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Special Article

Evidence-based evaluation of potential benets and safety of

beta-alanine supplementation for military personnel
Richard Ko, Tieraona Low Dog, Dennis KJ Gorecki, Louis R Cantilena, Rebecca B Costello,
William J Evans, Mary L Hardy, Scott A Jordan, Ronald J Maughan, Janet W Rankin, Abbie E Smith-Ryan,
Luis G Valerio Jr, Donnamaria Jones, Patricia Deuster, Gabriel I Giancaspro, and Nandakumara D Sarma

This Department of Defense-sponsored evidence-based review evaluates the safety

and putative outcomes of enhancement of athletic performance or improved
recovery from exhaustion in studies involving beta-alanine alone or in combination
with other ingredients. Beta-alanine intervention studies and review articles were
collected from 13 databases, and safety information was collected from adverse
event reporting portals. Due to the lack of systematic studies involving military
populations, all the available literature was assessed with a subgroup analysis of
studies on athletes to determine if beta-alanine would be suitable for the military.
Available literature provided only limited evidence concerning the benets of
beta-alanine use, and a majority of the studies were not designed to address safety.
Overall, the strength of evidence in terms of the potential for risk of bias in the quality
of the available literature, consistency, directness, and precision did not support the
use of beta-alanine by military personnel. The strength of evidence for a causal
relation between beta-alanine and paresthesia was moderate.
2014 International Life Sciences Institute and 2014 Her Majesty the Queen in Right of Canada Nutrition Reviews
Reproduced with permission of the Minister of Health.

INTRODUCTION endurance, about 60% of military personnel use one or

Congress dened the term dietary supplement in the
Dietary Supplement Health and Education Act of 1994 as
a product taken by mouth that contains a dietary ingre-
dient intended to supplement the diet. The dietary ingre-
dients in these products may include vitamins, minerals,
herbs or other botanicals, amino acids, and substances,
and may be found in many forms such as tablets, capsules,
liquids, or powders.1 Dietary supplements are available
over-the-counter as single- or multi-ingredient products
and are used by about half of the US population.2 Use
of dietary supplements by military personnel is well
documented in a review conducted by the Institute of
Medicine3 and other studies.4,5 To maintain tness and
more dietary supplements for promoting health, perfor-
mance enhancement, body building, and weight loss.6,7
The roles of active-duty service members involve height-
ened performance requirements, expectations of resil-
ience, and maintenance of optimal nutritional status.
Service members may be involved in demanding physical
tasks that require strength and endurance and may, thus,
be more similar to elite athletes than to the general popu-
lation.3 For example, the use of dietary supplements is
higher among Special Forces members, and Ranger units
appear to use supplements more frequently than do sol-
diers in conventional units. Individuals in these elite
combat units engage in extensive aerobic exercise and
strength training, factors that are associated with more

Aliations: R Ko, T Low Dog, DKJ Gorecki, L Cantilena, RB Costello, WJ Evans, ML Hardy, RJ Maughan, JW Rankin, AE Smith-Ryan, LG Valerio Jr,
GI Giancaspro and ND Sarma are expert volunteers or sta of the US Pharmacopeial Convention, Rockville, Maryland, USA. SA Jordan is an
expert volunteer with the US Pharmacopeial Convention, Rockville, Maryland, USA and Marketed Health Products Directorate of Health
Canada, Ottawa, Ontario, Canada. D Jones and P Deuster are with the Uniformed Services University of Health Sciences, Bethesda,
Maryland, USA.
Correspondence: ND Sarma, US Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, USA. E-mail:
dns@usp.org. Phone: +1-301-816-8354.
Key words: beta-alanine, dietary supplements, evidence-based review, military, paresthesia, physical performance and endurance

doi:10.1111/nure.12087
Nutrition Reviews Vol. 72(3):217225 217
extensive dietary supplement use than in the general mili-
tary population, especially with respect to strength train-
ing. Concerns regarding the benets and safety of dietary
supplement use by military personnel arise because these
individuals have a dierent motivation than the general
population and have unique mission-oriented challenges
and needs.
