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Journal of Functional Foods 78 (2021) 104357
1756-4646/© 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Health and ergogenic potential of oral adenosine-5′-triphosphate
(ATP) supplementation
Ralf J¨
ager
a
,
*
, Martin Purpura
a
, John A. Rathmacher
b
,
c
, John C. Fuller Jr.
d
, Lisa M. Pitchford
b
,
e
,
Fabricio E. Rossi
f
, Chad M. Kerksick
g
a
Increnovo LLC, 2138 E Lafayette Pl, Milwaukee, WI 53202, USA
b
MTI BioTech, Inc., 2711 S. Loop Dr., Suite 4400, Ames, IA 50010, USA
c
Dept. of Animal Science, Iowa State University, Ames, IA 50011, USA
d
Metabolic Technologies, LLC, 135 W Main St, Suite B, Missoula, MT 59802, USA
e
Dept. of Kinesiology, Iowa State University, Ames, IA 50010, USA
f
Immunometabolism of Skeletal Muscle and Exercise Research Group, Department of Physical Education, Federal University of Piauí (UFPI), 64049-550 Teresina, Piauí,
Brazil
g
Exercise and Performance Nutrition Laboratory, School of Health Sciences, Lindenwood University, St. Charles, MO, USA
ARTICLE INFO
Keywords:
ATP
Exercise performance
Cardiovascular health
ABSTRACT
Adenosine triphosphate (ATP) is the primary compound that provides energy to drive many processes in living
cells, including muscle contraction, neurotransmission, and cardiac function. Initial research used enteric-coated
ATP that displayed no apparent efcacy. However, ATP disodium supplementation has demonstrated improved
bioavailability and acute and chronic benets to cardiovascular health, muscular performance, body composi-
tion, and recovery while attenuating muscle breakdown and fatigue. In this review, we provide a critical
assessment of oral ATP’s bioavailability and its various health and ergogenic benets.
1. Introduction
1.1. ATP: Life’s energy reservoir
Adenosine triphosphate (ATP) was rst discovered in 1929 by the
German chemist Karl Lohmann, who isolated ATP from muscle and liver
extracts (Langen & Hucho, 2008). Found in every cell of the human
body, ATP has been dubbed as the currency of energy affecting virtually
every physiological process requiring energy. Energy, approximately
30.6 kJ/mole, is freed from the ATP molecule by a reaction that removes
one phosphate group. The resulting adenosine diphosphate (ADP) is
usually immediately recycled in the mitochondria where it is recharged
again into ATP via phosphorylation (i.e., the adding of a phosphate
group) (Fig. 1). Notably, each molecule of ATP in the human body will
be recycled 2,000–3,000 times in a single day.
Beyond powering cellular processes, levels of and the presence (or
absence) of intracellular ATP can communicate signals across cells once
released into the extracellular space. Known as ATP signaling, and rst
detected between nerve cells and muscle tissue, ATP signaling occurs
between a wide variety of cell types in the body (Khakh & Burnstock,
2009). While ATP’s role in increasing skeletal muscle calcium perme-
ability and other aspects of muscle contraction have been extensively
studied (Burnstock & Kennedy, 1985; Burnstock, 2007), ATP signaling,
due to the multiplicity of cell-surface ATP receptors found in a diverse
array of tissues and cell types (Burnstock & Wood, 1996), plays a crucial
role in a variety of biological processes including neurotransmission,
blocking of chloride efux, cardiac function, platelet function, vasodi-
latation and liver glycogen metabolism (Agteresch, Dagnelie, van den
Berg, & Wilson, 1999; Khakh & Burnstock, 2009). Initial research using
enteric-coated ATP questioned this formulation’s bioavailability after
oral administration. Recent studies, however, have demonstrated an
increased potential for oral ATP supplementation when administered as
ATP disodium. The purpose of this review was to summarize and assess
the available literature base surrounding the oral administration of ATP
relative to its bioavailability and health and physical performance
outcomes.
2. Methods
While conducting this systematic review, the checklist and owchart
* Corresponding author.
E-mail address: ralf.jaeger@increnovo.com (R. J¨
ager).
Contents lists available at ScienceDirect
Journal of Functional Foods
journal homepage: www.elsevier.com/locate/jff
https://doi.org/10.1016/j.jff.2021.104357
Received 22 September 2020; Received in revised form 1 January 2021; Accepted 2 January 2021
Journal of Functional Foods 78 (2021) 104357
2
of Preferred Reporting for Systematic Reviews and Meta-Analyses
(PRISMA) were used as a guide (Moher, Liberati, Tetzlaff, & Altman,
2009). The literature search process was performed in the PubMed,
Scopus and Google Scholar literature databases. The MeSh terms were
used and they included, “Adenosine-5’-triphosphate [Title] or ATP
[Title] AND exercise [Title] or athlete [Title] or physical activity [Title].
In order to increase the accuracy of the selection of articles searched on
Google Scholar, only articles that included related keywords were
selected. All clinical trials that involved humans and articles published
in the English language were included in this review. Articles excluded
were studies that used in vitro models, animal studies, reviews, journals
written in non-English language, and studies without access to full-text.
