JOURNAL OF THE INTERNATIONAL SOCIETY OF SPORTS NUTRITION
2023, VOL. 20, NO. 1, 2263409
https://doi.org/10.1080/15502783.2023.2263409

POSITION STAND

International society of sports nutrition position stand:essential amino acid supplementation on skeletal muscle andPerformance
Arny A. Ferrandoa, Robert R. Wolfea, Katie R. Hirsch b, David D. Churcha,
Shiloah A. Kviatkovsky a, Michael D. Robertsc, Jeffrey R. Stout d,Drew E. Gonzalez e, Ryan J. Sowinskie, Richard B. Kreider e, Chad M. Kerksick
Nicholas A. Burdg, Stefan M. Pasiakosh, Michael J. Ormsbee i, Shawn M. Arent
Paul J. Arcieroj,k, Bill I. Campbell l, Trisha A. VanDusseldorp m,n, Ralf Jagero,
Darryn S. Willoughbyp, Douglas S. Kalman q and Jose Antonio r

f
b

,
,

a

University of Arkansas for Medical Sciences, Center for Translational Research in Aging and Longevity,
Department of Geriatrics, Little Rock, AR, USA; bUniversity of South Carolina, Department of Exercise Science,
Arnold School of Public Health, Columbia, SC, USA; cAuburn University, School of Kinesiology, Auburn, AL,
USA; dUniversity of Central Florida, School of Kinesiology and Rehabilitation Sciences, Orlando, FL, USA;e
Texas A&M University, Exercise & Sport Nutrition Lab, Department of Kinesiology and Sports Management,College Station, TX, USA; fLindenwood University, Exercise and Performance Nutrition Laboratory, College of
Science, Technology, and Health, St Charles, MO, USA; gUniversity of Illinois Urbana-Champaign,Department of Kinesiology and Community Health, Urbana, IL, USA; hNational Institutes of Health, Office ofDietary Supplements, Bethesda, MD, USA; iFlorida State University, Institute of Sports Sciences andMedicine, Nutrition and Integrative Physiology, Tallahassee, FL, USA; jUniversity of Pittsburgh, Departmentof Sports Medicine and Nutrition, Pittsburgh, PA, USA; kSkidmore College, Health and Physiological Sciences,
Saratoga Springs, NY, USA; lUniversity of South Florida, Performance & Physique Enhancement Laboratory,
Tampa, FL, USA; mBonafede Health, LLC, JDS Therapeutics, Harrison, NY, USA; nJacksonville University,
Department of Health and Exercise Sciences, Jacksonville, FL, USA; oIncrenovo LLC, Whitefish Bay, WI, USA;p
University of Mary Hardin-Baylor, Human Performance Lab, School of Exercise and Sport Science, Belton,
TX, USA; qNova Southeastern University, Dr. Kiran C Patel College of Osteopathic Medicine, Department of
Nutrition, Davie, FL, USA; rNova Southeastern University, Department of Health and Human Performance,
Davie, FL, USA
ABSTRACTARTICLE HISTORY

Position Statement: The International Society of Sports Nutrition(ISSN) presents this position based on a critical examination ofliterature surrounding the effects of essential amino acid (EAA) sup­plementation on skeletal muscle maintenance and performance. This
position stand is intended to provide a scientific foundation toathletes, dietitians, trainers, and other practitioners as to the benefitsof supplemental EAA in both healthy and resistant (aging/clinical)
populations. EAAs are crucial components of protein intake inhumans, as the body cannot synthesize them. The daily recom­
mended intake (DRI) for protein was established to prevent

Received 20 September 2023
Accepted 21 September 2023
KEYWORDS

Protein; exercise

CONTACT Arny A. Ferrando
AFerrando@uams.edu
Center for Translational Research in Aging and Longevity,
Department of Geriatric, University of Arkansas for Medical Sciences, 4301 W. Markham St, Slot #806, Little Rock, AR
72205, USA© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/
licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) orwith their consent.

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A. A. FERRANDO ET AL.

deficiencies due to inadequate EAA consumption. The following
conclusions represent the official position of the Society: 1. Initialstudies on EAAs’ effects on skeletal muscle highlight their primaryrole in stimulating muscle protein synthesis (MPS) and turnover.
Protein turnover is critical for replacing degraded or damaged mus­cle proteins, laying the metabolic foundation for enhanced func­
tional performance. Consequently, research has shifted to examine
the effects of EAA supplementation – with and without the benefits
of exercise – on skeletal muscle maintenance and performance. 2.
Supplementation with free-form EAAs leads to a quick rise in periph­eral EAA concentrations, which in turn stimulates MPS. 3. The safe
upper limit of EAA intake (amount), without inborn metabolic dis­ease, can easily accommodate additional supplementation. 4. At rest,
stimulation of MPS occurs at relatively small dosages (1.5–3.0 g) andseems to plateau at around 15–18 g. 5. The MPS stimulation by EAAs
does not require non-essential amino acids. 6. Free-form EAA inges­
tion stimulates MPS more than an equivalent amount of intact
protein. 7. Repeated EAA-induced MPS stimulation throughout
the day does not diminish the anabolic effect of meal intake. 8.
Although direct comparisons of various formulas have yet to beinvestigated, aging requires a greater proportion of leucine to over­come the reduced muscle sensitivity known as “anabolic resistance.”
9. Without exercise, EAA supplementation can enhance functional
outcomes in anabolic-resistant populations. 10. EAA requirements
rise in the face of caloric deficits. During caloric deficit, it’s essential tomeet whole-body EAA requirements to preserve anabolic sensitivity
in skeletal muscle.

1. Methods
ISSN position stands are invited papers the ISSN editors and Research Council identify as
topics of interest to our readers that need position stands to provide guidance toreaders and the profession. Editors and/or the Research Council identify a lead author
or team of authors to perform a comprehensive literature review. The draft is then sent
to leading scholars for review and comment. The paper is then revised as a consensus
statement and reviewed and approved by the Research Council and Editors as theofficial position of the ISSN.

