Ingredientsβ-Hydroxy β-methylbutyric acid (HMB), otherwise known by its conjugate base β-hydroxy β-methylbutyrate, is a naturally produced substance in humans. HMB is a five-carbon organic acid synthesized endogenously as a downstream metabolite of leucine — a branched-chain amino acid (BCAA) — through its catabolic pathway. The compound is also referred to in the scientific literature by a number of synonymous names, including 3-hydroxy-3-methyl-butanoic acid, 3-hydroxyisobutyric acid, beta-hydroxy-beta-methylbutyric acid, and beta-hydroxy-beta-methylglutarate-CoA. The CAS number for the compound in its free acid form is CAS 625-08-1, as referenced in the metabolomics literature.
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). Two forms of HMB have been studied: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA appears to lead to increased appearance of HMB in the bloodstream when compared to HMB-Ca, though recent results are mixed.
HMB is used as a dietary supplement and as an ingredient in certain medical foods intended to promote wound healing and provide nutritional support for people with muscle wasting due to cancer or HIV/AIDS. HMB is also contained in several nutritional products and medical foods marketed by Abbott Laboratories (e.g., certain formulations of Ensure and Juven).
Small quantities of HMB occur naturally in various food products, including citrus fruit, avocado, asparagus, cauliflower, selected fish species, red wine, milk, and alfalfa. HMB is present in insignificant quantities in certain foods, such as alfalfa, asparagus, avocados, cauliflower, grapefruit, and catfish. These dietary sources provide only trace amounts. 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.
As an endogenous compound, HMB is produced mainly in muscles and the liver. Healthy individuals typically produce 0.2–0.4 g of HMB per day through normal metabolism. A healthy adult produces approximately 0.3 grams per day, while supplemental HMB is usually taken in doses of 3–6 grams per day.
The first reported chemical synthesis of HMB was published in 1877 by the Russian chemists Michael and Alexander Zaytsev. HMB was isolated from the bark of Erythrophleum couminga (a Madagascan tree) in 1941 by Leopold Ružička. The earliest reported isolation of HMB as a human metabolite was by Tanaka and coworkers in 1968 from a patient with isovaleric acidemia. These discoveries were chemical and clinical in nature and did not involve any systematic therapeutic use.
The metabolic origin of HMB was first characterized in 1988 when Nissen and colleagues investigated leucine metabolism, identifying HMB as a cleavage product derived from α-ketoisocaproic acid (α-KIC), with approximately 5% of dietary leucine undergoing conversion to HMB. The story of HMB begins with the initial work done by Steve Nissen's group at the University of Iowa aimed at improving the quality and quantity of meat produced from domestic animals. Their early manuscripts revealed that seven weeks of HMB feeding in broiler chickens resulted in a faster growth rate, reduction in mortality, and increased muscle yield.
The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at Iowa State University in the mid-1990s. Commercially, HMB became available in the late 1990s and was primarily marketed to athletes and exercising individuals. Subsequent clinical trials by Nissen's group further elucidated HMB's mechanistic role in attenuating muscle protein breakdown, particularly under catabolic conditions. HMB has been studied in humans for nearly three decades at doses ranging from 1.5 g/d to 6 g/d across a variety of populations and situations.
HMB has no documented history of traditional use in ethnobotanical or folk medicine traditions. It is an endogenous metabolite and a minor constituent of foods rather than a plant or herbal preparation. Its entire documented therapeutic use history is scientific and modern, beginning with animal studies in the late 1980s and human clinical trials from 1996 onward. There is no record of pre-scientific cultures isolating or deliberately using HMB as a remedy. Any precursor to HMB's contemporary use was indirect — the traditional use of high-leucine foods (meats, dairy, legumes) in athletic and recovery-oriented dietary practices predates the identification of the molecule itself, but such practices cannot be attributed to awareness of HMB specifically.
Beta-hydroxy-beta-methylbutyrate (HMB) is a natural metabolite of leucine, one of the essential amino acids. First, during reversible transamination, leucine is converted to alpha-ketoisocaproic acid (alpha-KIC) which, at the same concentration level as leucine, appears to be able to inhibit the breakdown of muscle proteins. Depending on whether alpha-KIC is in the mitochondria or cytoplasm, it is converted to isovaleryl-coenzyme A (isovaleryl-CoA) by KIC dehydrogenase or HMB by KIC dioxygenase, respectively. Conversion to isovaleryl-CoA inside liver mitochondria occurs with 95% probability, while only 5% of leucine is converted to HMB in the cytosol.