The risks and benets of consuming certain dietary
supplements may be multiplied for some groups of mili-
tary personnel because of their unique responsibilities
and tasks (e.g., aviators, those at altitude, or those con-
ducting special operations). Further, the term adverse
event8 may identify a dierent eect in the context of the
military: The success of a military operation depends on
each members optimal performance; thus, eects that
may not be perceived as a serious problem in the general
population (e.g., dehydration) could constitute a signi-
cant problem in the military context. For the military, the
distinction between adverse events and serious adverse
events8 is based on the extent of decrement to either the
performance or the survivability of service members after
taking into consideration their tasks (both physical and
mental), the environmental surroundings (e.g., high alti-
tude or extreme temperatures), and risks (e.g., bleeding,
dehydration, infection, or stress). For example, induction
of diuresis or minor allergic reactions by dietary supple-
ments may not be serious for the general population but
could aect the operational readiness of the military.
Accordingly, the Food and Drug Administration (FDA)
standard of safety evaluation for dietary supplements
(which is the determination of signicant or unreason-
able risk of illness or injury)9 may not be suitable for the
military population.
Beta-alanine is an increasingly popular dietary
supplement that sometimes is promoted as a perfor-
mance enhancer. The present evidence-based systematic
review evaluated the benets and safety of beta-alanine
with specic focus on its use by military personnel.
Beta-alanine is a nonessential nonproteogenic amino
acid that is present in food,10 can be formed in vivo by the
degradation of uracil,11 and is a precursor of muscle
carnosine (a dipeptide found in muscle). The Natural
Medicine Comprehensive Database12 lists about 100
dietary supplement products containing either beta-
alanine alone or in combination with other ingredients.
A conventional 800-mg dose of beta-alanine is
10 mg/kg body weight (bw) or 0.112 mmol/kg bw and
reportedly corresponds to the amount of beta-alanine (in
the dipeptide L-carnosine) from 150 g turkey breast meat
or 100 g of North Atlantic sea shrimp.13 The US Depart-
ment of Agriculture (USDA) National Nutrient Database
for Standard Reference14 does not include reference
values for the content of beta-alanine in foods. However,
FDAs Everything Added to Food in the United States
218
database recognizes beta-alanine as a constituent of
food.10
Scope of the review
The strategy in dening the scope of the review involved
consideration of the PICO method, which includes popu-
lation, intervention (or exposure in the case of observa-
tional studies), comparator, and outcomes of interest.15
The following PICO denitions indicate the scope of the
review and dene the inclusion criteria for the collection
and review of the literature. Population: aged 1950 years
to reect active-duty service members. Intervention:
reports concerning exposure to beta-alanine alone or in
combination with other ingredients from all forms of oral
supplementation. Comparator: original research studies
with an appropriate control group. Multi-ingredient
dietary supplements containing beta-alanine as one of
the primary components were included for benets
assessment if the independent and dependent eects of
beta-alanine could be separated. Outcomes benets:
benecial outcomes in terms of measures of athletic per-
formance or decreased recovery time from exhaustion
(e.g., strength and power, endurance, and recovery)16;
because of the limitations of the data, specic (limited)
intermediate or surrogate outcomes17,18 were not dened a
priori.Outcomes safety: not specied a priori; instead,all
reported adverse events were included in the review to
identify any safety signal.
METHODS
The methods employed in this evidence report generally
follow those outlined in the Agency for Healthcare
Research and Quality Methods Reference Guide15 and the
methods employed in the recent reviews from the
Agency,1921 with modications where cited.
The review was conducted by volunteer experts rep-
resenting the diverse areas of expertise required to prop-
erly evaluate beta-alanine in accordance with the Rules
and Procedures of the 20102015 USP Council of Experts.
