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Beta-alanine Presentation Topics General information and metabolism of beta-alanine Beta-alanine and muscle carnosine levels Beta-alanine and exercise performance Beta-alanine and aging Safety of beta-alanine Beta-alanine: Introduction Pushing through fatigue is a common challenge for athletes – Decline in muscle pH is a major contributor to fatigue Beta-alanine, via its role in synthesis of carnosine, can improve muscle cell buffering capacity – Carnosine is a dipeptide composed of beta-alanine and histidine Beta-alanine supplementation is often used by athletes to enhance workout capacity and delay fatigue Background on Beta-alanine, Muscle Carnosine Levels and Muscle Function Beta-alanine: What Is It? Beta-alanine is an amino acid structurally similar to L-alanine Not used in the synthesis of larger body proteins – No transfer-RNA (tRNA) for beta-alanine A key role for beta-alanine is synthesis of the dipeptide carnosine – Carnosine has been shown to improve the buffering capacity of muscle tissue – Carnosine is synthesized in the body from beta-alanine and histidine via carnosine synthase • Beta-alanine is rate-limiting – Degradation of carnosine occurs via plasma carnosinase 99% of the body’s carnosine is located within skeletal muscles Derave W, et al. Sports Med. 2010;40(3):247-263. Structures of Carnosine and Related HistidineContaining Dipeptides Imidazole ring Reprinted with permission from www.benbest.com/nutrceut/carnosine.html . Beta-alanine residue Functions of Carnosine Carnosine functions as a pH buffer in muscles – The imidazole ring of histidine has pKa = 6.1 – When bound to beta-alanine, the pKa increases to 6.8 – Ideal buffers are within the physiologic range of myocytes (pH 6.5 to 7.1) • As such, carnosine is an ideal buffer for muscle tissue – This was the first function of carnosine to be identified Additional functions of carnosine – – – – – Antioxidant Anti-glycation Metal chelation (divalent cations such as zinc, copper, ferrous iron) Activator of carbonic anhydrase Angiotensin-converting enzyme (ACE) inhibition Abbreviation: pKa, acid dissociation constant. Derave W, et al. Sports Med. 2010;40(3):247-263. Muscle Carnosine Levels and Exercise The rate of adenosine triphosphate (ATP) hydrolysis is high during high-intensity exercise – Aerobic metabolism (mitochondria) cannot keep up with the demand for ATP – Dependent on glycolysis (anaerobic pathway) for the difference • Leads to accumulation of lactate When a molecule of ATP is hydrolyzed, a hydrogen proton (H+) is released – H+ accumulate faster than muscle clearance rates at higher exercise intensity • Results in decreased intramuscular pH that is probably at least one contributor to fatigue • This, not lactate, is the real cause of “lactic acidosis” of exercise Carnosine’s buffering activity slows muscle pH decline – Additional histidine-related compounds also contribute (eg, anserine and balenine [ophidine]) to varying degrees, depending on species Robergs RA, et al. Am J Physiol Regul Integr Comp Physiol. 2004;287(3):R502-R516. Carnosine and Histidine-Related Compounds (HRC): Concentrations in the Muscles of Different Species Whales, as deep divers, are heavily dependent on anaerobic metabolism and have high content of HRC in muscle tissue (68.5 µmol/g wet muscle; 20 to 80 µmol/g balenine) Thoroughbred Horse Greyhound Dog Human Carnosine (µmol/g dry weight) 108.3 15.9 33.0 19.1 16.0 7.2 Anserine (µmol/g dry weight) Not detected 48.6 18.4 Not detected Total buffering capacity 117.7 8.5 105.2 9.1 79.5 8.0 Buffering capacity from dipeptides 36.0 5.3 26.0 10.1 5.3 2.4 30.6 24.7 6.7 % buffering capacity from dipeptides Buffering capacity = Microequivalent of H+ per g muscle dry weight to lower the pH from 7.1 to 6.5 Suyama M, et al. J Tokyo Univ Fish. 1977;63:189-196; Castellini MA, et al. J Comp Physiol. 