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Effect of slow-release β-Alanine tablets on absorption kinetics and paresthesia

DOI:10.1007/s00726-011-1169-7
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Jacques Décombaz
Jacques Décombaz
Jacques Décombaz
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Maurice Beaumont at Retired from Nestlé
Maurice Beaumont
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Jacques Vuichoud
Jacques Vuichoud
Jacques Vuichoud
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Florilene Bouisset
Florilene Bouisset
Florilene Bouisset
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Abstract

Oral β-alanine (βA) doses larger than 800 mg commonly result in unpleasant sensory symptoms (paresthesia). However, the association of form (pure vs. slow-release) with side-effects has not been fully described. The aim of this single-blinded, randomized three-arm clinical trial was to compare plasma kinetics and symptoms following βA bolus administration in solution or in slow-release tablet form. Eleven healthy adults ingested 1.6 g of a pure βA reference solution (REF), 1.6 g in slow-release βA tablets (TAB) or a placebo (PLA) after an overnight fast. During the next 6 h, urinary and plasma βA concentrations were measured and questionnaires about intensity, nature (pins and needles, itching, flushing, irritation, numbness, soreness), and spatial distribution of unusual sensations were filled in. TAB resulted in a smaller peak plasma concentration than REF (82 vs. 248 μmol L(-1), p<0.001), delayed time to peak (1.0 vs. 0.5 h, p<0.01) no difference in area under the curve, reduced loss in urine (202 vs. 663 μmol, p<0.0001), and improved retention (98.9 vs. 96.3%, p<0.001). Symptoms described as "pins and needles" were perceived rapidly on the skin of the arms and trunk after REF (Tmax=15 min) and their time course nearly mimicked plasma concentrations. Maximum intensity scores were weaker with TAB ("very low") than with REF ("low", p<0.001), while TAB and PLA did not differ with respect to side-effects. In summary, ingesting 1.6 g βA in slow-release tablets rather than pure in solution results in slower absorption kinetics, improved whole body retention and sensory side-effects that cannot be differentiated from PLA.
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ERRATUM
Erratum to: Effect of slow-release b-alanine tablets
on absorption kinetics and paresthesia
Jacques De
´combaz •Maurice Beaumont •
Jacques Vuichoud •Florilene Bouisset •
Trent Stellingwerff
ÓSpringer-Verlag Wien 2013
Erratum to: Amino Acids (2012) 43:67–76
DOI 10.1007/s00726-011-1169-7
In the original publication of Table 1, the last two entries
of the first column have been published with incorrect
units. The corrected Table 1is produced below:
The online version of the original article can be found under
doi:10.1007/s00726-011-1169-7.
J. De
´combaz (&)M. Beaumont J. Vuichoud F. Bouisset
T. Stellingwerff
Nestle
´Research Center, Lausanne, Switzerland
e-mail: decombaz.jac@bluewin.ch
Present Address:
T. Stellingwerff
Canadian Sports Centre-Pacific, Victoria, Canada
Table 1 b-Alanine pharmacokinetic analysis
TAB
a
REF
b
P
C
max
(lmol L
-1
) 81.9 ±27.5 248.2 ±112.7 0.0002
T
max
(min) 60.0 ±16.2 29.4 ±7.2 0.0015
AUC (lmol L
-1
h) 229.4 ±83.7 253.4 ±81.1 0.5504
K
a
(h
-1
) 3.55 ±2.69 11.98 ±7.21 0.0007
T
lag
(min) 17.4 ±9.6 14.4 ±4.2 0.6606
T
1/2
(min) 80.4 ±64.2 37.2 ±21.6 0.0485
Mean ±SD
C
max
peak concentration, T
max
time to peak, AUC area under the
curve, K
a
absorption rate constant, T
lag
time until first appearance in
plasma, T
1/2
half-time of disappearance
a
bA slow-release tablets
b
bA reference aqueous solution
123
Amino Acids
DOI 10.1007/s00726-013-1557-2
... Paresthesia is the only side effect of β-alanine supplementation that has been shown to occur in humans [13]. Described as an uncomfortable itchy or pins-and-needles sensation on the skin, paresthesia occurs within ~ 10-20 min following β-alanine ingestion [10] and is closely related with plasma β-alanine concentrations [51]. The mechanisms underpinning paresthesia seem to involve the Mas-related gene family of G-protein-coupled receptors, which are triggered by interactions with ligands including β-alanine [52]. ...
... Symptoms typically arise from a high dose of β-alanine with its intensity being closely associated with β-alanine concentrations in blood [47]. This means that paresthesia can be avoided if β-alanine is taken in the form of slow-release tablets [51] or if smaller and more frequent doses are ingested [51]. ...
... Symptoms typically arise from a high dose of β-alanine with its intensity being closely associated with β-alanine concentrations in blood [47]. This means that paresthesia can be avoided if β-alanine is taken in the form of slow-release tablets [51] or if smaller and more frequent doses are ingested [51]. ...
