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Psychobiological Responses to Aerobic Exercise in Individuals With Posttraumatic Stress Disorder: Psychobiological Responses to Exercise in PTSD

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Previous reports have shown improvements in mood and increases in endocannabinoids in healthy adults following a session of aerobic exercise, but it is unclear whether adults with posttraumatic stress disorder (PTSD) experience similar responses. The purpose of this study was to examine psychobiological responses (plasma endocannabinoids [eCBs], mood, and pain) to aerobic exercise in a sample of adults with a diagnosis of PTSD (n = 12) and healthy controls (n = 12). Participants engaged in an aerobic exercise session in which they ran on a treadmill for 30 min at a moderate intensity (70 to 75% maximum heart rate [MHR]). Results indicated improvements in mood states and reductions in pain for both groups following exercise, ds = 0.19 to 1.53. Circulating concentrations of N-arachidonylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), and oleoylethanolamide (OEA) significantly increased (ps = .000 to .050) following the aerobic exercise session for both groups. There were no significant time, group, or interaction effects (ps = .062 to .846) for palmitoylethanolamide (PEA) and 2-oleoylglycerol (2-OG). Although eCBs increased significantly for both groups, within-group effect size calculations indicated the healthy controls experienced a greater magnitude of change for AEA when compared with adults with PTSD, d = 1.21 and d = 0.45, respectively; as well as for 2-AG, d = 0.43 and d = 0.21, respectively. The findings from this study indicated that adults with and without PTSD reported significant mood improvements following 30 min of moderate-intensity aerobic exercise. In addition, the endocannabinoid system was activated in adults with and without PTSD, although effect sizes suggest that adults with PTSD may have a blunted endocannabinoid response to exercise.
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Journal of Traumatic Stress
xxxx 2018, 00, 1–12
Psychobiological Responses to Aerobic Exercise in Individuals With
Posttraumatic Stress Disorder
Kevin M. Crombie,1Angelique G. Brellenthin,1Cecilia J. Hillard,2and Kelli F. Koltyn1
1Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin, USA
2Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Previous reports have shown improvements in mood and increases in endocannabinoids in healthy adults following a session of aerobic
exercise, but it is unclear whether adults with posttraumatic stress disorder (PTSD) experience similar responses. The purpose of this study
was to examine psychobiological responses (plasma endocannabinoids [eCBs], mood, and pain) to aerobic exercise in a sample of adults
with a diagnosis of PTSD (n=12) and healthy controls (n=12). Participants engaged in an aerobic exercise session in which they ran on
a treadmill for 30 min at a moderate intensity (70 to 75% maximum heart rate [MHR]). Results indicated improvements in mood states
and reductions in pain for both groups following exercise, ds=0.19 to 1.53. Circulating concentrations of N-arachidonylethanolamine
(AEA), 2-arachidonoylglycerol (2-AG), and oleoylethanolamide (OEA) significantly increased (ps=.000 to .050) following the aerobic
exercise session for both groups. There were no significant time, group, or interaction effects (ps=.062 to .846) for palmitoylethanolamide
(PEA) and 2-oleoylglycerol (2-OG). Although eCBs increased significantly for both groups, within-group effect size calculations indicated
the healthy controls experienced a greater magnitude of change for AEA when compared with adults with PTSD, d=1.21 and d=
0.45, respectively; as well as for 2-AG, d=0.43 and d=0.21, respectively. The findings from this study indicated that adults with
and without PTSD reported significant mood improvements following 30 min of moderate-intensity aerobic exercise. In addition, the
endocannabinoid system was activated in adults with and without PTSD, although effect sizes suggest that adults with PTSD may have a
blunted endocannabinoid response to exercise.
Posttraumatic stress disorder (PTSD) is a prevalent, chronic
condition that results from exposure to a traumatic event (e.g.,
motor vehicle accident, combat, physical and sexual assault).