2. Introduction
The dietary “essential” amino acids (EAAs) – histidine, isoleucine, leucine, lysine, methio­nine, phenylalanine, threonine, tryptophan, and valine – are called “essential” because
they cannot be produced endogenously, and thus must be consumed for human survival.
In addition, arginine is considered a “conditionally” essential amino acid, meaning that incertain circumstances, the endogenous production of arginine fails to meet physiologicalneeds. The necessity of consuming all the EAAs has been well established over the last
100 years [1], and there are accepted daily requirements for each EAA as part of normal
dietary intake [2]. Daily requirements are based on the minimum amount of each EAA thatmust be consumed to avoid clinical symptoms of deficiency. Inadequate consumption ofjust one of the nine EAAs will cause symptoms of deficiency, including impaired protein

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synthesis [3]. Requirements for daily consumption of each EAA are conventionally met ascomponents of routine dietary protein intake. The amount and profile of EAAs in indivi­
dual dietary proteins, along with the digestibility of the protein bound EAAs, form thebasis for the quantitative assessment of the quality of the pure protein [4]. Proteins that
contain an abundant amount of all the EAAs in a highly digestible format are considered
to be “high-quality” proteins [4].
While the importance of meeting minimal requirements for each EAA through con­sumption of high-quality dietary protein intake has been recognized for many decades[5], the benefits attainable from consumption of free-form EAAs in amounts above andbeyond minimal requirements has only become fully appreciated in the past 25 years.
Products of single free amino acids, such as leucine or lysine, and compositions of small
groups of EAAs, most notably the branched chain amino acids (leucine, valine, andisoleucine; BCAAs) are available, but many studies have documented that greater benefits
are attained from compositions containing all the EAAs. Daily supplementation withcompositions of all the EAAs in free form has been shown to be beneficial in many
ways [6]. Most prominently, supplemental free-form EAA compositions stimulate protein
synthesis and protein turnover throughout the body, including the synthesis of newmuscle protein. Stimulation of muscle protein synthesis (MPS) by EAAs can produce
gains in muscle mass and quality, which translate to improvements in physical perfor­
mance and functional outcomes [7].
This document presents the position of the International Society of Sports Nutrition(ISSN) on the effect of dietary supplementation with free-form EAAs on MPS, muscle massand quality, and physical performance. Evaluation of the benefits of EAAs differs frommany of the other nutritional supplements evaluated by the ISSN in that there are wellaccepted requirements for daily EAA consumption. Also, rather than supplements con­taining only a single compound, such as creatine, there are almost limitless combinationsof the nine EAAs that can be made depending on the physiological demand. This
document will focus on supplementation of the diet in individuals meeting their dailyrequirements for EAAs through dietary consumption of protein. Only compositions con­taining the nine EAAs in free form will be considered in this document.

3. Mechanism of action
3.1. The importance of muscle protein turnover
The continuous renewal of degraded and damaged muscle protein is important inmaintaining muscle protein mass and function. In the post-absorptive state, a net
breakdown of muscle protein maintains a constant supply of plasma EAAs thatprovides precursors for protein synthesis in other tissues and organs. EAAs fromdietary intake restore the net loss of muscle protein by stimulating MPS. In normal
conditions, rates of MPS and muscle protein breakdown are equal over the course of
the day. If MPS exceeds the rate of muscle protein breakdown, muscle mass will
increase over time, with a potential gain in strength. Accelerated muscle protein
turnover (i.e. protein synthesis and breakdown increasing equally) without a gain in
net muscle protein mass may also benefit muscle function by replacing older,damaged muscle fibers with new, highly functioning fibers [8]. Thus, stimulation of

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MPS/turnover is the principal metabolic basis for increasing strength and physicalfunction. While changes in protein breakdown also play a role in controlling muscle
protein metabolism, stimulated MPS is the primary basis for the beneficial effects of
EAA supplements. Further, early investigations demonstrated that the amino acideffect on skeletal muscle was primarily through the stimulation of MPS, as muscle
protein breakdown was unchanged in an acute study [9]. Importantly, since themeasurement of muscle protein breakdown is not straightforward and problematicwith exogenous intake, MPS also represents a surrogate indicator of protein
turnover.

3.2. Control of muscle protein synthesis
The most definitive way in which to assess the effect of EAA supplements on physicalperformance is to measure metabolic and functional outcome responses over time whendifferent amounts and profiles of EAAs are provided, granted that all other variables areheld constant. However, months of treatment may be necessary to obtain reliable results
due to the slow turnover rate of muscle protein and difficulty in controlling all othervariables (diet, total EAA intake, activity, etc.). As a result, use of stable isotope tracer
methodology to quantify the acute response of MPS to a single dose of EAAs in humansubjects has become the accepted surrogate for predicting the anabolic response inmuscle. Aspects of protein synthesis, transcription and translation, can potentially beaffected by the consumption of EAAs: translational initiation and elongation in particular(see Figure 1a). The transcription of messenger RNA (mRNA) from DNA results from
activation of the relevant genes. Changes in the activation of genes are reflected in thenumber of specific mRNAs in the cell. The expression of mRNA is important because thephysical assembly of new proteins occurs on the mRNA. The complex initiation process
consists of several linked stages that are mediated by eukaryotic initiation factors (eIFs).
The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of theactivation of downstream eIFs that are mediators of MPS initiation (see Figure 1b). Bothtranscription and translational initiation of the protein synthetic process can be stimu­
lated by amino acids and exercise [13–16]. However, both mRNA transcription [17] andmTORC1 phosphorylation state [18] are usually poorly correlated with rates of MPS,
meaning that neither process is likely to be rate-limiting for MPS in most circumstances.
The translational control of protein synthesis by EAA availability has been recognizedsince 1958 [19]. Translation involves the successive linking of amino acids in the orderdictated by the mRNA code. Free intracellular amino acids are bound to correspondingtransfer RNAs (tRNAs), forming charged tRNA molecules. Charged tRNA molecules in turnsequentially transfer the attached amino acids to the sites on the mRNA that correspondto the code of the charged tRNA. Translational elongation can only proceed to completion
if adequate amounts of all required amino acid precursors are available. A relative
deficiency of any EAA will make that EAA limiting, with translational elongation being
terminated before the process is complete. Translational control of MPS requires that
adequate amounts of all EAAs are available to sustain increased MPS rates. In addition toproviding the necessary precursors for protein synthesis, EAAs increase the genes asso­
ciated with amino acid sensing, transport and mTORC1 regulation [20].

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841

Figure 1a. Protein synthesis: transcriptional initiation, elongation, and termination leading to the
production of mRNA in the nucleus, then exported to the cytosol to undergo translational initiation,elongation, and termination; producing a polypeptide which is folded into a protein.

3.3. Importance of the protocol used to measure MPS response to amino acidconsumption
The most commonly used method to measure MPS in human subjects is to determine therate of incorporation of a stable isotope tracer amino acid into muscle protein over time,
divided by the precursor enrichment [21]. This approach results in the calculation ofmuscle protein fractional synthetic rate (FSR). Since muscle mass is relatively constantacross several days, changes in FSR are conventionally considered to be a direct reflectionof MPS [21]. An alternative approach to measuring MPS is based on the arterial-venous
difference of unlabeled and labeled amino acid tracer and tracee, and the isotopic
enrichment of the intracellular free pool [22]. These two methods give comparable resultsfor MPS in human subjects [23]. In fact, the acute stimulation of MPS by consumption of
EAAs has shown to be reflected in the 24-hour protein balance across the leg [24].
Evidence supports the translation of differences in the acute response of MPS to EAA

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A. A. FERRANDO ET AL.