Safety of beta-alanine supplementation in humans: a narrative review
Article
Full-text available
Carnosine levels play a significant role in intracellular pH buffering during exercise. The limiting factor for muscle carnosine synthesis is the availability of β-alanine. Results from meta-analysis showed a significant positive effect of β-alanine supplementation on high-intensity exercise performance. Nonetheless, much less has been described about the safety of β-alanine. The available literature indicates no adverse events related to β-alanine usage; side effects such as paresthesia may be observed if a large single high dose of β-alanine is taken, but the symptom can be attenuated either by using splitting doses (< 1.6 g) or a sustained-release formula. No adverse effects have been reported up to 24 weeks of β-alanine supplementation (3.2 g.day⁻¹), but the adverse effects of longer supplementation periods are still unknown. Most of the existing clinical studies were not designed with safety evaluations as primary end points. β-Alanine is currently considered to be safe in healthy populations, at recommended doses, by the International Society of Sports Nutrition stands position, while the Australian Institute of Sports has established β-alanine as a safe performance-enhancing supplement with strong scientific evidence (grade A). Cohort studies are needed evaluating the safety of β-alanine among representative populations, and the effects of co-variables such as sex, age, and ethnicity.
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... This strategy may reduce, but not completely eliminate, the occurrence of paraesthesia [136]. A second option is to use sustained-release tablets; these have been shown to reduce the release of beta-alanine into the bloodstream, substantially lowering the incidence of paraesthesia in comparison to beta-alanine in rapid release format or dissolved in an aqueous solution [137,138]. ...
... Evidence-based supplement dose and timing should be used (Fig. 1), supported by the collection of data that can inform the individual athlete's responses to the use of buffering agents in methods that are practical within the specific conditions of their event [20,21]. Validated or previously cited scales can be used to quantify gastrointestinal symptoms (most relevant for sodium bicarbonate and sodium citrate [162]), and other side-effects routinely reported during beta-alanine supplementation regimes (e.g., paraesthesia) [137]. It is valuable, where possible, for the sports scientist to monitor increases in blood [HCO 3 − ] in conjunction with the use of extracellular buffering agents using portable blood-gas analysers. ...
Use of Buffers in Specific Contexts: Highly Trained Female Athletes, Extreme Environments and Combined Buffering Agents—A Narrative Review
Article
Full-text available
This narrative review evaluated the evidence for buffering agents (sodium bicarbonate, sodium citrate and beta-alanine), with specific consideration of three discrete scenarios: female athletes, extreme environments and combined buffering agents. Studies were screened according to exclusion and inclusion criteria and were analysed on three levels: (1) moderating variables (supplement dose and timing, and exercise test duration and intensity), (2) design factors (e.g., use of crossover or matched group study design, familiarisation trials) and (3) athlete-specific factors (recruitment of highly trained participants, buffering capacity and reported performance improvements). Only 19% of the included studies for the three buffering agents reported a performance benefit, and only 10% recruited highly trained athletes. This low transferability of research findings to athletes’ real-world practices may be due to factors including the small number of sodium citrate studies in females (n = 2), no studies controlling for the menstrual cycle (MC) or menstrual status using methods described in recently established frameworks, and the limited number of beta-alanine studies using performance tests replicating real-world performance efforts (n = 3). We recommend further research into buffering agents in highly trained female athletes that control or account for the MC, studies that replicate the demands of athletes’ heat and altitude camps, and investigations of highly trained athletes’ use of combined buffering agents. In a practical context, we recommend developing evidence-based buffering protocols for individual athletes which feature co-supplementation with other evidence-based products, reduce the likelihood of side-effects, and optimise key moderating factors: supplement dose and timing, and exercise duration and intensity.
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... This prevents the acidification and finally muscle fatigue (Baguet et al., 2010), one reason, why it is used by athletes during exercise. Remarkably, one side effect is itching commencing 15 min after oral consumption in humans and mice (Decombaz et al., 2012;Liu et al., 2012). ...
... In addition, the amplitude of the scratching movements directed against the cheek is lower than in the neck area, and it would therefore be more difficult to set a cutoff and distinguish it from stationary movements or walking. A few studies administered pruritogens orally in mice and humans to address food-induced pruritus as it is observed after the consumption of β-alanine enriched anabolic supplements and high doses of histamine (Decombaz et al., 2012;Maintz and Novak, 2007;Wohrl et al., 2004). ...
