Clen

Clenbuterol is a synthetic beta2-adrenergic receptor agonist, usually supplied as its hydrochloride salt. Beta-agonists were long used against bronchospasm, and some were later found to shift carcass composition in meat animals from fat toward skeletal muscle, a "repartitioning" effect (Lynch and Ryall, 2008). That led to illegal clenbuterol use in livestock and to human poisonings from residues in liver and meat (Kuiper et al., 1998).

Formula, molecular weight, CAS numbers, aliases and structure are from PubChem CID 2783 (clenbuterol) and CID 5702273 (clenbuterol hydrochloride).

Published work on clenbuterol falls into six areas. Each summary names the model. Mechanistic work is mostly in rodents and cells; human data come from small trials, case series and poisoning investigations.

Beta2-adrenergic signaling in muscle

Clenbuterol enlarged the tibialis anterior and medial gastrocnemius and blunted denervation atrophy in wild-type and beta1-receptor knockout mice, but not in mice lacking the beta2 receptor, which places both effects on the beta2-adrenergic receptor (Hinkle et al., 2002). In adult rats it raised phosphorylation of Akt, p70S6K and 4E-BP1 and lowered expression of the atrophy genes MuRF1 and MAFbx. The mTOR inhibitor rapamycin cut clenbuterol-induced hypertrophy by 37 to 97% and abolished its muscle-sparing effect during hindlimb suspension, though not after denervation (Kline et al., 2007). Models: knockout mice and rats.

Skeletal muscle fiber size and type in rodents

Adult female rats given 2 mg/kg every other day for six weeks showed a fiber-type shift in the soleus, a slow muscle: type I myosin heavy chain fell, type IIdx myosin appeared, and type II fibers became more numerous and about 25% larger in cross-section than in controls (Criswell et al., 1996). It can also injure muscle: a single 5 mg/kg challenge in adult male rats caused necrosis in 4.4% of soleus fibers at 12 hours (Burniston et al., 2002). Models: rats.

Heart: cardiotoxicity and assist-device studies

In the same rat study, cardiomyocyte necrosis peaked at about 1%, mostly in the left subendocardium, and the authors suggested that such irreversible damage may harm long-term health (Burniston et al., 2002). In rats with heart failure after coronary ligation, left ventricular ejection fraction was about 52% with clenbuterol versus 36% without, and in failing hearts unloaded by heterotopic transplantation, a model of assist-device support, it normalized myofilament calcium sensitivity (Soppa et al., 2008).

A single-center study added clenbuterol to a drug regimen in 15 patients with nonischemic cardiomyopathy on left ventricular assist devices (LVADs); 11 recovered enough for device removal, and one died of arrhythmia 24 hours after removal (Birks et al., 2006). In 7 LVAD patients given clenbuterol in stepwise increments, ejection fraction did not change, end-diastolic dimension grew and creatine kinase rose in 4 (George et al., 2006). Models: rats and small uncontrolled human studies.

Neuromuscular disease pilot studies

In a single-arm pilot, 20 people with spinal and bulbar muscular atrophy received clenbuterol daily for 12 months. Among the 16 who finished, 6-minute walk distance and forced vital capacity rose, strength and functional rating scores did not change, and serum creatine kinase increased; the authors rated it Class IV evidence (Querin et al., 2013).

A 52-week randomized, placebo-controlled phase I/II trial in late-onset Pompe disease added clenbuterol to enzyme replacement therapy. Eleven of 13 participants finished; walk distance rose 16 m (not significant), maximal inspiratory pressure rose 8%, muscle glycogen fell by half, and minor events included creatine kinase elevations, muscle spasms and tremor (Koeberl et al., 2018). Models: small human trials.

Adipocytes and lipolysis

In 3T3-L1 cells and rat primary adipocytes exposed to 1 nM to 10 µM clenbuterol, the drug did not trigger apoptosis, modestly reduced adipogenesis and raised basal lipolysis in mature primary adipocytes (Kim et al., 2010). It was a full lipolytic agonist in rat adipocytes but only a partial agonist in human adipocytes, weaker than fenoterol and salbutamol (Hollenga et al., 1990). Models: mouse cell line, rat and human adipocytes.

Livestock misuse and residue poisonings

No beta-agonist was permitted to promote growth in European farm animals, yet 1992 to 1993 residue monitoring found 0 to 7% positive samples across member states (Kuiper et al., 1998). In a 1992 outbreak of 113 cases in Catalonia, linked mainly to veal liver, more than half had nervousness, tachycardia, tremor, muscle pain and headache, starting 15 minutes to 6 hours after eating; none died (Salleras et al., 1995).

In Italy, 15 people were poisoned by beef holding 1,140 to 1,480 ng/g of clenbuterol, and 9 were hospitalized with tremor, palpitations, low potassium and high blood glucose (Brambilla et al., 2000). Models: residue surveillance and outbreak investigations.