Accompanying symptomatology often involves impaired or ab-
normal fear processing (e.g., spontaneous recollections and en-
hanced reactivity to cues associated with the traumatic experi-
ence), in addition to negative alterations in memory processes,
cognition, and mood (American Psychiatric Association [APA],
2013). Individuals with PTSD are often faced with numerous
other challenges if the PTSD is left untreated (e.g., comorbid
depression, anxiety, chronic pain, substance use disorders) and
are at a greater risk for experiencing comorbid physical condi-
tions (e.g., cardiovascular disease), which can exacerbate their
psychological symptoms (Buckley et al., 2004; Kessler & Chiu,
This research was supported by the University of Wisconsin Virginia Horne
Henry Fund and the Advancing a Healthier Wisconsin Endowment at the
Medical College of Wisconsin. The funding bodies had no role in the design
of this study, the analysis or interpretation of the data or the composition of
this manuscript.
Correspondence concerning this article should be addressed to Dr. KelliKoltyn,
Department of Kinesiology, University of Wisconsin – Madison, 2000 Obser-
vatory Drive, Madison, WI, 53706-1121. E-mail: Kelli.koltyn@wisc.edu
Copyright C2018 International Society for Traumatic Stress Studies. View
this article online at wileyonlinelibrary.com
DOI: 10.1002/jts.22253
2005). Unfortunately, PTSD is a complex, multifaceted disor-
der with limited efficacious treatment options, thus, additional
research is required to better understand and treat this disorder.
Exercise may be one such treatment option, as it has been
shown to be an effective intervention to improve physical and
mental health in both the general population and in several clini-
cal populations (e.g., participants with major depression or anx-
iety disorders; Blumenthal et al., 2007; Herring, Lindheimer,
& O’Connor, 2013). Despite this knowledge, exercise has only
recently been suggested as a potential treatment option to im-
prove PTSD symptoms. Although investigations are limited,
findings of reduced PTSD symptoms, anxiety, and depres-
sion suggest that exercise may be an efficacious treatment for
PTSD (Rosenbaum, Sherrington, & Tiedemann, 2015). How-
ever, more research is warranted in order to delineate the role of
exercise as a nonpharmacological treatment for improving men-
tal health outcomes in individuals with PTSD and to understand
the mechanism(s) behind the exercise-induced psychological
adaptations.
One possible explanation for the therapeutic benefits of ex-
ercise involves the activation of the endocannabinoid system
(eCB). The eCB system is present in the brain and periphery and
consists of receptors (cannabinoid type 1 [CB1] and cannabi-
noid type 2 [CB2]), eCB ligands (N-arachidonoylethanolamine
or anandamide [AEA] and 2-arachidonylglycerol [2-AG]), and
1
Crombie et al.
enzymes involved in the synthesis and degradation of the en-
dogenous ligands. In addition, there are several related biogenic
lipids that are not truly eCBs, but are often examined alongside
eCBs. Palmitoylethanolamide (PEA) and oleoylethanolamide
(OEA) are noncannabinoid fatty-acid ethanolamides that share
biosynthetic and metabolic pathways with AEA, but do not
activate cannabinoid receptors. Similarly, 2-oleoylglycerol (2-
OG), like 2-AG, is a 2-monoacylglycerol and has overlap-
ping mechanisms of synthesis and degradation with 2-AG such
that their concentrations often increase and decrease together
(Hillard, 2000; Hill & Gorzalka, 2009; Katona & Freund, 2012).
In the brain, eCB/CB1 receptor signaling subserves activity-
dependent, retrograde synaptic signaling. Far less is known
about the triggers for release of eCBs in the periphery; but it is
clear that, like in the brain, CB1 receptors inhibit neurotransmit-
ter release from peripheral nerve terminals. Activation of CB2
receptors reduces the release of cytokines from immune cells.
Given that the eCB system regulates neurotransmitter release
probability, eCB signaling has been implicated in the regulation
of numerous physiological and psychological functions, includ-
ing stress, emotional regulation, memory, nociception, higher
level cognitive functions, and regulation of the immune sys-
tem (Gorzalka, Hill, & Hilliard, 2008; Hill & Gorzalka, 2009;
Hillard, 2015).
