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Purpose: To examine eCB and mood responses to prescribed and preferred exercise among individuals with low, moderate, and high levels of physical activity. Methods: Thirty-six healthy adults (21±4yrs) were recruited from low (≤60min moderate-vigorous physical activity [MVPA]/wk), moderate (150-299min MVPA/wk), and high (≥300 MVPA/wk) physical activity groups. Participants performed both prescribed (approx. 70-75% max) and preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after exercise conditions. Results: Both preferred and prescribed exercise resulted in significant increases (p < 0.01) in circulating eCBs (AEA, 2-AG); however, increases in AEA (p < 0.05) were larger in the prescribed condition. Likewise, both preferred and prescribed exercise elicited positive mood improvements compared to pre-exercise values, but changes in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (p < 0.05). Changes in 2-AG concentrations were found to negatively correlate with changes in depression, tension, and total mood disturbance in the preferred condition (p < 0.05), and changes in AEA were positively associated with changes in vigor in the prescribed condition (p < 0.05). There were no significant group differences for mood or eCB outcomes. Conclusion: These results indicate that eCB and mood responses to exercise do not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.
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Endocannabinoid and Mood Responses to
Exercise in Adults with Varying Activity Levels
ANGELIQUE G. BRELLENTHIN
1
, KEVIN M. CROMBIE
1
, CECILIA J. HILLARD
2
, and KELLI F. KOLTYN
1
1
Department of Kinesiology, University of Wisconsin–Madison, Madison, WI; and
2
Neuroscience Research Center and
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI
ABSTRACT
BRELLENTHIN, A. G., K. M. CROMBIE, C. J. HILLARD, and K. F. KOLTYN. Endocannabinoid and Mood Responses to Exercise in
Adults with Varying Activity Levels. Med. Sci. Sports Exerc., Vol. 49, No. 8, pp. 1688–1696, 2017. Acute aerobic exercise improves
mood and activates the endocannabinoid (eCB) system inphysically active individuals; however, both mood and eCB responses to exercise
may vary based on habitual levels of physical activity. Purpose: This study aimed to examine eCB and mood responses to prescribed and
preferredexercises among individuals with low, moderate, and high levels ofphysical activity. Methods: Thirty-six healthy adults (21 T4yr)
were recruited from low (e60 min moderate–vigorous physical activity [MVPA] per week), moderate (150–299 min MVPA per week),
andhigh(Q300 MVPA per week) physical activity groups. Participants performed both prescribed (approximately 70%–75% max) and
preferred (i.e., self-selected) aerobic exercise on separate days. Mood states and eCB concentrations were assessed before and after ex-
ercise conditions. Results:Bothpreferredandprescribedexerciseresultedinsignificantincreases(PG0.01) in circulating eCB
(N-arachidonoylethanolamine [AEA] and 2-arachidonoylglycerol); however, increases in AEA (PG0.05) were larger in the prescribed con-
dition. Likewise, both preferred and prescribed exercise elicited positive mood improvements compared with preexercise values, but changes
in state anxiety, total mood disturbance, and confusion were greater in the preferred condition (PG0.05). Changes in 2-arachidonoylglycerol
concentrations were found to negatively correlate with changes in depression, tension, and total mood disturbance in the preferred condition
(PG0.05), and changes in AEA were positively associated with changes in vigor in the prescribed condition (PG0.05). There were no
significant group differences for mood or eCB outcomes. Conclusion: These results indicate that eCB and mood responses to exercise do
not differ significantly between samples with varying physical activity levels. This study also demonstrates that in addition to prescribed
exercise, preferred exercise activates the eCB system, and this activation may contribute to positive mood outcomes with exercise.
Key Words: ANANDAMIDE, 2-ARACHIDONOYLGLYCEROL, PREFERRED, SELF-SELECTED, DEPRESSION, ANXIETY
It is widely acknowledged that exercise is associated with
many psychological benefits, including reductions in
stress, tension, and anxiety (53). Although the specific
neurobiological mechanisms responsible for these outcomes
remain largely unknown, recent work in both animals and
humans indicates that the endocannabinoid (eCB) system,
which is activated by an acute bout of exercise, may play a
significant role (9,17,41).
The eCB is an expansive neuromodulatory network that
regulates synaptic excitability and neurotransmitter release. It is
composed of two primary receptors, CB1 and CB2, and two pri-
mary endogenous ligands, the eCB N-arachidonoylethanolamine
(AEA) and 2-arachidonoylglycerol (2-AG), as well as the
metabolizing enzymes for the eCB. CB1 receptors have been
found in almost all major regions of the brain and are heavily
expressed in areas that have been implicated in diverse
psychological processes such as reward and emotional regu-
lation (e.g., limbic system), memory (e.g., hippocampus),
nociception (e.g., periaqueductal gray), and higher level
cognitive functions (e.g., prefrontal cortex; for an extensive
review of the eCB system, see [27]).
Animal evidence indicates that various psychological re-
sponses to exercise as well as exercise behaviors are depen-
dent on eCB signaling. For example, blocking or mutating CB1
receptors before exercise abolishes anxiolytic and antinociceptive
effects typically observed with acute exercise (17,18). From a
behavioral standpoint, the eCB system has been found to reg-
ulate voluntary wheel running in rodents (16). Rodents that are
lacking CB1 receptors or have their CB1 receptors blocked
engage in 30%–40% less wheel running than control animals
(12). This reduction has been found to be specifically related to
the motivational aspects of wheel running (as opposed to the
ability to run) (43) and has been associated with eCB-induced
inhibition of GABA and facilitation of dopamine transmission
in reward-processing brain regions (8). Together, these results
suggest that the eCB system could contribute to the diverse
psychological benefits that result from exercise and may also
contribute to motivated exercise behaviors.
