beta-hydroxy beta-methylbutyric acid beta-hydroxy beta-methylbutyric acid β-hydroxy β-methylbutyric acid (hmb), otherwise known as its conjugate base, β-hydroxy β-methylbutyrate, is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wound healing and provide nutritional support for people with muscle wasting due to cancer or hiv/aids. in healthy adults, supplementation with hmb has been shown to increase exercise-induced gains in muscle size, muscle strength, and lean body mass, reduce skeletal muscle damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise. medical reviews and meta-analyses indicate that hmb supplementation also helps to preserve or increase lean body mass and muscle strength in individuals experiencing age-related muscle loss. hmb produces these effects in part by stimulating the production of proteins and inhibiting the breakdown of proteins in muscle tissue. no adverse effects from long-term use as a dietary supplement in adults have been found. not to be confused with β-hydroxybutyric acid. β-hydroxy β-methylbutyric acidtop: β-hydroxy β-methylbutyric acidbottom: β-hydroxy β-methylbutyrateclinical dataother namesconjugate acid form:β-hydroxyisovaleric acid3-hydroxyisovaleric acidconjugate base form:hydroxymethylbutyrateroutes ofadministrationby mouth or nasogastricatc codenonelegal statuslegal status us: dietary supplement un: unscheduled pharmacokinetic datametaboliteshmb-coa, hmg-coa, mevalonate, cholesterol, acetyl-coa, acetoacetate, β-hydroxybutyrateonset of actionhmb-fa: 30–60 minuteshmb-ca: 1–2 hourselimination half-lifehmb-fa: 3 hourshmb-ca: 2.5 hoursexcretionrenal (10–40% excreted)identifiers iupac name 3-hydroxy-3-methylbutanoic acid cas number625-08-1 ypubchem cid69362chemspider62571 yunii3f752311cdkeggc20827 ychebichebi:37084 ycomptox dashboard (epa)dtxsid20211535 echa infocard100.128.078 chemical and physical dataformulac5h10o3molar mass118.132 g·mol−13d model (jsmol)interactive imagedensity~1.1 g/cm3 at 20 °cmelting point−80 °c (−112 °f) (glass)boiling point128 °c (262 °f) at 7 mmhg smiles cc(c)(cc(=o)o)o inchi inchi=1s/c5h10o3/c1-5(2,8)3-4(6)7/h8h,3h2,1-2h3,(h,6,7) ykey:axfyfncponwuhw-uhfffaoysa-n y (verify) hmb is sold as a dietary supplement at a cost of about us$30–50 per month when taking 3 grams per day. hmb is also contained in several nutritional products, including certain formulations of ensure, juven, and myoplex. hmb is also present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, and catfish. the effects of hmb on human skeletal muscle were first discovered by steven l. nissen at iowa state university in the mid-1990s. as of 2018, hmb has not been banned by the national collegiate athletic association, world anti-doping agency, or any other prominent national or international athletic organization. in 2006, only about 2% of college student athletes in the united states used hmb as a dietary supplement. as of 2017, hmb has found widespread use as an ergogenic supplement among young athletes. uses available forms hmb is sold as an over-the-counter dietary supplement in the free acid form, β-hydroxy β-methylbutyric acid (hmb-fa), and as a monohydrated calcium salt of the conjugate base, calcium β-hydroxy β-methylbutyrate monohydrate (hmb-ca, cahmb). since only a small fraction of hmb's metabolic precursor, l-leucine, is metabolized into hmb, pharmacologically active concentrations of the compound in blood plasma and muscle can only be achieved by supplementing hmb directly. a healthy adult produces approximately 0.3 grams per day, while supplemental hmb is usually taken in doses of 3–6 grams per day. hmb is sold at a cost of about us$30–50 per month when taken in doses of 3 grams per day. hmb is also contained in several nutritional products and medical foods marketed by abbott laboratories (e.g., certain formulations of ensure, juven, and myoplex), and is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, and catfish. medical supplemental hmb has been used in clinical trials as a treatment for preserving lean body mass in muscle wasting conditions, particularly sarcopenia, and has been studied in clinical trials as an adjunct therapy in conjunction with resistance exercise. based upon two medical reviews and a meta-analysis of seven randomized controlled trials, hmb supplementation can preserve or increase lean muscle mass and muscle strength in sarcopenic older adults. hmb does not appear to significantly affect fat mass in older adults. preliminary clinical evidence suggests that hmb supplementation may also prevent muscle atrophy during bed rest. a growing body of evidence supports the efficacy of hmb in nutritional support for