazio, M Petitto, G Maddalena, F Contaldo and M Mancini. Obesity and cardiac function. Circulation, Vol 64, 477-482

12. Luiz Carlos C. Navegantes, Neusa M. Z. Resano, Renato H. Migliorini, and Ísis C. Kettelhut Catecholamines inhibit Ca2+-dependent proteolysis in rat skeletal muscle through beta2-adrenoceptors and cAMP. Am J Physiol Endocrinol Metab 281: E449-E454, 2001

13. Kim J, Shigetomi S, Tanaka K, Yamada ZO, Hashimoto S, Fukuchi S. The role of beta 2-adrenoceptor on the pathogenesis of insulin resistance in essential hypertension. Nippon Naibunpi Gakkai Zasshi. 1994 Jun 20;70(5):521-8

14. Astrup A, Buemann B, Christensen NJ, Toubro S, et al. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism 1992 Jul;41(7):686-688

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16. Maltin CA, Delday MI, Watson JS, Heys SD, Nevison IM, Ritchie IK, Gibson PH. Clenbuterol, a beta-adrenoceptor agonist, increases relative muscle strength in orthopaedic patients. Clin Sci (Lond). 1993 Jun;84(6):651-4.

17. Oya Y, Ogawa M, Kawai M. Therapeutic trial of beta 2-adrenergic agonist clenbuterol in muscular dystrophies. Rinsho Shinkeigaku. 2001 Oct;41(10):698-700

18. Pellegrino MA, D’Antona G, Bortolotto S, Boschi F, Pastoris O, Bottinelli R, Polla B, Reggiani C. Clenbuterol antagonizes glucocorticoid-induced atrophy and fibre type transformation in mice. Exp Physiol 89.1 pp 89-100

19. Oberbeck R, Schurmeyer T, Jacobs R, Benschop RJ, Sommer B, Schmidt RE, Schedlowski M. Effects of beta-adrenoceptor-blockade on stress-induced adrenocorticotrophin release in humans. Eur J Appl Physiol Occup Physiol 1998 May;77(6):523-6

20. Goldstein et al. Clenbuterol and anabolic steroids: a previously unreported case of myocardial infarcation with normal coronary arteriograms. Southern Medical Journal. 1998:780-784.

21. McNutt et al. Acute myocardial farcation in a 22-year-old world class athlete using anabolic steroids. Am. Journal of Cardiology. 1988:62-164.

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24. Chodorowski Z, Sein Anand J. Acute poisoning with clenbuterol–a case report. Przegl Lek. 1997;54(10):763-4.

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