Emerging Nutritional

Supplements for Strength

and Hypertrophy: An
Update of the Current
Literature
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Adam M. Gonzalez, PhD,1 David D. Church, PhD,2 Jeremy R. Townsend, PhD,3 and Reza Bagheri, MS4
1
Department of Health Professions, Hofstra University, Hempstead, New York; 2Department of Geriatrics, Donald W.
Reynolds Institute on Aging, Center for Translational Research in Aging & Longevity, University of Arkansas for Medical
Sciences, Little Rock, Arkansas; 3Department of Kinesiology, Exercise and Nutrition Science Graduate Program,
Lipscomb University, Nashville, Tennessee; and 4Department of Exercise Physiology, Faculty of Sport Sciences,
University of Isfahan, Isfahan, Iran

ABSTRACT
Several dietary supplements have been
proposed as a means of improving
muscle strength and hypertrophy when
combined with resistance training.
However, few have received sufficient
attention from sports scientists to pro-
duce robust evidence for being well
recommended. A growing body of liter-
ature has emerged for several dietary
ingredients with the potential to promote
muscular adaptations. Therefore, the aim
of this review is to provide an evidence-
based review of the efficacy of emerging
nutritional supplements to allow athletes,
coaches, and practitioners to make an
informed decision when considering their
use as a means of improving muscle
strength and hypertrophy.
INTRODUCTION
thletes are constantly seeking
As such, several supplements have
been proposed as a means of aug-
menting gains in strength and hyper-
trophy. Supplements are commonly
marketed to promote muscular adap-
tations through mechanisms such as,
but not limited to, enhancing high-
intensity exercise performance, de-
laying muscular fatigue, increasing
substrate availability, increasing mus-
cle contraction efficiency, and/or
promoting muscle protein synthesis.
However, a large majority of sports
supplements on the market have
not been adequately studied or con-
sistently supported in the literature.
Few supplements have received suffi-
cient attention from sports scientists
to produce robust evidence for being
recommended as a supplement to
augment strength (e.g., caffeine and
creatine), hypertrophy (e.g., creatine
and protein), and exercise perfor-
including citrulline malate (CitMal), ni-
trates, phosphatidic acid (PA),
branched chain amino acids (BCAAs),
b-hydroxy-b-methylbutyrate (HMB),
and betaine. The aim of this review is
to provide an evidence-based narrative
review of the efficacy of these emerging
nutritional supplements to allow ath-
letes, coaches, and practitioners to
make an informed decision when con-
sidering the use of each supplement as
a means of improving muscle strength
and hypertrophy.
CITRULLINE MALATE
Nitric oxide (NO) is a ubiquitous free-
radical gas that plays an important role
in a wide variety of signaling and reg-
ulatory processes of cellular and car-
diovascular function. In particular,
NO plays a critical role in several phys-
iological functions within the blood
vessels and skeletal muscle; NO may
promote vasodilation, along with

A
nutritional interventions to
improve training-induced
strength and hypertrophy outcomes.
Address correspondence to Dr. Adam M.
Gonzalez, Adam.Gonzalez@hofstra.edu.
mance (e.g., caffeine, creatine, bicar-
bonate, beta-alanine, and nitrates)
(83,96). Nevertheless, a growing body
KEY WORDS:
citrulline malate; nitrates; phosphatidic
of literature has emerged for several
acid; branched chain amino acids;
dietary ingredients with the potential
b-hydroxy-b-methylbutyrate; betaine
to promote muscular adaptations,

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 Emerging Nutritional Supplements
improving mitochondrial respiration,
glucose and calcium homeostasis, and
skeletal muscle contractility (16). Thus,
enhanced NO bioavailability may
enhance exercise performance and
delay fatigue during high-intensity
exercise. NO precursor supplements
have become a popular class of dietary
supplements as a means of increasing
the body’s capacity to augment NO
bioavailability, and citrulline is com-
monly marketed to strength/power
athletes primarily due to its potential
to boost NO production.
Citrulline is a nonessential amino acid
found predominantly in watermelon
and other melons and serves as an
endogenous precursor to arginine (38).
NO can subsequently be produced
through the arginine–NO pathway,
whereby arginine is converted to NO
and citrulline by the enzyme, NO syn-
thase (12). Notably, compared with an
acute supplemental dose of arginine,
citrulline supplementation has shown to
be a more efficient means of elevating
plasma arginine concentrations for sub-
sequent NO production (111). Unlike
arginine, oral ingestion of citrulline is not
subjected to significant catabolism in the
gut and is not extracted from systemic
circulation through hepatic clearance
(55,106,128,137). Therefore, over the
past decade, the attention has shifted
from arginine to citrulline as a means of
increasing NO biosynthesis and
improving performance. Along with
NO-boosting properties, citrulline has
also been linked to improved ammonia
clearance through the urea cycle (15)
and increased muscle protein synthesis
(albeit under protein deficient or cata-
bolic conditions) (54,71), thereby poten-
tially improving muscle function,
attenuating fatigue, and promoting mus-
cle growth. Before strength exercise, re-
searchers have most commonly
administered citrulline in the form of Cit-
Mal, whereby citrulline and malate are
combined in either a 1:1 or 2:1 ratio.
Malate is a tricarboxylic acid cycle inter-
mediate that has been suggested to
potentially increase oxidative ATP pro-
duction (10). However, studies have not
yet investigated the potential ergogenic
58 VOLUME 42 | NUMBER 5 | OCTOBER 2020
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properties of malate in isolation, and
studies have not yet compared citrulline
versus CitMal.