A growing accumulation of preclinical and clinical evidence
has also highlighted the important role of the eCB system in
the regulation of several processes central to PTSD (Berardi,
Schelling, & Campolongo, 2016; Trezza & Campolongo, 2013;
Hill & Patel, 2013). For instance, the eCB system is involved in
the activation and recovery of endocrine, nervous, and behav-
ioral systems following stress (Lutz, Marsicano, Maldonado,
& Hillard, 2015). Moreover, chronic pain is commonly re-
ported alongside PTSD (Andersen, Andersen, & Andersen,
2014), which is relevant as a wealth of preclinical data sug-
gest that the eCB system is involved in regulating nocicep-
tive functioning at all levels of the pain processing pathway
(Woodhams, Sagar, Burston, & Chapman, 2015). Additionally,
other researchers have reported findings that systemic adminis-
tration of AEA and 2-AG produces analgesia in animal models
of acute and chronic pain (Walker & Huang, 2002; Guindon,
Desroches, & Beaulieu, 2007). Additionally, preclinical find-
ings have demonstrated that fear processes are CB1-receptor
mediated, as disrupting eCB signaling (via removal or block-
ade of CB1 receptors) enhances fear acquisition, impairs the
extinction of conditioned fear responses, and increases anx-
iogenic behaviors (Mariscano et al., 2002). Moreover, there
is growing consensus among researchers that an underlying
feature of PTSD and several other psychological disorders in-
volves a dysregulated eCB system (Hill et al., 2013; Hill, Miller,
Carrier, Gorzalka, & Hilliard, 2009; Neumeister et al., 2013).
For instance, individuals with PTSD or depression have been
found to exhibit lower levels of eCBs (i.e., AEA and/or 2-AG)
and related lipids (PEA, OEA) compared with healthy trauma-
exposed controls without PTSD or depression (Hill et al., 2009;
Hill et al., 2013; Neumeister et al., 2013; Karabatsiakis et al.,
2015; Wilker et al., 2016), although Hauer et al. (2013) found
evidence of higher eCB tone (AEA, 2-AG, OEA) in individuals
with PTSD compared with controls. Thus, strategies to increase
eCB levels are thought to have therapeutic potential.
Treatments aimed at augmenting the eCB system have
yielded promising results. Although investigations have been
limited, pharmacological augmentation of the eCB system has
been shown to improve extinction learning in animals and hu-
mans (Bluett et al., 2014; Lutz et al., 2015; Rabinak et al., 2014;
Jetly, Heber, Fraser, & Boisvert, 2015; Fraser, 2009). Although
previous investigators have used exogenous, pharmacological
approaches, there is a strong rationale to investigate nonphar-
macological approaches (e.g., exercise) that activate the eCB
system. In addition to improving psychological health (e.g.,
anxiety and depression) in clinical populations (Blumenthal
et al., 2007; Herring et al., 2013), exercise has been found to
increase eCBs in humans (Brellenthin, Crombie, Hillard, &
Koltyn, 2017; Koltyn, Brellenthin, Cook, Sehgal, & Hillard,
2014; Raichlen, Foster, Gerdeman, Seillier, & Giuffrida, 2012;
Sparling, Giuffrida, Piomelli, Rosskopf, & Dietrich, 2003) and
animals (Galdino et al., 2014a, 2014b; Hill et al., 2010), which
suggests that (a) eCBs may be responsible for the exercise-
induced improvements in psychological outcomes, and (b) ex-
ercise may be a nonpharmacological treatment approach for
improving mental health outcomes in individuals with PTSD
due to its influence on the eCB system.
Clearly, if exercise is to be used as a treatment for improving
mental health outcomes among individuals with PTSD due to
its ability to enhance eCB signaling, it is essential to determine
if the eCB system responds to aerobic exercise to the same
extent in individuals with PTSD as it does in a healthy, non-
clinical population. Therefore, the purpose of this study was
to examine psychobiological responses (eCBs and mood) to a
moderate-intensity aerobic exercise session in individuals with
and without PTSD.
Method
Participants
For this initial pilot study, we estimated sample size for our
primary variable of interest (i.e., eCBs). Based on findings from
previous research conducted in our lab (Koltyn et al., 2014;
Brellenthin et al., 2017) that showed large effect size changes
in eCBs following exercise, the analysis was powered at 0.80,
with an alpha of .05, and a Cohen’s fvalue of 0.30 (medium
effect size). The mixed analysis of variance (ANOVA) power
analysis indicated that we would need 12 participants per group
(N=24).
