Sports Med
DOI 10.1007/s40279-016-0525-x
REVIEW ARTICLE
Co-ingestion of Nutritional Ergogenic Aids and High-Intensity
Exercise Performance
Alireza Naderi1 • Conrad P. Earnest2 • Ryan P. Lowery3 • Jacob M. Wilson3
Mark E. T. Willems4
Ó Springer International Publishing Switzerland 2016
Abstract Many sports involve repeated bouts of high-
intensity exercise. High-intensity exercise is compromised,
however, by the early onset of exercise-induced fatigue.
Metabolic by-products, ion dysbalance and amount of
phosphocreatine are considered the main peripheral causes
of fatigue during high-intensity exercise. Intake of nutri-
tional ergogenic aids is commonplace to enhance perfor-
mance of high-intensity exercise by offsetting the potential
mechanisms of fatigue. Creatine, probably one of the best
known nutritional aids to enhance performance of high-
intensity exercise, has convincingly substantiated its
ergogenic potential. Although multi-ingredient supple-
ments are now common, the justification for effectiveness
is mostly based on observations with single intake of those
ingredients. In this narrative review, the main focus is on
the evidence of the effect of co-ingestion of ergogenic aids
on performance of high intensity exercise for which the
single intake has shown beneficial effects on high-intensity
performance.
& Mark E. T. Willems
m.willems@chi.ac.uk
1
Department of Sport Physiology, Boroujerd Branch, Islamic
Azad University, Boroujerd, Iran
2
Exercise & Sport Nutrition Laboratory, Texas A&M
University, College Station, TX, USA
3 enhanced by the consumption of some ergogenic aids such
Department of Health Sciences and Human Performance,
The University of Tampa, 318 N Boulevard, Tampa,
FL 33606, USA
4
Department of Sport and Exercise Sciences, University of
Chichester, College Lane, Chichester, UK
•
Key Points
Studies on effects of co-ingestion of nutritional
ergogenic aids are more prevalent.
Co-ingestion of some ergogenic aids may improve
high-intensity exercise performance.
Sports nutritionists must have awareness of effects of
co-ingestion of nutritional ergogenic aids to better
advise athletes.
1 Introduction
Many sports include activities with high-intensity exercise
(HIE) over a sustained period, for example, in sprint and
middle distance running, or with short repeated bursts of
HIE interspersed with periods of low-intensity exercise in
team sports such as soccer, handball and basketball [1].
During HIE, energy is mainly supplied by phosphocreatine
(PCr), the anaerobic breakdown of carbohydrate (CHO) in
addition to the aerobic breakdown of substrates (in a range
of 30–90 %) [2]. Both aerobic and anaerobic processes of
substrate breakdown are limited by the rate (power) and
amount (capacity) of adenosine triphosphate (ATP) pro-
duction [1]. High-energy phosphate stores and the maximal
amount of lactate/proton production in skeletal muscle are
identified as important factors for the capacity of the
anaerobic energy system [1]. Such capacity can be
as creatine, b-alanine and sodium bicarbonate (NaHCO3)
[1]. It is the duration and type of exercise that will influ-
ence the contribution of fatigue processes in the neuro-
muscular and central nervous system (CNS).
123