reducing, or even reversing, the loss of muscle mass, muscle function, and muscle strength that occurs in hypercatabolic disease states such as cancer cachexia; consequently, the authors of two 2016 reviews of the clinical evidence recommended that the prevention and treatment of sarcopenia and muscle wasting in general include supplementation with hmb, regular resistance exercise, and consumption of a high-protein diet. clinical trials that used hmb for the treatment of muscle wasting have involved the administration of 3 grams of hmb per day under different dosing regimens. according to one review, an optimal dosing regimen is to administer it in one 1 gram dose, three times a day, since this ensures elevated plasma concentrations of hmb throughout the day; however, as of 2016 the best dosing regimen for muscle wasting conditions is still being investigated. some branded products that contain hmb (i.e., certain formulations of ensure and juven) are medical foods that are intended to be used to provide nutritional support under the care of a doctor in individuals with muscle wasting due to hiv/aids or cancer, to promote wound healing following surgery or injury, or when otherwise recommended by a medical professional. juven, a nutrition product which contains 3 grams of hmb-ca, 14 grams of l-arginine, and 14 grams of l-glutamine per two servings, has been shown to improve lean body mass during clinical trials in individuals with aids and cancer, but not rheumatoid cachexia. further research involving the treatment of cancer cachexia with juven over a period of several months is required to adequately determine treatment efficacy. enhancing performance a commercially available formulation of hmb. each size 000 gelatin capsule contains 1 gram of hmb-ca and an unspecified amount of microcrystalline cellulose and magnesium stearate. with an appropriate exercise program, dietary supplementation with 3 grams of hmb per day has been shown to increase exercise-induced gains in muscle size, muscle strength and power, and lean body mass, reduce exercise-induced skeletal muscle damage, and expedite recovery from high-intensity exercise. based upon limited clinical research, hmb supplementation may also improve aerobic exercise performance and increase gains in aerobic fitness when combined with high-intensity interval training. these effects of hmb are more pronounced in untrained individuals and athletes who perform high intensity resistance or aerobic exercise. in resistance-trained populations, the effects of hmb on muscle strength and lean body mass are limited. hmb affects muscle size, strength, mass, power, and recovery in part by stimulating myofibrillar muscle protein synthesis and inhibiting muscle protein breakdown through various mechanisms, including the activation of mechanistic target of rapamycin complex 1 (mtorc1) and inhibition of proteasome-mediated proteolysis in skeletal muscles. the efficacy of hmb supplementation for reducing skeletal muscle damage from prolonged or high-intensity exercise is affected by the time that it is used relative to exercise. the greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when hmb-ca is ingested 1–2 hours prior to exercise or hmb-fa is ingested 30–60 minutes prior to exercise. in 2006, only about 2% of college student athletes in the united states used hmb as a dietary supplement. as of 2017, hmb has found widespread use as an ergogenic supplement among athletes. as of 2018, hmb has not been banned by the national collegiate athletic association, world anti-doping agency, or any other prominent national or international athletic organization. side effects the safety profile of hmb in adult humans is based upon evidence from clinical trials in humans and animal studies. in humans, no adverse effects in young adults or older adults have been reported when hmb is taken in doses of 3 grams per day for up to a year. studies on young adults taking 6 grams of hmb per day for up to 2 months have also reported no adverse effects. studies with supplemental hmb on young, growing rats and livestock have reported no adverse effects based upon clinical chemistry or observable characteristics; for humans younger than 18, there is limited data on the safety of supplemental hmb. the human equivalent dose of hmb for the no-observed-adverse-effect level (noael) that was identified in a rat model is approximately 0.4 g/kg of body weight per day. two animal studies have examined the effects of hmb supplementation in pregnant pigs on the offspring and reported no adverse effects on the fetus. no clinical testing with supplemental hmb has been conducted on