From the studies that met eligibility criteria, extraction of data was done
in which the author names, year of publication, study setting or location,
study design, denite description and sample size, description of expo-
sure, description of outcomes, description of the control group, the study
ndings, and covariates involving data processing were identied. Full-
length article and data extraction were reviewed by two investigators
independently. During the extraction process, the investigators dis-
cussed any discrepancies until they reached a mutual agreement. If
needed, the corresponding authors of eligible articles were contacted for
additional information. Fig. 2 provides a PRISMA ow diagram to
illustrate these methods, and Table 1 is a summary table that addresses
the major research design elements of the applicable literature.
3. Bioavailability
Continuous intravenous administration of ATP has been shown to
signicantly increase erythrocyte ATP pools by 40–60% (Rapaport,
Salikhova, & Abraham, 2015). In addition, exogenously administered
ATP rapidly degrades to adenosine while ATP levels accumulate inside
erythrocytes. These changes suggest the presence of dynamic mecha-
nisms that facilitate the uptake of adenosine from blood plasma. From
here, ATP pools can then be released locally or globally from circulating
erythrocytes.
ATP is rapidly dephosphorylated to ADP by hydrolysis in acidic en-
vironments such as that found in the stomach. The intraluminal pH
changes rapidly from highly acidic (pH ~ 2.0) in the stomach to a pH of
approximately 6.0 in the duodenum and then gradually increases to a pH
of about 7.4 in the terminal ileum. ATP exhibits stability between pH 6.8
– 7.4 (Alberty, 1998), thus to protect ATP from the acidic environment
in the stomach, enteric-coated oral ATP supplements were used in early
absorption studies (Arts et al., 2012; Coolen et al., 2011; Jordan et al.,
2004). However, oral administration of a single acute high-dose
(5,000 mg) (Arts et al., 2012), 14 days of 150 or 225 mg per day (Jor-
dan et al., 2004), and 28 days of 250, 1,250 or 5,000 mg per day (Coolen
et al., 2011) of enteric-coated ATP all failed to signicantly increase
blood concentrations of ATP or its metabolites.
Later development realized that for effective duodenal absorption of
ATP into the bloodstream, the enteric coating needs to dissolve at pH
5.5, the average pH of the proximal duodenum. Therefore, one potential
explanation for the lack of change in ATP levels after oral administration
of enteric-coated ATP could be the buffering capacity of ATP as diso-
dium salt at pH 4.0–4.5 (Metzler, 1977). The enteric coating of the ATP
disodium requires a pH of 5.5 for dissolution. The enteric coating might
only partly dissolve and allow duodenal contents and water to penetrate
in the moment of disintegration. As a result, the ATP disodium could
keep the pH below 5.5, which would limit the extent to which dissolu-
tion occurs compromising its breakdown and subsequently its release of
ATP disodium at the duodenum where it could be absorbed into the
bloodstream.
Absorption of orally administered non-coated ATP (5 mg/kg/day
ATP for 30 days) was tested in an animal model (Kichenin & Seman,
2000). In this study, improvements in adenosine uptake, ATP synthesis,
and ATP exportation by red cells were found to occur. Using a human
infusion model, Rapaport and investigators infused ATP into advanced
malignancy cancer patients for eight hours over eight weeks (Rapaport
et al., 2015). These authors posited that ATP itself does not transport
across plasma membranes and is rst broken down to adenosine. From
there adenosine is then taken up by erythrocytes and subsequently ex-
pands the total erythrocyte ATP pool. These data suggest that, despite its
expected gastric instability, oral ATP supplementation may not require
an enteric coating to exert benecial physiological effects. Subse-
quently, Purpura et al., 2017 used a human investigation involving oral
uncoated ATP disodium supplementation for 15 days at a dose of 400 mg
per day. While adenosine was not measured in this investigation,
Fig. 1. Energy is freed from ATP by removing one of the phosphate groups yielding ADP. ADP is then recharged into ATP via phosphorylation.
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
3
supplementation was found to prevent decreases in ATP, ADP, and AMP
in the blood 30 min following high-intensity exercise in comparison to
the placebo (Purpura et al., 2017) (Fig. 3).
These ndings are important as prior investigations only examined
resting conditions and failed to identify any signicant increases in ATP
levels (Arts et al., 2012; Coolen et al., 2011; Jordan et al., 2004). It is,
therefore, hypothesized that an indirect mechanism for ATP re-synthesis
exists, whereby the chronic ingestion of oral non-enteric coated ATP
disodium increases the capacity of erythrocytes or other cellular com-
ponents or structures to synthesize and better sustain plasma ATP con-
centrations in response to the hypoxic perturbations, such as those
triggered by high-intensity exercise. It is further proposed that ATP and/
or its respective metabolites (i.e., ADP and AMP) may stimulate intra-
cellular ATP synthesis via reactions similar to the myokinase reaction or
by interacting with specic ATP and adenosine receptors on the cells
surface through a signalling effect (Freitas et al., 2019). As such, several
open questions remain regarding the potential or actual operative
functions which outline the observed bioavailability of oral ATP sup-
plementation, and more research is needed to better understand the
physiological and biochemical implications of these mechanisms with
and without external hypoxic triggers such as intense physical exercise.
