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Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature on the use of beta-hydroxy-beta-methylbutyrate (HMB) as a nutritional supplement. The ISSN has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. 2. If consuming HMB, an athlete will benefit from consuming the supplement in close proximity to their workout. 3. HMB appears to be most effective when consumed for 2 weeks prior to an exercise bout. 4. Thirty-eight mgkgBM-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. 5. Currently, two forms of HMB have been used: Calcium HMB (HMB-Ca) and a free acid form of HMB (HMB-FA). HMB-FA may increase plasma absorption and retention of HMB to a greater extent than HMB-CA. However, research with HMB-FA is in its infancy, and there is not enough research to support whether one form is superior. 6. HMB has been demonstrated to increase LBM and functionality in elderly, sedentary populations. 7. HMB ingestion in conjunction with a structured exercise program may result in greater declines in fat mass (FM). 8. HMB's mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations.

The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the mechanisms and use of beta-alanine supplementation. Based on the current available literature, the conclusions of the ISSN are as follows: 1) Four weeks of beta-alanine supplementation (4-6 g daily) significantly augments muscle carnosine concentrations, thereby acting as an intracellular pH buffer; 2) Beta-alanine supplementation currently appears to be safe in healthy populations at recommended doses; 3) The only reported side effect is paraesthesia (tingling), but studies indicate this can be attenuated by using divided lower doses (1.6 g) or using a sustained-release formula; 4) Daily supplementation with 4 to 6 g of beta-alanine for at least 2 to 4 weeks has been shown to improve exercise performance, with more pronounced effects in open end-point tasks/time trials lasting 1 to 4 min in duration; 5) Beta-alanine attenuates neuromuscular fatigue, particularly in older subjects, and preliminary evidence indicates that beta-alanine may improve tactical performance; 6) Combining beta-alanine with other single or multi-ingredient supplements may be advantageous when supplementation of beta-alanine is high enough (4-6 g daily) and long enough (minimum 4 weeks); 7) More research is needed to determine the effects of beta-alanine on strength, endurance performance beyond 25 min in duration, and other health-related benefits associated with carnosine.

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Beta-alanine is a non-proteogenic amino acid that is produced endogenously in the liver. In addition, humans acquire beta-alanine through the consumption of foods such as poultry and meat. By itself, the ergogenic properties of beta-alanine are limited; however, beta-alanine has been identified as the rate-limiting precursor to carnosine synthesis [1, 2], and has been consistently shown to increase levels of carnosine in human skeletal muscle. Doses of 4 to 6 g/day of beta-alanine have been shown to increase muscle carnosine concentrations by up to 64 % after 4 weeks [1], and up to 80 % after 10 weeks [3]. Baguet et al. [4] demonstrated that individuals vary in the magnitude of response to 5 to 6 weeks of beta-alanine supplementation (4.8 g/day), with high responders increasing muscle carnosine concentrations by an average of 55 %, and low responders increasing by an average of only 15 %. The difference between high and low responders seems, at least in part, to be related to baseline muscle carnosine content and muscle fiber composition [5].

Despite this, beta-alanine supplementation will still increase carnosine concentrations, regardless of low or high baseline levels [19, 20], with no upper limit for muscle carnosine concentrations having yet been identified. While cross-sectional studies have shown higher baseline carnosine contents in the gastrocnemius muscle of sprinters [7] and resistance-trained athletes [6] versus their untrained counterparts, beta-alanine supplementation has also been shown to increase muscle carnosine in both trained [20] and untrained [1] populations. A recent study by Bex et al. [21] suggests that increases in whole muscle carnosine concentrations may be slightly higher in trained athletes compared to non-athletes supplementing with beta-alanine, but more research is needed to replicate this finding and account for potential differences in single muscle fiber concentrations. Much of the research evaluating increases in muscle carnosine has been performed in young males, but evidence also suggests that beta-alanine supplementation is effective in females [22, 23] and the elderly [24].

Over the past ten years, beta-alanine has grown to become one of the most popular sports nutrition ingredients. Although relatively new, with the first human study published in 2006, beta-alanine use and formulation has expanded into nearly every pre-workout formula on the market, and a number of daily and recovery formulas. In summary, the purpose of the International Society of Sports Nutrition Position Stand is to provide a critical review on the effects of beta-alanine and thus provide reasonable guidelines for its use as an ergogenic aid. This Position Stand is presented as a general review of literature, including a relative effects analysis to evaluate performance effects.