In humans, several studies have found that an acute bout
of exercise leads to significant increases in circulating eCB
(23,32,41,42,50), and one of these studies reported that
exercise-induced eCB increases were associated with increases
Address for correspondence: Angelique Brellenthin, Ph.D., University of
Wisconsin–Natatorium, Room 1160 2000, Observatory Drive, Madison, WI
53706; E-mail: abrellenthin@wisc.edu.
Submitted for publication November 2016.
Accepted for publication March 2017.
0195-9131/17/4908-1688/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE
Ò
Copyright Ó2017 by the American College of Sports Medicine
DOI: 10.1249/MSS.0000000000001276
1688
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in positive affect in a small sample of recreationally fit in-
dividuals (41). Other than this preliminary investigation, the
relationship between eCB and mood outcomes after exercise
in humans remains largely unexplored. In addition, the afore-
mentioned studies focused on moderately active individuals,
so it is unknown whether the eCB response to exercise differs
among people who engage in varying amounts of physical
activity. Outside of the acute eCB response to exercise, basal
physiological differences in the eCB system between in-
dividuals with varying physical activity levels may also exist
(13,19), further emphasizing the need to understand how acute
eCB responses shape chronic exercise behaviors in humans.
Therefore, the aims of this investigation were to expand
upon the relationships between mood and eCB responses to
a prescribed exercise bout in healthy individuals with vary-
ing levels of physical activity (inactive/low, moderate, and
high). A secondary objective of this study was to charac-
terize mood and eCB responses to preferred exercise, which
in some instances has been shown to elicit greater mood
improvements than prescribed exercise (38,55).
METHODS
Study Participants
A power analysis (G*Power 3.1) was conducted to deter-
mine the sample size needed per group (three groups) to detect
a significant group difference in a repeated-measures (four
measurement points), between–within interaction design. The
analysis was powered at 0.80, with an alpha of 0.05, and a
Cohen’s f, medium effect size value of 0.25. Previous studies
have indicated there are large effect sizes for differences in
psychological outcomes between inactive and active partici-
pants (4,10,20), as well as large effect sizes for increases in
AEA after acute exercise (41,50). Because eCB responses to
exercise have not been compared across activity groups, a me-
dium rather than a large effect size was selected for this initial
investigation. The power analysis indicated that 10 participants
per group (n= 30) would be needed. To account for possible
participant attrition, the sample size was increased to 12 par-
ticipants per group (6 men and 6 women).
Before coming into the laboratory, potential participants
were screened via telephone about their estimated levels of
physical activity to ensure that invited participants would be
representative of all three activity groups (inactive/low, mod-
erate, and high). Thirty-six healthy young adults (18 men and
18 women) between the ages of 18–34 yr and without a history
or present diagnosis of any physical or psychiatric disorder
were recruited to participate in this study. All procedures were
approved by the University of Wisconsin Health Sciences In-
stitutional Review Board.
Questionnaires
Seven-day Physical Activity Recall. The Physical
Activity Recall (PAR) has been found to be a valid
assessment of general levels of physical activity and has
demonstrated acceptable reliability, with test–retest periods
ranging from 2 wk to 2 yr, indicating that it is reflective of
long-term activity patterns (45,48,49). The PAR was conducted
by a trained interviewer who was blinded to the physical ac-
tivity information provided during the phone screen. Through
a series of guided, standardized prompts, the participants
reported their morning, afternoon, and evening bouts (mode,
intensity, and duration of at least 10 min) of physical activity,
which occurred in the past 7 d. Results of the PAR were
used to group participants based on physical activity levels.
For the inactive/low active group, participants had to report
less than 60 min of moderate–vigorous physical activity
(MVPA) per week, within 150–299 min MVPA per week for
the moderately active group, and greater than 300 min MVPA
per week for the highly active group. Group distinctions were
basedonthe2008 Physical Activity Guidelines for Americans.
According to the guidelines, inactive adults do not engage in
physical activities beyond those required through daily living,
and health benefits are observed starting at 60 minIwk
j1
of
MVPA. Moderately active individuals attain 150–300 min
MVPA per week, and highly active individuals attain more
than 300 min of MVPA per week (40).
Profile of Mood States. The Profile of Mood States
(POMS) is a 65-item questionnaire that was administered to
examine the mood states of the participants before and after
each session. Six mood states are evaluated using the POMS:
tension, depression, anger, vigor, fatigue, and confusion, with
internal consistencies of each mood state ranging from >=
0.84–0.95 (36). The POMS has been shown repeatedly to be a
valid and sensitive measure of general mood (36). Total mood
disturbance was calculated by summing the scores from the
negative mood states, subtracting the vigor score, and adding
100 to account for negative values.