Literature search
Information was reviewed from 13 electronic databases
(PubMed, Embase, Cochrane Database of Systematic
Reviews, AMED, CENTRAL, CINAHL, DARE, MANTIS,
NTIS, International Pharmaceutical Abstracts, TOXLINE,
TOXNET, and AGRICOLA) and 3 adverse events report-
ing portals (FDA MedWatch, Health Canadas Canada
Vigilance Program, and WHO Uppsala Monitoring
Center) without language restriction.
Adverse event reports (AERs) that were submitted
electronically to Natural Medicines Watch via the Human
Nutrition Reviews Vol. 72(3):217225
Performance Resource Center by military personnel
were collected. The literature searches included data
from animal studies. The electronic search was supple-
mented by manual screening of the bibliographies of rel-
evant review articles. Authors of all included clinical
studies were contacted in an eort to obtain additional
unpublished missing information.
Key words that were used to search the literature and
the date of each search (from database inception) are
illustrated in Appendix SA (available in the Supporting
Information for this article online).
Inclusion screening
Two reviewers independently screened all identied
records using a standardized form that outlined the PICO
elements. Reasons for rejection of all full-text articles
were recorded.
Data extraction and synthesis
Data extraction forms were used to extract relevant infor-
mation, including study design, product quality specica-
tions, confounders and eect modiers, and PICO
parameters. Declared sources of funding and conicts
of interest were extracted from all studies. Statistical
analyses were conducted when the studies reported suf-
cient data to estimate both mean net change and the
standard error (SE) of the net change. Statistical analytical
tools of Cochranes RevMan22 were used to construct
meta-analysis and funnel plots.
Grading methodological quality
The quality of clinical studies was investigated by consid-
ering the methods used for randomization, allocation con-
cealment, and blinding, as well as the use of intent-to-treat
(ITT) analysis, well-described and valid primary out-
comes, and the dropout rate. The quality assessment
checklist for intervention studies was adopted from the
Cochrane Collaborations tool for assessing the risk of
bias.23 The three-category grading system was employed to
assess the potential for risk of bias from primary clinical
studies.24 The quality of review articles was evaluated
using the AMSTAR (a measurement tool to assess system-
atic reviews) checklist,25 with consideration of issues or
limitations concerning design, conduct, and analyses of
the reviews. The nature, quality, and quantity of adverse
events were analyzed from the available information.
Safety information from controlled trials
Each clinical trial was examined to determine whether it
reported adverse events. Adverse events in the people
Nutrition Reviews Vol. 72(3):217225
who received beta-alanine were compared with those in
the placebo group. This review assumed that such serious
adverse events were recorded if they were observed; thus,
both a record of zero or no mention of a serious adverse
event was interpreted to mean that no such events were
observed during the study.
Safety information from adverse events reports
Case reports from adverse events reporting portals,
namely, the FDA MedWatch reports from the Center for
Food Safety and Applied Nutrition (CFSAN) and Center
for Drug Evaluation and Research (CDER), Health Cana-
das Canada Vigilance Program, and WHO-UMC, were
reviewed if they existed. Because nonserious AERs8 may
not be reported to FDA by manufacturers, additional
information concerning all AERs was sought from 18
clinical study authors and manufacturers, but no replies
were received.