Heritability of Acute Pruritus - a Phenotyping and in Silico Gene Mapping Study in Inbred Mouse Strains
Thesis
  • Jan 2022
Itch, medically termed as pruritus, describes an unpleasant sensation on the skin which is followed by an urge to scratch. It is estimated that 20-27% of the world's population suffer from chronic pruritus at least once in their lifetime which underlines the clinical relevance of this symptom. Nevertheless, molecular research in the area of acute and chronic itch was neglected for a long time as itch was interpreted as subthreshold pain stimulus. In contrast to pain research, pruritus research is still at an early stage and a coherent picture of the molecules, receptors and signaling pathways involved in its processing is lacking. As a result, the treatment of chronic itch continues to be a clinical challenge. There is evidence that genetic predisposition and sex are important factors in mediating variable sensitivity. Around 70% of dark-skinned Africans experience severe itching after the administration of the antimalarial drug chloroquine, with little incidence observed among Asians and Europeans. In the present work, the hypothesis that the genetic background modulates individual susceptibility to itch was challenged and potentially causative gene candidates were identified by in silico gene mapping. In the first part of the study, the acute scratch behavior of male and female mice from 21 phylogenetically different inbred strains was quantified after intradermal injection of ten itch-provoking substances. For this purpose, small teflon magnets were implanted subcutaneously in both hind paws of each mouse under isoflurane anesthesia. For the measurement, the mice were placed in individual cages, which were surrounded by magnetic coils. Every movement of the mouse within the magnetic field induced an electric current and was registered oscillogaphically. Scratch movements in mice, similar to other four-legged animals, are limited to the hind paws and represent a characteristic movement, which is uniform, repetitive and fast. Therefore, running and scratching movements can easily be discerned automatically based on custom-designed software algorithms. At the beginning of measurements, mice were injected with a pruritogen intradermally into the neck fold every day and the acute scratching behavior measured in the following 30 minutes. In total, the five pruritogens BAM8-22, C48/80, SLIGRL, β-alanine and trypsin were injected on five consecutive days. The scratching behavior of the mice after intradermal PBS injection was regarded as baseline value, since the perforation of the skin with the injection needle and the wheal formation cause variable irritation. Evidently, the genetic background has a measurable and even large effect on scratching behavior. MAMy and NOD were highly sensitive while other strains, such as NZB and A, were almost resistant to the pruritogens. Sex had no systematic influence on the scratching behavior. This is in contrast to clinical studies which showed a higher prevalence of pruritus in female subjects. In the next step, the phenotypic data were aligned with genetic variation in the respective mouse strains with computer-based haplotype mapping and a group analysis algorithm. Then, the candidate genes were ranked according to their p-value to recognize the genes with the lowest p-values and supposedly strong correlation with the trait distribution. These genes were then subjected to a pathway analysis which revealed seven different functional gene clusters. These are related to biological processes and may relate to the development of itching. Furthermore, the genes were examined for their chromosomal location in order to identify potential clusters. It was found that the largest proportion (12.4%) of the genes is located on chromosome 7 with a total of 109 out of 879 identified candidate genes. Interestingly, chromosome 7 holds also a cluster of Mas-related G-protein-coupled receptors, for which data from transgenic animals already identified a crucial contribution to itch signaling. In a parallel experimental approach, the expression profile of lumbar dorsal root ganglia from two inbred mouse strains with opposite phenotypes was compared with single cell transcriptomics. The differentially expressed genes were brought together with the genes from the functional gene clusters of the pathway analysis and 48 overlapping genes were identified. These genes were subsequently examined for the effect of the existing single nucleotide polymorphisms (SNP) and their expression profile in murine tissues and organs. Dipeptidyl peptidase protein 6 (Dpp6) appeared as one particularly interesting candidate gene because it has a nucleotide exchange from cytosine to thymine in strains with low scratch activity at SNP position rs27366810. In the course of protein biosynthesis, this leads to early termination of translation by a stop codon on position 21. In addition, this protein is highly expressed in dorsal root ganglia and brain areas with involvement in itch signaling. In the last part of the study and, to rule out that increased scratching behavior is related with higher levels of basal activity in particular strains, the home-cage activity of all inbred strains was assessed over 24 hours in single cages. These were equipped with a system of photobeams to detect mouse movements in X, Y and Z directions. This fully automated experimental set-up enabled the quantification of the activity without experimenter-bias in a home cage-like environment. The activity data had no correlation with the scratch-data from the respective pruritogens and PBS illustrating that scratching was stimulus-induced and not influenced by variable activity levels. While pruritus is a complex sensory experience to which many proteins, receptors and ion channels contribute, the combination of behavioral phenotyping and computer-based haplotype mapping with single cell transcriptomics has identified new genetic factors which will lead the way to the identification of potent targets in further preclinical and clinical studies.
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... An additional factor to be taken into consideration are the possible side effects when using higher doses of carnosine. While the majority of pre-clinical studies have shown how this dipeptide is non-toxic [143] and extremely well tolerated by humans [144,145], with no known drug interactions, some studies have shown that carnosine (or its precursor, β-alanine) led to unwanted effects, such as anxiety-like effects in rats [146], and paresthesia [147] or increased perception of pain in humans [148]. ...