Figure 1b. mTOR signaling: regulation of mTORC1 by upstream stimuli; insulin, exercise (resistance,
endurance), glucose, and amino acids (Aa’s). Exercise leads to an energy deficit (increased AMP)
stimulating AMPK, inhibiting mTORC1 whereas glucose consumption raises ATP, inhibiting AMPK.
Insulin and resistance exercise activate the PI3K pathway, positively regulating mTORC1, while
endurance exercise activates CaMK, mostly promoting mitochondrial biogenesis. AA’s primarily
stimulate mTORC1 by promoting the phosphorylation and dephosphorylation of rag GTPases, rag
A/B and rag C/D, respectively. AA’s generally stimulate FNIP1/FLCN, promoting dephosphorylation of
rag C/D, however, some EAA’s (leucine, histidine, valine, threonine, isoleucine, methionine) act topromote phosphorylation of rag A/B; leading to an upregulation in mTORC1 and downstream
translation as well as glucose and lipid metabolism. Figures are derived from [10–12]. Abbreviations:
Akt, protein kinase B; AMPK, AMP-activated protein kinase; PI3K, phosphoinositide 3-kinase; Ca2 +,
calcium ion; CaMK, calcium/calmodulin-dependent protein kinase; FNIP1, folliculin-interacting protein
1; FLCN, folliculin (FLCN); mTORC1, mammalian target of rapamycin complex 1; FOX-O, forkhead box-O
transcription factors; PGC-1α, peroxisome proliferator-activated gamma coactivator-1 alpha; MuRF-1,
muscle ring-finger protein-1; eEF-2K, eukaryotic elongation factor-2 kinase; eEF2, eukaryotic elonga­tion factor-2; TSC1/2, Tuberous sclerosis proteins 1 (hamartin) +2 (tuberin); Rheb, Ras homolog
enriched in brain; LRS, leucyl-tRNA synthetase; SESN2, Sestrin-2; GATOR1/2, GAP (GTPase-activating
protein) activity toward Rags 1+2; SAM, s-adenosyl methionine; SAMTOR, s-adenosyl methionine
sensor for mTORC1; 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; P70-S6K,(S6K1) ribosomal protein S6 kinase beta-1; SREBP, sterol regulatory element binding protein; HIF-1α,
hypoxia-inducible factor-1 alpha; PDCD4, Programmed cell death protein 4; SKAR, S6K1 Aly/REF-like
substrate; eIF4E/B, eukaryotic translation initiation factor 4E+B.

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843

consumption to outcome parameters measured over weeks or months. For example, theeffect of daily consumption of an EAA-based formula in normal young healthy subjects
were compared to a placebo over 28 days of complete bed rest [7]. Daily consumption of
the EAA-based formula throughout the 28 days of bed rest ameliorated the loss of muscle
mass observed in those consuming the placebo by an amount predicted by the pre-bed
rest tracer study [7]. The predictive accuracy of the acute tracer method in this paradigm isparticularly impactful because activity and dietary intake were completely controlled overthe 28-day intervention [7].
The time period over which MPS is determined is important when interpreting thephysiological significance of acute changes in response to amino acid intake. A transient
increase in MPS is less likely to predict long-term gains in muscle mass and function
compared to a response that remains above the baseline value for three hours or more.
For example, consumption of leucine alone may elicit a transient response (1–2 h) inmuscle MPS, but this response must be interpreted with caution [25]. Consumption ofa sufficient amount of leucine alone may activate mTORC1 and associated molecules
involved in the initiation of the protein synthetic process and is reflected by a transient
increase in muscle protein MPS. However, the synthesis of muscle protein requires
adequate availability of all the component amino acids, including all nine EAAs. In theabsence of dietary intake, the EAAs needed to produce complete muscle proteins mustcome from endogenous sources. Initially, the additional EAAs needed for the synthesis ofcomplete muscle proteins may come from pools of free EAAs in the intracellular andextracellular fluid. However, the resulting depletion of free EAAs in those pools will limit
muscle protein synthesis because of inadequate precursor (available EAAs in amino acidpools) availability. The only other potential source of the necessary EAAs to maintain MPS
in this circumstance is accelerated protein breakdown, which will limit any net gain inmuscle protein that might be expected based on acute changes in MPS. Thus, theanabolic response (i.e. MPS – MPB) of muscle protein to consumption of a single EAA,
such as leucine, or small groups of EAAs (BCAAs) will be limited by the low availability ofthe other EAAs.
The paper by Fuchs and associates [26] provides evidence as to the interpretation of
the importance of sampling interval on muscle FSR response to amino acid intake. In thisstudy, muscle FSR was determined in response to consumption of the BCAAs, milk
protein, or branched chain keto acids, corresponding to leucine, valine, and isoleucine.
Muscle protein FSR was stimulated over the first two hours after consumption of all three
dietary supplements. However, 2–5 h after ingestion of each supplement, muscle protein
FSR remained stimulated only after consumption of milk protein. In other words, ingestionof either the BCAAs or their associated keto acids, failed to stimulate muscle protein FSR
from baseline after consumption [26]. The rate of muscle protein FSR was limited in hours
2–5 after their consumption by a decrease in the availability of the EAAs not provided in
the dietary supplement, as reflected by the decrease in plasma phenylalanine concentra­tion. The decrease in plasma EAAs was likely ameliorated to some extent by an increased
rate of muscle protein breakdown, thereby limiting the net anabolic effect of the stimula­tion of muscle protein FSR. In contrast, phenylalanine (as a reflection of EAAs) availability
was elevated 2–5 h after consumption of milk protein because of continued digestion andabsorption of all the EAAs, as well as availability of supporting non-essential amino acids.
The authors concluded that “these data suggest that in addition to the postprandial rise in844

A. A. FERRANDO ET AL.

Table 1. Dietary requirements of essential amino acids and safe upper limit of consumption
for adults.
Amino Acid
Histidine
Isoleucine
LeucineLysineMethionine
Phenylalanine
Threonine
Tryptophan
ValineRequirement (mg.kg/day)1
18
23
49
48
23
48
28
8
32

Safe upper limit mg/kg/day2 (reference)64 [27]117 [28]657 [29]
71 [30]71 [31]143 [32]
85 [33]64 [34]97 [2]

1

Refs [2,4], based upon DRIs; 2Above habitual intake.

plasma BCAA concentrations, other (essential) amino acids need to be provided to allow fora more prolonged postprandial increase in muscle protein synthesis rate” [26]. It is therefore
reasonable to rely primarily on data from studies in which MPS has been determined overan interval of 3 h or more after EAA consumption to expect translation of results tofunctional outcomes.

