Mechanisms of Action

Beta-alanine is a non-essential and non-proteinogenic amino acid produced endogenously in the liver from the degradation of uracil [28]. Alternative synthesis from pathways in the gut [29] and kidney [30] might also account for some endogenous production of beta-alanine, although the very low fasting concentrations in blood [31] suggest that endogenous synthesis is rather low and does not constitute a significant source of beta-alanine for the tissues. Beta-alanine and l-histidine are the precursors of carnosine synthesis in skeletal muscle, a reaction catalysed by the enzyme carnosine synthase [32, 33].

Carnosine is a cytoplasmic dipeptide abundantly found in excitable tissues, such as skeletal muscle [31], heart [34] and in some brain regions [35], although the highest concentrations of carnosine in humans are found in skeletal muscle. Several physiological functions have been attributed to carnosine in skeletal muscle, including antioxidant activity [36] and protection against protein glycation and carbonylation [37, 38]. Data from in-vitro studies with animal and human muscle fibres have also attributed other functions to carnosine, including calcium sensitising, regulation of the calcium transient (i.e. increased calcium release and reuptake from the sarcoplasmic reticulum), and excitation-contraction coupling [37, 39]. However, a recent whole-body study with humans did not support the hypothesis of increased carnosine to increase calcium sensitivity and calcium release, but supported the finding that carnosine may improve calcium reuptake [40]. Clearly, more studies investigating these issues are still required to clarify the physiological roles of carnosine. Despite some controversy, an undisputed function of carnosine is intracellular pH regulation [31], since its side chain (i.e. the imidazole ring) has a pKa of 6.83 [41, 42], making carnosine an obligatory physicochemical buffer. Since the pKa of carnosine is optimal for buffering within the muscle during high-intensity exercise, it could be an important contributor to performance and tolerance to exercises that are limited by H+ accumulation.

Carnosine synthase, the enzyme responsible for carnosine synthesis in skeletal muscle, has a greater affinity, as indicated by its Michaelis–Menten constant (K m ), for l-histidine (K m ~16.8 µmol/L) than for beta-alanine (K m ~1–2.3 mmol/L) [43, 44]. Moreover, plasma and intramuscular concentrations of l-histidine are substantially higher than beta-alanine [45]. Consequently, beta-alanine availability is the rate-limiting factor for the endogenous synthesis of carnosine within skeletal muscle. Subsequently, beta-alanine supplementation (over a period of 2 weeks or longer) induces significant increases in muscle carnosine content [31, 46, 47]. The typical increase in muscle carnosine following beta-alanine supplementation is 60–80 %, which is estimated to elevate the contribution of carnosine to whole muscle H+ buffering by ~2.7–5.3 mEq H+/kg dry mass over the exercise pH range [31], corresponding to an ~3–5 % increase in muscle buffering capacity. Although this is a conservative estimate of the contribution to the whole muscle, the specific contribution to the buffering capacity of type II fibres is considerably greater. Theoretically, such an increase in intracellular buffering capacity could translate into concomitant increases in performance and capacity during exercise limited by increasing muscle acidosis.

Effects on High-Intensity Exercise

A meta-analysis of the available evidence on beta-alanine and exercise [24] showed that beta-alanine improved exercise to a greater extent than placebo. The positive effect was due to improvements in exercise capacity tests but not performance tests, though this may have been due to the relatively low number of performance studies at the time of analysis. Since a capacity test requires the individual to exert to the point of volitional exhaustion, as opposed to a fixed point of cessation in a performance test, thereby resulting in a maximal production of H+, these data support the role of carnosine in acid–base balance. A highly significant effect was shown for exercises lasting 60–240 s, which strengthens the suggestion that the primary role of muscle carnosine is pH buffering. With the growing popularity of beta-alanine, numerous investigations have been published since this meta-analysis and have shed further light on the ergogenic potential of this nutritional supplement.