Several studies have investigated the
potential ergogenic effects of CitMal
supplementation on vascular function
in humans. In a recent review of the
literature, Gonzalez and Trexler (52)
concluded that acute administration of
citrulline or CitMal has consistently
shown to increase plasma citrulline
and arginine concentrations, along with
total nitrate and nitrite concentrations
(biomarkers that are indicative of NO
bioavailability). However, evidence sup-
porting acute improvements in vasodila-
tion and skeletal muscle tissue perfusion
after supplementation is scarce and
inconsistent. In addition, more recent
evidence suggested that 8 g CitMal does
not influence the diameter or blood flow
of the superficial femoral artery during
submaximal leg extension in recreation-
ally active males (124).
Regarding performance outcomes,
a recent systematic review and meta-
analysis by Trexler et al. (126) found a sig-
nificant, yet small, favorable effect of
citrulline-based supplements on acute
performance of high-intensity strength
and power tasks in comparison with
a placebo. Specific to resistance training,
several studies have reported that acute
ingestion of CitMal allows individuals to
complete more repetitions-to-failure
over a series of sets of single-joint and/
or multijoint exercises (48,97,131,132).
For example, resistance-trained males
were able to complete a significantly
greater number of repetitions during 5
sets of leg press, hack squat, and leg
extension to failure at 60% one repetition
maximum (1RM) (132). Likewise,
resistance-trained females performed sig-
nificantly more repetitions during 6 sets
of bench press and leg press to failure at
80% 1RM (48). Thus, acute CitMal sup-
plementation may improve resistance to
fatigue, which may promote a greater
anabolic stimulus from the training ses-
sion. However, other studies have re-
ported null findings on resistance
exercise performance, repetition volume,
and recovery after acute CitMal supple-
mentation (17,18,28,51,125).
To date, only one study has investi-
gated strength and hypertrophy out-
comes after chronic CitMal
supplementation in healthy, young in-
dividuals (64). During an 8-week resis-
tance training program, resistance-
trained males supplemented with
either citrulline plus glutathione
(2 g$d21 citrulline + 200 mg$d21
glutathione), CitMal (2 g$d21), or a pla-
cebo. In this study, neither supplemen-
tation protocol significantly improved
performance or body composition.
However, in comparison with the
aforementioned acute study designs,
a relatively small dose of CitMal was
administered and the resistance train-
ing program used did not seem to
induce meaningful strength and hyper-
trophy improvements regardless of the
supplemental group. Future studies are
necessary to investigate the effect of
chronic supplementation with larger
doses of CitMal in conjunction with
a resistance training program.
Despite some mixed findings, several
studies have reported that acute Cit-
Mal supplementation can enhance sev-
eral aspects of exercise performance
and recovery (52). Studies reporting
ergogenic effects with CitMal have
provided a 6–8 g dose approximately
1 hour before the onset of exercise.
Although loading protocols have not
been implemented before resistance
exercise, chronic dosing (.7 days)
has shown to exert favorable effects
on endurance and high-intensity exer-
cise performance (9,118,119). Short-
term supplementation of CitMal seems
to be safe and well-tolerated. Given the
positive effects observed from some in-
vestigations, future studies should con-
tinue to investigate the effects of both
acute and loading doses of CitMal on
muscular adaptations.
NITRATES
NO elicits a variety of actions within
the human body including vasodila-
tion, improved calcium handling,
mitochondrial respiration and biogen-
esis, and increased velocity of skeletal
muscle contractions (25,69,105). As
previously mentioned, NO precursors
 have become a popular category of
supplements with the intention of
increasing NO production and subse-
quently improving human perfor-
mance. When nitrates are consumed
in the diet, they are converted to NO
in the body by the nitrate–nitrite–NO
pathway to increase NO availability to
exercising tissues. A majority of
research studies to date have investi-
gated the effects of dietary nitrates, in
the form of nitrate-rich beetroot juice
(BRJ), on endurance exercise perfor-
mance showing improved exercise effi-
ciency by reducing the oxygen cost of
exercise (80,130,142).
Recent developments indicate that
nitrate supplementation may improve
blood flow to a larger extent in type II
muscle fibers (36). Furthermore, type II
muscle fibers may possess a greater
capacity for nitrate storage (70,91) with
increases in maximal knee extensor
velocities in healthy men and women
observed after nitrate supplementation
(26). Accordingly, some suggest that
athletes with a higher percentage of
fast-twitch muscle fibers may reap
superior benefits from nitrate supple-
mentation (70,141). Another potential
mechanism by which dietary nitrates
may improve performance is by
enhancing calcium handing in the
muscle, resulting in improved rate of
force development (57). However,
there are few studies regarding dietary
nitrate consumption and resistance
exercise performance in humans.
Most recently, Trexler et al. (125)
investigated the effects of a single dose
of BRJ (6.4 mmol; 400 mg nitrates) on
5 sets of 30 maximal isokinetic leg ex-
tensions in trained males. Although
BRJ significantly elevated plasma
nitrate concentrations, no differences
in blood flow, blood lactate, muscle
swelling, or exercise performance were
observed compared with placebo or
CitMal. Another study provided 12.9
mmol of BRJ (800 mg nitrate) or pla-
cebo 2.5 hours before repeated 20-s
sprint performance and isometric mid-
thigh pull performance (IMTP) in ado-
lescent males (11). Although there was
no benefit of BRJ supplementation on
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sprint power or fatigue, the BRJ condi-
tion did produce significantly greater
peak force values on the IMTP.