State–Trait Anxiety Inventory. The State–Trait Anx-
iety Inventory (STAI) is a 40-item questionnaire that was used
to assess participants’ anxiety (51). The STAI has repeatedly
been shown to have sound construct validity, and internal con-
sistencies are high, ranging from >= 0.86 to 0.95 (51). The
20-item trait anxiety subscale (general levels of anxiety)
was administered on the first day of testing, and the 20-item
state anxiety subscale (present levels of anxiety) was admin-
istered before and after exercise on preferred and prescribed
exercise days.
Commitment to Exercise Scale. For exploratory pur-
poses, the eight-item Commitment to Exercise Scale (CES)
was administered to assess participants’ psychological com-
mitment to and subjective feelings surrounding exercise (7).
This tool uses a series of visual analog scales anchored with
‘never’’ and ‘always’’ to assess for the presence of a path-
ological relationship with exercise. For example, items in-
quire about the degree to which a person feels a sense of guilt
when missing workouts, compromises social relationships for
exercise, or exercises despite being injured or sick. Responses
on the eight items demonstrated excellent internal consistency
(Cronbach’s >= 0.90). Composite scores from the CES range
eCB ACROSS PHYSICAL ACTIVITY LEVELS Medicine & Science in Sports & Exercise
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from 0 to 10 and represent the average distance along the
visual analog scales. Higher scores on the CES suggest a
greater degree of exercise dependency.
Procedures
Participants completed three experimental sessions. Ses-
sions for individual participants occurred at the same time of
day and were separated by 1 wk. Participants were instructed
not to eat within 2 h or exercise within 24 h of testing to
minimize eCB variations and any potential carryover effects
from previous exercise sessions.
Session 1. During the first session, participants pro-
vided written informed consent indicating they agreed with
and would adhere to outlined procedures. They next completed
a basic demographic questionnaire, the CES (7), and the trait
subscale of the STAI (51). They then reported their physical
activity behaviors by completing the 7-Day PAR with a trained
interviewer (48). Participants were grouped based on their self-
reported activity levels.
After completing questionnaires, participants completed a
submaximal V
˙O
2
treadmill test. Participants wore a heart rate
monitor (Polar, Lake Success, NY) and a face mask (Hans-
Rudolph, Kansas City, MO), and expired through a tube
connected to a Parvo Medics True One 2400 Metabolic cart
(TrueOne; ParvoMedics, Sandy, UT). Following the American
College of Sports Medicine Bruce protocol guidelines for
submaximal treadmill testing, participants walked or jogged
on a treadmill at an increasing rate and incline until 85% of
age-predicted max heart rate was achieved (15).
Sessions 2 and 3. Sessions 2 and 3 consisted of preferred
and prescribed exercise conditions, with the order randomized
and counterbalanced for each participant. Before exercise,
participants completed the POMS (36) and the state anxiety
subscale of the STAI (51) and then had their baseline blood
sample drawn. Standardized scripts were used to explain each
exercise condition as well as Borg’s RPE scale (6–20) (3).
The prescribed exercise condition consisted of a 10-min
warm-up at low to moderate intensity (40%–60% estimated
V
˙O
2max
), followed by 45 min at 70%–75% estimated V
˙O
2max
(monitored using heart rate ranges determined from the
submaximal test), and then finished with a 5-min walking
cool down. This duration and intensity of exercise has pre-
viously been shown to result in significant elevations in cir-
culating eCB (23,42,50). Heart rate and RPE were assessed
every 5 min during the exercise.
The preferred exercise condition consisted of a 10-min
warm-up at a low to moderate intensity, followed by the
participants’ choice of treadmill exercise intensity and du-
ration. When they indicated they had completed their ses-
sion, participants finished with a 5-min walking cooldown.
Heart rate and RPE were assessed every 5 min during ex-
ercise. For both conditions, participants were allowed to
drink water at any time during exercise, and the postexercise
blood draw was collected within 5 min of the end of exer-
cise. After the blood draw, they completed the postexercise
mood assessments (i.e., POMS and state anxiety).
eCB Assays
Blood draws were performed while participants were seated,
and samples were collected into ethylenediaminetetraacetic acid
vacutainers. Blood samples were immediately centrifuged at
4-C, and the plasma was separated into aliquots before freezing
at j80-C. After preparation, AEA and 2-AG as well as related
biogenic lipids, palmitoylethanolamide (PEA) and oleoylethano-
lamide (OEA), were quantified using isotope dilution, atmo-
spheric pressure, and chemical ionization liquid chromatography/
mass spectrometry as described previously (32).
Statistical Analyses
A one-way ANOVA was used to detect the presence of group
differences in baseline variables. A series of mixed-design,
repeated-measures ANOVAs were performed to assess activ-
ity group and condition changes in eCB and mood states from
pre- to postexercise. The overall alpha family-wise was set at
>
FW
= 0.05. Simple effects were calculated based on significant
interaction effects. Pearson’s rcorrelation coefficients were
determined to assess relationships among pre- to postexercise
changes in mood scores and eCB concentrations. To meet the
normality assumption for parametric tests, lipid concentrations
were logarithmically transformed before analyses.
RESULTS
Participant characteristics. Thirty-six men and women
with a mean age of 21 T4 yr were recruited for this study.