The adverse event data were analyzed by the type of
event,and those reports with events coded as serious8 were
specically identied and analyzed to identify whether the
reports actually involved beta-alanine, whether the data
were adequate for analysis, and whether or not the adverse
event qualied as a sentinel event.20 The causal relation
between beta-alanine and the reported adverse event was
explored using standard causality assessment tools (the
WHO causality scale26) with due consideration to the
inherent limitations of dietary supplement adverse event
reporting systems (e.g., incomplete data).27
Safety information from animal and in silico studies
The literature was searched for toxicological studies in
animals, and in silico screening was performed using
computerized prediction models. (In silico modeling pre-
dictions are based on the computational analysis from
Dr. Luis Valerio, CDER, FDA. Disclaimers: No proprietary
information is released from the computational models
or presented in this report. No review of data submitted
to FDA is presented here. The data in the report contain
computer-generated predictions and do not, in them-
selves, represent a complete analysis of risk or a nal
regulatory decision or policy regarding the safety of beta-
alanine. This analysis does not imply the ocial position
of FDA.) The research and validation testing of the com-
putational models have been published and are available
for review.2832
Rating the strength of the evidence
The general analytic framework for the assessment of
nutrients33 and the scientic principles established by the
Institute of Medicine for evaluating the safety of dietary
219
supplements34 were adopted in analyzing the strength of
the evidence with consideration of the risk of bias, con-
sistency, directness, and precision of the overall body of
evidence. The strength of evidence was assessed as high,
moderate, low, or insucient commensurate with
the level of condence in the true eect.15
RESULTS AND DISCUSSION
Literature search
The literature search tree is illustrated in Figure 1. The
screening process considered the relevance of a study for
inclusion based on appropriateness with regard to the
scope of the review. Additional information regarding
quality of the products, benets, or safety was not received
from beta-alanine manufacturers. The authors of three
clinical studies provided additional information. Authors
replies (which include non-peer-reviewed information)
are clearly marked in the Supporting Information for this
article online. Following inclusion screening (Table S1 in
the Supporting Information online), one study was
rejected because the average age of the study participants
was higher than 72 years.35 Of the 24 clinical studies,3658 4
studies5457 were excluded from analysis for benets
Electronic database search
(includes duplicates) n = 1,253
Excluded based on title and abstract
n = 1,111
Full text articles screened
n = 110
Included in background and
discussion
n = 52
Clinical studies n = 24; animal studies n = 26;
and review articles n = 7
Excluded n = 4; Reasons:
ineligible control group
(excluded for benefits
assessment)
Selected for detailed data extraction and quality
assessment for evaluation of the benefits:
clinical studies n = 20; review articles n = 7
Figure 1 Flow diagram of the literature search.
220
because they did not use appropriate control groups to
decipher the independent eects of beta-alanine.
Participants
Of the studies that met inclusion criteria, most involved
young adult men (predominantly in the age group of
1825 years). No age-dependent eects were reported in
any of the 20 studies (N = 266 in the beta-alanine inter-
vention groups). Two studies50,52 involved women (n = 25
in both studies combined). Unique eects attributable to
gender or specic national or ethnic groups were not
reported. None of the studies involved military personnel.
Participant characteristics are indicated in Table S2 in the
Supporting Information online.
Spontaneous AERs involved heterogeneous popula-
tions. Several AERs did not provide age and gender
details for those who experienced adverse events. Also,
information regarding prior medical history, concurrent
medications, and dose and duration of treatment was
missing in several AERs. Full case reports were not always
available or were not consulted in case of reports for
multi-ingredient products because the determination of
the role of beta-alanine itself could not be assessed from
these reports. All the reports from WHO-UMC involved
females.
Reference mining, expert
identified, and hand search
for related articles
n = 32
Excluded n = 1;
Reason: ineligible participants
Adve rse event case
reports n = 99
Selected for detailed data extraction and quality
assessment for safety evaluation:
clinical studies n = 24; AERs n = 99; animal and
mechanistic studies n = 26
Nutrition Reviews Vol. 72(3):217225
Interventions
Clinical intervention studies with beta-alanine varied in
terms of product composition, strength, and dosage form
(controlled-release as well as conventional formulations).
Table S3 in the Supporting Information online provides
details about the interventions with beta-alanine with or
without physical intervention. All of the intervention
periods were of short duration and lasted only 48 weeks.
Food-based interventions were not reported, with the
exception of one study of plasma beta-alanine levels fol-
lowing consumption of chicken broth.13 Observational
studies of dietary intake of beta-alanine or surrogate
measures were not available.