The Anti-Cancer Activity of the Naturally Occurring Dipeptide Carnosine: Potential for Breast Cancer
Article
Full-text available
  • Nov 2023
Carnosine is an endogenous dipeptide composed of β-alanine and L-histidine, possessing a multimodal pharmacodynamic profile that includes anti-inflammatory and anti-oxidant activities. Carnosine has also shown its ability to modulate cell proliferation, cell cycle arrest, apoptosis, and even glycolytic energy metabolism, all processes playing a key role in the context of cancer. Cancer is one of the most dreaded diseases of the 20th and 21st centuries. Among the different types of cancer, breast cancer represents the most common non-skin cancer among women, accounting for an estimated 15% of all cancer-related deaths in women. The main aim of the present review was to provide an overview of studies on the anti-cancer activity of carnosine, and in particular its activity against breast cancer. We also highlighted the possible advantages and limitations involved in the use of this dipeptide. The first part of the review entailed a brief description of carnosine’s biological activities and the pathophysiology of cancer, with a focus on breast cancer. The second part of the review described the anti-tumoral activity of carnosine, for which numerous studies have been carried out, especially at the preclinical level, showing promising results. However, only a few studies have investigated the therapeutic potential of this dipeptide for breast cancer prevention or treatment. In this context, carnosine has shown to be able to decrease the size of cancer cells and their viability. It also reduces the levels of vascular endothelial growth factor (VEGF), cyclin D1, NAD+, and ATP, as well as cytochrome c oxidase activity in vitro. When tested in mice with induced breast cancer, carnosine proved to be non-toxic to healthy cells and exhibited chemopreventive activity by reducing tumor growth. Some evidence has also been reported at the clinical level. A randomized phase III prospective placebo-controlled trial showed the ability of Zn–carnosine to prevent dysphagia in breast cancer patients undergoing adjuvant radiotherapy. Despite this evidence, more preclinical and clinical studies are needed to better understand carnosine’s anti-tumoral activity, especially in the context of breast cancer.
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... Frontiers in Nutrition 07 frontiersin.org carried out by Décombaz et al. (24), to measure paresthesias; instead, we employed an EVA (Visual Analog Scale) for this purpose. The reason for not utilizing the Decombaz scale was that they are validated to assess paresthesias immediately after product consumption. ...
Effect of a sustained-release formulation of β-alanine on laboratory parameters and paresthesia in recreational trained men: a randomized double-blind placebo-controlled study
Article
Full-text available
  • Sep 2023
Introduction Beta-alanine is a non-essential amino acid that has been a focus of increasing research by its role as ergogenic aid to improve muscle performance. Methods A randomized, double-blind and controlled trial was conducted to determine the effect of a nutritional supplement of a sustained-release formulation of β-alanine in recreational trained men. The active product was an innovative sustained-release β-alanine microgranules powder blend, administered at high doses (15 g/day) divided into 3 intakes during 30 days. There were 10 participants in the experimental group and 9 in the placebo group, with a mean age of 22.5 ± 3.3 years. Participants were testing at baseline and at the end of study. Results In the β-alanine group, there were statistically increases in serum triglycerides, LDL-cholesterol, and urea nitrogen at the end of the study as compared with baseline, although there were no differences with the control group. The occurrence of paresthesia, described above all as tickling, was the majority but presented VAS score less than 3/10 in almost all subjects. Discussion More studies are required to evaluate the changes in blood parameters that can be caused by high intake of β-alanine during a long period of time. Clinical trial registration ClinicalTrials.gov , identifier (NCT05334121).
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... • Las dosis agudas de liberación rápida que superen los 1600 mg por dosis pueden generar parestesias o hormigueos en la piel que puede durar hasta 1 hora (47,56,57) Esto es común en los suplementos "pre-workout", y algunos deportistas puede asociar erróneamente estos síntomas con "evidencia" de la efectividad del suplemento. ...
Guía de suplementación para profesionales de la salud y deporte. Parte I: Suplementos con nivel de evidencia fuerte.
Article
Full-text available
  • Jul 2023
Los alimentos deportivos y suplementos pueden tener un papel pequeño pero importante en los planes nutricionales deportivos de los atletas de alto rendimiento. Las organizaciones deportivas, los profesionales de las ciencias del deporte y de la salud y los entrenadores deberán considerar los siguientes puntos al recomendar a un deportista el uso de un suplemento o alimento deportivo: ¿su consumo es seguro?, ¿es efectivo?, ¿está permitido su uso en el deporte? Por lo anterior, el objetivo de esta guía de suplementación deportiva, adaptada del marco establecido por el Instituto Australiano del Deporte (IAD), es ofrecer información clara, resumida y actualizada acerca del uso seguro y la evidencia científica en torno a los suplementos y alimentos deportivos. El presente documento se construyó a partir del documento original “Australian Institute of Sport Position Statement. Supplements and Sports Foods in High Performance Sport” sumado a una revisión de la literatura llevada a cabo por los autores entre los meses de febrero y mayo de 2022, incluyendo ensayos clínicos aleatorizados y metaanálisis publicados en la base de datos PubMed en los últimos 10 años. Esta guía está dividida en 4 secciones según los niveles de evidencia y seguridad en su uso. El presente documento corresponde a la primera parte de la guía, que incluye los alimentos con nivel de evidencia fuerte de un efecto ergogénico y seguro para el deporte.