4. Safety
Consumption of EAAs has not been reported to cause adverse responses. Individuals withrare genetic diseases involving impairment of the ability to metabolize certain EAAs, suchas maple syrup urine disease (inability to metabolize the BCAAs), could have an adverse
response to supplements containing all the EAAs. However, inborn errors of metabolism
affecting the metabolism of an EAA are evident at an early age, and dietary adaptation isnecessary for health and possibly survival. It is therefore unlikely that an adult with aninborn error of metabolism that limits the safe consumption of EAAs would be unaware ofsuch a condition. It is also possible that an individual with renal disease could react poorly
to EAA supplementation, as a low protein diet is often recommended in kidney disease
due to the accumulation of urea and ammonia in blood. However, an EAA-based supple­
ment generally does not contribute to increased urea or ammonia production because ofincreased reutilization of non-essential amino acids for protein synthesis. However, there
is insufficient data available on individuals with impaired kidney function to determine
the safety of EAA-based dietary supplements.
Limited data are available upon which to base the safe upper limit of individual EAA
consumption. Table 1 lists consumption levels of each EAA that has been shown to besafe. The safe upper limits in Table 1 are expressed as the amount of each EAA consumed
above habitual intake. Thus, when considering the safe amounts of each EAA, these data
indicate that more than 100 g of supplemental EAAs can be safely consumed per day in an
American adult already consuming the average habitual dietary intake of approximately
40 grams per day. Reasonable dosage of an EAA supplement does not exceed 15 g,
meaning that even as much as three maximal doses per day is in line with normal daily
consumption of EAAs through dietary protein food sources. The following data on theeffects of supplemental EAA were derived in populations with adequate dietary protein
intake, unless stated otherwise.

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Key points:● Protein turnover ensures the continuous renewal of degraded and damaged muscle

protein and is important in maintaining muscle protein mass and function.
● The accepted surrogate for the measurement of protein turnover is the determina­tion of muscle protein synthesis by stable isotope tracer methodology. Thoughprotein breakdown is important in this process, the primary acute response of EAA
intake on skeletal muscle is the stimulation of protein synthesis.
● The safe upper limit of daily EAA intake permits substantial supplementation.

5. Consensus of FIndings
5.1. Eaas and muscle protein synthesis at rest
MPS is stimulated by consumption of EAA compositions [35] and inhibited by a reduced
availability of plasma EAAs [36]. The magnitude of increase in MPS following EAA con­sumption is a function of the amount ingested. At rest, an oral EAA dose as small as 1.5 g
has been reported to stimulate MPS [37] while the maximal effective dose, after which nofurther stimulation of synthesis is achieved in a single dose, is thought to be 15–18 gramsof EAA [38]. The stimulation of MPS by EAA consumption does not require simultaneous
consumption of non-essential amino acids (NEAAs) [35,38]. Inclusion of NEAAs toa mixture of 18 g of EAAs in the profile of beef protein had no effect on the EAAmediated stimulation of MPS [35]. Whereas consumption of NEAAs has no effect on
MPS when less than 18 g of EAAs are consumed, it is possible that when more than 18
g of EAAs are consumed NEAAs become limited by maximal rates of endogenous
production; however, more research is needed to explore this possibility.
EAA supplements stimulate MPS more than an equal amount of high-quality protein
either as an isolate [39] or as a component of a meal [40]. A oral 3 g dose of EAAs wasfound to stimulate MPS to a similar degree as 20 g of whey protein isolate, which contains
approximately 10 g of EAA [41]. Further, the addition of EAAs to whey protein has beenshown to significantly enhance the MPS response beyond whey protein alone [42]. The
superior stimulatory effect of free-form (individual EAAs only) EAAs is related to thegreater amount of EAA/gram compared to a dietary protein source [43]. Due to thehigh rate of intestinal absorption of free-form EAAs [44], rapid increases in circulatingplasma EAA concentrations drive inward transport into the muscle [23,45] resulting ina faster achievement of peak intramuscular EAA concentrations compared to other diet­ary protein sources. The importance of plasma EAA concentrations and the speed ofincrease to the peak concentration on the MPS response is unclear, but some studies havefound a relation between plasma EAA concentrations and MPS [46] and analysis of
consolidated data shows a correlation between the speed of rise to peak concentrationsof EAAs and MPS [43]. On the other hand, there was no difference in the MPS responsewhen the same dose of EAAs was given either as a single bolus or five smaller doses overtime [47]. Thus, there is agreement of a relationship between the dose of EAAs and the
MPS response, but the regulatory mechanisms linking dose and MPS are not agreed upon.
The overall impact of a dietary supplement on MPS over 24 hours depends not only
on the acute response to the consumption of the composition, but also on the846

A. A. FERRANDO ET AL.

Figure 2. The effect of 15 g of free-form EAA vs 70 g of lean beef protein and mixed meal ingestion on
plasma EAA kinetics. Adapted from references [50,51].

anabolic responses to normal meals. It is well established that the anabolic response
to a meal is reduced following pre-loading with a protein isolate [48]. In contrast, a 15
g dose of EAAs had no impact on the anabolic response to the subsequent meal [49].
However, it is important to note that free-form EAA supplementation results in a muchgreater rise in blood EAA concentrations than a meal of greater EAA quantity, as theyrequire no digestion and are quickly absorded. Figure 2 demonstrates the effects of 15
g of free-form EAA [50] on plasma concentrations compared to a mixed meal contain­
ing 70 grams of protein from beef protein [51]. Due to the slow digestion and releaseof dietary EAA after mixed meal consumption, blood levels are increased only mini­
mally, as compared to a rapid and robust increase following crystalline/free-form EAA
ingestion. Moreover, this rapid rise (a 3-fold or greater increase) predicts a greater
response of MPS [43].
The physiological state can affect the MPS response to EAAs. Aging is the mostcommonly studied non-clinical state in which the response to EAAs may be altered,termed anabolic resistance. Decreased responsiveness of MPS to consumption has
been well documented [52,53], but not consistently observed [54]. The different MPS
responses of older individuals to EAA consumption may be explained by differences inthe EAA profile of the composition. For example, on one occasion Katsanos et al.
provided elderly subjects a mixture of 6.7 g of EAAs in the profile found in whey
protein (27% leucine), and on a second occasion provided the same amount ofa mixture of EAAs with leucine comprising approximately 40% of the total of EAAs
[55]. In this study, the 40% leucine composition stimulated muscle protein synthesis
approximately 50% more than the lower leucine profile, despite containing the sameamount of total EAAs [55]. These results demonstrate the potential importance of the
EAA profile in a composition. However, there are almost limitless combinations of thenine EAAs, and there is minimal data directly comparing the effectiveness of different
EAA profiles in the same circumstance. Due to a lack of sufficient comparative data,

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847

the impact of different EAA profiles on MPS will not be discussed in this document.
Further research is required in this regard to determine optimal profiles for various
physiological requirements.

