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Phenylethylamine, a possible link to the
antidepressant eVects of exercise?
A Szabo, E Billett, J Turner
Abstract
Objectives—To determine in this pilot
study whether aerobic exercise aVects
phenylacetic acid concentration in the
urine.
Methods—Twenty healthy men provided
24 hour urine samples on two consecutive
days for the determination of phenylacetic
acid levels. Before and during day 1,
subjects refrained from physical activity;
on day 2 subjects ran on a treadmill at 70%
of their maximal heart rate reserve
(MHRR) for 30 minutes.
Results—The 24 hour mean urinary con-
centration of phenylacetic acid was in-
creased by 77% after exercise.
Conclusion—As phenylacetic acid con-
centration in urine reflects phenylethyl-
amine level, which is known to have
antidepressant eVects, phenylethylamine
may be linked to the therapeutic eVects of
physical exercise on depression.
(Br J Sports Med 2001;35:342–343)
Keywords: depression; exercise; phenylacetic acid; phe-
nylethylamine
The current consensus is that physical activity
has antidepressant eVects.
1
Indeed, doctors
widely recommend exercise either as treatment
for mild depression or as complementary treat-
ment to drug and/or psychotherapy in cases of
more severe depression.
1
The mode of action of
exercise, however, remains unclear.
Phenylethylamine is an endogenous neuro-
amine that has been linked to the regulation of
physical energy, mood, and attention.
2
Monoamine oxidase B selectively metabolises
phenylethylamine to phenylacetic acid. There
is evidence to indicate that levels of phenyl-
ethylamine and phenylacetic acid are very low
in the biological fluids of depressed patients.
3
As phenylethylamine turnover is very fast and
phenylacetic acid levels in the biological fluids
are far higher than phenylethylamine levels, it
has been suggested that phenylacetic acid
excretion is a better measure than phenylethyl-
amine for examining the modulatory role of
phenylethylamine. Studies on urinary excre-
tion of phenylacetic acid have shown that about
60% of unipolar and bipolar patients have
lower than normal levels.
2
Administration of
phenylethylamine or its precursor
L-phenylalanine, in conjunction with selegiline,
a selective monoamine oxidase B inhibitor, has
been reported to alleviate depression and to
produce improvements in mood. The eVects
are sustained and also apparent in some
patients who are insensitive to conventional
treatment.
23
In view of the links between exercise and
depression, and phenylethylamine and depres-
sion, the relation between exercise and phenyl-
ethylamine also deserves attention. Further-
more, phenylethylamine is involved in the
modulation of noradrenergic and dopaminer-
gic synapses.
2
In its role as an inhibitor of
noradrenergic reuptake, phenylethylamine may
be implicated in physical exercise. Considering
that there is a dynamic equilibrium between
central and peripheral phenylethylamine, be-
cause of its high lipid solubility and easy
passage through the blood/brain barrier, exam-
ination of the relation between phenylethyl-
amine (as measured by urinary phenylacetic
acid levels) and exercise is further warranted.
To the best of our knowledge, this study is the
first attempt to test the eVects of exercise on
phenylacetic acid levels.
Methods
Twenty healthy male volunteers (mean (SD)
age 22.1 (4.1) years) agreed to be tested by
signing an informed consent form. Their mean
(SD) body mass index was 23.5 (1.6), their
mean (SD) resting heart rate was 64 (7.8)
beats/min, and every week they exercised for
2.6 (1.4) hours aerobically and 1.4 (1.3) hours
anaerobically. The subjects refrained from
exercise for 24 hours (day 0) before the experi-
ment. Urine was then collected by the
volunteers for a 24 hour control non-exercising
period (day 1). On day 2, the participants ran
on a treadmill (Powerjog JX100) at 70% of
their maximal hear rate reserve (MHRR) for 30
minutes in the laboratory. This exercise inten-
sity was selected because a recent literature
review
4
shows that changes in mood are
commonly reported at 60–80% MHRR. On
completion of the exercise and before recovery,
subjects were asked to indicate the perceived
intensity of their workout on a three point
(light, moderate, hard) rating scale. After the
laboratory session, the participants collected
their urine for a further 24 hours (day 2). Once
collected, the urine was kept at 4°C until trans-
ported to the laboratory where it was frozen.
Phenylacetic acid levels in the samples were
stable using this protocol. Urinary volumes
were all in excess of 0.8 litres.
5
As the total
weight of phenylacetic acid in the 24 hour urine
was measured (mg/24 hours), the subjects were
free to consume water or other liquids ad libi-
tum.
The concentrations of urinary phenylacetic
acid were determined by the gas liquid
chromatography method of Gusovsky et al.
5
.