In general, muscle fatigue is described as an exercise-
induced reduction in the ability of muscle to produce force
or power [3]. For HIE, several fatigue mechanisms may be
operational, such as a lowering of ATP, accumulation of
inorganic phosphate (Pi) [4], muscle acidosis (i.e., the
accumulation of lactate and H?), increased extracellular
potassium, lowering of muscle glycogen, lowering of
muscle PCr stores as well as dehydration and electrolyte
imbalances [5]. There is strong evidence that we can delay
exercise-induced fatigue by nutritional manipulation [6].
Intake of ergogenic supplements is one of the most com-
mon methods used by athletes. It has been shown that the
intake of some sports supplements is able to delay the
factors contributing to fatigue in HIE, for example, sup-
plementation with NaHCO3 and b-alanine will enhance
buffering capacity in blood and muscle [7, 8]. Creatine
supplementation is useful for increasing PCr stores [9]. It
has been shown that caffeine intake reduced extracellular
potassium accumulation [10], and it is well-documented
that consumption of CHO-rich foods 3–4 h prior to exer-
cise increases muscle and liver glycogen stores and may
delay exercise-induced fatigue.
In the last decade, more attention has been given to
whether co-ingestion of nutritional supplements would
provide additional benefits for those athletes engaged in
HIE. For example, Tobias et al. [11] reported that the co-
ingestion of b-alanine with NaHCO3 provided an addi-
tional ergogenic benefit during four bouts of 30-s upper
body Wingate tests. Furthermore, Kilding et al. [12] indi-
cated that NaHCO3 and caffeine co-ingestion had no
additive effect compared with NaHCO3 and caffeine sup-
plementation alone.
This narrative review will focus on the effectiveness of
co-ingestion of sports supplements on HIE performance,
including caffeine? NaHCO3, b-alanine ? NaHCO3, b-
alanine ? creatine, creatine ? caffeine, and cre-
atine ? NaHCO3. The review will also provide informa-
tion on the metabolic regulation of HIE, the mechanisms of
fatigue during HIE and the effects of co-ingestion of sports
supplements on HIE performance. Scientific papers were
retrieved in accordance with an extensive search in
PubMed (2000–2015) and Google Scholar (2000–2015).
Computer search engines used the following combinations
of keywords: ‘‘high intensity exercise,’’ ‘‘exercise fatigue,’’
‘‘high intensity exercise fatigue,’’ ‘‘metabolism exercise,’’
‘‘high intensity exercise metabolism,’’ ‘‘sodium bicarbon-
ate beta-alanine exercise,’’ ‘‘beta-alanine NaHCO3 exer-
cise,’’ ‘‘beta-alanine exercise,’’ ‘‘sodium bicarbonate
exercise,’’ ‘‘caffeine sodium bicarbonate exercise,’’ ‘‘caf-
feine exercise,’’ ‘‘caffeine supplementation,’’ ‘‘creatine
sodium bicarbonate exercise,’’ ‘‘creatine supplementation
exercise,’’ ‘‘creatine beta-alanine exercise,’’ ‘‘beta-alanine
supplementation,’’ ‘‘caffeine creatine exercise,’’ and
123
A. Naderi et al.
‘‘caffeine creatine supplementation.’’ Selected studies were
limited to humans as participants in randomized controlled
trials. References cited in the retrieved articles were also
considered. In this review, co-ingestion of nutritional
ergogenic aids means the intake of supplements separately
at more or less the same time, whereas combined intake
would mean the intake at the same time due to their
presence in one product. This narrative review will provide
information on the metabolic regulation of HIE, mecha-
nisms of fatigue during HIE, followed by the effects of co-
ingestion of sports supplementation on HIE performance.
2 Metabolic Regulation in High-Intensity Exercise
(HIE)
Energy for exercise is provided by ATP regardless of
intensity or duration. The quantity of ATP in skeletal
muscle is approximately 3–5 lmol/g or 6 mmol/kg of fresh
muscle [13, 14]. For work to continue, ATP must be
replenished at a rate equal to ATP utilization, and the
utilization of ATP and its provider sources are dependent
on intensity. During HIE, ATP is provided directly by the
intramuscular stores of PCr (aka creatine phosphate) and
muscle glycogen. It should be further noted that these
systems do not function independently, but work syner-
gistically. For example, Hirvonen et al. [15, 16] demon-
strated in sprinters running between 40 and 400 m that
ATP and PCr stores appear to drop to a ‘‘critical’’ con-
centration that is maintained within a lower limit, physio-
logic window, while blood lactate increases corresponding
to distance in order to ‘‘protect’’ or maintain ATP pro-
duction in the face of continued work (Fig. 1).
Fig. 1 Schematic representation of energy provision during high-
intensity running performance (adapted from Hirvonen et al. [15,
16]). ATP adenosine triphosphate, PCr phosphocreatine
Supplementation and High-Intensity Exercise
2.1 Endogenous Synthesis and Stores of Adenosine
Triphosphate (ATP)
The provision of ATP is known as maximal ATP power and
generally follows the pattern of provision to energy where
small stores correspond to higher intensity exercise and
larger stores to lower intensity work. Despite low concen-