1981;143B:191-198; Abe H, Okuma E. Nippon Shokuhin Kagaku Kogaku Kaishi. 1995;42:827-834; Okuma E, Abe H. Comp Biochem Physiol. 1992;102A:37-41; Harris RC, et al. Comp Biochem Physiol. 1990;97A:249-251. Reprinted from Abe H. Biochemistry (Moscow). 2000;65(7):757-765. Factors That Influence Muscle Carnosine Levels Diet – Omnivores generally have higher levels than vegetarians Muscle fiber type – Fast twitch, glycolytic fibers have higher levels than slow twitch fibers Gender – Males generally have higher levels than females Exercise type – Those who exercise anaerobically tend to have higher levels than endurance athletes • Unknown whether training is the cause or whether there is an issue of predisposition to a given exercise based on proportions of existing types of muscle fiber Age – Weak negative correlation between age and carnosine levels – Could be explained by other factors that also correlate with age Everaert I, et al. Amino Acids. 2011;40(4):1221-1229; Derave W, et al. Sports Med. 2010;40(3):247-263. Differences Between Men and Women in Muscle Carnosine Content Men have higher carnosine levels than women Muscle Carnosine Content, mM 8 7 6 Men Women a 5 a 4 a 3 2 1 0 Soleus Reprinted from Everaert I, et al. Amino Acids. 2011;40(4):1221-1229. a P .004 Gastrocnemius Tibialis Anterior Effects of an Omnivorous vs Vegetarian Diet on Muscle Carnosine Levels Omnivores have higher carnosine levels than vegetarians Muscle Carnosine Content, mM 8 7 Omnivores b Vegetarians 6 a 5 4 a 3 2 1 0 Soleus Reprinted from Everaert I, et al. Amino Acids. 2011;40(4):1221-1229. a P < .05; b P < .10 Gastrocnemius Tibialis Anterior Effects of Exercise Type on Muscle Carnosine Levels Bodybuilders have higher carnosine levels in the vastus lateralis than untrained individuals1 Carnosine, mmoL/kg DW 60 50 a 40 Sprinters and rowers have higher carnosine levels than marathon runners and untrained individuals2 Athlete Carnosine levels, µmol/g Sprinters 4.93 0.76b Rowers 5.04 0.72b Marathoners 2.80 0.74 Untrained 3.75 0.86 30 20 10 0 Bodybuilders Untrained Abbreviation; DW, dry weight. 1Reprinted from Tallon MJ, et al. J Strength Cond Res. 2005;19(4):725-729. 2Adapted from Parkhouse WS, et al. J Appl Physiol. 1985;58(1):14-17. a P .001; b P < .01 Beta-alanine: Pathway Toward Muscle Carnosine Humans can derive beta-alanine from 2 different sources – Major source is diet via carnosine and anserine in flesh foods – Some endogenous synthesis from breakdown of pyrimidine nucleotides Carnosine is absorbed intact from intestine – Hydrolysis to amino acids occurs in plasma in humans because carnosinase is absent from intestine and muscle Beta-alanine and histidine are taken up by muscle tissue Carnosine is reformed in muscle cell by carnosine synthase Dietary Intake of Carnosine 3 main sources of carnosine in the US diet – Beef – Pork – Chicken Some meats are a significant source of anserine as well Carnosine is roughly 32% betaalanine by weight Estimated beta-alanine intake for young adult males is 200 to 750 mg/day Meat Carnosine Content, mg/100 g Beef, topside, rump 333 Pork, loin & shoulder 466 Lamb, leg 190 Chicken, breast 400 Chicken, leg 124 Chan KM, Decker EA. Crit Rev Food Sci Nutr. 1994;34(4):403-426; Hill CA, et al. Amino Acids. 