Hydroxymethylbutyrate (HMB), a substance that the body produces naturally from the amino acid leucine, has been rising in prominence as an ingredient in nutraceuticals designed to support muscle health, along with other emerging benefits.
 

What is HMB, and How Does It Work? 

“HMB was discovered in the 1990s by Drs. Steven L. Nissen and Naji N. Abumrad, who identified it as a metabolite of the essential amino acid leucine,” said Shawn Baier, vice president of business development, innovative ingredients at TSI Group, manufacturer of myHMB. “Early research demonstrated its ability to enhance muscle mass and strength, particularly in resistance-trained individuals … further studies expanded HMB’s applications, highlighting its benefits in elderly populations by reducing muscle loss and improving physical function.”

 In most studies, participants are administered up to 3 grams of HMB per day, and this dose tends to be safe and well-tolerated when taken chronically. In addition to being produced by the body, HMB is naturally present in certain foods. The amount of HMB a person can derive from an ordinary diet is about 0.3 grams per day.

 The body converts leucine to HMB at a rate of around 5%, so to achieve a target intake of 3 grams, one would need to consume 60 grams of leucine or 600 grams of protein, noted Douglas Kalman, PhD, RD, FACN, FISSN, a clinical associate professor at Nova Southeastern University and nutrition researcher, during ISSN’s 21st annual conference and expo.

 Since its discovery, over 50 human clinical studies, 40 reviews, and four meta-analyses involving HMB supplementation in both healthy and diseased populations have been published as peer-reviewed papers, according to TSI Group, Ltd.

 HMB has a dual mechanism of action that supports muscle health. First, it decreases muscle protein breakdown by disrupting proteolysis through the ubiquitin-proteasome pathway, a major enzymatic pathway for protein breakdown in muscle, Baier noted. “This process helps to blunt muscle damage and recover faster.”

 HMB also stimulates muscle protein synthesis through mechanisms such as the mTOR pathway, which directly increases myofibrillar protein synthesis. “Myofibrillar proteins make up the contractile apparatus in muscles,” said Baier. “HMB helps maintain this by increasing the phosphorylation of mTOR, thus activating the mTOR signaling pathway in muscle which stimulates the initiation of protein synthesis in the muscle.”

 “While the benefit of protein synthesis is shared with the essential amino acid leucine, HMB is more potent than leucine in promoting this change, and a study has shown that conversion of leucine to HMB is necessary for this increase in protein synthesis,” Baier added.

 According to Baier, HMB stands out from amino acids and other competing muscle health ingredients “due to its potent anti-catabolic properties. While amino acids like leucine are known for their role in muscle protein synthesis, HMB’s significant reduction in muscle protein breakdown provides a unique advantage. This dual benefit is especially important during periods of muscle stress, such as intense training, caloric restriction, or aging.” 
 

The Health Benefits of HMB 

HMB is associated with strength and endurance exercise improvements in recreational and elite athletes across several studies. 

 A 1996 study by Nissen, who discovered HMB, found that compared to training alone, HMB supplementation led to an 18.4% improvement in total body strength measures at 3grams in 41 untrained men. Similar strength results were found in a 2000 study which recruited 39 men and 36 women, who saw greater upper body strength gains and better fat-free and fat mass changes than placebo. A 2014 study on 20 resistance-trained men found that those who took 3 grams of HMB over the course of a 12-week exercise program gained 7.3 kg of lean body mass, compared to an average of 2.1 kg in the placebo group; that’s more than a 250% greater improvement. The treatment group also increased peak power by 58% and experienced three-times the improvement in total strength gains (bench, squat, and deadlift) than the placebo group.

 Since the early 2000s, clinical studies have suggested that HMB has a part to play in improving endurance outputs of high-level athletes, too, including: measures of endurance capacity in recreational runners and endurance trained-cyclists; maximal oxygen uptake and improved exercise time in elite rowers; and anaerobic performance in combat athletes (wrestling, judo, jiu jitsu).

 Because of its dual mechanism of action, several studies indicate HMB can accelerate recovery from muscle damage, as well as subjective soreness. HMB is linked to lower levels of post-exercise creatine kinase and lower 3-MH loss in urine (both markers of muscle breakdown) after both running and resistance training. These findings are in line with a study which found that, in 23 resistance-trained men, a single dose of HMB resulted in a full recovery of work capacity in 24 hours, while it remained depressed in the placebo group for 72 hours.