Br J Sports Med 2001;35:342–343342
Department of Life
Sciences, Nottingham
Trent University,
Nottingham, UK
A Szabo
E Billett
J Turner
Correspondence to:
Dr Billett, Department of
Life Sciences, Nottingham
Trent University, Clifton
Lane, Nottingham
NG11 8NS, UK
ellen.billett@ntu.ac.uk
Accepted 21 May 2001
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Each sample was run in the presence of a stand-
ard concentration of an internal control, phenyl-
propionic acid. Standards of phenylacetic acid in
the range 10–40 µg/ml were used to calibrate
the column. Peak areas of phen ylacetic acid/
phenylpropionic acid were calculated and used
in the analyses.
Results
In 18 of the 20 subjects, the level of phenyl-
acetic acid in the urine was higher after
exercise, increasing by 14–572% compared
with the values before exercising (fig 1). The
mean (SD) value of phenylacetic acid before
exercise was 99.4 (54.4) mg/24 hours and
176.0 (47.7) mg/24 hours after exercise. The
diVerence between the two measurements was
significant (F
1,19
= 26.6, p<0.0001; eVect size
(ES) = 1.2). The correlation between the two
sets of scores, however, was not significant
(r = 0.33, p = 0.09).
Discussion
These results show substantial increases in uri-
nary phenylacetic acid levels 24 hours after
moderate to high intensity aerobic exercise. As
phenylacetic acid reflects phenylethylamine
levels
3
, and the latter has antidepressant eVects,
the antidepressant eVects of exercise appear to
be linked to increased phenylethylamine con-
centrations. Furthermore, considering the
structural and pharmacolog ical analogy be-
tween amphetamines and phenylethylamine, it
is conceivable that phenylethylamine plays a
role in the commonly reported “r unners high”
thought to be linked to cerebral â-endorphin
activity. The substantial increase in phenyl-
acetic acid excretion in this study implies that
phenylethylamine levels are aVected by exer-
cise.
Although about 75% of subjects responded
relativ ely homogeneously, there was consider-
able interindividual variability in the phenyl-
acetic acid responses to exercise (fig 1).
Interestingly, 17 of the subjects rated the
exercise level as moderate, whereas three (11,
18, and 19 in fig 1) rated it as hard. Two of the
latter (subjects 18 and 19) also show ed the most
noticeable increase in phenylacetic acid in the
following 24 hours. (It should be noted that our
statistical conclusions would not change if the
outlier cases, 18 and 19, were disregarded.) The
lack of significant correlation between pheny-
lacetic acid levels before and after exercise indi-
cates that the former only accounted for about
11% (r = 0.33; r
2
= 0.11) of the changes in the
latter . Consequently, many factors may mediate
phenylacetic acid responses to exercise, possibly
including perceived and/or actual exercise
intensity. Determination of these factors re-
mains the object of future inquiries.
The present findings should serve as an
incentive for further research into the mecha-
nism(s) linking phenylethylamine to exercise.
Such research should consider some important
factors that were not addressed in this pilot
study. Firstly, the inclusion of a passive activity
control group is advised. Secondly, instead of
relying on MHRR as here, future studies need
to assess the actual V
O
2
MAX of the participants.
Thirdly, the changes in phenylacetic acid may
be diVerent in a sedentary sample in contrast
with the relatively fit and physically active sam-
ple tested here. Therefore the influence of
fitness on phenylacetic acid levels also needs to
be examined. Finally, the eVects reported here
should also be examined in a clinically
depressed population.
1 Mutrie N. The relationship between physical activity and
clinically defined depression. In: Biddle S, Fox K, Boutcher
S, eds. Physical activity and psychological well-being. London:
Routledge, 2000:46–62.
2 Sabelli H, Fink P, Fawcett J, et al. Sustained antidepressant
eVects of PEA replacement. J Neuropsychiatry 1996;8:168–
71.
3 Sabelli H, Javaid J. Phenylethlyamine modulation of aVect:
therapeutic and diagnostic implications. J Neuropsychiatry
Clin Neurosci 1995;7:6–14.
4 Ekkekakis P, Petruzzello S. Acute aerobic exercise and
aVect: current status, problems and prospects regarding
dose-response. Sports Med 1999;28:337–74.
5 Gusovsky F, Sabelli H, Fawcett J, et al. Gas-liquid chroma-
tographic determination of phenylacetic acid in urine. Anal
Biochem 1984;136:202–7.
Take home message
A 30 minute bout of moderate to high intensity aerobic exercise increases phenylacetic acid
levels in healthy regularly exercising men. The findings may be linked to the antidepressant
eVects of exercise.
Figure 1 Percentage diVerence in urinary phenylacetic acid after exercise. Phenylacetic
acid concentrations were measured as mg/24 hours and percentages are compared with
values obtained before exercise.
600
500
300
400
200
100
–100
0
Subjects
Difference in urinary phenylacetic acid
levels after exercise (%)
123 45 67891011121314151617181920
Phenylacetic acid and exercise: link to depression? 343
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doi: 10.1136/bjsm.35.5.342
2001 35: 342-343Br J Sports Med
A Szabo, E Billett and J Turner
antidepressant effects of exercise?
Phenylethylamine, a possible link to the
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