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... Paranesthesia is a consequence of an increase in the sensitivity of neuropathic pain-transmitting nociceptive neurons, which causes redness and an itching sensation on the skin [13,39]. Paranesthesia could be attenuated by fractionated lower doses (1.6 g per dose, in six-eight doses) or sustained release formulas [13] and consuming them with main meals to help improve absorption and better manage potential side effects [13,40]. ...
β-Alanine Supplementation in Combat Sports: Evaluation of Sports Performance, Perception, and Anthropometric Parameters and Biochemical Markers: A Systematic Review of Clinical Trials
Article
Full-text available
  • Aug 2023
β-alanine does not have an ergogenic effect by itself, but it does as a precursor for the synthesis of carnosine in human skeletal muscle. β-alanine and carnosine together help improve the muscles’ functionality, especially in high-intensity exercises such as combat sports. Therefore, β-alanine could be considered a nutritional ergogenic aid to improve sports performance in combat athletes. We aimed to critically review clinical trial evidence on the impact of β-alanine supplementation on sports performance, perception, and anthropometric parameters, as well as circulating biochemical markers in combat athletes. This systematic review was conducted following the specific methodological guidelines of the Preferred Report Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), the PICOS question model, the Critical Review Form of McMaster, and the PEDro scale. Furthermore, the Cochrane risk-of-bias assessment tool was used. The search was carried out in the SCOPUS, Web of Science (WOS), and Medline (PubMed) databases for studies published from the beginning of the database until July 31, 2023. Of the 41 registers identified, only 7 met the established criteria and were included in this systematic review. Overall, performance parameters related to strength, power, total exercise work capacity, and combat-specific parameters were significantly improved (p < 0.05). Perception parameters increased non-significantly (p > 0.05). Regarding biochemical parameters, carnosine increased significantly (p < 0.05), pH decreased non-significantly (p > 0.05), and the results for blood bicarbonate and blood lactate were heterogeneous. Finally, there was a non-significant (p > 0.05) improvement in the anthropometric parameters of lean mass and fat mass. β-alanine supplementation appears to be safe and could be a suitable nutritional ergogenic aid for combat athletes.
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... The plasma concentration of β-alanine rises in a dose-dependent manner, with peak plasma concentrations occurring ~30 min after ingestion 49,51 and lasting ~2.5 hours 52 . β-alanine is administered via a slow-release formula to minimize paresthesia, a known side effect of supplementation 52 . Moreover, if β-alanine is taken chronically at 3.2 g•day -1 for 4 weeks, skeletal muscle carnosine concentrations rise, and a greater volume of high-intensity work can be performed 49 . ...
Food for Thought: Physiological Considerations for Nutritional Ergogenic Efficacy
Article
Full-text available
Top-class athletes have optimized their athletic performance largely through adequate training, nutrition, recovery, and sleep. A key component of sports nutrition is the utilization of nutritional ergogenic aids, which may provide a small but significant increase in athletic performance. Over the last decade, there has been an exponential increase in the consumption of nutritional ergogenic aids, where over 80% of young athletes report using at least one nutritional ergogenic aid for training and/or competition. Accordingly, due to their extensive use, there is a growing need for strong scientific investigations validating or invalidating the efficacy of novel nutritional ergogenic aids. Notably, an overview of the physiological considerations that play key roles in determining ergogenic efficacy is currently lacking. Therefore, in this brief review, we discuss important physiological considerations that contribute to ergogenic efficacy for nutritional ergogenic aids that are orally ingested including: (1) the impact of first pass metabolism, (2) rises in systemic concentrations, and (3) interactions with the target tissue. In addition, we explore mouth rinsing as an alternate route of ergogenic efficacy that bypasses the physiological hurdles of first pass metabolism via direct stimulation of the central nervous system. Moreover, we provide real world examples and discuss several practical factors that can alter the efficacy of nutritional ergogenic aids including human variability, dosing protocols, training status, sex differences, and the placebo effect. Taking these physiological considerations into account will strengthen the quality and impact of the literature regarding the efficacy of potential ergogenic aids for top-class athletes.