trations of ATP and PCr within muscle, their ATP power is
exceptional. Especially noteworthy is the consideration of
creatine monohydrate as an ergogenic aid given its ability to
increase maximal ATP power. The available energy
capacity (mol ATP), maximal ATP power produced [per
mmol ATP/kg of dry muscle (dm)], exercise intensity
supported, and duration of activity allowed per energy
source is well established. With regard to anaerobic energy
sources, ATP stores within muscle (0.02 mol ATP) provide
*11.2 mmol ATP/kg dm and support very high-exercise
intensities lasting *1–2 s [17]. PCr stores (0.34 mol ATP)
produce 8.6 mmol ATP/kg dm and also support high-ex-
ercise intensities, and last approximately 30–120 s.
Anaerobic glycolysis via intramuscular glycogen stores
(5.2 mol ATP) produce 5.2 mmol ATP/kg dm, and support
high, rather than very high-intensity exercise [17]. Training
status also affects anaerobic glycolysis, as trained individ-
uals have a slower conversion rate of glycogen to ATP,
presumably as a function of shifting to being more efficient
at converting fatty acids [18]. Thus, the longer HIE persists,
the less reliant one becomes on ATP resynthesis by PCr.
2.2 Proton and Temporal Spatial Energy Buffer
Over the last 2 decades, supplementation with creatine
monohydrate has gained great application for its effec-
tiveness in increasing anaerobic capacity via the PCr
pathway, whereby PCr acts as a phosphate donor for the
resynthesis of ATP. Important to this discussion is that the
foremost function of PCr is to maintain a state of metabolic
flux or provision of ATP energy currency. When ATP is
used for energy, phosphate is hydrolyzed from ATP to
form adenosine diphosphate (ADP):
ATP þ H2 0 ! ATPase ! ADP þ Pi
The ratio of available ATP divided by ADP and Pi
provides both a biochemical measure and an in vivo signal
that dictates the control of cellular energetics. Continued
energy production or ‘‘metabolic flux’’ is predicated on the
fact that each biochemical pathway is unable to generate or
maintain a steady-state energy flux by itself [13]. Overall,
creatine monohydrate has been shown to increase energy
flux by acting as a temporal energy buffer by increasing the
ability of PCr to act as a hydrogen buffer consequent to
ATP hydrolysis [19]. When the creatine kinase reaction
favors ATP regeneration, H? is utilized, thus helping to
prevent the acidification of cells. The only known reaction
involving creatine and PCr is the reversible creatine kinase
reaction, which is controlled by creatine kinase [20]:
PCr þ ADP þ Hþ ! CPK ! CR þ ATP
in which CPK and CR are creatine phosphokinase and
creatine, respectively.
This reaction is moved to the right by removal of ATP
during energy production and to the left during energy
generation at sites at the mitochondria. The role of creatine
and PCr as a spatial energy buffer via the PCr energy
shuttle hypothesis is widely accepted [21, 22]. In this
model, a CPK-specific isoenzyme resides at a peripheral
terminus located at the myosin head. After phosphorylating
ATP via the CPK reaction, free creatine diffuses into the
cytosol and travels back to the mitochondria, where it
arrives at the energy-generating terminus in the mito-
chondria. Free creatine interacts with another specific
isoenzyme of CPK where PCr is formed from mitochon-
drial ATP. The PCr is then shuttled back to the site of
utilization or actin myosin complex. This becomes an
important consideration in that glycolysis is not reduced
during longer ([30-s) anaerobic work tasks with or without
creatine monohydrate supplementation. Therefore, optimal
stores of free creatine are important to energy production
and the shuttling of ATP derived from glycolysis.
2.3 Glycolysis Modulator
With the onset of sudden and intense exercise, glycolytic
flux typically increases several hundredfold. During HIE,
the resynthesis of ATP takes place primarily through the
simultaneous breakdown of PCr and anaerobic glycolysis
[23–25]. As intense exercise continues, PCr concentrations
fall dramatically in an effort to maintain ATP, thereby cre-
ating an increased need for replenishing ATP in the active
muscle. In vitro evidence suggests that glycolysis is stimu-
lated by the decline in PCr due to its removal as an inhibitor
of phosphofructokinase. When PCr levels decrease, phos-
phofructokinase becomes uninhibited, subsequently allow-
ing glycolysis to increase. This elevated rate of glycolysis
produces more ATP due to the increased energy demands
required of the active muscle [26]. PCr depletion is &300 %
faster than glycogen depletion [23], and as previously dis-
cussed, Hirvonen et al. [15, 16] have demonstrated the
reduction in PCr stores in sprints lasting from 40 to 400 m.
Similar observations have been observed during varied
bouts of cycling lasting from 6 to 30 s [23, 27, 28] and
repeated electrically stimulated muscle contractions lasting
1.6 s for 52–63 contractions at 20 Hz [29, 30]. While bodily
endogenous stores of ATP are relatively set, PCr and muscle
glycogen stores can be expanded via dietary manipulation
with creatine monohydrate and CHO ingestion.
123