There is clear evidence that exercises shorter than 60 s are unaffected by beta-alanine [48–50]. This consistent outcome contrasts the purported role of increased carnosine to increase the calcium sensitivity of the muscle and the calcium release from sarcoplasmic reticulum. This was confirmed by Hannah et al. [40], who showed no effect of beta-alanine on maximum and explosive voluntary contractions, but there was a reduction in half-relaxation time, suggesting an enhanced reuptake of calcium. Further mechanistic studies are required to determine the role of carnosine in calcium handling.

Several studies have shown the efficacy of increased muscle carnosine content through beta-alanine supplementation on high-intensity exercises lasting 1–4 min; exercise performance and capacity have been improved in a variety of cycling [46, 51–54], running [55, 56], and repeated-bout upper- and lower-body protocols [57, 58]. The majority of research reporting an ergogenic effect of beta-alanine supplementation is on exercise lasting 1–10 min, although not all agree [59–62]. Improvements in high-intensity cycling capacity at 110 % of maximum power output, a reliable cycling capacity test designed to last between 120–240 s [63], have consistently been shown, with improvements of 11.9 % [46], 12.1 % [54] and 14.0 % [64] in time-to-exhaustion in recreationally active participants following beta-alanine supplementation. These studies highlight the consistency in responses across individuals following supplementation during a high-intensity test limited by increasing acidosis.

Hobson et al. [24] showed an effect of beta-alanine on exercise lasting more than 240 s, although this result was likely due to the incremental nature of many of the tests employed, which are very low in intensity in the earlier stages [51, 52]. Two studies did not show any improvement on prolonged cycling time trial performance [53, 62], which is in line with the role of carnosine as an intramuscular buffer since fatigue during exercise of this duration is not associated with increasing acidosis.

Some doubt has been raised concerning the efficacy of β-alanine on athletes since sprint-trained individuals have been shown to have an elevated buffering capacity compared with their non-trained and endurance-trained counterparts [65, 66]. It has been argued that previously elevated muscle buffering capacity could minimise any improvements brought about via increased carnosine. This has gained some support from indirect evidence in studies with well-trained athletes who supplemented with beta-alanine and showed no improvements in performance [48, 50, 59, 60]. However, a recent study in our laboratory, specifically designed to address this topic, investigated the effects of beta-alanine supplementation on high-intensity cycling performance in both trained cyclists and non-trained individuals. Both groups showed a similar improvement in total work done (~3 %) following supplementation [58], indicating that beta-alanine is equally efficient in untrained and athletic populations. Indeed, there is now a growing body of evidence to support the effective use of beta-alanine among the elite athletic populations; athletes involved in 100- and 200-m freestyle swimming [67], 2000-m rowing [68–70] and 800-m running [55].

Possible Side Effects

The only currently known side effect reported in the literature from the use of beta-alanine is paraesthesia, which has been described as a prickly sensation on the skin that starts within 10–20 min following ingestion and lasts up to 1 h [31]. These symptoms typically arise from high doses of beta-alanine and are associated with the peak plasma beta-alanine level [31]. It has been suggested that beta-alanine stimulates a specific G-protein-coupled receptor expressed by sensory neurons located at the surface of the skin [71]. Although harmless, paraesthesia is unpleasant and may compromise the blinding of a research investigation; therefore, dosing strategies aiming to avoid paraesthesia are employed. To circumvent the occurrence of paraesthesia, studies have consistently staggered dosing protocols throughout the day. Harris et al. [31] were successful in reducing the incidence of paraesthesia with multiple doses of 800 mg every 3 h. A new sustained-release formulation has been developed that results in a lower peak plasma concentration from a single dose while release into blood and uptake into muscle is maintained over 6 h with minimal side effects [72].

In light of the current evidence suggesting no major side effects other than paraesthesia during supplementation of 2–16 weeks in duration [46, 47, 73], athletes can safely supplement with beta-alanine for this period of time prior to competition or throughout training. Future research should ascertain as to whether longer-term supplementation (>16 weeks) is free of any other side effects, although the preliminary results of a study we are currently conducting showed that beta-alanine supplementation did not alter clinical markers of health in 16 subjects who supplemented for 6 months.