2007;32(2):225-233. Reprinted from Cattlemen’s Beef Board and National Cattlemen’s Beef Association. Beef Facts: Antioxidant Properties and Meat. Available at: http://www.beef.org/uDocs/ACF2E.pdf. Accessed: February 20, 2011. Beta-alanine Supplementation Beta-alanine is the rate-limiting compound for carnosine synthesis – Histidine, an essential amino acid, is present in skeletal muscles in large concentrations (larger than the Km for carnosine synthase) The potential for increasing intramuscular carnosine stores over time with beta-alanine supplementation has been explored in a number of studies – Similar level of interest as creatine supplementation – Evaluated effects on carnosine stores in various muscles and fiber types – Evaluated effects on different types of exercise Doses of beta-alanine supplementation typically range from 2.4 to 6.4 g/day – Often given in multiple divided doses over the course of the day for better absorption Abbreviation: Km, Michaelis-Menten dissociation constant. Mean Beta-alanine Conc, µmol/L Plasma Beta-alanine Concentrations After Ingestion 1,000 Supplementation with beta-alanine increases peak beta-alanine levels in the blood much faster than does ingesting the equivalent amount of beta-alanine in the form of chicken broth 750 500 250 0 0 1 2 3 4 5 6 Time After Ingestion, hours Beta-alanine (40 mg/kg body weight ) Chicken broth with ~40 mg/kg beta-alanine as carnosine and anserine Reprinted from Harris RC, et al. Amino Acids. 2006;30(3):279-289. Effects of Beta-alanine Supplementation on Muscle Carnosine Levels Effect of Different Beta-alanine Dosing Regimens on Muscle Carnosine Levels Study of 21 physically active, meat eating male subjects 4 beta-alanine supplementation protocols for 28 days Muscle biopsies taken from vastus lateralis muscle I. 800 mg beta-alanine 4 times/day II. 8 daily doses ≤ 800 mg/dose; daily dose increased from 4 g/day week 1 to 6.4 g/day week 4 III. L-carnosine from chicken broth, 8 daily doses ≤ 2,000 mg carnosine per dose; daily dose increased from 10 g/d week 1 to 16 g/day week 4 IV. Placebo (maltodextrin) capsules Mean (SE) Carnosine, µmol/L Protocols I, II, and III effectively increased muscle carnosine concentrations compared with placebo (IV) Abbreviation: SE, standard error. Harris RC, et al. Amino Acids. 2006;30(3):279-289. Treatment Pre 4 Weeks I 19.58 (1.66) 27.38 (1.33) II 24.23 (2.36) 35.27 (2.76) III 23.15 (2.27) 39.52 (7.58) IV 23.63 (2.43) 25.49 (2.03) More Results on Increases in Muscle Carnosine Concentrations With Beta-alanine Supplementation 80 Carnosine Content, mM Carnosine Conc, µmol/kg DM Protocols I, II, and III effectively increased muscle carnosine concentrations in individual subjects1 Elevated carnosine persisted in 15 untrained subjects supplemented for 6 weeks with 4.8 g/day followed by 9 weeks of no supplementation2 60 40 20 0 ABCDE FGHIJ KLMNO PQRSTU Individual Subjects Abbreviation; DM, dry mass. a P < .05 from placebo. 1Reprinted from Harris RC, et al. Amino Acids. 2006;30(3):279-289. 2Reprinted from Baguet A, et al. J Appl Physiol. 2009;106(3):837-842. 12 A Soleus a 10 8 6 4 2 Supplementation 0 –9 –6 –3 0 3 6 9 12 12 B Tibialis Anterior a 10 8 6 4 Supplementation 2 0 –9 –6 –3 0 3 6 9 12 a Beta-alanine Placebo 12 C Gastrocnemius 10 8 6 4 Supplementation 2 0 –9 –6 –3 0 3 6 Time, weeks 9 12 Effects of Beta-alanine on Exercise Performance Beta-alanine Supplementation and Performance Some predictions can be made about the benefits of supplementation for particular athletes – Based on what is known about carnosine functions in muscle – Based on what is known about beta-alanine in carnosine formation High-intensity, anaerobic exercise is more likely to benefit vs submaximal work Beta-alanine, by itself, probably will not directly increase