To date, few studies have specifically
examined the effects of a single dose
of dietary nitrate before dynamic resis-
tance exercise performance consisting
of both eccentric and concentric mus-
cle actions. Williams et al. (135) pro-
vided 6.4 mmol of BRJ (400 mg nitrate)
or placebo to resistance-trained males
2 hours before completing 2 separate
bench press protocols. First, partici-
pants completed 2 sets of 2 repetitions
at 70% 1RM of the bench press in
a high-velocity, explosive manner. Sub-
sequently, participants completed 3
sets to failure on the bench press, sep-
arated by 2 minutes of rest, at 70%
1RM. Although maximal velocity and
power were unchanged, mean velocity
and mean power during the 2 3 2 pro-
tocol were higher in the BRJ treatment.
Furthermore, total repetitions com-
pleted during the fatiguing protocol
were higher after BRJ administration
indicating either reduced fatigue or
improved recovery between sets due
to acute nitrate consumption.
Three studies have implemented
a nitrate loading protocol before
a dynamic session of resistance exer-
cise (39,78). Mosher et al. (87) required
resistance-trained males to complete 3
sets of bench press to failure at 60%
1RM after 6 days of supplementation
with 6.4 mmol of BRJ (400 mg nitrate)
or placebo in a crossover fashion. Inter-
estingly, the BRJ treatment completed
more repetitions per set and greater
total repetitions compared to placebo
with no observed differences for lactate
concentrations or subjective fatigue.
Flanagan et al. (39) recruited 14
resistance-trained males to complete
a heavy back-squat protocol (60–90%
1RM) after 3 days of supplementation
with a nitrate-rich (;35.2 mg nitrate)
or nitrate-depleted nutritional bar. No
differences in total repetitions com-
pleted were observed possibly due to
a low daily nitrate dosage. Kramer et al.
(78) provided trained CrossFit athletes
with 8 mmol of potassium nitrate or
placebo for 6 days before completing
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a 30-second Wingate test, 2-km rowing
time trial, and a CrossFit workout in
a crossover fashion. Nitrate supple-
mentation provided a benefit for peak
power production in the Wingate test;
however, no differences were observed
for the CrossFit or 2-km rowing time
trial performance.
Although the focus of this review is
centered around supplements that pro-
mote strength and hypertrophy, there
is compelling evidence to suggest that
dietary nitrates may improve sport-
specific performance. Specifically,
a 2-day BRJ loading protocol signifi-
cantly increased distance covered in
a soccer-specific Yo-Yo intermittent
recovery level 1 test compared with
placebo (143), which was supported
by similar findings in male Dutch ama-
teur soccer athletes (90). Although
most studies have used a supplemental
form of nitrates, diets high in nitrate-
rich foods may also provide benefits
comparable with supplementation.
Porcelli et al. (100) found that 6 days
of a high-nitrate diet (;8.2 mmol/d;
500 mg) consisting of spinach and col-
lard greens significantly improved sub-
maximal knee extension and repeated
sprint performance in recreational
athletes.
Although the evidence supporting die-
tary nitrate consumption to promote
strength and hypertrophy seems opti-
mistic, to date, no chronic training
study has been completed to deter-
mine whether the observed effects
from single dosage and loading proto-
cols translate into meaningful changes
in muscular strength and hypertrophy.
Considering all we know regarding
dietary nitrates, it seems that dietary
nitrate loading (2–6 days; supplemen-
tation or high-nitrate diet) before resis-
tance or sport exercise performance is
preferred over a single dose for ergo-
genic potential with a specific dosage
amount still unclear. Based on early
work in this area, athletes consuming
400–800 mg of dietary nitrates may
experience performance benefits dur-
ing resistance exercise while low dos-
ages (35.2 mg) will not likely generate
an ergogenic effect. However, future
59
 Emerging Nutritional Supplements
work is required to determine
a minimal effective dose of dietary ni-
trates to enhance resistance exercise
performance. In addition, as nitrate
supplements have been reported to
vary considerably in actual nitrate con-
tent (45), athletes and consumers
should be aware that not all products
may prove ergogenic based on labeled
recommended dosages.
PHOSPHATIDIC ACID
Skeletal muscle growth is primarily
dictated by the process of muscle pro-
tein synthesis, and muscle mass accre-
tion is observed when muscle protein
synthesis exceeds muscle protein
breakdown (98). Although the molec-
ular pathways that control muscle
growth are not completely understood,
the mechanistic target of rapamycin
complex 1 (mTORC1) has been
deemed the master regulator of muscle
protein synthesis and plays a critical
role in mediating training-induced in-
creases in muscle hypertrophy (49).
mTORC1 is a multiprotein complex
that can be activated by several signals,
including growth factors, energy status,
amino acids, and mechanical stimuli
(13). The regulation of mTORC1 by
mechanical stimuli such as resistance
exercise seems to be mediated, in part,
by an increased abundance of intra-
muscular PA (93,145). Several lines of
evidence have suggested that PA plays
a critical role in modulating anabolic
signaling by serving as an upstream
regulator of mTORC1 (8,35,63,145).
Furthermore, exogenous PA has been
shown to increase mTORC1 signaling
in vitro (73,138,145).
PA is a phospholipid consisting of
a glycerol backbone with 2 fatty acid
chains and a phosphate group and is
naturally found in the body’s cell mem-
branes, albeit in small quantities (112).