5.2. Eaas and whole-body protein and energy balance
A net negative balance in proteins throughout the body other than muscle protein (i.e.
tissues and organs; reflected by whole-body rates of protein synthesis and breakdown)
will adversely affect muscle protein and thus physical performance. If an inadequate
amount of EAA precursors are available from dietary intake to meet the demand through­out the body, the breakdown of muscle protein and release of amino acids into the blood
will provide the necessary EAAs. Negative energy balance will also indirectly affect muscle
protein, as ingested EAAs will at least in part be directed to oxidation for energy produc­tion rather than being channeled to muscle protein synthesis [56]. A discussion of EAA
effects on muscle protein synthesis must therefore be considered in the context of thestatus of whole-body protein and energy balance.
Periods of caloric deficit are common in weight class and endurance sports such as
marathon running and distance swimming, where periods of intense training coupledwith the desire for low body weight may limit caloric intake [57]. Caloric deficit increases
whole body EAA requirements [58]. For example, five days of a 30% calorie deficit required
a 3-fold increase in EAA intake to produce a positive whole-body protein balance [58].
Failure to meet the increased whole-body EAA requirements will result in the net break­down of muscle protein to provide the necessary EAAs and cannot be fully reversed until
the whole-body requirements are satisfied.
Many clinical states induce changes in whole-body protein metabolism that affect EAA
requirements and muscle protein balance. There may be new demands for EAA precursors
for functions such as repair of damaged tissue, wound healing, and production of acutephase proteins. Coincidently, the normal anabolic response of skeletal muscle to dietary
EAAs is likely to be diminished (anabolic resistance) with these conditions. As a result, rapid
loss of muscle mass is a common complication of serious diseases and injury [59]. The same
response may occur, albeit to a lesser extent, following a strenuous workout or competitive
event, particularly in those athletes who are voluntarily or involuntarily in a caloric deficit.

5.2.1. Key points: EAA effects on muscle and whole-body protein● There is a dose-response of oral EAA on skeletal muscle protein synthesis whichplateaus at approximately 15–18 g.
● There is a relationship between plasma EAA kinetics and the stimulation of protein
synthesis.
● Oral EAA stimulate muscle protein synthesis to a greater extent than an equalamount of high-quality protein.
● The decreased anabolic response with aging requires a different EAA profile, mostnotably a greater proportion of leucine.
● Whole-body EAA requirements increase with caloric deficit. If this requirement is notmet, net breakdown of muscle protein will occur to furnish the necessary EAAs.

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5.3. EAAs and physical function in absence of exercise training
Several studies document that acute stimulation of MPS by free EAA compositionstranslates to long-term gains in muscle mass and function, even in the absence ofcontrol for dietary protein intake. Outcome studies have generally been performedin older individuals. Using a randomized, double-blinded, placebo-controlled
design, older women were assigned to receive either placebo, or 15 g EAA/d forthree months [60]. Ingestion of 7.5 g EAA acutely stimulated muscle protein FSR in
both groups at baseline [60]. Basal FSR at three months was increased only inthose receiving daily EAA supplementation, and the magnitude of the acuteresponse to EAA was unaltered after three months of EAA consumption.
Consistent with the muscle protein FSR data, lean body mass was increased
significantly in those receiving EAAs but not placebo [36]. In a similar study, 12
glucose-intolerant subjects ingested 11 g of EAAs two times per day between
meals for 16 weeks [61]. Diet and physical activity were not otherwise modified.
Lean body mass was increased by EAA consumption, and most importantly,
a variety of parameters of physical function were also improved [61]. In a groupof 38 older women (≥75 years), daily supplementation with 3 g of EAAs twice
per day for three months significantly improved walking speed [62]. Similar results
were observed in a study including 92 low-function older individuals given either
supplements of 15 g whey protein isolate, EAAs (12 g EAAs plus 3 g flavoring), or
nutrition education for 12 weeks [63]. Those receiving EAAs significantly improved
the distance walked in 6 minutes, grip strength, and leg strength (peak torquemeasured by Cybex). Those receiving whey protein also significantly improved the
distance walked in 6 minutes, but the improvement was significantly less thanthose receiving EAAs. Leg strength was not improved in the whey group.
Interestingly, the distance walked in the nutrition education group declined overthe 12-week intervention period [63]. As a testament to the potential positive
impact of EAA supplementation on functional improvements, the magnitude of
improvement observed in the 6-minute walk distance in those receiving EAAs wasapproximately the same as reported in a systematic review of studies reporting theresult of 2–6 months of resistance training in 241 individuals [64]. These results are
consistent with extrapolation of the acute effects of EAA administration on thecontrol of MPS [46] by blood pharmacokinetics [43]. In a study of healthy older
individuals confined to bed rest for 10 days, consumption of three doses of 15 g
EAAs per day mitigated declines in physical function evident in the subjects
receiving the caloric-equivalent placebo [65]. In summary, existing studies on theeffects of EAAs on functional outcomes in the absence of exercise training havelargely focused on aging or compromised populations. As the EAA are potent
stimulators of muscle and whole-body protein anabolism, these populations are
logical targets of primary investigation as they manifest an anabolic resistance inskeletal muscle that leads to muscle loss, functional weakness, comorbidities, andotherwise poor clinical outcomes. Thus, it is tempting to recommend additional
studies to determine the anabolic effect of EAAs in young healthy individuals in
the absence of exercise training.

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5.4. EAA interaction with exercise
Early cross-limb examination of amino acid effects on skeletal muscle demonstrated that
increased amino acid delivery at rest results in a stimulation of inward amino acidtransport into skeletal muscle (30–100%; dependent upon individual EAAs),a stimulation of protein synthesis (30–300%), and an improvement to a positive net
amino acid balance [9]. When lower-body resistance exercise was performed prior toamino acid infusion, greater effects were realized in the inward transport of some aminoacids, but more importantly, there were even greater increases in protein synthesis andnet muscle protein balance [9]. In each case, there was no change in muscle protein
breakdown. It is important to note that the combined effects of resistance exercise andincreased amino acid delivery are interactive. When the same resistance exercise was
performed without amino acid administration, there was both an increase in inward
transport of amino acids as well as muscle protein synthesis; however, net muscle balanceremained negative [66]. The absence of improvement in net balance was due to theupregulation of both protein synthesis and breakdown after resistance exercise alone[66]. Thus, resistance exercise alone does not result in muscle anabolism (net muscle
protein balance is negative). Anabolism occurs only when supported by the requisite
amino acid precursors. Figure 3 graphically represents the cross-limb balance of pheny­lalanine (a surrogate for amino acid balance since it is not metabolized in skeletal muscle)
when fasted, after resistance exercise alone, after amino acids alone are infused, and withcombined infused amino acids and resistance exercise. The interactive effects of orally
administered EAA and resistance exercise revealed similar results. Lower body resistance
exercise was followed by the administration of oral EAA or a complete amino acid mixture.
The results indicated that EAA after exercise improved muscle net balance to the same
extent as a complete mixture, providing additional evidence [38] that when given in
conjunction with exercise, only the EAA are required to stimulate muscle anabolism [67].
Bolus oral ingestion of EAA after lower body resistance exercise also increased protein
synthesis and muscle net balance, regardless of whether the drink was consumed one or
three hours after exercise [68]. There are indications that the benefits of EAAs on skeletal
muscle may not entirely rely on the stimulation of MPS. EAA supplementation improved
histological evidence of muscle damage and reduced the loss of muscle strength, even in
the absence of any changes in MPS [69].