3 Mechanisms of Fatigue in HIE
3.1 Adenosine Triphosphate (ATP)
and Phosphocreatine (PCr) Relationship
Fatigue during HIE encompasses a number of integrated
components involving bioenergetics, ionic dysbalance and
neuromuscular factors. For the purposes of this review, we
will only discuss those factors related to metabolic sub-
strates. Overall, PCr correlates strongly with the develop-
ment of fatigue and decline in muscular force exhibited
during exercise [31]. This was also demonstrated by
Infante et al. [32], who showed a direct relationship
between external work and PCr breakdown in the frog
rectus abdominis. Spande and Schottelius [33] further
showed a direct relationship between force production and
PCr stores in tetanically stimulated isolated mouse soleus
muscle. In humans, Hirvonen et al. [15, 16] concluded that
the slowing of running speed may be related to a decline in
energy production brought forth from ATP and PCr stores
in that type II muscle fibers possess higher initial levels of
PCr and, consequently, greater rates of PCr utilization than
type I muscle fibers [34–37]. Hultman et al. [31] has shown
a significant decrease in PCr concentration associated with
5-min cycling bouts at 0 watts (W) (*6.8 PCr mmol/
g dm), 65 W (*5 PCr mmol/g dm), 130 W (*3 PCr
mmol/g dm) and 195 W (*1.5 PCr mmol/g dm). In order
to maintain continued force production, the rate of PCr
resynthesis must increase to meet the higher energy
expectations required by the active muscle. It must be
further appreciated that during high-intensity, intermittent
exercise, the rate of PCr resynthesis plays an important role
in the force capabilities muscle can generate during
sequential bouts of exercise, owing to the heavy reliance on
substrates of PCr and ATP. To this end, it has been cal-
culated that 80 % of the ATP production for the last of ten
6-s sprints on a cycle ergometer is derived from PCr.
If PCr resynthesis is not given adequate recovery time,
performance is impaired and power output is decreased [27,
38–40]. When recovery is prolonged, increased PCr con-
centrations are correlated with greater power output during
consecutive cycle ergometer sprints allowing 90 and 180 s
as rest periods, respectively [40]. As PCr concentrations
decrease, the conversion of muscle glycogen must continue
at a sufficient rate (e.g., glycolytic rate) to maintain power
output or fatigue will ensue without a decrease in exercise
intensity, as the rate of glycolysis is also associated with
exercise intensity, as depicted in Fig. 2.
3.2 Acid Base Status and Lactate Accumulation
It has been postulated that the decline in power output
observed during HIE may be the result of lactic acid
123
A. Naderi et al.
Fig. 2 Schematic representation of decreased glycolytic rate associ-
ated exercise intensity during workloads designed to elicit exhaustion
at predetermined times [41]
accumulation in the muscle that dissociates to the lactate
anion and hydrogen cation. Subsequently, intracellular pH
decreases causing several performance attenuating effects
in both the intracellular and extracellular milieu. Increased
hydrogen concentration may affect the contractile appara-
tus by affecting calcium and/or myosin ATPase [42] as
well as the CPK equilibrium reaction [43]. The resulting
acidosis may then also affect the key glycolytic enzymes
phosphorylase and phosphofructokinase [44]. While cre-
atine has been the subject of numerous research reports, the
capacities of a number of additive constituents to offset
fatigue during exercise and/or increase recovery following
exercise have been investigated. These include co-ingest-
ing various supplements such a creatine with b-alanine or
NaHCO3, as well as other supplements, such as caffeine.
4 The Effects of Sodium Bicarbonate (NaHCO3)
and Caffeine Co-ingestion on Performance
Caffeine (1,3,7-trimethyl-xanthine) is one of the most
popular dietary supplements used by athletes. Caffeine
supplementation at dosages of 3–6 mg/kg improved aero-
bic long-duration exercise performance through its mech-
anism of action including effects on the CNS, increasing
free fatty acid mobilization and direct effect on muscle
contraction [45]. For high-intensity, short-duration exer-
cise, a number of studies have demonstrated that caffeine
supplementation leads to decreased extracellular potassium
concentration and increased plasma catecholamine con-
centration, which could delay fatigue and improve perfor-
mance [5, 10, 46]. NaHCO3 is an extracellular buffer
having an important role in maintaining blood pH. In
effect, supplementation with NaHCO3 elevates the extra-
cellular buffering capacity and enhances HIE performance
Supplementation and High-Intensity Exercise
[47]. Theoretically, intake of NaHCO3 along with caffeine
could have a beneficial additive effect for those athletes
involved in HIE. Christensen et al. [48], in a double-blind,
randomized, placebo study, investigated the ergogenic
effect of NaHCO3 plus caffeine in 12 elite, well-trained
rowers (six open-weight, six light-weight) during a 6-min
maximal performance test for 4 days. Total distance, mean
power and perceived exertion were measured in the study.
The rowers were supplemented with 3 mg/kg caffeine with
calcium as a placebo, 300 mg/kg NaHCO3 with dextrose as
a placebo, or caffeine (3 mg/kg) ? NaHCO3 (300 mg/kg)
with calcium and dextrose as placebo. These dosages were
given at 45 min (caffeine) and 75 min (NaHCO3) prior to a
maximal performance test. The results indicated that total
distance for all rowers given caffeine and caffeine?
NaHCO3 was longer than for those given placebo and
NaHCO3. Mean power for all rowers given caffeine and
caffeine? NaHCO3 was also higher than for placebo and
NaHCO3. However, no differences were observed in
average distance on the first, second, third and fourth days
of the test. There was no difference in perceived exertion
between all groups during 6-min maximal performance
test. The authors found that ingestion of caffeine and caf-
feine? NaHCO3 improved 6-min maximal rowing test but
caffeine? NaHCO3 had no additional benefits in all rowers
and NaHCO3 had no ergogenic effect [48]. The lack of
enhanced performance in the NaHCO3 group is thought to
be related to lower blood flow in rowing, which could
result in reduced leg H? ion release such that intramuscular
leg acidification is not a limiting factor in rowing exercise
compared with running and cycling [48]. In a review paper
by Juel [49], it was noted that training adapts the pH reg-
ulation in blood and skeletal muscle. This may blunt or
prevent a performance effect with NaHCO3 intake in well-
trained individuals. Also, Pruscino et al. [50] showed that
the ergogenic effect of caffeine ingestion alone was limited
when it was co-ingested with NaHCO3. However, the
authors showed that either NaHCO3 alone or caffeine and
NaHCO3 led to enhanced performance in two series of
200-m swimming freestyle [50]. In addition, Kilding et al.
[12] showed that ingestion of caffeine (3 mg/kg) and
NaHCO3 (300 mg/kg) alone enhanced high-intensity
cycling time trial performance in ten well-trained cyclists.
Mean power output was higher in caffeine, NaHCO3 and
caffeine? NaHCO3 trials (2.4, 2.6 and 2.7 %, respec-
tively), resulting in faster performance times (-0.9, -1.2
and -1.2 %), with no additional improvement with co-
ingestion of caffeine? NaHCO3 [12]. Carr et al. [51]
reported gastrointestinal discomfort when NaHCO3 was
co-ingested with caffeine, which may have prevented
enhanced performance during exercise. However, no dis-
comfort with NaHCO3 intake was observed in the study of
Christensen et al. [48]. Recently, it was reported that co-
ingestion of NaHCO3 and caffeine resulted in an
improvement in judo performance compared with placebo.
However, when caffeine and NaHCO3 were supplemented
alone, the performance was not improved. This synergistic
effect was attributed to reuptake of K? by muscle fibers by
co-ingestion of NaHCO3 and caffeine. The authors also
reported that when NaHCO3 intake is divided into three
doses and spaced 30 min apart (0.1 g/kg of body weight at
120, 90 and 60 min before exercise), gastrointestinal dis-
tress is prevented [52]. Collectively, it seems that there is a
discrepancy between the results of the studies (Table 1).
Thus, future research should address the effects of co-
ingestion of caffeine and NaHCO3 in different exercise
models, e.g., in those in which gastrointestinal discomfort
does not seem to compromise the performance enhance-
ment [53].
5 The Effects of NaHCO3 and b-Alanine Co-
ingestion on Performance
Carnosine is a dipeptide that is synthesized from b-alanine
and histidine amino acids and has been identified as an
important intramuscular buffer [7]. There are a number of
studies that reported on the co-ingestion of b-alanine with
NaHCO3 in an attempt to increase both intra- and extra-
cellular buffering capacity [54–56]. In theory, increase of
muscle carnosine content and blood HCO3- levels may
improve exercise performance and postpone or minimize
muscle fatigue in those athletes who are exposed to the
intramuscular acidosis mediated by the HIE. Danaher et al.
[54] examined the effects of 6 weeks of b-alanine sup-
plementation (4.8 g/4 weeks and 6.4 g/2 weeks thereafter)
with NaHCO3 (300 mg/kg 90 min prior to the test) on
muscle carnosine content, blood pH, HCO3- and physical
performance during repeated sprint ability tests (five
repeats of 6-s maximal effort cycling bouts separated by
24 s rest) and a cycling capacity test at 110 % of maximal
power. The results demonstrated an increase in the muscle
carnosine content in gastrocnemius and soleus muscles by
62 % and 88 % in the b-alanine group and the groups
supplementing with b-alanine ? NaHCO3, and NaHCO3
had higher blood pH and HCO3- levels. In addition, there
was no difference in peak and average power output and
total work done during the repeated sprint ability test fol-
lowing co-ingestion of b-alanine ? NaHCO3 compared
with either b-alanine or NaHCO3 alone and placebo (cal-
cium carbonate). The investigators also found that co-
ingestion of b-alanine ? NaHCO3 during the cycling
capacity test at 110 % resulted in a higher time to
exhaustion by 16 % and 14 % with b-alanine compared
with placebo, but no additional improvement was shown
between b-alanine alone and b-alanine ? NaHCO3 and
123
 A. Naderi et al.