 HMB is especially effective in promoting muscle health among untrained, sedentary, older, and even bedridden people, who face the biggest challenges in maintaining muscle mass. It serves as a signaling molecule which can suppress the body’s production of enzymes and genetic factors that promote the breakdown of muscle tissue. 

 Age-related decline in muscle, known as sarcopenia, affects one third of adults over the age of 50, and is associated with fatigue, loss in strength and energy, and poor mobility, a review published in Age and Aging noted. “Unlike many other muscle health ingredients that primarily focus on protein synthesis, HMB’s significant anti-catabolic properties are crucial for addressing age-related muscle loss and even more advanced sarcopenia,” said Baier.

 While older adults can’t metabolize and convert dietary protein to muscle tissue as efficiently as younger people, research suggests that older and younger adults achieve similar body composition responses when administered HMB, both in terms of lean mass and body fat loss, suggesting that this ingredient can help to overcome age-related slowdowns in protein turnover. A 2021 meta-analysis of eight studies in populations over the age of 65 linked HMB to increased muscle mass, through measures of both known mechanisms of action.

 Several studies investigating the potential benefits of HMB found that it can help to counter atrophy caused by muscle disuse. This can be especially important during illness, injury, or recovery from medical procedures. 

 Adults who were subject to bed rest for 10 days, followed by 8 weeks of rehab, experienced significantly greater preservation of muscle mass compared to the control group, in one 2013 study. Another study found HMB prevented significant decreases in quad muscle strength after knee replacement surgery in 23 patients. HMB also appeared to improve musculoskeletal recovery and quality of life indices in liver transplant recipients, critically ill trauma patients, stage four cancer patients, and people with HIV.

 HMB is also emerging as a useful tool for weight management, with studies suggesting that it can lead to improved body composition outcomes during weight loss, even in the absence of a diet or exercise plan. It might also increase how well muscles can break down and metabolize adipose tissue. This may be especially important with the rise of GLP-1 medication usage, in which muscle loss is a common side effect. More recently, supplementation with HMB and vitamin D was linked to a reduction in fat stores, and an improved ratio between muscle and fat content in 43 middle-aged participants, per a 2023 study.

 Studies have found that HMB may have complementary or synergistic activities with other nutrients and ingredients. Some of the most well-studied combinations include HMB with creatine, protein, vitamin D, ATP, omega-3s, and more. 
 

HMB and Protein 

HMB might help to enhance the anabolic activities of proteins. This is particularly true for plant proteins, which tend to have lower concentrations of leucine than animal-sourced counterparts. 

 In one study, adding HMB to soy protein significantly improved net protein balance, compared to soy protein alone, when given to participants as a first meal after a 36-hour fast. Similarly, HMB and whey protein had a superior role in helping athletes fully recover from a workout compared to whey alone.
 

HMB and ATP 

ATP is considered to be an energy currency shared across all cells and has a role to play in blood flow (enhancing nutrient and oxygen delivery to muscle), muscular excitability, and anabolic signaling, research suggests. Therefore, it’s often considered for combination formulas with HMB. 

 The combined benefits of HMB and ATP to strength, lean mass, muscle thickness, power improvement, and performance during overtraining were significantly greater than either ingredient alone, according to a small 12-week human clinical study.
 

HMB and Vitamin D

Combining HMB with vitamin D may be critical to ensuring that older adults fully realize the benefits of HMB. Addressing vitamin D deficiencies appears particularly important when it comes to HMB’s efficacy in older adults.  

 A year-long study funded by the National Institutes of Health found that HMB co-administered with vitamin D was linked to improved measures of muscle function in adults over the age of 60, which remained significant even for a subgroup of adults who were unable or unwilling to exercise.
 

HMB and Creatine 

HMB and creatine monohydrate appeared to have synergistic/complementary benefits compared to either ingredient alone in improving outcomes in a fitness test to exhaustion among elite male traditional rowers, who supplemented with either a placebo, creatine, HMB, or both for a period of 10 weeks.

 In a review and meta-analysis of six studies, the combination of HMB at 3 grams per day and creatine at 3-10 grams per day showed stronger impacts on muscle strength, body composition, and markers of muscle damage than either ingredient alone.
 