4. Effects of ATP supplementation on muscular performance and
body composition
It is hypothesized that the improvement in ATP turnover (e.g., pre-
vention of ATP decline or improvement in ATP:ADP ratio) through oral
supplementation of ATP could allow athletes to maintain performance
through longer periods of exertion and consequently delay the onset of
fatigue. Theoretically, this heightened performance would allow for a
Fig. 2. Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) ow diagram for selection of eligible articles.
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
4
Table 1
Summary table of studies examining outcomes related to ATP administration. Studies are rst grouped into absorption, sports, and then non-sports studies. Individual
references are sorted alphabetically within each group within the table.
Study Design Subjects Methods Supplementation Duration Main Findings (Effect of ATP)
Absorption Studies
Arts et al.
(2012)
Randomized,
placebo-
controlled, cross-
over
8 healthy men (2) and
women (6)
(age =27 ±6 yrs)
Blood sampling 5000 mg ATP disodium
as proximal-release and
distal-release pellets
1 Week No effect on blood ATP
concentrations.
Coolen et al.
(2011)
Randomized,
double-blind,
placebo-
controlled
32 healthy men (29 ±14
yrs)
Blood sampling 0, 250, 1250 or 5000 mg
ATP disodium. In
addition, 5000 mg dose
on days 0 and day 28.
4 Weeks All patterns of ATP
supplementation for 4 weeks did
not lead to changes in blood or
plasma ATP concentrations, only
resulted in increased uric acid
concentrations.
Jordan et al.
(2004)
Randomized,
double-blind,
placebo-
controlled
27 men (high dose ATP
N =9, 29 ±8 yrs; Low Dose
ATP N =9, 30 ±7 yrs;
placebo N =9, 29 ±6 yrs)
Blood sampling 150 mg or 225 mg of
enteric coated ATP
disodium
14 Days Acute supplementation non-
signicantly increased total blood
ATP levels (225 mg: +11%;
150 mg: +10%), chronic
supplementation had no effect on
whole blood ATP, or plasma ATP
concentrations.
Purpura et al.
(2017)
Randomized,
double-blind,
placebo-
controlled
42 resistance trained men
(ATP N =21, Placebo
N =21, age =20 ±3 yrs)
Blood sampling 400 mg ATP disodium
for 14 days
15 Days No effect on resting ATP levels,
but prevented exercise-induced
declines in ATP and ADP levels
(p <0.05).
Sports Studies
Freitas et al.
(2019)
Randomized,
double-blind,
placebo-
controlled, cross-
over
11 recreationally resistance
trained men (28 ±6 yrs)
Lower body
resistance exercise
400 mg ATP disodium;
30 min pre-exercise
Single dose Signicantly improved athletic
performance: higher total weight
lifted (p =0.05). Signicantly
greater oxygen consumption
during exercise (p =0.021).
J¨
ager et al.
(2014)
Pilot study 12 resistance-trained men
(age =24 ±4 yrs)
Acute arm exercise 400 mg ATP disodium
30 min pre-breakfast
12 Weeks Signicantly increased blood ow
and brachial dilation at weeks 1,
8, and 12 (p <0.05).
Jordan et al.
(2004)
Randomized,
double-blind,
placebo-
controlled
27 men (high dose ATP
N =9, 29 ±8 yrs; Low Dose
ATP N =9, 30 ±7 yrs;
placebo N =9, 29 ±6 yrs)
Anaerobic exercise
performance
150 mg or 225 mg of
enteric coated ATP
disodium
14 Days At 225 mg dose, increased 1RM,
repetitions to fatigue, and total
lifting volume at post-test
Purpura et al.
(2017)
Randomized,
double-blind,
placebo-
controlled
42 resistance trained men
(ATP N =21, Placebo
N =21, 20 ±3 yrs)
Sprint protocol 400 mg ATP disodium
before breakfast; on day
15, 30 min pre-exercise
15 Days Signicantly increased Wingate
peak power in later bouts
compared to baseline. Prevented
the decline in muscle excitability
in later bouts (p <0.0001).
Rathmacher
et al.
(2012)
Randomized,
double-blind,
placebo-
controlled, cross-
over
16 recreationally active men
(N =8) and women (N =8)
(25 ±3.9 yrs)
Strength and fatigue
testing
2 ×200 mg ATP
disodium; pre-
breakfast/dinner
15 Days Improved leg muscle low peak
torque in set 2 (p <0.01); tended
to decrease leg muscle fatigue in
set 3 (p <0.10).
Wilson et al.