CAF and NaHCO3 alone improved performance, but

NaHCO3 and CAF ? NaHCO3 improved swimming

there was no change in time to exhaustion following

additional effects in all rowers, NaHCO3 had no

maximal rowing, but CAF ? NaHCO3 had no
NaHCO3 supplementation [54]. However, a few studies

Only ingestion of CAF improved performance

CAF ? NaHCO3 co-ingestion improved judo
also reported that NaHCO3 supplementation alone further

CAF and CAF ? NaHCO3 improved 6-min

CAF ? NaHCO3 had no additive effect

improved exercise performance compared with either b-
alanine and NaHCO3 co-ingestion or b-alanine alone in
repeated running sprint tests [57] and maximal sprint
swimming [58]. In contrast, Tobias et al. [11], in a ran-
domized, double-blind, placebo-controlled study, exam-
ined the effect of 4 weeks of b-alanine
(6.4 g/day) ? placebo (dextrose), NaHCO3 (500 mg/kg
for 7 days during the fourth week) ? placebo (dextrose),
performance

performance
and b-alanine (6.4 g/day) ? NaHCO3 (500 mg/kg) during
four bouts of 30-s upper body Wingate tests with a 3-min
effect
Results

recovery in each bout. It was observed that total work

performed for b-alanine ? NaHCO3 (14 %) was more
efficient than NaHCO3 (7 %) and b-alanine (8 %) alone
[11]. Mean power was also greater in all four bouts in the
Special judo fitness

3-km cycling time

NaHCO3 ? b-alanine group compared to the b-alanine

200-m freestyle
6-min maximal

group (second and third bouts) and the NaHCO3 group

2 9 maximal
Exercise test
Table 1 Human studies on the effects of sodium bicarbonate (NaHCO3) and caffeine (CAF) co-ingestion on performance

6 9 2000-m

time trials

(fourth bout), with post-exercise blood lactate increased in

ergometer
rowing

rowing

all groups and rate of perceived exertion only affected by

trial
test

b-alanine and NaHCO3 alone [11]. It is likely that the

additive effect of b-alanine ? NaHCO3 is related to the
intermittent super maximal test, which resulted in greater
prior to the test, 60

45 and 75 min prior

30 and 90 min prior

45 and 90 min prior

120, 90 and 60 min

60 and 90–120 min

intramuscular acidosis in comparison with continued HIE

min prior to the

prior to the test

[59]. The chronic NaHCO3 loading during the fourth week

to the test

to the test

to the test

(500 mg/kg) may have resulted in further enhancement of

the blood buffering capacity in comparison with those
Timing

test

studies that used an acute protocol with NaHCO3 supple-

mentation (300 mg/kg prior to the test). Furthermore,
Hobson et al. [60] reported in highly trained rowers a
possible additional benefit in 2000-m rowing ergometer
performance following b-alanine ? NaHCO3 compared
6.2 mg/kg CAF ? 300
3 mg/kg CAF ? 300

3 mg/kg CAF ? 300

6 mg/kg CAF ? 300

300 mg/kg NaHCO3

with b-alanine alone. Also, some studies indicated that co-

? 6 mg/kg CAF

mg/kg NaHCO3

mg/kg NaHCO3

mg/kg NaHCO3

mg/kg NaHCO3
Supplementation

ingestion of b-alanine with NaHCO3 had a further non-

significant improvement in total work done, time to
Daily dose

exhaustion and performance [55, 61]. It seems that dis-

crepancies in findings of co-ingestion of NaHCO3 with b-
alanine in the studies may be due to different exercise
protocols, the characteristics of the subjects, and different
protocols of NaHCO3 supplementation (Table 2). Further
n = 10, judokas

n = 10, cyclists

n = 6, freestyle
n = 12, rowers

n = 8, rowers

research is required on the effect of chronic NaHCO3

swimmers

loading with b-alanine co-ingestion during HIE.