Information concerning the quality of the beta-
alanine products was available in only three publica-
tions.45,48,49 The most common dose range for beta-alanine
alone in clinical investigations was between 800 and
1,600 mg, orally, 24 times/day (aggregating to 1.66.4 g/
day).
Three studies5557 investigated the eects of a
multi-ingredient formulation containing beta-alanine
(IntraXcell manufactured by Athletic Edge Nutrition,
Miami, Florida), and another study54 did not provide the
composition for a multi-ingredient formulation contain-
ing beta-alanine (Redline Extreme, manufactured by Vital
Pharmaceuticals, Davie, Florida) because of the formula-
tions proprietary nature. These four studies did not
employ appropriate controls to investigate the indepen-
dent eects of beta-alanine. Although these four studies
were excluded from analysis in the benets evaluation,
they were assessed for safety information. Three studies
investigated the eects of beta-alanine in combination
with creatine,49,53,58 and one investigated the eects of beta-
alanine in combination with sodium bicarbonate.45 The
spontaneous AERs from FDA MedWatch and Health
Canadas Canada Vigilance Program were led for multi-
ingredient formulations. WHO-UMC reports involved a
single-ingredient product called Abufene (manufactured
by Bouchara Recordati, France) (beta-alanine 400 mg).59
Quality of clinical studies
Most of the study designs were reported as random allo-
cation and double-blinded. However, the majority of the
studies did not include specic information regarding the
method of randomization nor did they address how to
reduce other sources of bias. Several studies did not indi-
cate reasons for high dropout rates or uneven sizes of study
groups. Information regarding conict of interest was not
adequately detailed, even when the coauthors represented
the manufacturers of the products under study. Statistical
analyses of results for several studies were not possible
because the results were reported as percentage incre-
Nutrition Reviews Vol. 72(3):217225
ments (not mean standard deviation). The overall
quality of the primary clinical studies is indicated in
Table S4 in the Supporting Information online).
Quality of review articles
All of the seven available review articles6066 were deemed
narrative rather than systematic. They did not address the
majority of the questions posed by the 11-point AMSTAR
questionnaire.25
Table S5 in the Supporting Information online pro-
vides the AMSTAR grading of review articles.
Evidence for the benets of beta-alanine
Table S6 and Appendix SB (both available in the Support-
ing Information) include the main outcomes from studies
concerning the benets of intervention with beta-alanine.
Evidence for the benets of beta-alanine in combination
with creatine and sodium bicarbonate is presented in
Appendix SC in the Supporting Information online. The
studies investigated eects on several parameters, includ-
ing muscle strength, power measurements, muscle endur-
ance, high-intensity sprint, total work done at high
intensity, anaerobic power measurements, aerobic capac-
ity, ventilatory threshold, time to exhaustion and exercise
performance, repeated line drill, and eect on muscle
carnosine levels. Although a trend toward enhanced per-
formance (not statistically signicant) was reported in
some studies, several studies reported dierences within
the same group rather than eects of intervention com-
pared to placebo. Because beta-alanine is conventionally
used by athletes over a long period of time (several
months to years), the lack of long-term studies limits the
assessment of benets. The quality of these studies varied
greatly: many interventions were poorly documented and
did not provide information regarding product quality
and study design parameters. Little information about
combination products was available. Importantly, beta-
alanine interventions did not produce enhancement of
athletic performance in several clinical study models
(trained and untrained populations and dierent doses/
duration of intervention), and insucient evidence was
available to relate beta-alanine use by military personnel
(whether in theater or under routine training) with
enhancement of athletic performance or improved recov-
ery from exhaustion.