strength – May improve training, indirectly benefitting strength • Increased training capacity, higher quality of reps at heavier weights Individuals with low muscle carnosine levels may benefit more from beta-alanine supplementation, including – Elderly – Vegetarians Effects of beta-alanine are not immediate, requires a period of loading – Timing of ingestion relative to exercise is not critical Beta-alanine Supplementation and Cycling Performance Influence of Beta-alanine on High-Intensity Cycling Capacity (Hill et al, 2007) 25 male, physically active subjects (n = 13 beta-alanine, n = 12 matching placebo) Beta-alanine supplementation for 4 weeks in all 13 subjects; 8 of these subjects supplemented for an additional 6 weeks (10 weeks total) – Total daily doses increased from 4 g/day in week 1 to 6.4 g/day in weeks 4 to 10 • Total daily dose was subdivided into 8 doses of no more than 800 mg Subjects completed a cycle performance test and muscle biopsy before and after supplementation Hill CA, et al. Amino Acids. 2007;32(2):225-233. Results of Hill et al, 2007 100 7.3 ± 1.3 P < .01 b-Ala 8.6 ± 3.1 P < .05 Increase in Total Work Done (TWD) followed an increase in muscle carnosine levels 15 10 5 0 100 51.6 ± 3.1 58.8 ± 3.4 63.1 ± 5.3 0 15 Placebo 10 50 0 55.1 ± 2.8 0w 56.2 ± 2.8 4w 54.9 ± 3.9 10 w Reprinted from Hill CA, et al. Amino Acids. 2007;32(2):225-233. 1.7 1.1 ± 1.1 ± 1.5 4 w 10 w D from 0 w 5 0 D TWD, kJ Total Work Done, kJ 50 – Increased carnosine by 58.8% and 80.1% at 4 and 10 weeks, respectively Muscle carnosine increase was similar across both fiber types – Carnosine was initially 1.7 times higher in type IIa fibers vs type I fibers Effects of Beta-alanine on Sprint Performance in Endurance Cycling (Van Thienen et al, 2009) 21 male subjects (moderately to well-trained cyclists) 8 weeks’ supplementation with beta-alanine or placebo (maltodextrin) capsules – 2 g/day weeks 1 and 2 – 3 g/day weeks 3 and 4 – 4 g/day weeks 5 to 8 Rode cycle ergometer before and after supplementation, in order 1. 2. 3. 4. 110 minutes at 50% to 90% of maximal lactate steady state (MLSS) 10-minute time trial (maximal effort) 5-minute period at 50% MLSS 30-second sprint (maximal effort) Van Thienen R, et al. Med Sci Sports Exerc. 2009;41(4):898-903. Results of Van Thienen et al, 2009 Mean Peak 350 +11.4% 1200 Power Output, W 1100 1095 1105 1070 993 1000 900 +5.0% 800 717 700 693 330 Power Output, W Placebo b -Ala b -Ala Placebo 310 290 270 711 727 250 600 Pretest Posttest Pretest Posttest Mean and peak power output in the sprint test were significantly increased by 5.0% and 11.4%, respectively, by beta-alanine Van Thienen R, et al. Med Sci Sports Exerc. 2009;41(4):898-903. 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Pretest Posttest Mean power output in the time trial was not significantly altered; the beta-alanine group had more consistent improvements in power on a minute-by-minute basis Effects of Beta-alanine on Neuromuscular Fatigue and Ventilatory Threshold in Women 22 normal-weight women (ages 26 to 29 years) were subjects in a 4 week beta-alanine supplementation trial Dose of beta-alanine or placebo (maltodextrin) was 800 mg 4 times/day for the first week, and 1,600 mg 4 times per day for the remaining 3 weeks Subjects performed a graded exercise test (cycle ergometer) before and after the supplementation period 2 key variables of interest – Ventilatory threshold (VT): point at which pulmonary ventilation increases disproportionately to oxygen consumption – Physical working capacity at neuromuscular fatigue threshold (PWCFT): the highest power output that results in a nonsignificant (P < .05) increase in muscle activation of the vastus lateralis over time Stout JR, et al. Amino Acids. 