In order to recruit participants, newspaper advertisements,
class announcements, and flyers were posted around campus
and at health clinics throughout the greater community. For
the PTSD group, the recruiting materials noted that men and
women between the ages of 18 and 45 years who have a current
diagnosis of PTSD were needed for a research study aimed at
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Psychobiological Responses to Exercise in PTSD
Table 1
Baseline Sample Demographics
Control PTSD
Variable MSD M SD
Age (years) 22.00 4.70 26.10 6.70
Sex (women, nand %) 9 75.0% 9 75.0%
Body mass index (kg/m2) 22.50 2.90 25.30 6.90
Anxiety (BAI) 3.25 7.00 13.58*** 7.60
Depression (BDI-II) 1.67 1.92 14.33*** 9.70
Sedentary time (min/day) 660.80 103.30 579.30 188.90
Light-intensity PA (min/day) 128.80 51.20 104.50 54.50
Moderate-intensity PA (min/day) 54.9 15.7 44.5 28.5
Meets WHO PA Guidelines (naand %) 5 41.6% 5 41.6%
Note. PTSD =posttraumatic stress disorder; BAI =Beck Anxiety Inventory; BDI-II =Beck Depression Inventory II; PA =physical activity; WHO =World Health
Organization.
aOut of 12.
***p<.001.
investigating changes in mood and biomarkers in blood follow-
ing a 30-min bout of exercise. For the control (non-PTSD)
group, the recruiting materials noted that healthy men and
women between the ages of 18 and 45 years were needed for
a research study aimed at investigating changes in mood and
biomarkers in blood following a 30-min bout of exercise. Par-
ticipants were matched on age, sex, and physical activity levels.
In total, 24 men and women (n=6 men and n=18 women)
between the ages of 18 and 45 years (M=25.0, SD =5.6)
without a history or present diagnosis of physical or psychotic
disorders participated in this study. Participants from the PTSD
group (n=12) had a current diagnosis (from their primary
psychologist or psychiatrist) of PTSD stemming from one or
more of the following traumas: sexual/physical assault (n=8),
emotional/psychological abuse (n=3), motor vehicle accident
(n=2), combat/war-related event (n=2). Exclusion criteria
for participants from both groups included being pregnant or
planning on becoming pregnant; currently smoking; responding
“yes” to any of the seven questions on the Physical Activity
Readiness Questionnaire (PAR-Q); taking medications for any
chronic diseases such as high blood pressure or diabetes; or
having a current or past diagnosis of a psychotic disorder, or
any medical, cognitive, or neurological disorders. Participants
were instructed not to eat within 2 hours or exercise within
24 hours of testing to minimize eCB variations and any potential
carry-over effects from past-day participation in exercise.
The mean number of PTSD symptoms indicated by the PTSD
group was 10.36 (SD =4.92) with a mean symptom severity
score of 51.25 (SD =18.50). Table 1 summarizes the baseline
characteristics of the sample. There were no significant differ-
ences between groups for age (p=.170), sex (p=1.000),
or body mass index (p=.204). However, the PTSD group
had significantly higher baseline anxiety and depression scores
compared with the control group, F(1,22) =7.31, p<.001 and
F(1,22) =13.23, p<.001, respectively.
Procedure
All procedures were approved by the Health Sciences In-
stitutional Review Board at the University of Wisconsin—
Madison. Participants reported to the laboratory on the day of
their scheduled study visit. In order to verify that participants
met inclusion and exclusion criteria, participants completed
a neuropsychiatric interview (Mini-International Neuropsychi-
atric Interview, MINI; Sheehan et al., 1998), led by a trained
research assistant, in a private sound-dampened chamber in the
laboratory after signing an informed consent document. Par-
ticipants then completed various questionnaires including the
PTSD Checklist-Civilian (PCL-C; Weathers et al., 1993); Beck
Anxiety Inventory (BAI; Beck & Steer, 1990); Beck Depression
Inventory-II (BDI-II; Beck, Steer, & Brown, 1996); Profile of
Mood States (POMS; McNair, Lorr, & Droppleman, 1971);
Positive and Negative Affect Schedule (PANAS; Watson,
Clark, & Tellegen, 1988); State-Trait Anxiety Inventory (STAI;
Spielberger, Gorsuch, Lushene, Bagg, & Jacobs, 1983); and
McGill Pain Questionnaire—Short Form (MPQ-SF; Melzack,
1987). Next, participants had 5 mL of blood drawn (BD Va-
cutainer, K3E EDTA K3 collection tubes; Greiner Bio-One,
Monroe, North Carolina) immediately before they engaged in
a 30-min moderate-intensity aerobic exercise session (see be-
low). Upon completion of the exercise session, participants
immediately had their blood drawn and then completed ques-
tionnaires that assessed mood (POMS, STAI, PANAS) and pain
(MPQ-SF). After completing the postexercise questionnaires,
participants were provided with an accelerometer (Actigraph
GT3X+, Actigraph, Pensacola, FL) to wear for 7 days in or-
der to quantify physical activity (PA). Participants were also
asked to complete an activity log in conjunction with wearing
the accelerometer. Accelerometry data were used to assist in
matching participants from both groups and was corroborated
with self-reported PA levels obtained from the previsit phone
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Crombie et al.