There were no significant differences between groups for age,
body mass index, or trait anxiety (P90.05). There were
significant group differences for estimated V
˙O
2max
(F
2,33
=
7.31, PG0.01), exercise commitment scores (F
2,33
= 15.97,
PG0.001), and amount of time spent in MVPA (F
2,33
=
31.72, PG0.001). Pairwise comparisons indicated that esti-
mated V
˙O
2max
and exercise commitment were significantly
lower (PG0.01) in the low activity group compared with the
moderate and high activity groups. Self-reported MVPA
minutes were significantly different (PG0.05) between all
three activity groups (see Table 1), and MVPA was signifi-
cantly correlated with estimated V
˙O
2max
(r= 0.57, PG
0.001). Average preexercise concentrations in AEA were
inversely associated with MVPA (r=j0.33, P= 0.05) but
TABLE 1. Sample characteristics.
Low
(n= 11)
Moderate
(n=12)
High
(n=13)
Overall
(n=36)
Age (yr) 20.6 T2.4 19.8 T1.1 22.6 T5.5 21.1 T3.8
BMI (kgIm
j2
) 23.8 T5.3 22.7 T2.0 23.4 T3.4 23.4 T3.4
Estimated V
˙O
2max
(mLIkg
j1
Imin
j1
)
41.3 T6.8** 49.9 T5.0 51.1 T7.9 47.6 T7.8
MVPA (minIwk
j1
)* 37.2 T22.2 203.0 T43.9 570.5 T261.2 285.1 T280.6
CES 2.4 T1.3** 6.7 T2.8 6.6 T1.8 5.4 T2.8
Trait anxiety 33.4 T8.4 33.0 T9.2 33.2 T9.3 33.2 T8.7
Data are presented as mean TSD.
BMI, body mass index.
*Significant difference (PG0.05) between all three groups.
**Low activity group was significantly different (PG0.01) from moderate and high activity
groups.
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not estimated V
˙O
2max
(r=j0.05, P= 0.77). No significant
associations were found between baseline lipid concentra-
tions and other variables.
Preferred and prescribed condition characteris-
tics. In the prescribed condition, there were significant group
differences for treadmill speed (F
2,33
=5.75,PG0.01).
Pairwise comparisons indicated that the low activity group
had slower treadmill speeds (PG0.01) than the high activity
group. There were no group differences for RPE in either the
prescribed or the preferred conditions (P90.05), although
there was a significant condition difference for estimated ex-
ercise intensity such that participants elected to exercise at a
relatively higher percentage of their estimated V
˙O
2max
in the
preferred compared with the prescribed condition (F
1,33
=
7.74, PG0.01). In the preferred condition, there were sig-
nificant group differences for preferred duration (F
2,33
=5.47,
PG0.01) and treadmill speed (F
2,33
=23.69,PG0.001).
Pairwise comparisons indicated that the high activity group
exercised for significantly longer durations (PG0.05) than
the low and moderate groups, and the low activity group se-
lected significantly slower treadmill speeds (PG0.001) than
the moderate and high groups. There were no significant
differences in the timing of blood draws between groups or
between conditions (P90.05) (see Table 2).
eCB and mood responses to exercise. The results
indicated that there were significant time effects for 2-AG
(F
1,33
=24.46,PG0.001) and PEA (F
1,33
=17.59,PG0.001),
with the concentrations of both lipids increasing signifi-
cantly from pre- to postexercise. There were also significant
condition–time interactions for AEA (F
1,33
= 5.12, PG0.05)
and OEA (F
1,33
= 7.04, PG0.05). AEA and OEA increased
significantly after both exercise conditions; however, analysis
of simple effects indicated that postexercise plasma concen-
trations of AEA (F
1,33
=4.47,PG0.05) and OEA (F
1,33
=
10.04, PG0.01) were greater in the prescribed compared with
the preferred condition. There were no main effects or in-
teractions for activity group for any eCB or lipid responses to
either preferred or prescribed exercise (P90.05), and effect
size estimates (G
2
) for group–time interactions were small
(AEA = 0.015, PEA = 0.020, OEA = 0.019, 2-AG = 0.039)
(see Fig. 1).
The results indicated that there were significant decreases
in tension (F
1,33
= 4.1, PG0.05), depression (F
1,33
= 8.09,
PG0.01), anger (F
1,33
= 5.51, PG0.05), and increases in
vigor (F
1,33
= 23.84, PG0.001) after both exercise condi-
tions. There were significant condition–time interactions for
confusion (F
1,33
= 4.39, PG0.05), total mood disturbance
(F
1,33
= 5.03, PG0.05), and state anxiety (F
1,33
= 5.45, PG
0.05), and analysis of simple effects indicated that re-
ductions in confusion (F
1,33
= 10.19, PG0.01), total mood
disturbance (F
1,33
= 18.14, PG0.001), and state anxiety
(F
1,33
= 6.55, PG0.05) occurred in the preferred but not the
prescribed condition (P= 0.26–0.65). There were no sig-
nificant main effects or interactions for activity group for
any mood state responses to either preferred or prescribed
exercise (P90.05), and effect size estimates (G
2
) for group–
time interactions were small to medium (tension = 0.081,
depression = 0.023, anger = 0.055, vigor = 0.093, fatigue =
0.029, confusion = 0.063, total mood disturbance = 0.083,
and state anxiety = 0.041) (see Fig. 2).
Associations between eCB and mood responses
to exercise. In the preferred condition, changes in 2-AG
were negatively associated with changes in tension (r=
j0.59, PG0.01), depression (r=j0.45, PG0.01), and
total mood disturbance scores (r=j0.40, PG0.05) after
exercise. In the prescribed condition, changes in AEA were
associated with changes in vigor (r= 0.37, PG0.05).