Figure 3. Muscle net balance of phenylalanine (umol/kg/min) during fasting, resistance exercise alone(RE), complete amino acid administration/infusion alone (AA), and with combined AA and RE. An
interactive effect between RE and AA administration is demonstrated. Data derived from references[9,66].

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The interactive effects of EAAs and resistance exercise are reflected in translation
initiation signaling in the muscle. Volunteers were given a placebo, leucine, BCAA, or
EAA solution after resistance exercise. The results indicated that 90 min following exercise
recovery, activation of ribosomal protein S6K1 and eukaryotic translation initiation factor
4E-BP1, as well as a sustained reduction of 4E-BP1:eIF4E interaction, was greatest with EAAs[70]. While a 9-fold increase was observed for S6K1 expression in the EAA trial, the overall
stimulation of translation initiation was most effective with EAAs, resulting in progressive
increases in translation initiation (placebo < leucine < BCAAs < EAAs) [70]. A study involving
young men corroborated the upregulation of the mammalian target of rapamycin complex
1 (mTORC1) signaling pathway after resistance exercise but also noted that an EAA
supplement maintains mTORC1 in peripheral regions of muscle fibers that is closer to its
direct activator Rheb [71]. The authors hypothesized that the “intracellular localization ofmTOR may serve to prime the kinase for future anabolic stimuli” [71]. The effects of EAA andresistance exercise upon upregulation of anabolic signaling is consistent with aging. EAAs
plus resistance exercise increases peripheral EAA concentrations equally in both young andolder subjects [72]. Regardless of age, increases in mTOR (Ser2481) and ribosomal protein
S6 (Ser235/236) were demonstrated with the combined treatment [72], suggesting an
improved muscle sensitivity to the combined stimuli. further, post-exercise EAA adminis­
tration in older men leads to an increase in satellite cell proliferation [73]. The metabolic
product of this signaling is an improvement in muscle protein synthesis. In addition, older
women performed unilateral knee extension and then consumed 1.5 or 6 g of an EAA
formula with varying amounts of leucine, or 20 or 40 g of whey protein. The results
indicated that 1.5 g and 6 g doses of EAAs were as effective as 40 g of whey protein in
the stimulation of acute muscle (myofibrillar) protein synthesis [37].

5.5. Supplementation strategies: EAA timing
Timing of EAA administration in relation to resistance exercise must be considered.
Subjects given EAAs immediately before or after resistance exercise both realized
a 130% increase in arterial and muscle phenylalanine concentrations [74]. However, theeffect on net phenylalanine uptake (an indirect measure of net protein synthesis) wasmuch greater when the drink was consumed just prior to exercise [74]. It is important tonote that each treatment resulted in a positive net phenylalanine balance; however, theimproved amino acid delivery (blood flow X arterial EAA concentration) when consumed
immediately before exercise resulted in an approximate 3-fold greater delivery of aminoacids [74]. The stimulatory effect of resistance exercise on muscle blood flow, whencombined with the greater amino acid delivery from consumption prior to exercise,results in a greater anabolic response in skeletal muscle. This is consistent with a recent
review denoting the relationship between peripheral EAA increases and the stimulation ofmuscle and whole-body protein synthesis [43]. Additional work does not confirm thesefindings, as a carbohydrate/EAA solution given before resistance exercise did not enhance
post-exercise muscle protein synthesis [75]; however, methodological differences/inter­
pretations and carbohydrate intake may complicate the consistency in interpretation.
Further, evidence indicates that a second EAA bolus one hour following a first duplicatesthe muscle anabolism of the first administration, indicating that synthetic mechanisms are
not dormant after an initial stimulation [76].

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5.6. EAA interaction with other exercise modalities
Due to the strong interactive effects demonstrated with EAAs and resistance
exercise, the preponderance of work has focused on this combination. The dataon the combination of EAAs and aerobic exercise is also consistent with its effects
on skeletal muscle protein anabolism. In young adults performing 90 min of inten­
sity matched cycle ergometry or weighted load carriage (30% of body mass)
exercise on a treadmill with or without EAAs (consumed every 30 minutes through­out exercise bout), muscle protein synthesis was greater during each exercise
mode with EAAs [77]. However, load carriage and EAAs resulted in a greater
increase in MPS both during and after exercise [77]. These results indicate thatthe loading of skeletal muscle provides a stronger stimulus for the combined
effects of EAAs and exercise. The interaction of EAAs and aerobic exercise is also
consistent in aging. Older volunteers (72 ± 1 yrs) were randomized to receive 15 g/dof EAAs or 15 g/d EAAs plus 3 d/wk supervised aerobic exercise training. Consistent
with previous findings, acute EAA intake pre-intervention increased MPS [78].
However, post 24-week intervention, the combined EAAs and aerobic exercisegroup had a greater muscle synthetic response to EAAs than the EAA groupalone [78], indicating that consistent exercise further sensitizes skeletal muscle tothe anabolic effects of EAAs. Most importantly, the improved sensitivity of skeletal
muscle to EAAs resulted in greater muscle quality and 400 m walking speed in the
EAA plus aerobic exercise group [78].
High-intensity and intermittent exercise/training (HIIT), and most team sports (i.e.
soccer, basketball, hockey, tennis, etc.) require components of both aerobic and anaero­
bic/resistance training. Studies with protein suggest that high-intensity exercise under­
taken with increased protein availability (i.e. performed in a fed state with protein) may
synergistically enhance muscle hypertrophy [79]. Other potential benefits include
increased mitochondrial biogenesis, exercise recovery, aerobic capacity, and improved
sprint performance [80]. To date, the limited investigations utilizing EAA and HIIT are notyet definitive. In untrained, overweight/obese adults, 8 weeks of high-intensity interval
training (HIIT; 6–10 × 1 min@90% max W: 1 min rest) elicited significant increases in thighmuscle size, cross-sectional area, volume, and quality, but was not synergisticallyenhanced by a low dose of EAA (3.6 g twice daily) [81]. In addition, VO2 was also increased
with HIIT but not synergistically enhanced by EAA [82]. In the same cohort, there were no
acute (3.6 g pre-exercise) or chronic (after 4 and 8 weeks of 3.6 g twice daily) effects of EAA
supplementation on time to exhaustion or workload progression [83]. While there is noevidence to suggest EAA supplementation is detrimental or attenuates physiological
adaptations associated with HIIT, there is not enough evidence to draw conclusions as
to the benefits on adaptation and performance. However, there is reason to expect an
EAA interaction with aerobic exercise. Moderate treadmill walking alone (45 min at 40%
peak VO2) in both young and older men increased muscle protein synthesis immediately
after exercise, with the younger response maintained up to one hour post- exercise [84].
Synthesis of fibrinogen was also elevated in both groups up to three hours post-exercise[84]. Amino acid delivery was greater immediately post-exercise, again denoting theexercise effect on limb blood flow. Thus, if increased blood flow is combined witha greater delivery of amino acids by oral intake, one would expect muscle anabolism.