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... While this might seem evident, this is remarkable as fasted plasma samples were taken >8 h after the last supplement intake and pharmacokinetics (plasma BA is back to baseline after 5 h after acute BA supplement intake) and BA half-life (after 80 min) are rather short. 27 Our findings are further confirmed by those of Blancquaert et al., who found that after BA supplementation (6 g/day), fasted plasma BA was elevated the morning after last BA supplement intake on Day 12 (+123% of mean baseline value) and Day 23 (+169% of mean baseline value) of the supplementation period. 28 Also, a study in vegetarians found that 800 mg of BA supplementation per day for 12 weeks resulted in an increase of 27.2% of fasted plasma BA. 29 Additionally, they showed in mice (serum) 26 and in humans (plasma) that change in fasted circulating BA determined change in muscle carnosine concentration after BA supplementation (soleus; r = 0.591; gastrocnemius; r = 0.442), 30 suggesting that circulating BA is a good predictor of the amount of carnosine loading. ...
Efficacy of 12 weeks oral beta‐alanine supplementation in patients with chronic obstructive pulmonary disease: a double‐blind, randomized, placebo‐controlled trial
Article
Full-text available
  • Aug 2022
Background: Beta-alanine (BA) supplementation increases muscle carnosine, an abundant endogenous antioxidant and pH buffer in skeletal muscle. Carnosine loading promotes exercise capacity in healthy older adults. As patients with chronic obstructive pulmonary disease (COPD) suffer from elevated exercise-induced muscle oxidative/carbonyl stress and acidosis, and from reduced muscle carnosine stores, it was investigated whether BA supplementation augments muscle carnosine and induces beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress in patients with COPD. Methods: In this double-blind, randomized, placebo (PL)-controlled trial (clinicaltrials.gov identifier: NCT02770417), 40 patients (75% male) with COPD (mean ± standard deviation: age 65 ± 6 years; FEV1 % predicted 55 ± 14%) were assigned to 12 weeks oral BA or PL supplementation (3.2 g/day). The primary outcome, i.e. muscle carnosine, was quantified from m. vastus lateralis biopsies obtained before and after intervention. Co-primary outcomes, i.e. incremental and constant work rate cycle capacity, were also assessed. Linear mixed model analyses were performed. Compliance with and side effects of supplement intake and secondary outcomes (quadriceps strength and endurance, and muscle oxidative/carbonyl stress) were also assessed. Results: Beta-alanine supplementation increased muscle carnosine in comparison with PL in patients with COPD (mean difference [95% confidence interval]; +2.82 [1.49-4.14] mmol/kg wet weight; P < 0.001). Maximal incremental cycling capacity (VO2 peak: +0.5 [-0.7 to 1.7] mL/kg/min; P = 0.384, Wpeak: +5 [-1 to 11] W; P = 0.103) and time to exhaustion on the constant work rate cycle test (+28 [-179 to 236] s; P = 0.782) did not change significantly. Compliance with supplement intake was similar in BA (median (quartile 1-quartile 3); 100 (98-100)%) and PL (98 (96-100)%) (P = 0.294) groups, and patients did not report side effects possibly related to supplement intake. No change was observed in secondary outcomes. Conclusions: Beta-alanine supplementation is efficacious in augmenting muscle carnosine (+54% from mean baseline value) without side effects in patients with COPD in comparison with PL. However, accompanied beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress were not observed.
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Influence of B-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity
Article
Full-text available
  • Feb 2007
Muscle carnosine synthesis is limited by the availability of β-alanine. Thirteen male subjects were supplemented with β-alanine (CarnoSyn™) for 4 wks, 8 of these for 10 wks. A biopsy of the vastus lateralis was obtained from 6 of the 8 at 0, 4 and 10 wks. Subjects undertook a cycle capacity test to determine total work done (TWD) at 110% (CCT110%) of their maximum power (Wmax). Twelve matched subjects received a placebo. Eleven of these completed the CCT110% at 0 and 4 wks, and 8, 10 wks. Muscle biopsies were obtained from 5 of the 8 and one additional subject. Muscle carnosine was significantly increased by +58.8% and +80.1% after 4 and 10 wks β-alanine supplementation. Carnosine, initially 1.71 times higher in type IIa fibres, increased equally in both type I and IIa fibres. No increase was seen in control subjects. Taurine was unchanged by 10 wks of supplementation. 4 wks β-alanine supplementation resulted in a significant increase in TWD (+13.0%); with a further +3.2% increase at 10 wks. TWD was unchanged at 4 and 10 wks in the control subjects. The increase in TWD with supplementation followed the increase in muscle carnosine.
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Alanine as a small molecule neurotransmitter
Article
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  • Oct 2010
This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.