DISCUSSION
eCB responses to exercise. Aerobic exercise was
found to activate the eCB system, which agrees with previ-
ous work conducted in humans (23,42,50). There were sig-
nificant increases in AEA as well as 2-AG after both
preferred and prescribed exercise bouts. With the exception
of Cedernaes et al. (5), previous studies using aerobic ex-
ercise have reported nonsignificant increases in circulating
2-AG. Data from a few of these studies indicated that there
were medium to large effect size increases (14,41) or an
observable trend for increases in 2-AG after exercise (50).
These studies had small sample sizes, ranging from 8 to 16
exercising participants, suggesting they may have been in-
sufficiently powered to detect changes in 2-AG. Cedernaes
et al. (5) (n= 16) did report a significant increase in 2-AG
after 30 min of cycling and speculated that a portion of the
increase in 2-AG might have been related to the natural
circadian rhythm of 2-AG. One investigation has found no
discernable pattern of 2-AG for 24 h (54), whereas another
reported that 2-AG levels increased steadily throughout the
morning (approximately 15%–20% per hour) and plateaued
around 12:30 p.m., regardless of food intake (i.e., lunch)
(21). Therefore, although it is possible that some of the in-
crease in 2-AG was related to its circadian rhythm while it
was approaching this midday peak, it remains plausible that
TABLE 2. Exercise session characteristics.
Low Moderate High
Duration (min) Prescribed 45 45 45
Preferred 26.5 T7.2 25.4 T5.0 36.1 T12.3*
RPE Prescribed 12.8 T0.9 12.4 T0.9 12.9 T1.0
Preferred 12.3 T1.6 13.9 T1.3 13.4 T2.0
%V
˙O
2max
Prescribed 75.3 T8.6 72.1 T6.5 68.6 T8.4
Preferred**** 74.7 T7.8 80.4 T7.6 74.6 T15.5
Speed (kmIh
j1
) Prescribed 7.4 T1.1*** 8.5 T1.0 9.2 T1.8
Preferred 7.6 T1.0** 10.6 T1.1 10.5 T1.3
Time of blood
collection (h:min)
Prescribed
Pre 11:27 (1:21) 11:53 (1:23) 11:18 (1:23)
Post 12:32 (1:22) 12:57 (1:22) 12:23 (1:21)
Preferred
Pre 11:17 (1:15) 11:54 (1:24) 11:22 (1:18)
Post 12:03 (1:18) 12:39 (1:23) 12:13 (1:23)
Data are presented as mean TSD.
*Significant difference (PG0.05) from other groups.
**Significant difference (PG0.001) from other groups.
***Significant difference (PG0.05) between low and high active groups.
****Significant difference between sessions, with preferred session performed at higher
relative V
˙O
2
workloads.
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2-AG responded to exercise because it increased approxi-
mately 28% and 55% from baseline in the preferred and
prescribed conditions, respectively.
The current investigation also found that there were sig-
nificant increases in PEA and OEA after aerobic exercise.
Although not classified as true eCB because they do not
bind to cannabinoid receptors, both PEA and OEA are
N-acyletha nolamines, which share synthetic and degradative
mechanisms with AEA, so it is not surprising that they
would increase in circulation alongside AEA (27). Because
they do not bind to CB1 receptors, PEA and OEA have not
beenroutinelyexploredwithregardtopsychologicalout-
comes, which are thought to be influenced by CB1 activity
in the central nervous system. However, they may contribute
to other well-documented effects of exercise. For instance,
PEA has been found to be neuroprotective, having both anti-
inflammatory and antinociceptive effects within the central
nervous system (35), whereas OEA has anorexigenic prop-
erties potentially contributing to appetite suppression after
intense exercise (22,46).
There were no differences in eCB at baseline or in their
responses to exercise between the low, moderate, and high
activity groups. The evidence for basal differences in eCB
among groups with varying physical activity levels remains
equivocal. Although the present investigation did not find
group differences in eCB concentrations at baseline, there
was a significant inverse association between self-reported
MVPA and baseline AEA concentrations. Conversely, others
have found that AEA levels were positively correlated with
objectively measured MVPA in overweight women (13),
whereas another study found that AEA levels were depressed
in a group of highly active runners who also endorsed criteria
for exercise dependence (1). Gasperi et al. (19) found no
differences in basal levels AEA and 2-AG between active and
sedentary, normal weight men; however, they did find dif-
ferences in fatty acid amide hydrolase activity (the enzyme
that degrades AEA) particularly in response to increases in
IL-6, a proinflammatory cytokine, among the physically ac-
tive men compared with the sedentary men. The authors
speculated that the effect of IL-6 on fatty acid amide hydro-
lase activity was a metabolic adaptation that occurred to ne-
gotiate the repeatedly increased eCB concentrationsthat occur
with habitual exercise (19). This notion makes sense given the
large body of evidence indicating that the eCB system acts to
both mount an appropriate, systemic stress response and bring
the body back to homeostasis once the stressor has passed
(for a review, see [25]). It is possible that the lack of group
differences in eCB responses to exercise were a result of
good general health and fitness in this young adult sample
because the estimated V
˙O
2max
values for all three groups
were in the good to excellent categories based on normative
data for 20–29 yr olds (24). Similarly, Gasperi et al. (19) found
FIGURE 1—Mean and SE for the two eCB, AEA (anandamide) and 2-AG (2-AG), and related lipids, PEA and OEA, before and after prescribed and
preferred exercisesin the low, moderate, and high active groups as well as the overall sample. *Significant main effect of time for 2-AG and PEA (PG0.001).