This reaction is catalyzed by ketoisocaproate dioxygenase (4-hydroxyphenylpyruvate dioxygenase; 4-HPPD; EC 1.13.11.27; CAS 9029-72-5), which has been detected in the livers of rats and humans. In valproate-treated patients, HMB can also be formed from leucine by the "ESCH 1 pathway," which involves dehydrogenation of isovaleryl-CoA to methylcrotonyl-CoA, and conversion of methylcrotonyl-CoA to 3-hydroxyisovaleryl-CoA by short-chain enoyl-CoA hydratase (ESCH 1; EC 4.2.1.17).
Once produced or absorbed, the human body has the ability to convert HMB in the muscle and liver to HMG-CoA, a precursor of cholesterol that is essential for the creation or repair of cell membranes.
HMB is a leucine metabolite, which is one of three branched-chain amino acids. HMB plays multiple roles in the human body, of which the most important ones include protein metabolism, insulin activity, and skeletal muscle hypertrophy. The branched-chain amino acid (BCAA) leucine acts as both a "trigger" for the initiation of protein synthesis and as a substrate for newly synthesized protein. As a BCAA, leucine can be metabolized within skeletal muscle, leaving open the possibility that leucine metabolites might possess anabolic properties.
The primary mode of action of HMB appears to be through its dual mechanism to enhance muscle protein synthesis and suppress muscle protein breakdown. HMB's activation of mTORC1 is independent of the leucine-sensing pathway (Sestrin2-GATOR2 complex). HMB consumption attenuated muscle protein breakdown (MPB) by −57% in an insulin-independent manner. Exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB), albeit perhaps via distinct and/or additional mechanisms compared to leucine.
The ergogenic effects of HMB supplementation are related to the enhancement of sarcolemma integrity, inhibition of protein degradation (ubiquitin pathway), decreased cell apoptosis, increased protein synthesis (mTOR pathway), stimulation of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, and enhancement of muscle stem cell proliferation and differentiation. Both leucine and its metabolites (α-ketoisocaproate [KIC] and HMB) are capable of ameliorating protein degradation in skeletal muscle. Furthermore, the inhibitory effects of HMB (50 μM) on protein degradation are more potent than those of leucine at a physiologically relevant concentration. The mechanism of HMB action is associated with the PI3K/Akt signaling pathway.
HMB and leucine both increased anabolic signaling (mechanistic target of rapamycin; mTOR), though this was more pronounced with leucine (p70S6K1 signaling ≤90 min vs. ≤30 min for HMB). This suggests that while HMB activates protein synthesis pathways, it does so with a slower kinetic profile than its precursor leucine, and may operate through independent downstream mechanisms.
HMB may help reduce muscle damage and promote muscle recovery, which can promote muscle growth and repair. HMB may also have anti-inflammatory effects, which could contribute to reducing muscle damage and soreness. HMB has antioxidant and anti-inflammatory properties that ameliorate muscle loss by stimulating protein synthesis and by decreasing proteolysis.
Among its downstream fates, HMB serves as a precursor for the mevalonate pathway (via HMG-CoA), contributing to cholesterol biosynthesis and the structural integrity of cell membranes, particularly the sarcolemma. This is one proposed mechanism by which HMB helps maintain the structural integrity of muscle cell membranes under mechanical stress.
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; in trained and competitive athletes, evidence is mixed on whether it meaningfully augments resistance training–induced gains in lean mass and strength.
A 2009 meta-analysis of double-blind randomized controlled trials in young men found that supplementation with HMB during resistance training incurs small but clear overall and leg strength gains in previously untrained men, but effects in trained lifters are trivial. The HMB effect on body composition is inconsequential. Specifically, there were small benefits to lower-body (9.9% ± 5.9%) and average strength (6.6 ± 5.7%), but only negligible gains for upper-body strength in untrained lifters. In trained lifters, all strength outcomes were trivial.
In the context of competitive athletes, a meta-analysis restricted to trained and competitive athletes found that HMB supplementation interventions present a trivial non-significant effect size in all variables studied (bench press ES=0.00, leg press ES=0.09, body mass ES=-0.01, fat-free mass ES=0.16, and fat mass ES=-0.20; all cases p>0.05). This constitutes weak evidence for meaningful benefit in already-trained athletes.
A systematic meta-analysis specifically focused on young subjects concluded that eleven trials measuring lean body mass changes found a mean difference between supplemented and placebo groups of 0.29 kg (95% CI −0.01, 0.60, p = 0.06). The HMB-supplemented groups gained an average of 1.57 kg ± 1.75 kg and the placebo groups gained 1.17 kg ± 1.45 kg of fat-free mass. These findings indicate that HMB's effects on lean mass in young trained individuals are, at best, modest and not consistently statistically significant.
HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. HMB consumption in close proximity to an exercise bout may be beneficial to increase muscle protein synthesis and attenuate the inflammatory response.