(2013)
Randomized,
double-blind,
placebo- and diet-
controlled
21 resistance-trained men
(ATP N =11, Placebo
N =10, age =23 ±1 yrs)
Phase 1 - periodized
resistance-training,
Phase 2 -
overreaching cycle,
Phase 3 - two-week
taper
400 mg ATP disodium
on non-training days
pre-breakfast or 30 min
pre-exercise
12 Weeks Signicantly increased lean body
mass (p <0.001) and muscle
thickness (p <0.02) over training
alone. Signicantly increased
total strength and vertical jump
power (p <0.001).
Non-Sports Studies
Bannwarth
et al.
(2005)
Randomized,
double-blind,
parallel-group,
placebo-
controlled
162 men and women (ATP
N =81, 43 ±10 yrs; placebo
N =80 41 ±10 yrs) with a
diagnosis of subacute lower
back pain.
One-month therapy 90 mg ATP disodium One Month Signicantly improved RDQ at
day 7 (p =0.02). Signicantly less
use of rescue analgesic.
de Freitas
et al.
(2018)
Randomized,
double-blind,
placebo-
controlled, cross-
over
11 hypertensive women
(62 ±5 yrs)
Walking exercise 400 mg ATP disodium;
30 min pre-exercise
Single dose Faster recovery of heart rate
variability; reduced systolic blood
pressure after exercise (p <0.05).
Hirsch et al.
(2017)
Randomized,
double-blind,
placebo-
controlled
53 subjects (23 men, 30
women; 55 ±6 yrs)
Weight loss
parameters and ow
mediated dilation
200 mg ATP disodium,
200 mg ATP disodium
plus 1,000 mg
GlycoCarn, 1,000 mg
GlycoCarn
90 Days Signicantly decreased in blood
glucose, malondialdehyde levels,
waist and hip circumference, and
waist/height ratio; signicantly
increased ow-mediated dilation
(p ≤0.05).
Ju et al.
(2016)
Case study 7-year-old boy with ATP1A3
mutation, presenting with
recurrent hemiplegic
episodes
2 Year therapy 20-to100 mg ATP
disodium twice a day;
gradually increased
2 Years Signicantly lower frequency and
shorter duration of hemiplegic
episodes. Marked amelioration of
alternating hemiplegia of
childhood episodes, and
(continued on next page)
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
5
greater completion of work, which sets the stage for greater exercise
training adaptations. These potential benets of ATP disodium supple-
mentation were investigated in a series of clinical studies (Freitas et al.,
2019; Jordan et al., 2004; Purpura et al., 2017; Rathmacher et al., 2012;
Wilson et al., 2013).
Jordan et al. published one of the rst investigations to examine the
acute impact of two different doses (150 and 225 mg) of non-enteric
coated ATP (Jordan et al., 2004). Twenty-seven healthy, previously
active males were supplemented in a randomized, double-blind fashion
to either a placebo, 150 mg, or 225 mg doses of ATP for a period of
14 days. After 7 and 14 days of supplementation, participants completed
two Wingate tests and three sets of maximal bench press repetitions with
70% of a pre-determined one-repetition maximum (1RM). Results from
this study showed that 225 mg of enteric-coated ATP signicantly
increased the number of repetitions to fatigue during the rst of three
sets of bench press repetitions (+18.5%, p <0.007) as well as total
lifting volume (+22%, p <0.003) in comparison to baseline. These
changes, however, were not statistically different than the non-
signicant improvements also observed in the placebo and low dose
group (150 mg enteric-coated ATP) for repetitions completed and total
lifting volume. No changes were observed in sets 2 or 3 of completed
bench press repetitions nor any anaerobic power metrics collected
during the Wingate tests. No within or between-group differences were
observed for lactate or blood ATP concentrations. Results from this
study are challenging to reconcile as the authors used an enteric-coated
ATP formulation and a lower dose than most other investigations
(225 mg vs. 400 mg). Further, from a timing perspective, the authors
administered the supplements three hours before testing versus the more
typical 30-min window and as such, timing of ATP administration may
be another factor to consider when evaluating these results.
Freitas and investigators examined the impact of a single 400 mg
dose of non-enteric coated ATP in a randomized, double-blind, crossover
study design in 11 healthy, previously active males (Freitas et al., 2019).
Thirty minutes after ingestion, participants completed a series of half-
squat repetitions with 80% of their 1RM. Performance was recorded
as total repetitions completed, and oxygen consumption, lactate and
hemodynamic parameters were also assessed. In comparison to placebo,
the total weight lifted was signicantly increased (Placebo:
3995.7 ±1137.8 vs. ATP: 4967.4 ±1497.9 kg, p =0.005) when the ATP
dose was provided. Signicant group effects were found whereby heart
rates were higher after the 4th set (p <0.001) and oxygen consumption
(p =0.021) was higher in ATP when compared to placebo. No differ-
ences between conditions were found for lactate or blood pressure
(Fig. 4).
The impact of ATP supplementation on repeated bouts of maximal
exercise performance was investigated by Purpura et al. using a ran-
domized, double-blind, placebo-controlled approach (Purpura et al.,
2017). Healthy males (n =42) completed a 14-day supplementation
protocol of 400 mg/day and on the 15th day took their prescribed dose
30 min before completing ten repeated 6-second cycling sprints with
Table 1 (continued )
Study Design Subjects Methods Supplementation Duration Main Findings (Effect of ATP)
improved psychomotor
development.