Carnosine (-Alanyl-L-histidine) is a naturally occurring dipeptide with numerous potential physiological functions and is formed by combining its constituent amino acids, L-histidine and beta-alanine, with the assistance of the enzyme carnosine synthetase. Carnosine is predominantly stored within skeletal muscle, and can vary widely between species [16]. Carnosinase, the enzyme that catalyzes the breakdown of carnosine, is present in serum and various tissues in humans, but is absent in skeletal muscle [25] and many animals. It is important to note that carnosinase is not present in most non-primate mammals [26], which must be considered when evaluating carnosine supplementation and data obtained from animal models. Therefore, oral carnosine supplementation is an inefficient method of augmenting muscle carnosine levels in humans, as ingested carnosine is ultimately metabolized before reaching skeletal muscle [27].

The potential physiological roles of carnosine extend beyond its function as a proton buffer. Previous research has suggested that reactive oxygen species (ROS), which are produced at an elevated rate during exercise [33], may contribute to muscle fatigue and exercise-induced muscle damage under certain circumstances [34, 35]. Carnosine has been shown to act as an antioxidant by scavenging free radicals and singlet oxygen [36, 37], thereby reducing oxidative stress. Carnosine can further reduce oxidative stress by chelating transition metals, such as copper and iron [37]. In doing so, these transition metals are prevented from reacting with peroxides in the Fenton reaction, which results in the production of free radicals. Carnosine is abundant in human skeletal muscle, and may influence these contributors to fatigue and oxidative stress by buffering excess protons [28], scavenging free radicals [36, 37], and chelating transition metals [37]. As the rate-limiting precursor to carnosine synthesis, beta-alanine supplementation has been shown to consistently elevate carnosine in a variety of populations, and may therefore improve performance during high-intensity exercise and/or enhance the quality of training in athletes participating in strength and power sports [38].

The supplementation strategy for beta-alanine is important to maximize its effects. To date, research suggests that beta-alanine requires a chronic loading dose of 4 to 6 g daily in divided doses of 2 g or less, for a minimum of two weeks (which results in a 20-30 % increase in muscle carnosine concentrations) [4], with greater benefits seen after 4 weeks (40-60 % increase) [19, 39]. To increase muscle carnosine, a larger dose of 6 g, divided into 4 equal doses would be more advantageous. Additionally, if supplementing with a non-time release version, consuming a total daily dose of 6 g would be important for augmenting muscle carnosine [40]. Single large boluses of beta-alanine have been shown to induce paraesthesia (i.e. tingling), and have not been effective for performance outcomes likely due to strong paraesthesia, rapid changes in pH, higher excretion rates, and inability to effectively load the muscle contents. Combining beta-alanine consumption with a meal during beta-alanine loading has also been shown to be effective for further augmenting muscle carnosine levels [41]. In addition, a recent meta-analysis [42] suggested that supplementation with a total ingestion of 179 g of beta-alanine (the average dose across all studies) resulted in a median performance improvement of 2.85 % compared with a placebo. Washout time, or time required for values to return to baseline, may vary between non-responders and responders, requiring 6 to 15 weeks to return to normal [4]. Despite these findings, the maximal concentration or retention of carnosine in human muscle is not well known; thus, we cannot yet provide information on the optimal loading or maintenance doses.

Paraesthesia (i.e., tingling) is the most widely known side effect of beta-alanine and is commonly experienced in individuals consuming more than 800 mg of beta-alanine in a non-sustained release form [1]. It appears that the symptoms of paraesthesia are substantially reduced with the use of sustained-release formulations. In studies using the non-sustained release supplement, paraesthesia has generally been reported to disappear within 60 to 90 min following supplementation [40]. It is hypothesized that beta-alanine activates Mas-related genes (Mrg) [43], or sensory neuron specific G-protein coupled receptors. Specifically, MrgD, which is expressed in the dorsal root ganglion, terminates in the skin [44]. It is likely that activation of MrgD from beta-alanine results in paraesthesia on the skin. To date, there is no evidence to support that this tingling is harmful in any way. The paraesthesia side effect is typically experienced in the face, neck, and back of hands. Although not all individuals will experience paraesthesia, it is typically dose-dependent, with higher doses resulting in greater side effects. Recent data also suggests that males of Asian descent may experience a reduced effect, with Asian females experiencing greater paraesthesia [45]. Moreover, there is no known mechanism to explain why certain individuals may be predisposed to experiencing paraesthesia. Currently, there is no safety data on the long-term use of beta-alanine (i.e., > 1 year). However, due to the non-essential nature of this constituent (i.e., beta-alanine is produced endogenously), the likelihood of safety concerns are low. 17dc91bb1f