2007;32(3):381-386. Effects of Beta-alanine Supplementation on Ventilatory Threshold and Physical Working Capacity P < .001 P < .001 VT, L/min 2 P < .001 13.9% ↑ 12.6% ↑ 150 100 1 50 0 0 Placebo b-Ala Placebo Abbreviations: PWCFT, physical working capacity at neuromuscular fatigue threshold; VT, ventilatory threshold. Reprinted from Stout JR, et al. Amino Acids. 2007;32(3):381-386. b-Ala PWCFT, watts P < .001 200 Effects of Beta-alanine Supplementation on VO2max and Time to Exhaustion 3 2000 1500 VO2max, L/min 2 1000 1 500 0 0 Placebo b-Ala Abbreviations: TTE, time to exhaustion; VO2max, maximal oxygen uptake. Reprinted from Stout JR, et al. Amino Acids. 2007;32(3):381-386. Placebo b-Ala TTE, seconds P < .05 Beta-alanine and High-Intensity Interval Training Two 6-week high-intensity interval training (HIIT) studies were conducted1,2 – Both studies showed positive physiologic adaptations to HIIT • Delay in muscular fatigue in male subjects as measured by electromyographic fatigue measures after cycle ergometer use1 • Increased ventilatory threshold in women after graded exercise tests on a Corival cycle ergometer2 – However, neither showed an additive benefit of beta-alanine (6 g/day split into 4 daily doses along with dextrose) 1Smith AE, et al. Eur J Appl Physiol. 2009;105(3):357-363. AA, et al. J Strength Cond Res. 2010;24(5):1199-1207. 2Walter Study of Beta-alanine + Creatine on PWCFT 51 young adult men (mean age = 24 years, mean body weight = 82 kg) studied for 28 days Treatments were – – – – – Placebo: 34 g dextrose Cr: 5.25 g creatine monohydrate plus 34 g dextrose BA: 1.6 g beta-alanine plus 34 g dextrose CrBA: 5.25 g creatine monohydrate plus 1.6 g beta-alanine plus 34 g dextrose Treatments were given 4 times/day for 6 consecutive days, then 2 times/day for the remaining 22 days Measures of PWCFT at beginning and end of supplementation Abbreviations: PWCFT, physical working capacity at neuromuscular fatigue threshold. Stout JR, et al. J Strength Cond Res. 2006;20(4):928-931. Effects of Supplementation on Physical Working Capacity 250 a b PWCFT ,W 200 PWCFT increased after beta-alanine supplementation and creatine + beta-alanine supplementation 150 100 50 0 Placebo BA Cr CrBA greater than placebo, P = .004, 2 = 0.17 (large) b Significantly greater than placebo, P = .011, 2 = 0.13 (medium) a Significantly Abbreviations: BA, beta-alanine; Cr, creatine monohydrate; CrBA, creatine monohydrate plus beta-alanine; PWCFT, physical working capacity at neuromuscular fatigue threshold; 2, effect size. Reprinted from Stout JR, et al. J Strength Cond Res. 2006;20(4):928-931. Beta-alanine Supplementation: Sprinting and Rowing Beta-alanine, Rowing, and Sprinting Study of 18 elite Belgian rowers1 – 7-week beta-alanine supplementation (5 g/day) or placebo – Muscle carnosine, 2,000-m ergometer test before and after supplementation – Beta-alanine group was 4.3 seconds faster, placebo group 0.3 seconds slower (P = .07) – Muscle carnosine elevation was positively correlated with performance enhancement Study of 15 trained sprinters2 – 4-week beta-alanine supplementation (4.8 g/day) or placebo – Increase in knee extension torque during 4th and 5th bout with beta-alanine showed tendency for decreased fatigue – 400 m sprint time or isometric endurance was not affected 1Baguet 2Derave A, et al. J Appl Physiol. 2010;109(4):1096-1101. W, et al. J Appl Physiol. 