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The plasma concentration‐time profile of beta‐alanine using a controlled‐release formulation (Carnosyn ® )
Article
  • Mar 2008
Carnosine (β‐Alanylhistidine) synthesis in muscle cells is limited by the availability of β‐Alanine, but can be increased 80% or more when the diet is supplemented with β‐Ala. This is of interest to athletes since increased levels of muscle Carnosine have been shown to improve exercise performance. Above 10mg/kg bwt, however, β‐Ala in solution or rapidly‐dissolving capsules causes symptoms of paraesthesia, despite the amount being less than that available from normal‐size portions of meat. PURPOSE To investigate β‐Ala absorption using a controlled‐release formulation. METHOD Three males and 3 females were given 1600mg β‐Ala dissolved in water (C), 2 × 800mg β‐Ala controlled release tablets (T2) and 4 tablets (T4), on separate occasions. Controlled release tablets were Carnosyn™ supplied by Collegiate Sports Nutrition. Plasma from 100μl capillary blood samples was collected over 6h, initially every 0.25h, and analysed for β‐Ala by HPLC. RESULTS Subjects reported significant paraesthesia with C, no symptoms with T2 and zero/trace symptoms with T4. Peak β‐Ala (P) with C was 219±78μM with return to ~10uM at 3h. Increases in P were greatly attenuated with T2 (126±36μM) and T4 (177±123μM) but greatly extended (>50μM at 3h). Areas under the plasma concentration curve were C: 286±48; T2: 309±154; T4: 518±220 μM.h. with C or T2 vs T4: P<0.05; C vs T2: P>0.05. CONCLUSION : T2 was bioequivalent to C but did not cause paraesthesia.
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Muscle Carnosine Metabolism and beta-Alanine Supplementation in Relation to Exercise and Training
Article
  • Jan 2010
Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by carnosine synthase from the amino acids L-histidine and beta-alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of beta-alanine can substantially elevate (up to 80%) the carnosine content of human skeletal muscle. Interestingly, muscle carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although carnosine is not involved in the classic adenosine triphosphate-generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High carnosine concentrations are found in individuals with a high proportion of fast-twitch fibres, because these fibres are enriched with the dipeptide. Muscle carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of beta-alanine. Sprint-trained athletes display markedly high muscular carnosine, but the acute effect of several weeks of training on muscle carnosine is limited. High carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. beta-Alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the sports science community.
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Comparative study of the validity of four French McGill Pain Questionnaire (MPQ)
Article
Four different French versions of the McGill Pain Questionnaire (MPQ) have been published: 3 are MPQ translations in Canadian French and 1 (QDSA) is an MPQ reconstruction in (France) French. The aim of our work was to study the validity of these available questionnaires for use in France. The validity was evaluated by 44 French physicians. Various validity criteria were studied: item, dimension, subclass and pain descriptor intensity. A new French MPQ was also developed. Significant validity differences emerged between the different MPQ versions. This study confirms the satisfactory validity of the QDSA. The validity of the newly developed French MPQ was equal but not better than the QDSA. A 15-item short MPQ-QDSA version was also developed. For studies with patients from France, it is recommended that the QDSA or the short MPQ-QDSA versions be used.
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The effect of 4 weeks β-Alanine supplementation and isokinetic training on carnosine concentrations in type I and II human skeletal muscle fibres
Article
  • May 2009
Seven male students were supplemented with β-alanine (β-ALG) for 4weeks (6.4gday−1) and seven with a matching placebo (PLG). Subjects undertook 4weeks of isokinetic training with the right leg (T) whilst the left leg was untrained (UT), serving as a control. Each training session consisted of 10×10 maximal 90° extension and flexion contractions at 180°/s using a Kin-Com isokinetic dynamometer, with 1min rest between bouts. Muscle biopsies were taken from the vastus lateralis immediately before and at the end of the supplementation period. Following freeze drying muscle fibres were dissected and characterised by their MHC profile, as type I, IIa, IIx, or as hybrids of these. Carnosine was measured by HPLC. There was a significant increase in carnosine in both T and UT legs of the β-ALG (9.63±3.92mmolkg−1 dry muscle and 6.55±2.36mmolkg−1 dry muscle respectively). There was a significant increase in the carnosine content of all fibre phentotypes, with no significant difference between types. There were no significant differences in the changes in muscle or in fibres between the T and UT legs. In contrast there was no significant change in the carnosine content in either the T or UT legs with placebo. The results indicate that 4weeks training has no effect on the muscle carnosine content. Whilst an increase was seen with β-alanine supplementation, this was not further influenced by training. These findings suggest that β-alanine availability is the main factor regulating muscle carnosine synthesis.