Significant condition–time interaction for AEA and OEA (PG0.05). Changes in pre- to postexercise AEA and OEA plasma concentrations were greater
in the prescribed than the preferred condition. There were no significant group effects.
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no differences in eCB concentrations between sedentary and
active men and also observed that both groups had relatively
high cardiorespiratory fitness.
Increases in AEA and OEA were greater in the prescribed
versus the preferred condition. Overall, participants performed
significantly more work (% V
˙O
2max
duration in minutes) in
the prescribed versus the preferred condition, and these find-
ings did not differ between groups. The greater amount of total
work (and thus greater physicalstress) may simply explain the
differential AEA and OEA responses. However, although to-
tal work within the prescribed condition did not differ between
groups, it is still possible that the prescribed condition was
especially physically stressful for the low activity group. For
instance, because estimated V
˙O
2max
did not differ between the
moderate and high activity groups, they were combined into
one ‘‘high’’ group for an exploratory analysis and compared
with the low activity group. Although most lipid and mood
outcomes remained nonsignificant between the newly formed
low and high groups, there were significant group–condition
interactions for both AEA and OEA. Post hoc analyses in-
dicated that increases in AEA and OEA were greater in the
prescribed than preferred condition for the low activity group,
but increases in AEA and OEA were not different between
the conditions for the high activity group.
As an extension of the greater work performed in the
prescribed condition, it is also possible that larger AEA and
OEA concentrations arose from differences in hydration status
and plasma volume changes between the two conditions
(23,30). Fluid intake and plasma volume were not measured
in this study to test this possibility. Finally, another potential
explanation is that eCB values could have continued to in-
crease after the termination of preferred exercise, reaching the
levels observed after prescribed exercise. For instance, AEA,
OEA, PEA, and 2-AG continue to increase in concentration
for up to 15 min after exercise (5,23). Because our prescribed
bout was 45 min long and the average preferred bout was
29 min long, it is possible that eCB concentrations in the
preferred condition could have approached the greater levels
observed in the prescribed condition had there been another
blood draw 15 min after exercise (thus approximating the
45 min total duration in the prescribed bout).
In addition to stress processes, eCB have also been linked
to motivational aspects of physical activity in animals. For
instance, the amount of daily wheel running, which is often
considered to be a reinforcing behavior in rodents (16), has
been found to negatively correlate with basal concentrations
of AEA in mice (2), and disrupting CB1 receptors has been
showntosignificantlyreducevoluntary wheel running (11,12).
The effects of eCB manipulation are more pronounced among
animals that have been selectively bred to engage in high
amounts of wheel running compared with control animals (31).
Additional reports have shown that eCB signaling contrib-
utes specifically to the motivational aspects of wheel running
possibly through eCB and GABA interactions influencing
FIGURE 2—Means and SE for mood outcomes before and after prescribed and preferred exercises. Preexercise values depicted by BLACK bars.
Postexercise values depicted by WHITE bars. Prescribed condition responses on the left, preferred condition responses on the right. *Significant time
effect (PG0.05). Significant condition–time interaction (PG0.05), with mood improvements being greater in the preferred compared with the
prescribed condition. There were no significant activity group differences for any mood outcome so entire sample averages are shown.
eCB ACROSS PHYSICAL ACTIVITY LEVELS Medicine & Science in Sports & Exercise
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dopamine transmission in reward-processing brain regions such
as the striatum and ventral tegmental area (8,11,17,43).
From a motivational perspective, it was hypothesized that
individuals who engaged in varying amounts of voluntary
physical activity may have underlying differences in their eCB
system. Although there were no differences in eCB responses
to exercise between the physical activity groups in either con-
dition, it is interesting that baseline AEA levels were inversely
associated with self-reported MVPA but were not significantly
associated with V
˙O
2max
,althoughMVPAandV
˙O
2max
were
strongly associated with each other. These results suggest that
the eCB system may relate to motivated exercise behaviors
apart from basic physiological adaptations to stress (i.e., im-
proved fitness) that occur with routine physical activity.
Similarly, Antunes et al. (1) reported that runners with high
activity levels who also met criteria for exercise dependence
according to the Exercise Dependence Scale had lower basal
levels of eCB, greater mood disturbance, and a blunted eCB
response to acute exercise compared with highly active in-
dividuals who had the same level of activity as the ‘‘dependent’’
group but did not fit the criteria for exercise dependency (i.e.,
they may have had differences in underlying motivational
processes). Compared with Antunes et al. (1), the moderate and
high activity groups in the present study did not score signifi-
cantly different on the CES. This suggests that although the
moderate and high activity groups had significantly different
self-reported physical activity levels, they may not have had
differences in their eCB responses because they did not differ
in their self-reported commitment to or motivations surround-
ing exercise, and there was little evidence suggesting that this
sample exhibited a pathological relationship with exercise.