Considering the limitations of the literature, the
strength of evidence is insucient to assess with con-
dence the true eect of beta-alanine. The review identied
an absence of evidence concerning the dose,the modifying
eect of combination products, occupational factors,
and/or factors such as sex, age, or ethnicity. Because the
available evidence does not support a beta-alanine
221
enhancement of athletic performance or improvement in
recovery from exhaustion in active adults, insucient
information exists with regard to beta-alanine supplemen-
tation as an adjunct to improving performance of the
roles, occupations, and behaviors of active-duty service
members. Recently, a European Food Safety Authority
panel also concluded that the available evidence does not
support a benecial physiological eect from increasing
muscle carnosine stores and that a cause-and-eect rela-
tionship has not been established between the consump-
tion of beta-alanine and an increase in time to exhaustion
or an increase in physical performance during short-term,
high-intensity exercise.67
The present review explored the possibility of con-
ducting a meta-analysis of the studies to assess the out-
comes of athletic performance and improved recovery
from exhaustion. However, such an analysis was not fea-
sible due to limitations of the available information. A
detailed discussion on the limitations that precluded such
a meta-analysis and the reasons for discounting the
observations from a recent meta-analysis68 are presented
in Appendix SB in the Supporting Information online.
Safety outcomes
A detailed discussion of the safety-related outcomes and
the strength of evidence is presented in Appendix SD in
the Supporting Information online. AERs from clinical
studies and WHO-UMC (Tables S7 and S11 in the Sup-
porting Information) provided information concerning
beta-alanine alone. The spontaneous AERs from FDA
MedWatch and Health Canadas Canada Vigilance
(Tables S8S10 in the Supporting Information) were
related to beta-alanine in multi-ingredient products. The
majority of spontaneous case reports were insuciently
documented to support an informed judgment about a
relationship between the use of beta-alanine and the
adverse event in question. A causality algorithm was not
applied in the analysis of AERs, because all the suspected
products (except for Abufene) involved a combination of
several ingredients, which aected causality assignation
to beta-alanine. All the AERs identied as serious
involved beta-alanine as one ingredient in multi-
ingredient products, and none involved beta-alanine
alone (Tables S8 and S10 in the Supporting Information
online). Because of this, causality of reactions associated
with combination products could not be assigned speci-
cally to beta-alanine alone. A meta-analysis of the adverse
events could not be performed because the data were not
systematically reported in clinical studies.
Safety information from clinical studies and AERs
indicated paresthesia as a short-term adverse reaction.
The overall strength of the evidence concerning the use
of beta-alanine and its relation to paresthesia came from
222
the dose-response correlation, temporal correlation of
the eect, high frequency of occurrence in the exposed
population, correlation to plasma levels (and lack of
correlation following use of a sustained-release formula-
tion), and data from both published clinical studies and
AERs. However, the caveats of the available information
included lack of data about plasma levels in non-
responders versus responders, lack of sequential plasma
concentrations in a coordinated clinical study, pre- and
postprandial eects, variable dose and duration interven-
tions that could aect the reliability of the data, lack of a
well-dened mechanism of action, lack of product analy-
sis in AERs, missing information concerning the reasons
for participant dropouts, and limited post-marketing sur-
veillance. Further, clinical studies reported in the litera-
ture were not designed with safety evaluations as primary
endpoints. Information concerning cumulative long-
term eects or tolerance to paresthesia following long-
term use was not available from the literature. Because
of missing information, that which is available amounts
to moderate evidence concerning paresthesia follow-
ing short-term exposure to beta-alanine. Reports of
paresthesia from clinical studies and from WHO-UMC
reports for beta-alanine met the rst two criteria for sen-
tinel events,20 specically, 1) documentation that an
adverse event occurred and 2) temporal correlation, but
the limited clinical information concerning paresthesia
did not, with reasonable certainty, exclude alternative
explanations for the reaction. Further, the reaction did
not meet the denition of a serious AER.8,69 The Joint
Commission, the organization that accredits and certies
healthcare organizations in the United States, designates
adverse reactions as sentinel events only if they are unex-
pected occurrences that involve death or serious physical
or psychological injury or the risk thereof.70 Although
paresthesia does not seem to be a serious reaction in the
general population following consumption of a conven-
tional dose of 800 mg, the seriousness of the reaction for
military personnel is unclear.