2007;103(5):1736-1743. Beta-alanine, Rowing, and Sprinting Study of 19 physically active college men – Beta-alanine supplementation (4 g/day for 1 week and 6 g/day for 4 weeks) or placebo (rice flour) – Subjects did a pre- and post-test of 2 sets of 5 × 5-second sprints with 45-second recovery, separated by 2 minutes of active recovery between sets • Also measured horizontal power during sprint – Beta-alanine supplementation had no effects on horizontal power or sprint performance Sweeney KM, et al. J Strength Cond Res. 2010;24(1):79-87. Beta-alanine, Beta-alanine + Creatine, and Resistance Training Summary of Weight Training Studies on Beta-alanine Supplementation of 4.5 g beta-alanine/day for 30-days increased bench press training volume (but not squat or combined squat and bench press) and decreased subjective feelings of fatigue in college football players during training camp1 In experienced, weight-training men, 4.8 g beta-alanine/day for 30 days increased number of squat repetitions performed and training volume in the squat exercise2 – No changes in hormonal profiles noted 1Hoffman 2Hoffman JR, et al. Nutr Res. 2008;28(1):31-35. J, et al. Int J Sports Med. 2008;29(12):952-958. Summary of Weight Training Studies on Beta-alanine A chicken breast meat extract drink (2 g combined carnosine and anserine) fed twice per day for 30 days blunted exercise-induced increases in epinephrine, norepinephrine, and growth hormone compared with placebo1 In a study of 26 Vietnamese sports science students,2 10 weeks of beta-alanine supplementation (6.4 g/day) taken with a resistance training program did not increase – – – – – 1Goto Body mass Whole body strength Isokinetic force production Muscular endurance Body composition K, et al. J Strength Cond Res. 2011;25(2):398-405. IP, et al. Amino Acids. 2008;34(4):547-554. 2Kendrick Effect of Creatine Plus Beta-alanine on Weight Training Performance Study of 33 male strength/power athletes over a 10-week resistance training program – Athletes from college football team with at least 2 years of resistance training experience 3 study groups: – CA: 10.5 g/day creatine monohydrate plus 3.2 g/day beta-alanine – C: 10.5 g/day creatine monohydrate only – P: 10.5 g/day dextrose Both CA and C increased 1-RM for bench press and squat – Creatine probably drove these results The CA group decreased % body fat and increased lean body mass more than P group Hoffman J, et al. Int J Sport Nutr Exerc Metab. 2006;16(4):430-446. Results From Hoffman et al, 2006, Focused on Training Volume 12,000 8,000 a a 7,000 10,000 6,000 5,000 kg kg 8,000 6,000 4,000 3,000 4,000 2,000 2,000 0 1,000 P CA C Average weekly training volume for squat exercise: creatine + beta-alanine increased training volume (effect size >1.47) a 0 P CA C Average weekly training volume for bench press exercise: creatine + beta-alanine increased training volume (effect size = 0.78) P < .05 Abbreviations: C, creatine monohydrate; CA, creatine monohydrate plus beta-alanine; P, placebo. Reprinted from Hoffman J, et al. Int J Sport Nutr Exerc Metab. 2006;16(4):430-446. Beta-alanine Supplementation and the Elderly Effect of Beta-alanine on Neuromuscular Fatigue in Elderly Subjects 90-day study of 26 subjects (9 males, 17 females), 55 to 92 years of age – Subjects from independent living communities in Florida Supplemented with either beta-alanine or microcrystalline cellulose placebo (800 mg TID in each case) for duration of study No training protocol PWCFT was measured in these subjects before and after supplementation Abbreviations: PWCFT, physical working capacity at neuromuscular fatigue threshold; TID, three times per day. Stout JR, et al. J Int Soc Sports Nutr. 2008;5:21. Effects of Supplementation on Physical Working Capacity PWCFT increased 28.6% after beta-alanine