Long and
Zhang
(2014)
Randomized,
double-blind,
placebo-
controlled
244 total knee replacement
patients (ATP N =119,
60 ±5 yrs; placebo N =113,
59 ±5 yrs)
4 Weeks therapy 120 mg ATP disodium
three times a day
4 Weeks Signicantly improved
quadriceps strength and pain
scores at postoperative days 7, 14,
21, and 28 (p ≤0.05). Decreased
need for analgesics by 5% and
shortened the length of hospital
stay by 12%.
Rossignol
et al.
(2005)
Double-blind
(only trial 1),
randomized
placebo-
controlled
Trial 1 (ATP N =80, 41 ±10
yrs; placebo N =80, 43 ±10
yrs); Trial 2 (ATP N =81,
41 ±11 yrs; without ATP
N =76, 44 ±10 yrs)
30 Days therapy 90 mg ATP disodium 90 days ±5 days Improved RDQ (p =0.02). ATP
group patients were three times
less likely to report a condition
that had worsened or remained
unimproved at 90 days (p =0.02).
Fig. 3. Delta changes in blood ATP (A), ADP (B), and AMP (C) levels from pre-
exercise to 30 min post-Wingate exercise in participants supplemented with
ATP disodium or a placebo for 15 days (*p <0.05 different from placebo group)
(Purpura et al., 2017).
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
6
30 s of rest between each sprint. As expected, maximal power output
decreased in both groups, but performance was better maintained dur-
ing the latter bouts (8th bout [Mean difference: 102.6 W; 95% CI:
21.6–183.5 W] and 10th bout [Mean difference: 90.8 W; 95% CI:
9.8–171.8 W]) when ATP was provided. Moreover, effect sizes were
calculated for each of the ten sprint cycling bouts before and after
supplementation. The average effect sizes (d) were 0.128 (range:
d = − 0.01 to 0.29) and 0.314 (range: d = − 0.18 to 0.79) for the placebo
group and ATP supplemented groups, respectively. No impact was re-
ported for vertical jump power, reaction time, or muscle activation;
however, muscle excitability increased signicantly in the ATP group
(+21.5%, p <0.02) after bout 2 and helped to prevent the decline
observed in the placebo group. While more research is needed, the lack
of observed change for some outcomes (vertical jump) and not others
(maximal power output) could be explained by the bioenergetic demand
initiated by the repeated bouts of exercise. In an additional study that
examined the impact of ATP supplementation on fatigue prevention,
Rathmacher et al. had participants complete three sets of 50 maximal
knee extensions to induce fatigue after supplementing with ATP (two
doses of 200 mg/day) or placebo using a randomized, double-blind,
placebo-controlled, crossover design (Rathmacher et al., 2012). No
differences were detected in high peak torque, power, or total work with
ATP supplementation. ATP supplementation did, however, improve low
peak torque in set number two (ATP: 67.2 N-m vs. placebo: 62.3 N-m,
p <0.01), and torque fatigue tended to be improved with ATP (ATP:
57.8% vs. placebo: 60.5%, p <0.10) in the third set of maximal repeti-
tions (Fig. 5). Two key discussion points arise from this study. First,
results from this study provide additional evidence that ATP supple-
mentation may lack the ability to exert ergogenic outcomes during the
early phases of an intense bout of exercise, but it does seem to enhance
resistance to the accumulation of fatigue that inevitably results from
maximal muscular contractions. Second, this study used a split dose
(2 ×200 mg) supplementation protocol and, it is important to note,
participants did not supplement on the day of the testing, missing out on
the potential acute benets of ATP supplementation.