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Effect of two β-Alanine dosing protocols on muscle carnosine synthesis and washout
Article
Carnosine (β-alanyl-L-histidine) is found in high concentrations in skeletal muscle and chronic β-alanine (BA) supplementation can increase carnosine content. This placebo-controlled, double-blind study compared two different 8-week BA dosing regimens on the time course of muscle carnosine loading and 8-week washout, leading to a BA dose-response study with serial muscle carnosine assessments throughout. Thirty-one young males were randomized into three BA dosing groups: (1) high-low: 3.2 g BA/day for 4 weeks, followed by 1.6 g BA/day for 4 weeks; (2) low-low: 1.6 g BA/day for 8 weeks; and (3) placebo. Muscle carnosine in tibialis-anterior (TA) and gastrocnemius (GA) muscles was measured by 1H-MRS at weeks 0, 2, 4, 8, 12 and 16. Flushing symptoms and blood clinical chemistry were trivial in all three groups and there were no muscle carnosine changes in the placebo group. During the first 4 weeks, the increase for high-low (TA 2.04 mmol/kgww, GA 1.75 mmol/kgww) was ~twofold greater than low-low (TA 1.12 mmol/kgww, GA 0.80 mmol/kgww). 1.6 g BA/day significantly increased muscle carnosine within 2 weeks and induced continual rises in already augmented muscle carnosine stores (week 4-8, high-low regime). The dose-response showed a carnosine increase of 2.01 mmol/kgww per 100 g of consumed BA, which was only dependent upon the total accumulated BA consumed (within a daily intake range of 1.6-3.2 g BA/day). Washout rates were gradual (0.18 mmol/kgww and 0.43 mmol/kgww/week; ~2%/week). In summary, the absolute increase in muscle carnosine is only dependent upon the total BA consumed and is not dependent upon baseline muscle carnosine, the muscle type, or the daily amount of supplemented BA.
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Effect of beta-Alanine Plus Sodium Bicarbonate on High-Intensity Cycling Capacity
Article
We examined the effect of β-alanine supplementation plus sodium bicarbonate on high-intensity cycling capacity. Twenty males (age = 25 ± 5 yr, height = 1.79 ± 0.06 m, body mass = 80.0 ± 10.3 kg) were assigned to either a placebo (P) or a β-alanine (BA; 6.4 g·d(-1) for 4 wk) group based on power max, completing four cycling capacity tests at 110% of power max (CCT110%) to determine time to exhaustion (TTE) and total work done. A CCT(110%) was performed twice (habituation and baseline) before supplementation (with maltodextrin [MD]) and twice after supplementation (with MD and with sodium bicarbonate [SB]), using a crossover design with 2 d of rest between trials, creating four study conditions (PMD, PSB, BAMD, and BASB). Blood pH, Lactate, bicarbonate and base excess were determined at baseline, before exercise, immediately after exercise, and 5 min after exercise. Data were analyzed using repeated-measures ANOVA. TTE was increased in all conditions after supplementation (+1.6% PMD, +6.5% PSB, +12.1% BAMD, and +16.2% BASB). Both BAMD and BASB resulted in significantly improved TTE compared with that before supplementation (P ≤ 0.01). Although further increases in TTE (4.1%) were shown in BASB compared with BAMD, these differences were not significant (P = 0.74). Differences in total work done were similar to those of TTE. Blood bicarbonate concentrations were significantly (P ≤ 0.001) elevated before exercise in PSB and BASB but not in PMD or BAMD. Blood lactate concentrations were significantly elevated after exercise, remaining elevated after 5 min of recovery (P ≤ 0.001) and were highest in PSB and BASB. Results show that BA improved high-intensity cycling capacity. However, despite a 6-s (∼4%) increase in TTE with the addition of SB, this did not reach statistical significance, but magnitude-based inferences suggested a ∼70% probability of a meaningful positive difference.
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Important role of muscle carnosine in rowing performance
Article
The role of the presence of carnosine (β-alanyl-L-histidine) in millimolar concentrations in human skeletal muscle is poorly understood. Chronic oral β-alanine supplementation is shown to elevate muscle carnosine content and improve anaerobic exercise performance during some laboratory tests, mainly in the untrained. It remains to be determined whether carnosine loading can improve single competition-like events in elite athletes. The aims of the present study were to investigate if performance is related to the muscle carnosine content and if β-alanine supplementation improves performance in highly trained rowers. Eighteen Belgian elite rowers were supplemented for 7 wk with either placebo or β-alanine (5 g/day). Before and following supplementation, muscle carnosine content in soleus and gastrocnemius medialis was measured by proton magnetic resonance spectroscopy ((1)H-MRS) and the performance was evaluated in a 2,000-m ergometer test. At baseline, there was a strong positive correlation between 100-, 500-, 2,000-, and 6,000-m speed and muscle carnosine content. After β-alanine supplementation, the carnosine content increased by 45.3% in soleus and 28.2% in gastrocnemius. Following supplementation, the β-alanine group was 4.3 s faster than the placebo group, whereas before supplementation they were 0.3 s slower (P = 0.07). Muscle carnosine elevation was positively correlated to 2,000-m performance enhancement (P = 0.042 and r = 0.498). It can be concluded that the positive correlation between baseline muscle carnosine levels and rowing performance and the positive correlation between changes in muscle carnosine and performance improvement suggest that muscle carnosine is a new determinant of rowing performance.
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