supplementation 100 a 90 PRE 80 POST PWCFT 70 60 50 40 30 20 10 0 a Beta-alanine P < .05. Abbreviations: PWCFT, physical working capacity at neuromuscular fatigue threshold. Reprinted from Stout JR, et al. J Int Soc Sports Nutr. 2008;5:21. Placebo Beta-alanine: Safety General Safety Profile of Beta-alanine Toxicology studies in animals (up to 90 days) have shown no beta-alaninerelated adverse effects up to 1,000 mg/kg/day No clinically significant adverse effects of beta-alanine have been observed in any human trials with beta-alanine; the longest supplementation trial ~10 weeks with up to 6.4 g/day – Caveat: These studies generally have not measured biochemical laboratory panel values, but there have been no reports of illness or injury associated with beta-alanine in these studies Hypothetical interactions with taurine (absorbed by same intestinal transporter as beta-alanine) – Taurine is a nonessential amino acid – Theoretical risk typically comes from studies of cultured cells depleted of taurine and incubated with beta-alanine – No evidence of taurine depletion with beta-alanine supplementation observed Side effects – Main side effect is mild-to-moderate paresthesia (typically a tingling sensation in hands, upper trunk, head, and face) • Like the hand or foot “falling asleep” Beta-alanine and Paresthesia Paresthesia has not been observed with feeding of carnosine from chicken broth With beta-alanine ingestion, paresthesia usually occurs within ½ hour of ingestion Symptoms typically last < 1 hour, often < ½ hour Paresthesia is generally absent or very mild at doses of up to 800 mg at one time (reason for divided dosing in previous studies) – Symptoms present, but mild, at 1.6 g/day and increase with larger doses Not everyone feels the paresthesia Symptoms are largely related to the rapidity and/or magnitude of the rise in plasma beta-alanine – Timed-release pills may help to slow absorption of beta-alanine, reducing overall amount of paresthesia No long-lasting effects have been observed Why Does Beta-alanine Cause Paresthesia in Some Individuals? The cause is not clearly known, but it appears that beta-alanine can function as a neurotransmitter Beta-alanine is a structural analog of gamma-aminobutyric acid (GABA) and glycine, the major inhibitory neurotransmitters in the brain – Beta-alanine can react with their receptors A G-protein coupled receptor (TGR7) from the MrgD family has been identified in the sensory neurons of the dorsal root ganglia – Beta-alanine appears to interact with this receptor – Beta-alanine may modulate the pain sensation through this receptor Beta-alanine may be a ligand for other potential receptors in the brain as well Beta-alanine: Overall Summary Beta-alanine is the rate-limiting amino acid for synthesis of carnosine in muscles Carnosine plays several important roles in muscle, the most recognized is a muscle pH buffer during intense exercise – Decline in muscle pH is a contributing factor to fatigue Beta-alanine supplementation consistently elevates muscle carnosine – At least 28 days’ supplementation needed to boost muscle carnosine levels Beta-alanine supplementation can improve performance in certain highintensity exercise types in doses ranging from 2.4 to 6.4 g/day – Especially cycling Beta-alanine, with or without creatine, may help boost workout capacity in strength athletes There are no known safety concerns with beta-alanine supplementation up to 6.4 g/day – Paresthesia is a common short-term side effect, but can be minimized with divided doses or extended-release preparations – Taking beta-alanine with food may reduce paresthesia by slowing absorption