HMB Market Trends 

The global HMB market is predicted to expand at a CAGR of 6% to 2030, according to a report from Fact.MR.

 Marketing certainly hasn’t strayed from the earliest audience of athletes seeking to bulk up and improve performance. 

 This is where single-ingredient HMB formulations are thriving, especially for products containing HMB in its free acid form, as sports nutrition consumers remain dialed in on emerging delivery and dosage technologies. 

 One example is Muscletech’s HMB supplements, which features BetaTOR HMB free acid as a standalone ingredient focused on its key dual mechanisms of action. HMB single-ingredient supplements by Optimum Nutrition and other companies are also placing marketing emphasis on clinical studies suggesting improved athletic output, and reduced markers of muscle damage. 

 New dietary supplements featuring HMB as a main ingredient are orienting toward healthy aging, noted Baier. “With HMB being researched for its ability to address age-related muscle loss and enhance physical function in older adults, it’s often formulated into healthy aging products.” 

 For healthy agers, manufacturers have taken notice of research on the HMB and vitamin D combination formula. NOW, Xymogen, and several other supplement brands feature HMB supplements containing a sizeable dose of vitamin D3. Life Extension’s Wellness Code ready-to-mix powder, which features HMB and D3, is marketed toward aging adults seeking to preserve healthy muscle function. The company recommends mixing it into pre- or post-workout drinks or protein powders to help rebalance the rates at which muscle protein synthesis and muscle protein breakdown occur. Meanwhile, Power Life by Tony Horton is a protein powder featuring several add-ons to aid in protein absorption, with HMB and vitamin D3 making the cut along with chromium and several antioxidants. 

 For a more mainstream audience, “there is also a shift towards more convenient dosage formats, with HMB now available in ready-to-drink beverages, powders, and functional foods,” Baier noted, and amino acid-HMB combinations are one major venue for ready-to-drink and ready-to-mix varieties. 

 Klean Athlete’s Orange Cream-flavored powder features HMB, a blend of nine essential amino acids, glutamine, and vitamin D3. HMB and creatine combos are also especially popular, with Transparent Labs, Wilderness Athlete, Bionyx, and several other companies marketing HMB and creatine powder formulas. 

 HMB is also expanding into functional food/beverage formats. “Products such as protein bars, recovery shakes, and infused beverages with HMB are becoming more common, catering to athletes and fitness enthusiasts seeking convenient ways to enhance their performance and recovery,” Baier said. 

 HMB is also standing out in weight loss formulations, or products designed to support the nutritional needs of those taking GLP-1 medication, as a means of preserving muscle mass. “When individuals lose weight, especially through caloric restriction, there is a significant risk of losing muscle mass along with fat. HMB helps to mitigate this issue by preserving lean muscle tissue even when overall caloric intake is reduced.” 

 Burn Lab Pro, a weight loss formula featuring HMB, is marketed to those seeking a supplement to complement dietary and lifestyle changes comprising a larger fat loss program. Making note of several apparent HMB benefits, such as the protection of lean muscle, and more targeted fat burning, the product is designed to “drive the final nail in the coffin of unwanted body fat.” 
 

Manufacturing Supplements with HMB 

According to TSI Group, HMB is a versatile ingredient from a formulation standpoint, allowing for a certain degree of tailoring to specific sports applications, or delivery formats. 

 There are two forms of HMB commonly seen in dietary supplements: Calcium HMB, a mono-hydrated calcium salt combined with HMB to create a powder; and HMB free acid (HMB-FA), which is the metabolite in a free acid liquid form. 

 Calcium HMB, the first form to hit the market, is a white crystalline powder, leading to elevated plasma levels of HMB at 30 minutes with peak levels achieved at roughly 2hours post-ingestion. 

 HMB free acid has greater bioavailability (97% higher plasma concentrations than calcium HMB and 25% greater clearance to tissues), as well as a faster absorption peak of about 30 minutes, according to TSI Group. 

 However, ISSN’s 2013 position (which is slated for an update soon) is that research on HMB-FA is “still in its infancy and there is not enough research to support whether one form is superior.” 

 Across the available dosage forms, HMB is suitable for a variety of dietary supplement and nutrition product applications, including capsules, tablets, powders, beverages, bars, and more. 
 

About the Author: Mike Montemarano has been the associate editor of Nutraceuticals World since 2020. He can be reached at mmontemarano@rodmanmedia.com.