PA can also be found naturally in food
sources including cabbage, tomatoes,
and cucumbers, however, at very low
levels (;0.2–0.55 mg/g) (120). Based
on the evidence suggesting that PA
directly activates anabolic signaling
pathways, researchers have begun
investigating the potential for
60 VOLUME 42 | NUMBER 5 | OCTOBER 2020
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supplemental PA to enhance training-
induced muscular adaptations in
resistance-trained men. To date, 5 stud-
ies have examined the effect of oral PA
supplementation (250–750 mg per day)
in conjunction with a resistance train-
ing program (2,34,50,60,73). In the first
study by Hoffman et al. (60), supple-
menting with 750 mg PA during an
8-week resistance training program
did not significantly improve strength
or hypertrophy measures. Neverthe-
less, using a magnitude-based inference
statistical procedure, it was reported
that PA likely and very likely improved
maximal squat strength and lean body
mass accretion (PA: 1.7 kg; placebo:
0.1 kg), respectively. It is, however,
worth noting that the timing of supple-
mentation was not controlled, and
resistance training sessions were not
supervised by the researchers in this
study (60). Similarly, Andre et al. (2)
found no significant improvements in
strength or hypertrophy measures
when providing lower dosages of PA
(375 or 250 mg per day) during an 8-
week resistance training program.
Likewise, this research group also used
the magnitude-based inference statisti-
cal procedure and reported that PA
likely benefited rectus femoris cross-
sectional area and lean body mass
accretion (despite the average change
being 375 mg PA: 1.3 kg; 250 mg PA:
0.5 kg; placebo: 1.6 kg) and very likely
improved leg press strength. Notably,
the use of magnitude-based inferences
has been criticized, and doubts have
been cast on the conclusions that can
be drawn from the statistical procedure
(108). There have been 2 studies show-
ing more promising outcomes. Joy
et al. (73) reported that 8 weeks of
PA supplementation (750 mg per
day) significantly increased markers
of strength (i.e., leg press strength
and total strength) along with rectus
femoris cross-sectional area and lean
body mass (PA: 2.4 kg; placebo: 1.2
kg) when combined with a resistance
training program. Using a similar study
design, Escalante et al. (34) also re-
ported significant improvements in
maximal strength and lean body mass
(PA: 1.9 kg; placebo: 0.8 kg). However,
PA (750 mg) was provided as part of
a multi-ingredient supplement also
containing leucine, HMB, and vitamin
D3; thus, it is difficult to determine
whether the effects were attributable
to solely PA in this study (34). Finally,
Gonzalez et al. (50) reported no signif-
icant effects on muscle thickness and
strength measures after 8 weeks of PA
supplementation in combination with
a resistance training program.
In summary, only one training study
has reported significant improvements
in strength and hypertrophy outcomes
after 8 weeks of PA supplementation
(73), whereas the other used a multi-
ingredient supplement (34). Two stud-
ies (2,60) found no significant benefit of
8 weeks of PA supplementation but re-
ported small ergogenic effects using the
magnitude-based inference statistical
procedure. Finally, the most recent
study (50) failed to show significant
improvements in strength and hyper-
trophy after 8 weeks of PA supplemen-
tation in conjunction with a resistance
training program. To further confound
matters, acute administration of PA has
actually shown to interfere or blunt
anabolic intramuscular processes.
Smeuninx et al. (115) recently per-
formed the first in vivo mechanistic
investigation of orally ingested PA in
humans. The findings showed that
acute PA ingestion (through a multi-
ingredient supplement containing 750
mg PA along with other phospholi-
pids) interfered with resistance
exercise-induced intramuscular ana-
bolic signaling and muscle protein syn-
thesis in older males. The attenuation
in intramuscular anabolic activity sug-
gests that PA supplementation would
not be an effective means of enhancing
long-term gains in muscle strength and
hypertrophy. The cause of the
observed interference effect remains
unknown. However, these findings
are similar to those reported by Mob-
ley et al. (86) whereby PA coingestion
blunted whey protein-mediated muscle
protein synthesis in rodent skeletal
muscle.
Despite the inconclusive research find-
ings, a dosage of up to 750 mg PA per
 day has been provided in short-term
(i.e., 8 weeks) research studies, with
no side effects reported. Currently, an
optimal dose and timing scheme (if
one exists) remains unclear. To date,
the effect of PA supplementation on
muscle strength and hypertrophy re-
mains equivocal; however, one study
does suggest that supplementation
may offer a small advantage for
improving maximal strength and mus-
cle growth over an 8-week period.
Additional mechanistic and long-term
research studies are necessary to deter-
mine the efficacy and safety of PA as
a means of improving exercise-
induced muscular adaptations.
BRANCHED CHAIN AMINO ACIDS
Muscle protein comprised 20 amino
acids, 9 of which are essential amino
acids (EAAs). EAAs either cannot be
synthesized by the body or the rate of
synthesis does not match the demand
of the body. Only 3 of the 9 EAAs
are BCAAs (leucine, isoleucine,
and valine); however, they make up
approximately 25% of skeletal muscle
amino acids (53). BCAAs (particularly
leucine) appear unique among the
EAAs as key regulators of muscle pro-
tein synthesis (144). For example, leu-
cine has shown to activate the
mTORC1 pathway in animal (3,27)
and human skeletal muscle (133), and
the signaling response has shown to
be enhanced with the addition of
the other 2 BCAA (isoleucine and
valine) (84). However, stimulation of
mTORC1 signaling only indicates pro-
tein synthesis has been stimulated not
sustained, a result that is evident when
mTORC1 signaling is measured
beyond 90 minutes after leucine inges-
tion (22). Nonetheless, the idea that
BCAA supplementation modulates
muscle protein synthesis and augments
muscle strength and hypertrophy has
been perpetuated for decades.