This is the area where HMB has generated the most consistent and clinically relevant evidence. HMB is a nutritional supplement that has demonstrated favorable effects on muscle protein turnover, potentially contributing to beneficial impacts on sarcopenia.
A 2025 meta-analysis of 21 RCTs involving 1,935 participants all older than 50 years found that HMB oral supplementation showed a positive impact in improving muscle mass (appendicular skeletal muscle mass: WMD = 1.56 kg, 95% CI: 0.03–3.09 kg; and lean mass: WMD = 0.28 kg, 95% CI: 0.16–0.41 kg), strength (handgrip strength: WMD = 0.54 kg, 95% CI: 0.04–1.04 kg and five-time chair stand test: WMD = –0.73 s, 95% CI: –1.35, –0.11 s), and physical function (gait speed: WMD = 0.06 m/s, 95% CI: 0.01–0.10 m/s).
When HMB is combined with resistance training in older adults, effects are more nuanced. A 2025 umbrella meta-analysis of ten trials (n = 596) found that resistance training plus HMB produced modest and borderline significant improvements in handgrip strength (SMD 0.24; 95% CI 0.00–0.48; p = 0.05) and moderate benefits in Short Physical Performance Battery (SPPB) scores (SMD 0.54; 95% CI 0.12–0.95; p = 0.01). However, no significant effects were observed for gait speed, appendicular lean mass, muscle quality, fat mass, or body weight (p > 0.05).
In contrast, a 2025 network meta-analysis of 19 RCTs in 997 healthy older adults concluded that HMB supplementation combined with resistance training failed to significantly improve muscle strength (SMD = −0.22, 95% CI: −0.57, 0.12) or muscle mass (MD = 0.05, 95% CI: −0.33, 0.44) in healthy older adults, with HMB ranking lowest in SUCRA values (strength: 8.7%; muscle mass: 23.9%). These conflicting results across meta-analyses reflect heterogeneity in populations, exercise protocols, and co-supplementation strategies.
Pre-operative and peri-operative contexts in older adults have also been studied. Previous interventions in older adults who underwent orthopedic surgery found that HMB accelerated wound healing, reduced dependence on bed rest and immobilization period, and increased muscle strength.
Of all reviewed nutrients, only L-leucine and its metabolite HMB have been shown to attenuate tumor-induced muscle wasting by directly modulating muscle protein synthesis and proteolysis. Cancer cachexia is a complex metabolic syndrome characterized by involuntary skeletal muscle loss and is associated with poor clinical outcome, decreased survival, and negatively influences cancer therapy.
A systematic review found that considering higher-quality studies, evidence of a beneficial effect of HMB supplementation was found in four of four studies for muscle mass, two of two for muscle function, three of three for hospitalization, and five of seven for survival. In contrast, no beneficial effects of HMB on quality of life or body weight was found in two of four and three of five studies, respectively. No serious adverse effects directly related to the nutrition intervention were reported. Although limited, current evidence suggests that HMB supplementation has a beneficial effect on muscle mass and function in patients with cancer. Well-designed trials are needed to further explore the clinical benefit.
A key clinical study used a combination formulation: patients were randomly assigned in a double-blind fashion to either an isonitrogenous control mixture of nonessential amino acids or an experimental treatment containing β-hydroxy-β-methylbutyrate (3 g/d), L-arginine (14 g/d), and L-glutamine (14 g/d) [HMB/Arg/Gln]. A mixture of HMB, arginine, and glutamine was found to be effective in increasing body weight in weight-losing patients with advanced (stage IV) cancer. The increase in body weight was attributed to an increase in fat-free mass. Many cancer cachexia trials have used HMB in combination with other amino acids, which complicates attributing specific effects to HMB alone.
In combination with the amino acids arginine and glutamine, HMB has been used for treating weight loss, weakness, and diarrhea in people with AIDS (AIDS-related wasting). It seems to reduce the destructive breakdown of muscle in people with AIDS. A double-blind, placebo-controlled study cited in the literature (Clark et al., 2000; JPEN J Parenter Enteral Nutr 24:133–9) used a combination of HMB, glutamine, and arginine in HIV-associated wasting. As with cancer cachexia trials, most HIV/AIDS wasting studies have used multi-ingredient formulations, making HMB's independent contribution difficult to isolate.
In endurance and martial arts athletes, HMB supplementation revealed positive effects on specific aerobic capacity variables. However, this evidence is based on a limited number of studies with heterogeneous populations and methodologies, and the overall level of evidence for aerobic performance enhancement remains preliminary and inconsistent.
Compared with placebo, HMB supplementation resulted in a net decrease in total cholesterol (5.8%, p < 0.03), a decrease in LDL cholesterol (7.3%, p < 0.01), and a decrease in systolic blood pressure (4.4 mm Hg, p < 0.05). These effects on surrogate markers of cardiovascular health could result in a decrease in the risk of heart attack and stroke. Because of the small number of published studies, it has not been possible to conclude the exact effects of HMB on cardiovascular parameters, oxidative stress, and inflammatory markers. The interpretation of outcomes should be taken cautiously.