The reports from WHO-UMC present a signal for
pruritus or itching following beta-alanine consumption.
These reactions were not observed in clinical studies, and
the molecular mechanism for the reactions is not known.
Typically, pruritus involves a histamine-mediated allergic
reaction. It is not certain whether increased carnosine
(beta-alanyl-L-histidine) levels following beta-alanine
consumption inuences precursor availability for hista-
mine production and release (as shown in cell culture and
animal studies).71,72 However, such a possibility seems
unlikely because a controlled-release formulation of beta-
alanine that increased muscle carnosine levels was not
associated with symptoms of pruritus.48
Evidence is absent to determine with condence
the adverse and modifying eects of other ingredients
Nutrition Reviews Vol. 72(3):217225
on short-term and long-term use of beta-alanine in
combination with specic ingredients. Although caeine
is a widely used substance, no study has systematically
investigated the eects of combining beta-alanine with
caeine. Similarly, the available evidence concerning the
lowest dose at which beta-alanine is associated with
paresthesia or adverse eects other than paresthesia (such
as pruritus) is inadequate. No evidence exists concerning
the dose-modifying eect of beta-alanine used in combi-
nation products, the inuence of occupational factors
such as environmental extremes on adverse eects, or the
association of adverse eects with clinical factors such as
patient sex, age, or ethnicity.
STRENGTHS, RESEARCH GAPS, AND
RECOMMENDATIONS FOR FUTURE RESEARCH
The strengths of this report lie in the systematic collection
of literature, critical data extraction, detailed documenta-
tion, transparent methods to assess the scientic litera-
ture, and the procedure for unbiased selection of studies.
The review was conducted using validated and widely
accepted evidence-based systematic review methods
from the Agency for Healthcare Research and Quality.
Volunteer members of the USP Expert Panels rened the
scope of the review and analyzed the available evidence to
prepare a thorough and unbiased systematic review of the
literature based on prespecied criteria. Further, this
review documents important variables that aect beta-
alanine use as a dietary supplement. This report does not
make clinical or policy recommendations. The work pro-
vides a foundation that facilitates rapid and ecient
updates as needed.
Although dietary supplements are widely used by
military service members, their purported benets and
safety for military personnel have not been systematically
studied. Future studies should explore the implications of
the use of supplements with consideration given to the
specic roles, occupations, and behaviors of military per-
sonnel. Endpoints for the studies must be well dened and
validated before they are used to measure outcomes. Simi-
larly, the eects of environmental extremes in combina-
tion with commonly used supplements (e.g., caeine) and
multiple ingredients should be explored. Better available
data will enable better decision-making on the appropriate
and safe use of supplements by military personnel.
Future studies should also characterize the products
used in interventions with details regarding the quality of
the product, appropriate control group, and potential
confounders. Studies should describe which adverse
events were monitored. Adverse event reports should
follow reporting guidelines such as the extension of the
CONSORT statement for harms. Review articles should
consider the AMSTAR checklist for conducting system-
Nutrition Reviews Vol. 72(3):217225
atic reviews of information relevant to the benets and
safety of dietary supplements.
The long-term eects of beta-alanine interventions
are unknown, and researchers should evaluate cumulative
long-term eects and the likelihood of tolerance. Large
cohort studies with multivariate analyses are needed to
fully understand the benets and safety of beta-alanine
among representative populations in order to understand
the eects of variables such as sex, age, and ethnicity.
A number of beta-alanine studies reported here are
not well designed and are missing critical information.
Future research should address confounders and insu-
ciency of evidence identied in the current review as the
research gaps (e.g., risk of bias, sample size, and missing
information). Adequately powered, double-blind, placebo
controlled studies with relevant and validated study
parameters should be conducted to generate information
that can provide answers with a high degree of condence.