Several lines of evidence suggest that
ingestion of BCAAs stimulate
mTORC1 signaling (5,75,84). How-
ever, few studies have investigated
the muscle protein synthesis response
after administration of isolated BCAAs
Copyright © National Strength and Conditioning Association. Unauthorized reproduction of this article is prohibited.
(i.e., without concurrent ingestion of
the other EAAs or an intact protein
source) (41,67). Fuchs et al. (41)
showed that ingestion of 6 g BCAAs
increased muscle protein synthesis
from 0 to 2 hours after ingestion but
did not maintain this elevation from 2
to 5 hours after ingestion, whereas 30 g
of milk protein (providing an equiva-
lent amount of BCAAs) did sustain
muscle protein synthesis in healthy
older men. In healthy young men, Jack-
man et al. (67) reported that ingestion
of 5.6 g BCAAs after resistance exercise
significantly increased muscle protein
synthesis by 22% in comparison with
a placebo. However, the muscle pro-
tein synthesis response has shown to
be ;50% greater after a dose of whey
protein containing similar amounts of
BCAAs (i.e., 20–25 g whey) compared
with the equivalent dose of BCAAs
(24,139). The lack of a sustained mus-
cle protein synthesis response has also
been reported in healthy young men
after resistance exercise when 6.3 g of
BCAAs were added to a mixed mac-
ronutrient beverage containing 6.25 g
of whey protein isolate as compared to
a mixed macronutrient beverage con-
taining 25 g dose of whey protein iso-
late (23). Therefore, BCAAs seem to
spark a transient, but not sustained,
muscle protein synthesis response
compared with a complete protein
source. Dietary supplementation of
BCAAs alone cannot support a robust
and prolonged muscle protein synthe-
sis response as the availability of other
EAAs will rapidly become rate limit-
ing. Furthermore, there is currently no
evidence that BCAA ingestion inhibits
postexercise muscle protein break-
down in humans.
One potential utility of BCAA supple-
mentation is for a role in recovery after
high-intensity, muscle-damaging exer-
cise. For example, VanDusseldorp et al.
(129) had resistance-trained men sup-
plement with either 0.22 g/kg/d of
BCAAs or placebo for 8 days before
completing a muscle damaging resis-
tance exercise protocol. The BCAA
group displayed reduced plasma crea-
tine kinase (muscle damage marker)
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concentrations, improved recovery of
knee extensor isometric force, and
lower feelings of perceived soreness
after the muscle damaging bout. In line
with this finding, recent meta-analyses
(40,103) have indicated that BCAA
supplementation may improve exercise
recovery and attenuate markers of
muscle damage. However, none of
the studies compared BCAAs with
a complete protein source. Although
it is possible that BCAA supplementa-
tion offers a non-negligible improve-
ment on muscle recovery compared
with a placebo, the effect would likely
be inferior to a complete protein source
containing all EAA.
Currently, there are few studies investi-
gating the long-term effects of isolated
BCAA supplementation on training-
induced strength and hypertrophy out-
comes. Spillane et al. (117) supple-
mented untrained men with either 9
g/d of BCAAs (taken 4 d/wk) or a pla-
cebo during an 8-week resistance train-
ing program. The BCAA group did not
display significant improvement in body
composition, upper-body strength and
endurance, or lower-body strength and
endurance as compared to those who
ingested a placebo (117). Furthermore,
the addition of 3 g BCAAs to 40 g whey
protein did not yield superior benefits
on body composition and strength out-
comes in resistance-trained men during
a 10-week resistance training program,
in comparison with 40 g whey plus 8 g
casein protein (76). Dudgeon et al. (31)
showed that BCAA supplementation
(14 g/d; 7 g before and after training)
enhanced the retention of lean mass and
strength in resistance-trained males
adhering to a hypocaloric diet (degree
of caloric restriction was not defined)
and an 8-week resistance training pro-
gram. However, these results have been
scrutinized, and the applicability of the
reported effects remains question-
able (30).
Owing to leucine’s vital role in maxi-
mally activating muscle protein syn-
thesis after protein ingestion (6),
studies have also investigated the ef-
fects of leucine alone on muscle
strength and hypertrophy in young,
61
 Emerging Nutritional Supplements
healthy populations undergoing resis-
tance training. One study showed that
supplementing 4 g/d of leucine
enhanced strength (as indicated by
5RM strength) during a 12-week resis-
tance training program in untrained
males, despite no differences in body
composition compared with a placebo
(66). However, Aguiar et al. (1) failed to
show benefit of isolated leucine supple-
mentation (3 g/d) on muscle strength
and hypertrophy during an 8-week
resistance training program in
untrained males. Furthermore, Mobley
et al. (85) compared the effects of sup-
plementing twice daily with 3 grams of
leucine versus other dietary protein
sources (i.e., whey and soy) standard-
ized to containing an equivalent dose
of leucine during a 12-week resistance
training program in untrained men.
Although all supplement groups expe-
rienced similar changes in measures of
strength and hypertrophy compared
with the placebo group, only the whey
protein group increased skeletal muscle
satellite cell number—a finding worthy
of further investigation. Although few
data exist, it seems that current training
studies do not support the use of iso-
lated BCAAs or leucine for increasing
strength and hypertrophy.
Based on the available literature,
supplementation with BCAAs or
leucine in isolation to promote
strength and hypertrophy gains is
not warranted. BCAA supplements
may offer limited utility compared
with complete protein sources.