Subjects

6 The Effects of Caffeine and Creatine

Co-ingestion on Performance
Christensen et al. [48]

Pruscino et al. [50]

Kilding et al. [12]
Felippe et al. [52]

Creatine is produced from the amino acids glycine, argi-

Carr et al. [51]

nine and methionine in the kidney, liver and, in a lesser

amount, the pancreas [62]. The majority of creatine is
Study

stored in skeletal muscle, and it exists in phosphorylated

and free forms. It is well-documented that creatine

123
Supplementation and High-Intensity Exercise

No additive effect of b-alanine and NaHCO3 co-

supplementation leads to an ability to maintain intensity

b-alanine ? NaHCO3 had a minimal additional

Chronic b-alanine ? NaHCO3 intake enhanced
performance compared with NaHCO3 and b-

No additional effect of b-alanine ? NaHCO3

ingestion, no effect of NaHCO3 on cycling
during HIE due to the more rapid regeneration of ATP [63].

NaHCO3 enhance performance, no additive

additional effect of b-alanine ? NaHCO3

NaHCO3 improved performance more than

b-alanine improved performance with no

It was reported that with co-ingestion of caffeine with
creatine, the ergogenic benefit of creatine was unaffected

effect of b-alanine ? NaHCO3

[64]. In addition, Vanakoski et al. [65] reported that cre-

alanine supplementation alone

atine and caffeine co-ingestion do not show pharmacoki-
netic interaction. Also, Hespel et al. [66] demonstrated that

NaHCO3 ? b-alanine
4 days of creatine loading decreased muscle relaxation
time, whereas chronic caffeine supplementation resulted in
increased muscle relaxation time [66]. This result may
explain the lack of an ergogenic effect with co-ingestion of

effect
Results

time

caffeine and creatine reported by Vandenberghe et al. [64],

with potentially an insufficient washout period for creatine
(i.e., 3 weeks) and the timing of the caffeine intake (i.e.,
2 9 100 maximal sprint swimming
Repeated sprint ability and cycling

4 bouts upper body Wingate tests

about 20 h before post-test). In line with this, Harris et al.

2 9 100 time trial swimming

[67] reported that effects of creatine loading were blunted

by gastrointestinal discomfort with intake of creatine and
4-min cycling time trial

Cycling capacity test

caffeine (2–24 h after post-test cessation). Other studies,

Repeated sprint test

however, showed an increase in intramuscular creatine

capacity test

following co-ingestion of creatine with caffeine [65, 66].

Exercise test
Table 2 Human studies on the effects of sodium bicarbonate (NaHCO3) and b-alanine co-ingestion on performance

Subsequently, it was shown that ingestion of caffeine after

creatine supplementation improved exercise performance.
In the study by Doherty et al. [68], it was observed that the
acute ingestion of caffeine (5 mg/kg 1 h prior to the test)
2 weeks, 4 weeks, 90 min

4 weeks, 2 weeks, 90 min

4 weeks, 60 min prior to

4 weeks, 60 min prior to

4 weeks, 90 min prior to

after 6 days of creatine loading (4 9 5 g) improved time to

exhaustion during running on the treadmill at 125 % of
Duration and timing

prior to the test

prior to the test

4 weeks, 1 week

maximum oxygen uptake by over 10 % compared with

4 weeks, 2 days

baseline and placebo trials. In addition, Lee et al. [69]

the test

the test

the test

examined the acute effect of caffeine ingestion after cre-

atine loading on intermittent high-intensity sprint perfor-
mance. Twelve physically active males were assigned to
either creatine ? caffeine or creatine ? placebo groups.
65 mg/kg b-alanine ? 300 mg/kg

alanine ? 300 mg/kg NaHCO3

The subjects were supplemented with 0.3 g/kg of creatine

4.8 g b-alanine, 6.2 g b-alanine,

6.4 g b-alanine ? 500 mg/kg

4.8 g b-alanine ? 300 mg/kg

6.4 g b-alanine ? 300 mg/kg

for 5 days ? 6 mg/kg placebo or 0.3 g/kg creatine for

6 g b-alanine ? 300 mg/kg

5 days, followed by 6 mg/kg of caffeine 1 h prior to an

3.2 g b-alanine, 6.4 g b-
300 mg/kg NaHCO3

intermittent high-intensity sprint test (6 9 10-s sprints with

60 s active recovery). In this test, mean and peak power
Supplementation

were increased after creatine ? caffeine supplementation

Daily dose

NaHCO3

NaHCO3

NaHCO3

NaHCO3

NaHCO3

during the test compared with baseline (i.e., the subjects

performed the test before consumption of any ergogenic
aids), and creatine ? placebo provided greater mean and
peak power compared with baseline. This study also
n = 8, recreationally

revealed a positive ergogenic effect of caffeine ingestion

n = 24, team sport

n = 12, physically
n = 13, swimmers

n = 18, swimmers
n = 13, cyclists
n = 40, combat

after creatine loading [69]. However, recently, Trexler

active males

active males

et al. [70] observed that co-ingestion of coffee (8.9 g

athletes

athletes
Subjects

instant coffee with 303 mg caffeine content) and caffeine

anhydrous (0.3 g/kg) during creatine loading (20 g) for
5 days did not enhance strength and sprint performance in
Danaher et al. [54]

Ducker et al. [57]

De Salles Painelli

physically active men. In agreement with a study by Harris

Tobias et al. [11]

Mero et al. [58]

Bellinger et al.