pregnant women, and pregnant and lactating women are advised not to take hmb by metabolic technologies, inc., the company that grants licenses to include hmb in dietary supplements, due to a lack of safety studies. pharmacology diagram of the anabolic biomolecular signaling cascades that are involved in myofibrillar muscle protein synthesis and mitochondrial biogenesis in response to physical exercise and specific amino acids or their derivatives (primarily l-leucine and hmb).abbreviations and representations • pld: phospholipase d • pa: phosphatidic acid • mtor: mechanistic target of rapamycin • amp: adenosine monophosphate • atp: adenosine triphosphate • ampk: amp-activated protein kinase • pgc‐1α: peroxisome proliferator-activated receptor gamma coactivator-1α • s6k1: p70s6 kinase • 4ebp1: eukaryotic translation initiation factor 4e-binding protein 1 • eif4e: eukaryotic translation initiation factor 4e • rps6: ribosomal protein s6 • eef2: eukaryotic elongation factor 2 • re: resistance exercise; ee: endurance exercise • myo: myofibrillar; mito: mitochondrial • aa: amino acids • hmb: β-hydroxy β-methylbutyric acid • ↑ represents activation • τ represents inhibition pharmacodynamics several components of the signaling cascade that mediates the hmb-induced increase in human skeletal muscle protein synthesis have been identified in vivo. similar to hmb's metabolic precursor, l-leucine, hmb has been shown to increase protein synthesis in human skeletal muscle via phosphorylation of the mechanistic target of rapamycin (mtor) and subsequent activation of mtorc1, which leads to protein biosynthesis in cellular ribosomes via phosphorylation of mtorc1's immediate targets (i.e., the p70s6 kinase and the translation repressor protein 4ebp1). supplementation with hmb in several non-human animal species has been shown to increase the serum concentration of growth hormone and insulin-like growth factor 1 (igf-1) via an unknown mechanism, in turn promoting protein synthesis through increased mtor phosphorylation. based upon limited clinical evidence in humans, supplemental hmb appears to increase the secretion of growth hormone and igf-1 in response to resistance exercise. as of 2016, the signaling cascade that mediates the hmb-induced reduction in muscle protein breakdown has not been identified in living humans, although it is well-established that it attenuates proteolysis in humans in vivo. unlike l-leucine, hmb attenuates muscle protein breakdown in an insulin-independent manner in humans. hmb is believed to reduce muscle protein breakdown in humans by inhibiting the 19s and 20s subunits of the ubiquitin–proteasome system in skeletal muscle and by inhibiting apoptosis of skeletal muscle nuclei via unidentified mechanisms. based upon animal studies, hmb appears to be metabolized within skeletal muscle into cholesterol, which may then be incorporated into the muscle cell membrane, thereby enhancing membrane integrity and function. the effects of hmb on muscle protein metabolism may help stabilize muscle cell structure. one review suggested that the observed hmb-induced reduction in the plasma concentration of muscle damage biomarkers (i.e., muscle enzymes such as creatine kinase and lactate dehydrogenase) in humans following intense exercise may be due to a cholesterol-mediated improvement in muscle cell membrane function. hmb has been shown to stimulate the proliferation, differentiation, and fusion of human myosatellite cells in vitro, which potentially increases the regenerative capacity of skeletal muscle, by increasing the protein expression of certain myogenic regulatory factors (e.g., myod and myogenin) and gene transcription factors (e.g., mef2). hmb-induced human myosatellite cell proliferation in vitro is mediated through the phosphorylation of the mitogen-activated protein kinases erk1 and erk2. hmb-induced human myosatellite differentiation and accelerated fusion of myosatellite cells into muscle tissue in vitro is mediated through the phosphorylation of akt, a serine/threonine-specific protein kinase. pharmacokinetics this graph shows the plasma concentration of hmb (in units of micromoles per liter of blood plasma) over time following ingestion of a 1 gram dose of the calcium or free acid form of hmb. comparison of pharmacokinetics between dosage forms (absorption, elimination half-life, plasma clearance, and excretion) the free acid (hmb-fa) and monohydrated calcium salt (hmb-ca) forms of hmb have different pharmacokinetics. hmb-fa is more readily absorbed into the bloodstream and has a longer elimination half-life (3 hours) relative to hmb-ca (2.5 hours). tissue uptake and utilization