Thus, it would seem more logical
to consume a post-workout whole
protein supplement (i.e., whey) or
a food source/supplement contain-
ing all the EAAs together with a rich
supply of BCAA to promote a robust
anabolic response, in addition to any
potential benefits on alleviating
muscle damage and improving exer-
cise recovery. Ultimately, it seems
unlikely that BCAA supplementa-
tion would offer any advantage for
a strength and power athlete con-
suming adequate amounts of dietary
protein ($1.6 g/kg/d) from high-
quality protein sources.
62 VOLUME 42 | NUMBER 5 | OCTOBER 2020
Copyright © National Strength and Conditioning Association. Unauthorized reproduction of this article is prohibited.
b-HYDROXY-b-METHYLBUTYRATE
Supplementation with the leucine
metabolite, HMB, has been suggested
to enhance strength and body compo-
sition when combined with resistance
training (74). Several mechanisms have
been proposed for the action of HMB
including increased satellite cell prolifer-
ation, increased growth hormone and
insulin-like growth factor 1 (IGF-1)
expression, attenuation of circulating
proinflammatory cytokine expression,
and promotion of intramuscular choles-
terol synthesis (61,109). However,
HMB’s primary mechanisms of action
for promoting gains in muscle strength
and hypertrophy are generally consid-
ered to relate to its effects on protein
metabolism in skeletal muscle. HMB
has shown to increase muscle protein
synthesis through stimulation of
mTORC1 (33,133,134), while also sup-
pressing muscle protein breakdown
through inhibition of signaling cascades
involved in degradation of intracellular
proteins, such as the ubiquitin–
proteasome pathway (116,134). The
effects of HMB supplementation on
strength and hypertrophy has been
extensively studied in a variety of pop-
ulations, yet the conflicting findings
often make it difficult to offer practical
recommendations to athletes (61,109).
Studies investigating the effect of
HMB in its calcium salt form (HMB-
Ca) on strength and body composi-
tion, when combined with a resistance
training program, have offered incon-
clusive findings. Several studies have
reported some favorable outcomes
(32,44,72,77,88,94,101) while others
have failed to find significant benefits
on strength and hypertrophy
(79,92,104,114,122). The discrepant
findings may be explained by several
factors including participants’ training
status, implementation of different
training protocols, and differences in
dietary control. The most pertinent
may be training status as studies with
untrained individuals have reported
positive effects on strength and hyper-
trophy (44,72,88), whereas those with
resistance-trained individuals typically
fail to show ergogenic effects
(79,92,104,114,122). In effort to expli-
cate the conflicting findings, several
meta-analyses have been performed
as the growing body of literature devel-
oped (62,89,107,109,140). In 2009,
Rowlands and Thomson (107) meta-
analyzed the effectiveness of HMB
on strength and body composition in
trained and untrained young men, con-
cluding that HMB exerted small effects
on strength gains in previously
untrained men, whereas the effect in
trained lifters was trivial; the effect of
HMB on body composition was also
trivial in both groups. In line with these
findings, a 2018 meta-analysis by
Sanchez-Martinez et al. (109) found
no effect of HMB supplementation
on strength and body composition in
trained and competitive athletes. Most
recently, a meta-analysis by Holland
et al. (62) suggested that HMB may
have a small, positive impact on fat free
mass in athletes, although the effect
seemed to be specific to when protein
intake is suboptimal (,1.6 g/kg/d).
Much of the research to date regarding
HMB’s effects on strength and hyper-
trophy has been performed with the
administration of HMB-Ca; however,
HMB in its free acid form (HMB-FA)
has recently shown to provide
improved plasma bioavailability
(42,43). The greater absorption rate,
peak plasma concentration, and clear-
ance rate observed after HMB-FA sup-
plementation has been purported to
result in greater intramuscular HMB
bioavailability and thus provide a supe-
rior stimulus on muscle protein metab-
olism, exercise recovery, and muscular
adaptations (113). Nevertheless,
despite observed differences in bio-
availability, HMB-Ca has recently
shown to provide a comparable effect
on stimulating muscle protein synthe-
sis and suppressing muscle protein
breakdown compared with HMB-FA
(134). To date, few studies have exam-
ined the effect of chronic HMB-FA
supplementation on training-induced
strength and hypertrophy outcomes
(7,82,121,127,136). Initial data sup-
ported substantial anabolic properties
of HMB-FA demonstrating sizable
 increases in lean body mass along with
substantial decreases in body fat per-
centage after 12 weeks of supplemen-
tation in conjunction with a resistance
training program (82,136). However,
these studies have been subjected to
considerable scientific scrutiny and
skepticism (47,65,99), and more recent
studies have shown to be largely
underwhelming in comparison show-
ing small increases in some markers
of strength (7,127) with no beneficial
effects on hypertrophy (121,127).
Moreover, 2 studies have compared
HMB forms showing no superiority
of HMB-FA over HMB-Ca for pro-
moting hypertrophy, whereby both
forms failed to promote significantly
greater muscle growth compared with
placebo (121,127). In addition, neither
HMB form seemed to significantly
alter markers of muscle strength and
power in comparison with a placebo
group (121,127), with the exception
of a small, but significant improvement
reported for lower body strength in the
HMB-FA group in comparison with
the HMB-Ca and placebo groups
(127). Finally, another leucine metabo-
lite that has been proposed to possess
anabolic effects (i.e., a-hydroxyisocap-
roic acid) has also failed to enhance
muscle growth and strength develop-
ment during resistance training (121).