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Regarding exercise interactions, free form EAAs may be considered over intact
protein (whey) on the basis of ease of consumption proximal to and during
exercise. Oral free-form EAA formulas require little to no digestion, entail minimal
gastric load, and are rapidly absorbed and transported to the periphery. For thisreason, they are ideal for consumption prior to the performance of rigorous
exercise.

6. Eaas and clinical conditions and outcomes
Beneficial effects of supplementation of the diet with EAAs have been demonstrated ina wide variety of clinical conditions. Conditions largely associated with aging havebeen a frequent target of EAA therapy, including sarcopenia [62,85], long-term-careacquired infections [86], low physical function [63], and heart failure [40,87,88].
Beneficial effects of EAAs have also been reported in the following conditions orsituations: rehabilitation [89–92]; stroke [93,94]; bed rest/immobilization [8,65,95–97];
peripheral artery disease [98]; renal failure [99–103]; inflammation [104,105]; critical
illness [106]; lung cancer [107]; cystic fibrosis [108]; chronic obstructive pulmonary
disease [109–111]; wound healing [112]; brain injury [113,114]; metabolic syndromeand cardiovascular risk factors [115–117]; obesity [118,119]; liver fat [115,120–122]; anddiabetes [123–127]. Importantly, in all of these studies beneficial effects were observed
despite the absence of control of the consumption of EAAs contained in dietary
protein, implying the importance of the rapid and complete absorption of free EAAs
in clinical circumstances in which digestion may be impaired and anabolic resistance isprevalent. The findings in clinical populations point to the need and potential impact
of EAA supplementation surrounding rehabilitation efforts from orthopedic injuries
and associated surgery. These scenarios represent the most likely clinical environments
where competitive athletes will find themselves and it remains an under-served area of
research.

6.1. Key points: EAA, exercise, and function● The anabolic effects of EAA and exercise are interactive, in that the response to the

combination is greater than the sum of the individual responses. The increase of
exercise-induced limb blood flow is contributory to this response by increasing EAA
transport into skeletal muscle.
● The combination of EAAs and aerobic exercise, as well as other modalities of muscle
loading, is also anabolic to skeletal muscle.
● EAA given prior to exercise results in greater anabolism than if consumed after
completion of exercise; however, a lesser anabolic effect can be realized within
an hour after exercise cessation.
● In the absence of exercise stimulus, EAA administration in anabolically resistantpopulations, such as aging and clinical pathologies, has been shown to be beneficial
to clinical outcomes and efficacious in the restoration of strength and functional
performance.

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7. Remaining questions
The metabolic effects of EAAs have been elegantly articulated. In addition, their metabolic
interaction with both resistance and aerobic exercise have been established. Thus, there isa metabolic basis for the translation of EAA supplementation to performance outcomes.
As mentioned previously, the substantial anabolic effect of free-form EAA supplementa­tion is consistent with their efficacy in populations that would most benefit from theirutilization. For this reason, the overwhelming majority of longitudinal work examining
EAA supplementation and functional outcomes has occurred in aging or clinical popula­tions characterized by muscle anabolic insensitivity, muscle loss, and/or muscle weakness.
Less work has documented the long-term effects/outcomes associated with EAA utiliza­tion in athletic populations. In addition, further work defining the optimal profile of EAAs,
as well as the optimal dosage and timing for specific circumstances, would be beneficial.

8. Final summary and conclusions
The following 15 points constitute the Position Statement of the Society. They have been
approved by the Research Council of the Society:(1) Free-form EAA supplementation (not derived from exogenous intact protein) isa robust stimulator of muscle protein synthesis and turnover.
(2) EAAs stimulate muscle protein synthesis more than an isonitrogenous protein
isolate.
(3) EAA ingestion produces a rapid rise in peripheral concentrations and inward
transport of amino acids into skeletal muscle.
(4) EAA stimulation of muscle protein synthesis can occur with multiple dosages anddoes not interfere with meal effects.
(5) Individual or groups of EAAs may initiate the stimulatory process; however,significant and sustained stimulation occurs when all EAAs are consumed.
(6) EAA stimulation of protein synthesis at rest occurs in dosages ranging from 1.5 g
to 18 g.
(7) A greater percentage of leucine (%/g) contained in ingested compositions of EAAs
is required to maximally stimulate muscle protein synthesis populations (aging,clinical pathologies) that demonstrate anabolic resistance.
(8) In anabolic resistant populations, longitudinal EAA supplementation improves
functional outcomes.
(9) The effects of EAAs and exercise are interactive, such that the combined effects
are magnified. This interaction is due to a greater delivery of EAAs to exercisingmuscle by increased blood flow and higher blood EAA concentrations.
(10) Anabolic responses are consistently reported with combinations of EAA ingestion
with either resistance or aerobic exercise. This effect is preserved with aging.
(11) Free form EAA supplementation is well within the safe upper limit of habitual daily
consumption.
(12) EAA supplementation is efficacious in the vast majority of clinical studies andconditions.

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(13) Numerous longitudinal studies involving EAA supplementation in aging popula­tions consistently report favorable improvements in metabolic as well as func­
tional outcomes.
(14) More research is needed to examine the potential impact of EAA administration inathletic populations that are intentionally or unintentionally undergoing energy
deprivation on changes in muscle protein metabolism and associated perfor­
mance and body composition changes.
(15) More research is needed to examine the role of EAA administration to athletic
populations that go through unexpected and sudden periods of inactivity likely
secondary to acute injuries and rehabilitation periods that routinely follow surgi­
cal interventions.

Acknowledgments
Figures 1a and 1b were made with the assistance of Biorender.com.