A 2025 systematic review and meta-analysis including 15 controlled trials and 712 participants examined the hormonal response to HMB. The studies evaluated the impact of HMB supplementation on hormonal outcomes, including testosterone, cortisol, insulin-like growth factor-1 (IGF-1), and growth hormone (GH). The review concluded that testosterone levels showed a statistically significant elevation with HMB, while no significant changes were found in cortisol, IGF-1, or GH. The evidence quality was graded using the GRADE framework, and the authors noted that overall evidence quality was low to moderate, limiting definitive conclusions.
A randomized, single-blind, placebo-controlled pilot trial enrolled 24 patients (14 HMB and 10 placebo) with liver cirrhosis. Each patient received dedicated counseling including nutrition and physical activity recommendations. Patients were randomized to receive 3 g/day of HMB or placebo (sorbitol powder) for 12 consecutive weeks. HMB was well tolerated by patients, and no adverse events were documented. The study suggested the efficacy of 12-week HMB supplementation in promoting improvements in muscle performance in compensated cirrhotic patients, though further studies with a greater number of patients are required.
HMB has been studied in humans for nearly three decades at doses ranging from 1.5 g/d to 6 g/d across a variety of populations and situations. Evidence suggests that an optimal dosage of 3 grams per day maximizes strength and lean body mass gains, while higher doses, such as 6 grams per day, do not confer additional benefits.
A body-weight-based dosing reference has also been cited: the optimal effects of HMB can be achieved at 3.0 grams per day when given as calcium salt of HMB, or 0.038 g/kg of body weight per day. Thirty-eight mg·kg·BM-1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized.
The pharmacokinetics of the different commercial forms differ. 1 g of HMB-Ca resulted in a peak HMB level in blood two hours following ingestion, while 3 g resulted in peak HMB levels 60 minutes after ingestion at 300% greater plasma concentrations (487 vs. 120 nmol·ml-1), and greater losses in urine (28% vs. 14%), for 3 and 1 g HMB-Ca ingestion, respectively. Peak HMB concentrations were also delayed by an hour and significantly lower (352 nmol·ml-1) when the HMB-Ca dosage was combined with 75 g of glucose.
In clinical trials for cancer cachexia, a common formulation studied has been HMB at 3 g/day combined with L-arginine (14 g/d) and L-glutamine (14 g/d). In liver cirrhosis studies, 3 g/day of HMB for 12 consecutive weeks has been used. In lipid-profile studies, dosages ranged from 1,500 to approximately 6,000 mg/day.
Regarding timing, the 2013 ISSN position stand concluded that if consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout.
The available safety/toxicity data suggest that chronic HMB-Ca and HMB-FA consumption are safe for oral HMB supplementation in humans up to at least one year. Human studies have reported no negative impacts on cholesterol, blood glucose, liver, or kidney functions at dosages of up to 6 grams per day for extended periods. Objective data collected across multiple experiments indicate that HMB can be taken safely as an ergogenic aid for exercise and that objective measures of health and perception of well-being are generally enhanced.
Although most studies report mild side effects (e.g., gastrointestinal discomfort) with HMB, other studies have reported no adverse effects.
A study in college-aged men reported no changes in liver enzymes, lipids, renal function, or immune system markers after 8 weeks of HMB supplementation. The pilot trial in liver cirrhosis patients similarly found that HMB was well tolerated by patients, and no adverse events were documented.
There are no negative effects of HMB-Ca and HMB-FA on glucose tolerance and insulin sensitivity in humans. There may be improvements in glucose metabolism in younger adults.
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.
The safety of HMB has not been extensively studied in pregnant women or children, and available data do not support definitive conclusions for these groups. The vast majority of clinical safety data derives from adult populations, primarily healthy adults and older adults with sarcopenia or chronic illness.
Across the literature, several methodological concerns recur. The results of studies on the efficacy of HMB supplementation in clinical trials have been inconsistent. Early positive studies on HMB in resistance training were predominantly conducted by or affiliated with the researchers who originally discovered and patented HMB, raising questions about potential publication bias. Independent replications have generally produced smaller or null effects, particularly in trained athletes. The 2023 ABCD Supplement Classification Framework updated by the Australian Institute of Sport (AIS) categorizes HMB as Class C evidence. Meta-analyses consistently show that effects are most reliable in untrained individuals and clinical populations (older adults, disease-related muscle wasting) rather than in healthy, trained athletes.
Health conditions that Hydroxymethylbutyrate may help support.
Body systems that Hydroxymethylbutyrate may help support.
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