In summary, HMB has shown to
exhibit anabolic and anticatabolic ac-
tions in skeletal muscle. The most typ-
ical dosing strategy implemented in
the literature is the administration of
3 g of HMB per day. Moreover,
HMB seems to be a safe dietary sup-
plement in otherwise healthy popula-
tions demonstrating no differences in
blood chemistry, hematology, or uri-
nalysis values after chronic supplemen-
tation (136) and limited to no reports
of adverse effects. Despite some studies
reporting extraordinary changes in
strength and hypertrophy with HMB
supplementation (77,82,136), the
majority of the research in trained in-
dividuals do not support such changes.
Based on the most recent evidence, it
seems that when ingesting an optimal
amount of protein ($1.6 g/kg/d),
Copyright © National Strength and Conditioning Association. Unauthorized reproduction of this article is prohibited.
HMB supplementation would offer
negligible effects on body composition
and strength (68,121,127). Further-
more, despite a lack of research in hu-
mans, it has been speculated that HMB
may attenuate muscle loss during a sus-
tained caloric deficit (95)—a situation
common among weight class and
physique-based athletes. Although
conjectural, HMB supplementation
would likely only confer a small bene-
ficial impact on muscle mass during
a caloric deficit when protein intake
is suboptimal (62). However, restrict-
ing protein during periods of caloric
restriction is not recommended for
strength/power and physique-based
athletes (56). More research is needed
to elucidate the role of HMB supple-
mentation during periods of caloric
restriction in conjunction with a resis-
tance training program.
BETAINE
Betaine (trimethylglycine) is the amino
acid glycine with 3 methyl groups
attached. Betaine serves 2 primary roles
in human physiology. The first is acting
as a methyl donor for the transmethy-
lation of homocysteine potentially
increasing IGF-1 sensitivity and
mTORC1 signaling (19). Betaine also
acts as an osmolyte maintaining fluid
balance and protecting cells against
dehydration, which may have beneficial
effects on muscle protein synthesis
(4,59). Betaine can be obtained through
the diet as sugar beets, wheat bran, spin-
ach, and beets; however, the average
adult only obtains 100–400 mg of beta-
ine per day from their diet (19). This
combined with the fact that supplemen-
tal betaine has been shown to increase
lean mass and decrease fat mass in pigs
has prompted interest in its use as a die-
tary supplement for athletes (37).
Betaine was first shown to be efficacious
for increasing general strength and endur-
ance in 1952 in patients with polio (14).
However, researchers have recently
begun to investigate the effects of supple-
mental betaine in healthy individuals. For
example, Apicella et al. (4) performed
a crossover study where 12 young trained
men ingested either 2.5 g of betaine or
Strength and Conditioning Journal | www.nsca-scj.com
placebo for 14 days. Significantly higher
growth hormone and IGF-1 concentra-
tions, along with lower cortisol concen-
trations, were observed after an acute
bout of whole-body exercise after the
betaine supplementation period. These
results may provide a rationale for the
beneficial effects that have been observed
with studies investigating betaine supple-
mentation and body composition. Using
resistance-trained males, Cholewa et al.
(21) demonstrated that 6 weeks of betaine
supplementation (2.5 g/d) in conjunction
with resistance training increased lean
body mass and decreased fat mass as
compared to a placebo. In a subsequent
study by Cholewa et al. (20), active, resis-
tance training naı̈ve, young women had
significantly greater reductions in body fat
when betaine (2.5 g/d) was ingested
alongside an 8-week resistance training
program; however, there were no signif-
icant differences noted for measures of
muscle growth. On the contrary, Schwab
et al. (110) did not report significantly
greater changes in body composition after
12 weeks of betaine supplementation (6
g/d) in obese adults undergoing a hypoe-
nergetic diet without altering physical
activity. Thus, based off the limited evi-
dence, it seems that chronic betaine sup-
plementation may have beneficial effects
on body composition when resistance
training is performed.
The effect of betaine supplementation on
strength measures are mixed after sub-
chronic (10–14 days) and chronic (6–9
weeks) supplementation periods. Hoff-
man et al. (59) observed no effect of 15
days of betaine supplementation (2.5 g/d)
on vertical jump, bench press throw, or
Wingate test performance in active
college-aged men. In a follow-up study,
the same group (58) found no effect of 15
days of betaine supplementation (2.5 g/d)
on peak concentric or eccentric power
during an isokinetic chest press in active
college-aged men. These results are in
agreement with Trepanowski et al.