Disclosure statement
AAF is an inventor of EAA-based compositions (US11,273,138 B2, US20140343112,
US20200253908). The results of some of these compositions are referred to under “EAAs andclinical conditions and outcomes (refs 40, 60, 89).” RRW is a shareholder in the Amino Company, LLC.
RRW is an inventor of EAA-based compositions (U.S. Patent 9,597,367 B2; US Patent 9,364,463 B2; US
Patent 16/761,175, US20100179089, US20090252684, US20090203606, US8703725B2,
ES2274299T3, EP1865944B1, US 2008/0268038 A1, US20200253908, US10022358B2, US11,273,138
B2, US20140343112, US11,241,399 B2). DDC has received honoria, consulting fees, and performed
free-lance work related to protein metabolism. He currently serves on the Advisory Board for Shifted
Supplements. SK has no conflict in terms of financial or business interests related to this manuscript.
SK has received grants to conduct research on dietary supplements; has served as a paid consultant
for industry; and has received honoraria for speaking engagements and conferences. MDR reports
current research contracts and gifts from several industry sponsors. MDR also acts as a consultant forindustry entities in accordance with rules established by Auburn University’s Conflict of Interest(COI) Policies. JRS has no conflict of interest related to this manuscript in terms of financial or
business interests. Over the past 25 years, he has received grants and contracts to conduct researchon dietary supplements; served as a paid consultant for industry; and received honoraria forspeaking at conferences and writing lay articles about sports nutrition ingredients and topics. RJS
has no conflict in terms of financial or business interests related to this manuscript. RJS has
conducted research on dietary supplements. RBK has conducted sponsored research on nutritional
supplements through grants and contracts awarded to the universities he has been affiliated,
received honorarium for presenting research related to dietary supplements, served as an expert
on cases related to dietary supplements, and consulted with industry on product development
including dietary supplements containing essential amino acids. CK has no conflicts of interest toreport on the content of this paper. CK has consulted with and received external funding fromcompanies who sell certain amino acids and dietary ingredients and has received remunerationfrom companies for delivering scientific presentations at conferences. He has also been paid in anadvisory capacity from companies that manufacture various dietary ingredients including protein.
NAB has no conflict in terms of financial or business interests related to this manuscript. NAB has
received research grants, consulting fees, and speaking honoraria from PepsiCo, the National
Cattlemen’s Beef Association, The Pork Check Off, National Dairy Council, and Alliance for Potato
Research and Education (APRE). SMP has no conflict in terms of financial or business interests
related to this manuscript. Furthermore, the opinions expressed in this article are those of

JOURNAL OF THE INTERNATIONAL SOCIETY OF SPORTS NUTRITION

855

Dr. Pasiakos and do not reflect the view of the National Institutes of Health, the Department of
Health and Human Services, or the United States government. Any citations of commercial organi­zations and trade names in this report do not constitute an official NIH endorsement of approval of
the products or services of these organizations. MJO has no conflict in terms of financial or businessinterests related to this manuscript. MJO is a member of the International Protein Board that
disseminates knowledge on protein and protein products. MJO has received grants and contracts
to conduct research on dietary supplements; has served as a paid and unpaid consultant forindustry; has received honoraria for speaking at conferences and writing lay articles about sports
nutrition ingredients and topics. SMA has no current conflicts of interest specifically related to EAAs/
protein. He has received other funding from dietary supplement companies for research, honoraria
for speaking at conferences or as an advisory board member, and consulting. PJA has no conflict interms of financial or business interests related to this manuscript. PJA is Founder and CEO of PRISE
LLC, a health and wellness company providing consulting services to organizations and individuals
to enhance health and performance. He serves as a paid consultant for Isagenix International LLC,
a health and wellness company providing nutrition supplements. He is an advisory board memberof the International Protein Board (IPB) and receives funding to conduct research on dietary
supplements; he receives honoraria for keynote presentations and financial compensation forbooks and lay articles about sports nutrition ingredients and topics. BIC has no conflict in termsof financial or business interests related to this manuscript. BIC has received grants and contracts to
conduct research on dietary supplements; has served as a paid consultant for industry; has received
honoraria for speaking at conferences and writing lay articles about sports nutrition ingredients andtopics; is a member of the International Protein Board that disseminates knowledge on protein andprotein products; and has served as an expert witness on behalf of the plaintiff and defense in cases
involving dietary supplements; and receives compensation for writing and providing educational
services related to exercise and nutrition-related topics. TAV has no current conflicts of interest
specifically related to EAAs/protein. She has received other funding from dietary supplementcompanies for research, honoraria for speaking at conferences/writing lay articles, and consulting
in industry. RJ has no conflict in terms of financial or business interests related to this manuscript. RJ
is an inventor of patents on dipeptides (US patent US20230053297, US20230113817, US11026991).
RJ has received grants and contracts to conduct research on dietary supplements; has served asa paid consultant for industry; has received honoraria for speaking at conferences and has served as
an expert witness on behalf of the plaintiff and defense in cases involving dietary supplements. DW
has no conflict in terms of financial or business interests related to this manuscript. DW has received
grants and contracts to conduct research on dietary supplements; has served as a paid consultant
for industry; has received honoraria for speaking at conferences and writing lay articles about sports
nutrition ingredients and topics; and has served as an expert witness on behalf of the plaintiff anddefense in cases involving dietary supplements. DSK has no conflicts of interest to declare. In thepast, DSK has conducted research on amino acids and protein products, none currently. JA is theCEO of the ISSN. The ISSN receives occasional funding and support from companies the manufac­
ture and sell amino-acid containing supplements.
The opinions expressed in this article are those of the authors and do not reflect the view of the
National Institutes of Health, the Department of Health and Human Services, or the United States
government. Any citations of commercial organizations and trade names in this report do notconstitute an official NIH endorsement of approval of the products or services of theseorganizations.

Funding
D.D.C. is currently supported by a National Institutes of Health (NIH) Clinical Research Loan
Repayment Award. Research reported in this publication was supported by the National Center
For Advancing Translational Sciences of the National Institutes of Health under Award Number (TL1
TR003109 and UL1 TR003107). The content is solely the responsibility of the authors and does notnecessarily represent the official views of the National Institutes of Health.

856

A. A. FERRANDO ET AL.

ORCID
Katie R. Hirsch
http://orcid.org/0000-0002-0899-0139
Shiloah A. Kviatkovsky
http://orcid.org/0000-0002-1775-2917
Jeffrey R. Stout
http://orcid.org/0000-0001-6114-1649
Drew E. Gonzalez
http://orcid.org/0000-0002-7279-4968
Richard B. Kreider
http://orcid.org/0000-0002-3906-1658
Chad M. Kerksick
http://orcid.org/0000-0003-0458-7294
http://orcid.org/0000-0002-1939-7656
Michael J. Ormsbee
Shawn M. Arent
http://orcid.org/0000-0003-0647-0591
Bill I. Campbell
http://orcid.org/0000-0002-4106-3871
http://orcid.org/0000-0001-9057-2720
Trisha A. VanDusseldorp
Douglas S. Kalman
http://orcid.org/0000-0003-0882-9748
Jose Antonio
http://orcid.org/0000-0002-8930-1058

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