Mood responses to exercise. Acute aerobic exer-
cise, whether preferred or prescribed, was able to elicit im-
provements in several mood states, including reductions in
tension, depression, and anger, and increases in vigor. Pre-
ferred exercise was able to elicit additional improvements in
confusion, total mood disturbance, and state anxiety. There
were no differences between physical activity groups in mood
outcomes to exercise in either condition. Several studies have
found that psychological improvements (e.g., reductions in
state anxiety and mood disturbance) are greater after exercise
in physically active compared with nonactive individuals
(20,39), although others have found no differences in mood
changes after exercise in low and high active groups (47), or
that mood improvements are the greatest in individuals with
more negative mood states before exercise, regardless of physical
activity level (44). Although there appeared to be greater levels
of mood disturbance and state anxiety before the preferred
condition, paired samples t-tests examining baseline levels of
mood states between the two conditions were all nonsignifi-
cant (Pvalues from 0.14 to 0.53). Furthermore, in both con-
ditions, preexercise values for mood disturbance and state
anxiety were below published norms for a young adult popu-
lation (51,52). It has also been suggested that allowing in-
dividuals to choose or ‘‘self-select’’ parameters of their exercise
session may lead to greater psychological benefits (55), and
this notion could be particularly relevant in populations with
varied exercise experiences and histories (38). Although the
evidence supporting this idea is mixed and seems to vary
based on the sample and instruments used to assess affect and
mood, initial reports indicate that allowing adults to engage in
preferred or self-selected exercise (as opposed to prescribing
exercise) may promote increased physical activity participa-
tion in the future, potentially by enhancing mood outcomes
during and after exercise bouts (33).
Associations between eCB and mood responses
to exercise. Increases in 2-AG and AEA were associated
with positive mood outcomes, including reductions in ten-
sion, depression, and total mood disturbance (2-AG) as well
as increases in vigor (AEA). These findings are in line with
previous work indicating that increases in AEA were asso-
ciated with increases in positive affect after exercise (41).
Beyond mood, additional studies have examined exercise-
induced changes in eCB and other psychological outcomes
such as perceived stress (5) and perceived exertion (23) and
have not found significant associations. This study also did
not find significant associations between RPE and eCB.
These mixed findings suggest that although eCB are mobi-
lized in response to a stressor, they may not be synthesized
in a linear fashion with the perceived magnitude of the stress.
These results also suggest that eCB may be particularly influ-
ential on emotional- or pleasure-related processes. For instance,
the evidence demonstrating that peripheral concentrations of
eCB are able to influence central processes originates from
preclinical research showing that animals will self-administer
intravenous injections of both AEA and 2-AG, and this reward-
seeking behavior is mediated by CB1 receptors (28,29). Also
related to reward and reinforcement processes, Antunes et al.
(1) found that AEA concentrations were decreased at baseline
and during a 14-d period of abstinence from physical activity,
which aligned with worsening mood outcomes in ‘‘exercise-
dependent’’ adults compared with highly active control par-
ticipants, although mood states and AEA were not directly
correlated in that study.
In the broader literature, eCB dysfunction has been asso-
ciated with several psychiatric conditions, including major
depressive disorder, posttraumatic stress disorder, and sub-
stance use disorders (26,34). In addition, it was documented
in healthy adults that chronic administration of rimonabant,
a CB1 inverse agonist, during weight loss trials led to increased
symptoms of depression and suicidal thoughts compared with a
placebo control (6), suggesting a causal relationship between
low CB1 activity and psychopathology. In animals, the eCB
system is important for adapting to chronic stress (25), so it is
possible that a dysfunctional eCB system could contribute to
maladaptive stress responses, such as the manifestation of de-
pressive symptoms. In humans, there is preliminary evidence
which suggests that physically active individuals are better able
to modulate their eCB activity in the context of inflammatory
and immune processes compared with sedentary individuals,
despite there being no significant differences in basal eCB
levels (19). There is considerable evidence that interactions
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between inflammation and the brain may underlie the etiol-
ogy of depression, suggesting that the ability to regulate in-
flammatory processes could be instrumental in lowering the
risk of depression or other stress-related psychological dis-
orders (37). Moving forward, it will be important to deter-
mine whether exercise is protective against the long-term
psychological effects of stress because of its ability to activate
or perhaps regulate the eCB system.
In conclusion, both prescribed and preferred exercises elic-
ited beneficial mood outcomes and increased concentrations of
AEA and 2-AG among inactive to highly active individuals.
An important extension of this research will be to determine
whether eCB adaptations occur with an exercise training
program not only in healthy adults but also in patient
populations where eCB dysfunction has been observed and
where exercise has been shown to have therapeutic effects
(e.g., major depressive disorder).
This work was supported by the American College of Sports
Medicine, the University of Wisconsin Virginia Horne Henry Fund,
and the Research and Education Component of the Advancing
a Healthier Wisconsin Endowment at the Medical College of
Wisconsin.
The authors of this manuscript have no conflicts of interest to de-
clare. The results of this study do not constitute endorsement by the
American College of Sports Medicine. The results are presented
clearly, honestly, and without fabrication, falsification, or inappropriate
data manipulation.
