Introduction Studies utilizing beta-hydroxy-beta-methylbutyrate (HMB) supplementation in trained populations are limited. No long-term studies utilizing HMB free acid (HMB-FA) have been conducted. Therefore, we investigated the effects of 12 weeks of HMB-FA supplementation on skeletal muscle hypertrophy, body composition, strength, and power in trained individuals. We also determined the effects of HMB-FA on muscle damage and performance during an overreaching cycle. Methods A three-phase double-blind, placebo- and diet-controlled randomized intervention study was conducted. Phase 1 was an 8-week-periodized resistance-training program; Phase 2 was a 2-week overreaching cycle; and Phase 3 was a 2-week taper. Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of HMB-FA; and assessment of these, as well as cortisol, testosterone, and creatine kinase (CK) was performed at weeks 9 and 10 of the overreaching cycle. Results HMB-FA resulted in increased total strength (bench press, squat, and deadlift combined) over the 12-week training (77.1 ± 18.4 vs. 25.3 ± 22.0 kg, p < 0.001); a greater increase in vertical jump power (991 ± 168 vs. 630 ± 167 W, p < 0.001); and increased lean body mass gain (7.4 ± 4.2 vs. 2.1 ± 6.1 kg, p < 0.001) in HMB-FA- and placebo-supplemented groups, respectively. During the overreaching cycle, HMB-FA attenuated increases in CK (−6 ± 91 vs. 277 ± 229 IU/l, p < 0.001) and cortisol (−0.2 ± 2.9 vs. 4.5 ± 1.7 μg/dl, p < 0.003) in the HMB-FA- and placebo-supplemented groups, respectively. Conclusions These results suggest that HMB-FA enhances hypertrophy, strength, and power following chronic resistance training, and prevents decrements in performance following the overreaching.

2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer’s disease. In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1–2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. This study is registered at ClinicalTrials.gov (NCT03176940).

Background: Older adults supplemented for 1 year with β‐hydroxy‐β‐methylbutyrate, arginine, and lysine (HMB/ARG/LYS) were previously shown to have significant gains in fat‐free mass (FFM) but not muscular strength. Objective: Recently, increasing levels of serum vitamin D have been associated with an increase in muscle function, particularly in the elderly. To determine if vitamin D status may have limited strength gain in participants supplemented with HMB/ARG/LYS, the authors performed post hoc analysis of strength based on the participants' vitamin D status. Methods: Elderly (age 76.0 ± 1.6 years) adults were recruited for a double‐blinded, controlled study and were randomly assigned to either an isonitrogenous control (n = 37) or HMB/ARG/LYS (n = 40) for the yearlong study. Participants were further segregated based on their vitamin D status of either <30 or ≥30 ng 25OH‐vitD₃/mL serum, and an analysis was performed on the 4 cohorts. Results: Regardless of vitamin D status, HMB/ARG/LYS resulted in significantly increased FFM (P < .02), but only in those with vitamin D status ≥30 ng 25OH‐vitD₃/mL was there a significant increase in strength with HMB/ARG/LYS (P < .01). Control‐supplemented participants, regardless of vitamin D status, and the HMB/ARG/LYS‐supplemented participants with vitamin D status <30 ng 25OH‐vitD₃ failed to show improvements in strength. Conclusions: The nutrient cocktail of HMB/ARG/LYS alone was effective in increasing muscle mass regardless of vitamin D status, but accompanying strength increases were observed only when participants also had adequate vitamin D status indicating a synergistic effect between the HMB/ARG/LYS and vitamin D.

The primary aim of this study was to determine whether supplementation with calcium β-hydroxy-β-methylbutyrate (HMB) and vitamin D₃ (D) would enhance muscle function and strength in older adults. Older adults over 60 years of age with insufficient circulating 25-hydroxy-vitamin D (25OH-D) levels were enrolled in a double-blinded controlled 12-month study. Study participants were randomly assigned to treatments consisting of: (a) Control + no exercise, (b) HMB+D + no exercise, (c) Control + exercise, and (d) HMB+D + exercise. The study evaluated 117 participants via multiple measurements over the 12 months that included body composition, strength, functionality, and questionnaires. HMB+D had a significant benefit on lean body mass within the nonexercise group at 6 months (0.44 ± 0.27 kg, HMB+D vs −0.33 ± 0.28 kg, control, p < .05). In nonexercisers, improvement in knee extension peak torque (60°/s) was significantly greater in HMB+D-supplemented participants than in the nonsupplemented group (p = .04) at 3 months, 10.9 ± 5.7 Nm and −5.2 ± 5.9 Nm, respectively. A composite functional index, integrating changes in handgrip, Get Up, and Get Up and Go measurements, was developed. HMB+D + no exercise resulted in significant increases in the functional index compared with those observed in the control + no exercise group at 3 (p = .03), 6 (p = .04), and 12 months (p = .04). Supplementation with HMB+D did not further improve the functional index within the exercising group. This study demonstrated the potential of HMB and vitamin D₃ supplementation to enhance muscle strength and physical functionality in older adults, even in individuals not engaged in an exercise training program.

While chronic β-Hydroxy β-Methylbutyrate (HMB) supplementation (≥ 2 wk) lowers exercise induced muscle damage, its acute or timing effects have not been examined. The purpose of this study was to investigate the acute and timing effects of oral HMB supplementation on serum creatine kinase (CK), lactate dehydrogenase (LDH), muscle soreness, and maximal voluntary contraction (MVC).

Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on an analysis of the literature regarding the effects of β-Hydroxy-β-Methylbutyrate (HMB). The following 12 points have been approved by the Research Committee of the Society: 1. HMB is a metabolite of the amino acid leucine that is naturally produced in both humans and other animals. 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. 2. 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. 3. 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. 4. 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). 5. HMB may help reduce muscle damage and promote muscle recovery, which can promote muscle growth/repair. HMB may also have anti-inflammatory effects, which could contribute to reducing muscle damage and soreness. 6. HMB consumption in close proximity to an exercise bout may be beneficial to increase muscle protein synthesis and attenuate the inflammatory response. HMB can provide a beneficial physiological effect when consumed both acutely and chronically in humans. 7. Daily HMB supplementation (38 mg/kg body weight) in combination with exercise training may improve body composition through increasing lean mass and/or decreasing fat mass with benefits in participants across age, sex, and training status. The most pronounced of these improvements in body composition with HMB have been observed in studies with robust resistance training programs and dietary control. 8. HMB may improve strength and power in untrained individuals, but its performance benefits in trained athletes are mixed and increase with an increase in study duration (>6 weeks). HMB's beneficial effects on athletic performance are thought to be driven by improved recovery. 9. HMB supplementation appears to potentially have a positive impact on aerobic performance, especially in trained athletes. The mechanisms of the effects are unknown. 10. HMB supplementation may be important in a non-exercising sedentary and aging population to improve muscle strength, functionality, and muscle quality. The effects of HMB supplementation with exercise are varied, but the combination may have a beneficial effect on the treatment of age-associated sarcopenia under select conditions. 11. HMB may be effective in countering muscle disuse atrophy during periods of inactivity due to illness or injury. The modulation of mitochondrial dynamics and lipid metabolism by HMB may be a potential mechanism for preventing disuse atrophy and aiding rehabilitation beyond HMB's effects on rates of muscle protein synthesis and degradation. 12. The efficacy of HMB in combination with certain nutrients may be enhanced under select conditions.