Wilson and colleagues had 21 resistance-trained males supplement
with either 400 mg/day of ATP or placebo in a randomized, double-
blind, placebo-controlled fashion in conjunction with a 12-week heavy
resistance training program (Wilson et al., 2013). The 12-week protocol
consisted of an eight week periodized resistance-training program, two
weeks of an overreaching cycle, and two weeks of tapering. Using this
approach, ATP supplementation led to signicantly greater improve-
ments in muscle thickness (as determined by ultrasound) and maximal
strength and vertical jump power (Wilson et al., 2013). Specically, the
ATP group experienced signicant increases in squat 1RM (p <0.001)
and deadlift 1RM (p <0.001) resulting in signicantly greater im-
provements in total strength (PLA: +5.9% [22.4 ±7.1 kg] vs. ATP:
+12.6% [55.3 ±6.0 kg], p <0.001). Additionally, signicantly greater
improvements in vertical jump power were found for ATP supplemen-
tation (PLA: +11.6% [614 ±52 W] vs. ATP: 15.7% [796 ±75 W],
p <0.001). Interestingly, no changes were observed for bench press 1RM
(p =0.65) or Wingate peak power (p =0.48). The discordance of
observed change in upper-body strength and lower-body strength is
somewhat surprising; however, the amount of musculature involved
may be a key consideration as previous work involving caffeine and
acute resistance training performance has resulted in a similar pattern of
outcomes. Additionally, no change was observed in Wingate peak power
(p =0.48) between PLA and ATP supplemented individuals. While both
outcomes are intended to assess a representation of power, the time and
relative energetic demand between a vertical jump and Wingate
anaerobic capacity test are noticeably different and the role of ATP in
energy homeostasis can seemingly operate as a key difference in these
outcomes and their associated ndings from this study. Wilson et al. also
assessed changes in body composition. Lean mass gains occurred in both
groups, but changes were found to be signicantly greater in the ATP
supplemented group (PLA: +2.92% [~2 kg increase] vs. ATP: +5.91%
[~4 kg increase], p <0.009) (Wilson et al., 2013). Similarly, muscle
thickness levels were found to also increase to a greater extent in the
ATP group (PLA: +4.9% [2.5 ±0.6 mm] vs. ATP: +9.4%
[4.9 ±1.0 mm], p <0.02). (Fig. 6). Notably, the improvements in body
Fig. 4. Acute ATP supplementation signicantly increased training volume and
number of repetitions (*p <0.05 different from placebo group) (Freitas
et al., 2019). Fig. 5. ATP supplementation improved peak torque (A) and reduced fatigue in
later sets of 50 maximal knee extensions (B) (*p <0.05 and
#
p <0.1, different
from placebo group) adopted from Rathmacher et al. (2012).
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
7
composition in resistance-trained males over 12 weeks align with earlier
ndings that 90 days of ATP supplementation in a healthy, older
(~55 years) population improved waist (-3.05 cm, p =0.04) and hip
circumference (-3.05 cm, p =0.007), and waist-hip ratio (-0.02,
p =0.03), independent of any exercise or physical activity intervention
(Hirsch et al., 2017).
5. ATP supplementation and recovery
Unaccustomed exercise stress or high volumes of exercise are com-
mon circumstances for physically active individuals and can result in
brief periods of overreaching, a period where the body is too stressed to
adequately recover. Twelve weeks of oral supplementation with ATP
(400 mg/day) in young, resistance-trained males has been shown to
attenuate losses of strength and power during a two-week overreaching
period (Wilson et al., 2013). Total strength (sum of squat, bench press,
deadlift 1RM) decreased in the control group (−5.0%, −22.6 ±5.1 kg)
whereby total strength loss was signicantly attenuated in the ATP
supplemented group (−2.2%, 12.0 ±2.5 kg, p <0.007). Moreover, the
two-week overreaching protocol led to a 5.0% decrease in vertical jump
power in the PLA group, whereas a signicantly smaller decline (only
2.2%) was observed in the ATP group (p <0.001) (Fig. 7).
Outcomes reported by Long et al. on performance and clinical out-
comes in 232 patients who underwent total knee arthroplasty indicated
greater recovery of force production in ATP supplemented individuals 7
(92.8 vs. 82.9 N), 14 (119.3 vs. 105.2 N), 21 (130.8 vs. 121.2 N), and 28
(190.2 vs. 175.3 N) days after surgery (all p <0.05 between groups) as
well as decreases in reported pain levels 7 (3.05 vs. 3.68), 14 (2.58 vs.
2.96), 21 (2.10 vs. 2.48), and 28 (1.56 vs. 1.98) days after surgery (in all
instances data is presented as ATP vs. PLA, p <0.05 between groups)
(Fig. 8, Long & Zhang, 2014). However, no differences were observed
between groups in either outcome at one or three days after surgery.
These outcomes are intriguing, as they suggest that, while a measurable
benet of ATP supplementation in recovery from surgery may not be
realized until at least day three of supplementation, the benets may
extend beyond 28 days of supplementation. Additional studies have
highlighted the potential for ATP administration to impact medical re-
covery and to have implications related to pain. For example, ATP
supplementation signicantly shortened the length of hospital stay by
12% (PLA: 2.5 ±0.7 days vs. ATP: 2.2 ±0.8 days, p =0.003) and
reduced the need for rescue pain medication by 5% (PLA:
Fig. 6. ATP supplementation signicantly increased lean body mass (A), muscle thickness (B), strength (C), and power (D) during a multi-week, controlled resistance
training program (*p <0.05 different from placebo group) (16). Adapted from Wilson et al. (Wilson et al., 2013).
Fig. 7. ATP supplementation reduces losses of strength (A) and power (B)
during an overreaching cycle (*p <0.05 different from placebo group) (Wilson
et al., 2013).
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
8
1300 ±202 mg vs. ATP: 1235 ±185 mg, p =0.012) (Long & Zhang,
2014). Two other studies, one by Moriyama et al. (2004) and another by
Hayashida et al. (2005) both indicated positive potential for ATP infu-
sion in terms of pain management. The Moriyama study infused ATP
(dosage of 1 mg /kg) or a glucose control once per week for 12 weeks in
eight patients with postherpetic neuralgia and found improvements in
continuous and paroxysmal pain. Additionally, the Hayashida et al.
study infused 12 postherpetic neuralgia with either ketamine, lidocaine,
or ATP and found that ATP responders developed signicant pain relief
over a nine-hour period of time.