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... They found both groups experienced symptom improvement over time, with those engaging in more exercise experiencing greater and faster responses. However, if exercise is sequenced immediately before therapy (thereby "priming" a person to be ready for therapy), the acute psychological (e.g., lower anhedonia, improved mood, higher self-efficacy) and biological (e.g., increased brain-derived neurotrophic factor [BDNF], endocannabinoids) changes that result from exercise may better prepare patients for engaging in the post-exercise therapy sessions (14)(15)(16)(17)(18). Improved mood and anhedonia have been found to last at least 30 min after exercise in adults with DEP, indicating that a standard 50-min post-exercise therapy session could capitalize on these short-term effects (15). ...
... Lastly, the PHQ-9 was used to evaluate weekly changes in self-reported depressive symptoms. This is a 9-question self-report instrument used to assess presence and severity of depressive symptoms, with scores categorized as minimal (0-4), mild (5-9), moderate (10)(11)(12)(13)(14), moderately severe (15)(16)(17)(18)(19), and severe (20-27) depression (36). ...
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Importance: Depression is the leading cause of mental health-related disease burden and may be reduced by physical activity, but the dose-response relationship between activity and depression is uncertain. Objective: To systematically review and meta-analyze the dose-response association between physical activity and incident depression from published prospective studies of adults. Data sources: PubMed, SCOPUS, Web of Science, PsycINFO, and the reference lists of systematic reviews retrieved by a systematic search up to December 11, 2020, with no language limits. The date of the search was November 12, 2020. Study selection: We included prospective cohort studies reporting physical activity at 3 or more exposure levels and risk estimates for depression with 3000 or more adults and 3 years or longer of follow-up. Data extraction and synthesis: Data extraction was completed independently by 2 extractors and cross-checked for errors. A 2-stage random-effects dose-response meta-analysis was used to synthesize data. Study-specific associations were estimated using generalized least-squares regression and the pooled association was estimated by combining the study-specific coefficients using restricted maximum likelihood. Main outcomes and measures: The outcome of interest was depression, including (1) presence of major depressive disorder indicated by self-report of physician diagnosis, registry data, or diagnostic interviews and (2) elevated depressive symptoms established using validated cutoffs for a depressive screening instrument. Results: Fifteen studies comprising 191 130 participants and 2 110 588 person-years were included. An inverse curvilinear dose-response association between physical activity and depression was observed, with steeper association gradients at lower activity volumes; heterogeneity was large and significant (I2 = 74%; P < .001). Relative to adults not reporting any activity, those accumulating half the recommended volume of physical activity (4.4 marginal metabolic equivalent task hours per week [mMET-h/wk]) had 18% (95% CI, 13%-23%) lower risk of depression. Adults accumulating the recommended volume of 8.8 mMET hours per week had 25% (95% CI, 18%-32%) lower risk with diminishing potential benefits and higher uncertainty observed beyond that exposure level. There were diminishing additional potential benefits and greater uncertainty at higher volumes of physical activity. Based on an estimate of exposure prevalences among included cohorts, if less active adults had achieved the current physical activity recommendations, 11.5% (95% CI, 7.7%-15.4%) of depression cases could have been prevented. Conclusions and relevance: This systematic review and meta-analysis of associations between physical activity and depression suggests significant mental health benefits from being physically active, even at levels below the public health recommendations. Health practitioners should therefore encourage any increase in physical activity to improve mental health.
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Exercise is rewarding, and long-distance runners have described a runner’s high as a sudden pleasant feeling of euphoria, anxiolysis, sedation, and analgesia. A popular belief has been that endogenous endorphins mediate these beneficial effects. However, running exercise increases blood levels of both β-endorphin (an opioid) and anandamide (an endocannabinoid). Using a combination of pharmacologic, molecular genetic, and behavioral studies in mice, we demonstrate that cannabinoid receptors mediate acute anxiolysis and analgesia after running. We show that anxiolysis depends on intact cannabinoid receptor 1 (CB1) receptors on forebrain GABAergic neurons and pain reduction on activation of peripheral CB1 and CB2 receptors. We thus demonstrate that the endocannabinoid system is crucial for two main aspects of a runner’s high. Sedation, in contrast, was not influenced by cannabinoid or opioid receptor blockage, and euphoria cannot be studied in mouse models.
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The aim of this study was to identify the possible association between biochemical markers of exercise addiction and affective parameters in a sample of athletes during 2 weeks of withdrawal exercise. Eighteen male runners were distributed into a control group (n = 10) composed of runners without exercise addiction symptoms and an exercise addiction group (n = 8) composed of runners with exercise addiction symptoms. The volunteers performed a baseline evaluation that included affective questionnaires, blood samples, body composition and an aerobic test performed at ventilatory threshold I. After the baseline evaluation, the groups started an exercise withdrawal period that was sustained for 2 weeks. During exercise withdrawal, an actigraph accelerometer was used to monitor the movement index, and CK and LDH were measured in blood samples to validate the non-exercise practice. At the end of the exercise withdrawal period, a blood collection, aerobic test and mood scale was performed in the re-test. The results showed that at the end of the experimental protocol, when compared with the control group, the exercise addiction group showed an increase in depression, confusion, anger, fatigue and decreased vigor mood that improved post-exercise, along with low levels of anandamide at all time-points evaluated and a modest increase in β-endorphin post-exercise. Moreover, the exercise addiction group showed a decrease in oxygen consumption and respiratory exchange ratio after the exercise withdrawal period, which characterized a detraining phenomenon. Our data suggest that a 2-week withdrawal exercise period resulted in an increase of negative mood in exercise addiction; additionally, exercise addiction showed low levels of anandamide.