(123) who observed no significant im-
provements in lower- (vertical jump) or
upper-body (bench press throw) muscu-
lar power after 14 days of betaine supple-
mentation (2.5 g/d) in resistance-trained
men. Nevertheless, a significant increase
63
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64 VOLUME 42 | NUMBER 5 | OCTOBER 2020

Emerging Nutritional Supplements

Table
Summary of the emerging nutritional supplements for strength and hypertrophy
Supplement Commonly studied Potential mechanisms of action Current state of the evidence
dose

Citrulline 6–8 g/d; 1 h before Enhanced NO bioavailability May induce a small, favorable effect on acute performance of high-intensity strength and
malate exercise Improved blood flow power tasks
Improved ammonia clearance Despite some mixed findings, studies have shown that acute supplementation may
Increased muscle protein synthesis allow individuals to complete more repetitions-to-failure during resistance exercise
More research is needed to investigate strength and hypertrophy outcomes after
chronic supplementation
Nitrates 6.4–12.9 mmol Enhanced NO bioavailability May improve force and power production during isometric and dynamic exercise
(400–800 mg); 2 h Improved blood flow to type II May allow individuals to complete more repetitions-to-failure during resistance exercise
before exercise muscle fibers More research is needed to investigate strength and hypertrophy outcomes after
Enhances skeletal muscle calcium chronic supplementation
handling
Phosphatidic 750 mg/d Enhanced intramuscular anabolic Effects on muscle strength and hypertrophy remains equivocal
acid signaling Acute administration of PA has actually shown to interfere or blunt anabolic
Increased muscle protein synthesis intramuscular processes
BCAA ;6–14 g/d Increased muscle protein synthesis Promotes a transient, but not sustained, muscle protein synthesis response compared
Suppression of muscle protein with a complete protein source
breakdown May accelerate recovery and reduce muscle damage (yet, studies have not compared
Recovery after high-intensity, with a complete protein source)
muscle-damaging exercise. The use of isolated BCAAs or leucine for increasing gains in strength and hypertrophy is
not supported in the current research
BCAA supplements likely offer limited utility compared with complete protein sources
When ingesting an optimal amount of protein ($1.6 g/kg/d), BCAA supplementation
would likely offer negligible effects on body composition and strength
HMB 3 g/d Increased muscle protein synthesis Extensive amount of studies offering conflicting findings regarding effects on muscle
Suppression of muscle protein strength and hypertrophy
breakdown Ergogenic effects are mostly observed in untrained individuals compared to resistance-
trained individuals
HMB-free acid does not appear to induce a greater effect on strength and hypertrophy
outcomes compared with HMB-calcium
When ingesting an optimal amount of protein ($1.6 g/kg/d), HMB supplementation
would likely offer negligible effects on body composition and strength
Betaine 2.5 g/d Acts as an osmolyte and methyl May be effective for reducing body fat
donor Despite some mixed findings, beneficial effects have been noted for markers of strength
and hypertrophy
BCAA 5 branched chain amino acid; HMB 5 b-hydroxy-b-methylbutyrate; NO 5 nitric oxide; PA 5 phosphatidic acid.
 in total repetitions and total volume load
was noted during a 10-set bench press
protocol after betaine supplementation
(123). A lack of significant increase in
measures of muscular strength (bench
press and squat 1RM) and power (max-
imal-velocity repetitions for the bench
press and squat exercises using 60%
1RM) has also been observed in untrained
men supplemented with 2 g/d of betaine
for 10 days (29). However, there have
been some promising outcomes after sub-
chronic betaine supplementation. Lee
et al. (81) found an increase in bench press
throw power and isometric force after 14
days of betaine supplementation (2.5 g/d)
in healthy, recreationally active men. In
addition, Pryor et al. (102) demonstrated
that 7 days of betaine supplementation
(2.5 g/d) improved cycling sprint power
in recreationally active men and women.
However, in chronic training studies
investigating the effect of betaine supple-
mentation (2.5 g/d) in resistance-trained
men (6 weeks of resistance training and
supplementation) and active, resistance
training naı̈ve women (8 weeks of resis-
tance training and supplementation), no
betaine-induced benefits were observed
on strength measures (20,21).
Although preliminary in nature, the evi-
dence suggests that betaine supplementa-
tion may be an effective approach for
reducing body fat (46). Some beneficial
effects have also been noted for strength
and power performance, along with meas-
ures of hypertrophy, after betaine supple-
mentation. However, these are not
consistent findings. Researchers have
investigated dosages ranging from 2 to 5
g/d betaine, and 2.5 g/d split into 2 equal
servings throughout the day which are the
most common dosing strategies in the lit-
erature. There is an apparent need for
more research (e.g., dose response studies,
chronic training studies, etc.) before a con-
sensus on the efficacy of betaine supple-
mentation for improving measures of
strength and hypertrophy can be reached.
SUMMARY AND PRACTICAL
APPLICATIONS
Several supplements have been pur-
ported to promote strength and
Copyright © National Strength and Conditioning Association. Unauthorized reproduction of this article is prohibited.
muscle mass when combined with
a resistance training regimen. How-
ever, few have received the scien-
tific attention required to make
evidence-based recommendations
to athletes (i.e., caffeine, creatine,
and whey protein). This article pro-
vided an overview of the growing
body of evidence surrounding some
popular supplements that have been
purported to augment training adap-
tations (Table).
Further research is required to pro-
vide athletes with better information
to guide their decisions about the use
of several supplements. Sports scien-
tists should continue to investigate
the potential of these supplements
to enhance strength and hypertro-
phy to expand upon evidence-based
recommendations of efficacy and
safety. Athletes and bodybuilders
are recommended to use the evi-
dence provided in this article to
guide their decisions about the use
of these emerging nutritional
supplements.
Conflicts of Interest and Source of Funding:
The authors report no conflicts of interest
and no source of funding.
Adam M.
Gonzalez is an
assistant profes-
sor in the Exer-
cise Science
program at Hof-
stra University in
Hempstead.
David D.
Church is a post-
doctoral fellow at
The Center of
Translational
Research in
Aging and Lon-
gevity at the
University of
Arkansas for
Medical Sciences in Little Rock.
Strength and Conditioning Journal | www.nsca-scj.com
Jeremy R.
Townsend is an
assistant profes-
sor in the Exer-
cise and
Nutrition Science
graduate pro-
gram at Lips-
comb University
in Nashville.
Reza Bagheri is
a PhD student of
Exercise Physiol-
ogy at the Uni-
versity of Isfahan
in Isfahan.
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