The potential for ATP to favorably impact recovery of lost strength
and power after overtraining or surgical intervention points to some
interaction of ATP availability with skeletal muscle health. Rates of
muscle protein breakdown are increased during injury, inactivity
(muscle disuse atrophy), energy restriction, and as a normal process of
aging (age-related muscle loss or sarcopenia) (Tipton, Hamilton, &
Gallagher, 2018). Wilson and investigators (Wilson et al., 2013)
collected 24-hour urine samples from healthy, resistance-trained males
who supplemented with 400 mg/day of ATP or placebo in a randomized,
double-blind fashion to assess changes in urinary 3-methyl-histidine, a
marker of myobrillar protein breakdown. ATP supplementation was
found to signicantly (p <0.007) prevent (Week 8: 0.143 ±0.007 vs.
Week 10: 0.131 ±0.012
μ
mol/mg) the 23.7 ±4.5% increase in level of
urinary 3-methyl-histidine observed in the placebo group (Week 8:
0.123 ±0.004 vs. Week 10: 0.152 ±0.005
μ
mol/mg, (Fig. 9). ATP sup-
plementation did not appear to have an impact, however, over changes
in C-reactive protein (p =0.99), cortisol (p =0.86), free testosterone
(p =0.93), total testosterone (p =0.83), creatine kinase (p =0.91) or
perceived recovery score (p =0.61).
6. Health and clinical applications of ATP supplementation
ATP has varying effects within the cardiovascular system, including
constriction, dilation, and the repair of blood vessels (Khakh & Burn-
stock, 2009). If an endothelial cell is damaged at a wound site, it spills
ATP which breaks down to ADP. ADP then binds to receptors on plate-
lets, which respond by aggregating to form a blood clot that closes the
wound (Khakh & Burnstock, 2009). Moreover, changes in blood ow
produce “shear stress” on endothelial cells lining blood vessel walls,
causing the endothelial cells to release ATP, which activates receptors
on nearby endothelial cells that respond by releasing nitric oxide, which
makes the vessels relax (Khakh & Burnstock, 2009). Potential implica-
tions of ATP supplementation on vascular health have been studied
using ow-mediated dilation (FMD), which measures the ability of an
artery to dilate in response to a shear stress stimulus. In a pilot study,
twelve healthy, resistance-trained males were supplemented for
12 weeks with 400 mg/day of ATP supplementation. No placebo was
administered in the pilot trial. After 0, 1, 4, 8, and 12 weeks of supple-
mentation, blood ow changes in the brachial artery were assessed using
ow-mediated dilation in conjunction with an acute upper-arm exercise
protocol (J¨
ager et al., 2014). Blood ow and brachial artery diameter
signicantly increased when ATP supplementation was provided, but
the lack of control group in this study compromises the ability to more
fully understand the potential of ATP to impact blood ow (Fig. 10). In
addition, acute and long-term benets of ATP supplementation on car-
diovascular health in non-athletic populations have been reported (de
Freitas et al., 2018). In 11 hypertensive older women (61.8 ±5.0 years),
a randomized, double-blind, placebo-controlled trial with a single
Fig. 8. ATP supplementation decreases losses in strength (A) and improved perceived pain (B) following total knee replacement surgery (*p <0.05 different from
placebo group) (Long & Zhang, 2014).
Fig. 9. ATP supplementation decreases urinary levels of 3-methyl-hisitidine
(3MH), a marker of myobrillar protein breakdown during an overreaching
cycle (*p <0.05 different from placebo group) (Wilson et al., 2013).
Fig. 10. Release of ATP activates receptors on endothelial cells which respond
by releasing nitric oxide, inducing improved blood ow (A). ATP supplemen-
tation alone did not increase blood ow, but ATP did signicantly enhance the
post-exercise increase in blood ow (B), as measured by ultrasonography of the
brachial artery. (*p <0.05 different from placebo group) (19). Adapted from
J¨
ager et al. (2014).
R. J¨
ager et al.
Journal of Functional Foods 78 (2021) 104357
9
400 mg ATP disodium dose induced faster recovery of heart rate vari-
ability and reduced systolic blood pressure after 30 min of aerobic ex-
ercise. Hirsh et al. completed a randomized, double-blind, placebo-
controlled investigation in 53 overweight and obese elderly men and
women over a 90-day protocol of 100 mg/day, 2x/day of ATP supple-
mentation (Hirsch et al., 2017). While no statistically signicant
changes were observed in comparison to the changes observed in the
placebo group, the ATP group experienced signicant increases (from its
respective baseline) in blood ow (2.8%, p =0.003) and malondialde-
hyde (0.92
μ
M, p =0.02) and decreases in blood glucose (−6.3 mg/dL,
p =0.02), waist circumference (−3.05 cm, p =0.04), hip circumference
(−3.05 cm, p =0.007), waist-to-hip ratio (−0.02, p =0.03).