Sale et al. [61]

et al. [67], the authors reported mild gastrointestinal dis-

et al. [56]

tress in the creatine and caffeine group. Taken together,

caffeine supplementation after creatine loading could pro-
[55]
Study

vide an ergogenic benefit for athletes.

123
 A. Naderi et al.

Table 3 Human studies on the effects of creatine (CR) and caffeine (CAF) co-ingestion on performance
Study Subjects Supplementation Exercise test Results
Daily dose Duration and timing

Trexler et al. [70] n = 54, physically 4 9 5 g (20 g) CR, 5 days Repeated sprint test, Neither CR alone, nor
active males 300 mg/day CAF, 1 RM and in combination with
8.9 g COF containing repetitions to CAF or COF,
303 mg CAF fatigue enhanced strength
and sprint
performance
Lee et al. [69] n = 12, physically 300 mg/kg CR, 5 days, 60 min prior 6 9 10-s CAF improved
active males 6 mg/kg CAF to the test high-intensity performance after
sprints CR ingestion
Doherty et al. [68] n = 12, active males 300 mg/kg CR, 6 days, 60 min prior Treadmill running CAF improved
5 mg/kg CAF to the test at 125 % VO2max performance after
CR ingestion
VO2max maximum oxygen uptake, COF coffee, RM repetition maximum

More research is warranted to examine the effects of co-
ingestion of caffeine and creatine on HIE performance
[71], especially during maintenance dosing protocols of
creatine supplementation (Table 3).
7 The Effects of NaHCO3 and Creatine
Co-ingestion on Performance
It is well-established that creatine supplementation
improves HIE performance mediated by ATP/PCr regen-
eration [72]. Also, acute NaHCO3 intake increases the
extracellular buffering capacity [8]. In general, it is
hypothesized that co-ingestion of creatine with NaHCO3
may provide additional ergogenic benefit for HIE models.
To date, only a few studies have examined the potential
effect of co-ingesting creatine and NaHCO3. Barber et al.
[73] examined the effect of creatine (20 g creatine for
2 days) ? NaHCO3 (500 mg/kg) on the performance of six
repeated Wingate sprints. It was reported that cre-
atine ? NaHCO3 co-ingestion improved relative peak
power (7 %) compared with placebo and creatine had a
4 % improvement in comparison with placebo, while co-
ingestion of creatine ? NaHCO3 showed a greater atten-
uation of decline in relative peak power during six repeated
Wingate tests when compared with creatine and placebo.
However, it was attributed to greater bicarbonate blood
levels followed by NaHCO3 supplementation [73]. Mero
et al. [74] reported that 6 days of creatine loading along
with NaHCO3 supplementation at a dose of 300 mg/kg
improved the second bout of 2 9 100-m freestyle swim-
ming performance by 0.9 s compared with placebo. The
mechanisms of action for the ergogenic benefits of co-
ingestion of creatine and NaHCO3 have been related to
greater efflux of H? ions from working muscle allowing
greater work and intensity to be performed [73, 74]. Con-
versely, more recently, Griffen et al. [75] examined the
effect of creatine ? NaHCO3 co-ingestion during repeated
Wingate tests by measuring indices of mechanical power
output and total work done. The results specified that
creatine (20 g/7 days) and NaHCO3 supplementation
(300 mg/kg) alone induced an improvement on indices of
mechanical power output. However, no effect was
observed on co-ingestion of creatine ? NaHCO3 in com-
parison with creatine alone, but there was a small effect on
total work done for creatine ? NaHCO3 co-ingestion; co-
ingestion of creatine ? NaHCO3 also improved perfor-
mance compared with NaHCO3 alone. Overall, no additive
effect was shown in co-ingestion of creatine ? NaHCO3
[75]. Discrepancies between the results of these studies and
those of the study by Griffen et al. [75] may have been
related to inadequate washout of creatine and inadequate
NaHCO3 dosage used in the latter study compared with
other studies. Although these studies showed conflicting
results on the effect of creatine and NaHCO3 co-ingestion,
it seems that there is a minimal additive benefit for co-
ingestion of creatine and NaHCO3 (Table 4), and yet more
research is warranted regarding chronic co-ingestion by
well-trained and elite athletes with different exercise tests.
8 The Effects of b-Alanine and Creatine
Co-ingestion on Performance
Creatine monohydrate is the most studied, effective nutri-
tional ergogenic aid currently available for effects on lean
body mass and HIE capacity [76]. Supplementation with
creatine can increase the total resistance training volume

123
Supplementation and High-Intensity Exercise

via ATP resynthesis, and total training volume has been

closely linked with skeletal muscle accretion [77]. In

No additional benefits of CR ? NaHCO3

addition, improvements in repeated sprint performance,

CR ? NaHCO3 improved swimming

No improvement by CR ? NaHCO3
bench press strength, fatigue resistance, body weight, and
relative lifting volume can be observed within a relatively
short period of time [77]. Moreover, creatine supplemen-
tation has been demonstrated to increase the activation of
satellite cells and myonuclei in muscle following chronic
resistance training [78], and long-term studies have

performance
observed that those supplementing with creatine can
experience beneficial body composition adaptations [76].
Results

b-Alanine supplementation has been demonstrated to

augment muscle carnosine concentrations in humans [79–
81]. Harris et al. [7] concluded that carnosine plays a
critical role as an intracellular buffer within the skeletal
muscle of humans as well as having antiglycation and
6 9 10-s repeated Wingates