The limitations and research gaps identied here
may aect the interpretation and conclusions of this
review. Systematic reviews should be updated according
to the accepted practices73 when new information
addressing the research gaps becomes available.
CONCLUSION
This evidence-based systematic review observed that the
limited available literature did not support the use of
beta-alanine supplementation alone or in combination
products for enhancement of athletic performance or
improved recovery from exhaustion in active adults.
Paresthesia was consistently reported as an adverse reac-
tion, and its eects must be considered with respect to the
roles, occupations, and behaviors of active-duty service
members.
Evidence is absent or insucient to address with con-
dence such topics as the optimal serving size, modifying
eect of combination products, the eects of environmen-
tal extremes, variability with sex, age, or ethnicity, or the
eect of beta-alanine consumption on the roles, occupa-
tions, and behaviors of active-duty service members.
The main caveats of the available literature include
the following: poorly documented interventions, poten-
tial risk of bias, questions regarding validity of the study
parameters, and the challenge of determining the role of
beta-alanine in AERs involving multi-ingredient prod-
ucts. Limitations of the available information were iden-
tied, and recommendations were made to address the
research gaps.
Acknowledgments
Richard Ko, Louis R. Cantilena, Rebecca B. Costello,
William J. Evans, Mary L. Hardy, Scott A. Jordan, Ronald J.
223
Maughan, Janet W. Rankin, and Abbie E Smith-Ryan are
members of the USP Beta-Alanine Review Expert Panel.
Tieraona Low Dog, Dennis K.J. Gorecki, Louis R.
Cantilena, Rebecca B. Costello, and Scott A. Jordan are
members of the USP Evidence-Based Reviews Expert
Panel. Luis Valerio is FDA liaison to the USP Dietary
Supplements Expert Committee. Gabriel I. Giancaspro
and Nandakumara D. Sarma are USP sta, all at the US
Pharmacopeial Convention, Rockville, MD 20852, USA.
Donnamaria Jones and Patricia Deuster are sta with
Uniformed Services University of Health Sciences,
Bethesda, MD 20814, USA. Note: All authors served as
USP expert volunteers or sta: the opinions expressed here
are theirs only and do not reect ocial positions of the
US and Canadian governments or any of their agencies.
The authors thank the following colleagues at USP:
Stefan Schuber, PhD, MS, for editorial assistance; Carlos
Celestino, JD, for legal counsel; Hellen Oketch, PhD, for
technical help; and Walter Hauck, PhD, for statistical
analysis.
Funding. This review was conducted by the authors at the
United States Pharmacopeial Convention (USP) pursuant
to a contract with the US Department of Defense. The
funding body took no part in the acquisition or interpre-
tation of data. The authors assume full responsibility for
the veracity and validity of the data and the presentation
of the manuscript.
Declaration of interest. The authors have no relevant
interests to declare.
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SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article at the publishers website:
Figure S1 Eect of beta-alanine supplementation on
muscle carnosine levels forest plot.
Figure S2 Beta-alanine versus placebo funnel plot.
Table S1 Inclusion screen.
Table S2 Participants.
Table S3 Intervention.
Table S4 Quality of primary clinical studies.
Table S5 AMSTAR grading of review articles.
Table S6 Benets outcomes.
Table S7 Safety information from clinical studies.
Table S8 MedWatch CFSAN reports.
Table S9 MedWatch CDER reports.
Table S10 Canada vigilance program reports.
Table S11 WHO UMC reports.
Table S12 Endpoints for computational analysis.
Table S13 Clinical adverse eects models.
Table S14 Preclinical toxicity models.
Table S15 QSAR model predictions.
Table S16 Modeling structural similarity with
beta-alanine.
Appendix SA Exact search strings.
Appendix SB Evidence for benets of beta-alanine
alone.
Appendix SC Evidence for benets of beta-alanine in
combination products.
Appendix SD Safety information.
225