Finally, several clinical applications of ATP and adenosine have been
reported (Agteresch et al., 1999). Oral ATP supplementation at a dosage
of 90 mg/day signicantly reduced participant’s self-assessment of their
disability levels and reduced the usage of rescue analgesics in 181 men
and women with category 1 or 2 subacute lower back pain (Bannwarth
et al., 2005). In a separate publication from the same research group,
patients who supplemented with ATP were three times less likely to
report a condition that had worsened or remained unimproved and took
fewer rescue drugs (Rossignol et al., 2005). Finally, in a pediatric case
study of a child with alternating hemiplegia, an intractable neurological
disorder, reported that oral ATP supplementation reduced both the
frequency and duration of hemiplegic episodes (Ju et al., 2016). While
the results of these early studies are promising, additional studies on oral
ATP supplementation in clinical conditions are warranted.
7. Future perspectives
Currently, ATP disodium has demonstrated the potential to impact
several physiologic effects which may confer acute to long-term benets
on exercise performance and health. While preliminary bioavailability
research has been completed, more research is needed to fully under-
stand the kinetics and specics of how the ingested molecules are
transported through the digestive system and deposited in the circula-
tion. Thus, immediate research efforts should focus on elucidation of the
mechanism responsible for the observed outcomes in the literature.
Future studies should investigate the potential ability of acute ATP
disodium supplementation to impact various types of exercise perfor-
mance and evaluate if there is a dose-dependent effect. As the knowl-
edge base surrounding ATP supplementation and exercise performance
matures, the next wave of research should investigate the potential for
additive or even synergistic effects of co-administering ATP with other
nutritional supplements that possess different or similar mechanisms-of-
action. As an example, co-administration of ATP with beta-hydroxy-
beta-methylbutyrate (HMB) has previously been shown to result in
signicant improvements in resistance training adaptations observed in
resistance-trained males who followed a resistance training and sup-
plemented with a combination of HMB and ATP for a period of 12 weeks
(Lowery et al., 2016). Results of this study have been criticized for
discrepancies in how the data was reported and methodological ap-
proaches used (Phillips et al., 2017), thus more follow-up work should
be completed with this and other potential combinations of candidate
nutrients. Of interest are supplements known to demonstrate buffering
capacity in the body (i.e., creatine, beta-alanine, and bicarbonate) which
could potentiate the half-life of ATP either in the gut or possibly the
blood when co-administered.
Future research should also ascertain if these physiological mecha-
nisms may differ between populations, such as in young vs. old, men vs.
women, and untrained vs. trained individuals. In reference to aging,
signicant interest exists involving the role and impact of mitochondrial
health as it relates to the aging process and longevity (Vendelbo & Nair,
2011). While the relationship between mitochondrial health and aging
has been found in some but not all studies, a relationship between ATP
production and aging has been observed in some studies and subse-
quently deserves more detailed investigation into its potential.
Moreover, clinical populations such as individuals with chronic
obstructive pulmonary disease or intermittent claudication are both
characterized by peripheral muscle weakness that can limit exercise
capacity resulting in a reduction in quality of life in these patients. As
such, supplementation of ATP disodium could be an important strategy
to improve oxygen delivery or utilization by the peripheral muscles and
improve quality of life in these people.
8. Conclusion
The available literature on ATP disodium when provided in a dose of
at least 400 mg approximately 30 min before a workout or 20–30 min
before breakfast on non-exercise days provides insight into its potential
to reduce fatigue (Purpura et al., 2017; Rathmacher et al., 2012), in-
crease strength and power (Wilson et al., 2013), improve body compo-
sition (Hirsch et al., 2017; Wilson et al., 2013), maintain muscle health
during stress (Long & Zhang, 2014; Wilson et al., 2013), increase re-
covery and reduce pain (de Freitas et al., 2018; Khakh & Burnstock,
2009; Wilson et al., 2013). Additionally, other literature indicates a role
for ATP in improving cardiovascular health (Hirsch et al., 2017; Ju et al.,
2016; Rossignol et al., 2005). The divergent ndings surrounding ATP
supplementation and an unidentied mechanism of action continue to
preclude stronger conclusions from being made at this time. Therefore,
additional research is needed to identify and clarify the cellular mech-
anism responsible for the observed changes as well as to replicate the
ndings already published in the literature.
9. Ethics statement
This manuscript is a review article and did not include any human
subjects and animal experiments.
Author contribution
RJ and MP took the lead in writing the manuscript. All authors dis-
cussed the results and contributed to the nal manuscript.
Declaration of competing interest
The authors declare the following nancial interests/personal re-
lationships which may be considered as potential competing interests:
JCF is an employee of Metabolic Technologies, LLC an afliate of TSI
USA LLC, the manufacturer of Peak ATP. JAR and LMP are employees of
MTI BioTech, Inc. which has a partnership with TSI USA, LLC. RJ and
MP are consultants to TSI USA, LLC. All other authors do not declare
competing interests.
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