6 9 10-s repeated Wingates

2 maximal 100-m freestyle

antioxidant properties. More importantly, b-alanine sup-

plementation has been shown to enhance physical perfor-
mance during HIE bouts, delay the onset of neuromuscular
fatigue [82], increase aspects of military performance [84],
Exercise test

swimming
Table 4 Human studies on effects of creatine (CR) and sodium bicarbonate (NaHCO3) co-ingestion on performance

and may have indirect effects on lean body mass [83].

Recent studies have investigated the effects of the co-
ingestion of these two efficacious supplements [84–89]. It is
suggested that the increase in skeletal muscle PCr and
carnosine concentrations via supplementation with creatine
6 days, 2 h prior to the

monohydrate and b-alanine, respectively, will work syn-

ergistically to delay fatigue by decreasing the reliance on
anaerobic glycolysis and reducing intramuscular hydrogen
and timing

ion [88]. When both creatine and b-alanine were combined

Duration

7 days

2 days

in a multi-ingredient supplement, it improved lower body

test

muscular endurance [87], body composition [86] and

strength [86] and even reduced subjective measures of
fatigue [87]. Other studies have also seen synergy when co-
ingesting the two supplements. Zoeller et al. [89] reported
20 g CR, 300 mg/kg

20 g CR, 500 mg/kg

20 g CR, 300 mg/kg

increases in endurance performance during a graded exer-

Supplementation

cise test. Similarly, Stout et al. [88] and Hoffman et al. [84]
Daily dose

NaHCO3

NaHCO3

NaHCO3

showed increases in physical working capacity at neuro-

muscular fatigue threshold, strength, and lean tissue
accruement. Recently, Kresta et al. [85], however, found no
synergistic benefits in body composition, graded exercise
test performance, and Wingate anaerobic capacity tests in
n = 9, well-trained males

recreationally active women. However, it is likely that tests

n = 13, trained males

n = 16, competitive

that were selected for measurement and time points may

partly explain the differences from previous studies. For
instance, Green et al. [90] reported no increases in peak
swimmers

power with short-term creatine supplementation. Further-

Subjects

more, Hobson et al. [91] reported that the ergogenic effects

of b-alanine supplementation were limited to exercises
lasting about 60–240 s. Lastly, in the aforementioned study
Mero et al. [74]
Griffen et al.

by Kresta et al. [85], neither PCr nor muscle carnosine

Barber et al.

levels were elevated following the 4-week supplementation

[75]

[73]
Study

period, which may be explained by the sex and training

status of the individuals used in the study [85].

123
 A. Naderi et al.

Table 5 Human studies on the effects of b-alanine and creatine (CR) co-ingestion on performance
Study Subjects Supplementation Exercise test Results
Daily dose Duration and
timing

Kresta et al. n = 32, recreationally 6.1 g b-alanine 4 weeks Graded cycling Little additive effect
[85] active females 300 mg/kg CR 1 week exercise test of b-alanine ? CR
100 mg/kg CR 2–4 weeks
Zoeller et al. n = 55, male athletes 1.6 g b-alanine ? 34 g glucose 4 weeks Graded cycling b-Alanine ? CR
[89] 5.25 g CR ? 34 g glucose exercise test may enhance
endurance
1.6 g b-alanine ? 5.25 g
performance
CR ? 34 g glucose
Stout et al. n = 51, male athletes 1.6 g b-alanine ? 34 g glucose 4 weeks Incremental cycling b-Alanine delayed
[88] 5.25 g CR ? 34 g glucose exercise test neuromuscular
fatigue, no additive
1.6 g b-alanine ? 5.25 g
effect of b-
CR ? 34 g glucose
alanine ? CR

Overall, the evidence is compelling that the co-ingestion References

of creatine and b-alanine can have ergogenic potential
(Table 5). Athletes and strength practitioners may enhance
training adaptations and performance with co-ingestion of
creatine and b-alanine.
9 Conclusions
Co-ingestion of nutritional ergogenic aids is common
practice among athletes involved in HIE. Co-ingestion of
NaHCO3 with b-alanine as well as creatine and b-alanine
seems to have an evidence base regarding the benefit to
HIE; however, the effectiveness may still depend on
training status and specific exercise modality. Future
research should address not only the potential ergogenic
effect of co-ingestion of supplements but also the mecha-
nisms of a synergistic action. Although multi-ingredient
supplements are widely available, the lack of an evidence
base to support the amounts present in the supplementation
needs to be addressed. Such research endeavors are
methodologically challenging but are required to enhance
our scientific understanding of the beneficial effects of co-
ingestion and provide justified professional advice to ath-
letes regarding the benefits of co-ingestion of supplements.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the prepa-
ration of this article.
Conflict of interest Conrad Earnest is the Director of Research for
Nutrabolt International and a research scientist at Texas A&M
University. Alireza Naderi, Ryan Lowery, Jacob Wilson and Mark
Willems declare that they have no conflicts of interest relevant to the
content of this review.
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