screen. Accelerometers were returned and compensation ($50
USD) for participation was distributed 1 week following the
study visit.
Measures
PTSD and other psychiatric disorders. In order to de-
termine the presence of PTSD and other psychiatric disorders,
trained study staff administered the MINI (Sheehan et al., 1998),
a structured interview developed by psychiatrists and clinicians
to assess various psychological conditions. Participants also
completed a self-report PTSD symptom questionnaire (PCL-C;
Weathers et al., 1993) in order to assess the number and severity
of PTSD symptoms. The PCL-C is a standardized self-report
rating scale used in clinical and research settings for screening,
diagnosing, and monitoring symptom change regarding PTSD.
The PCL-C is comprised of 17 items corresponding to the key
symptoms of PTSD. Respondents were asked to indicate how
much they have been bothered by a symptom over the past
month using a 5-point Likert scale (1 =not at all,2=a lit-
tle bit,3=moderately,4=quite a bit,5=extremely). A
total symptom severity score ranging from 17 to 85 (PTSD
general population, M=45.80; SD =16.10) can be obtained
by summing the scores from each of the 17 items (α=.879).
The PCL-C has been shown to be reliable and valid in civil-
ians and military personnel and veterans (Weathers et al., 1993;
Blanchard, Jones-Alexander, Buckley, & Forneris, 1996).
Anxiety and depression. Clinical self-report assessments
of anxiety (BAI; Beck & Steer, 1993) and depression (BDI-
II; Beck et al., 1996) were also administered. The BDI-II is a
21-item (α=.923) self-report rating inventory that measures
symptoms of depression. Participants responded to the 21 items
using a 4-point Likert-type scale (0 =not at all,1=mildly,
2=moderately,3=severely). Each item was summed to give
a total depression score ranging from 0 to 63. A total score of
0 to 13 indicates minimal depression, 14 to19 indicates mild
depression, 20 to 28 indicates moderate depression, and 29 to
63 indicates severe depression.
The BAI is a validated 21-item self-report rating inventory
used for measuring anxiety. Participants responded to the 21
items (α=.893) using a 4-point Likert-type scale (0 =not at
all,1=mildly,2=moderately,3=severely). Similar to the
BDI-II, each item was summed to give a total anxiety score
ranging from 0 to 63. Cut scores have been established, with
a summed score of 0–9 indicating minimal anxiety, 10 to 16
indicating mild anxiety, 17 to 29 indicating moderate anxiety,
and 30 to 63 indicating severe anxiety. The BDI-II and BAI
are two of the most widely used instruments for measuring
depression and anxiety, respectively, and both have been shown
to be reliable and valid in both psychiatric and nonpsychiatric
populations (Beck et al., 1996).
Mood. In order to assess acute mood states prior to and
following exercise, participants completed the POMS (McNair
et al., 1971), STAI (Spielberger et al., 1983), and PANAS
(Watson et al., 1988). The POMS is a validated 65-item
(α=.935) rating scale used to assess several mood states,
including tension, depression, confusion, anger, fatigue, vigor,
and total mood disturbance (TMD). The 65 adjectives are rated
by participants on a 5-point Likert-type scale (0 =not at all,
1=a little,2=moderately,3=quite a bit,4=extremely).
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. Normative values
for the POMS subscales in an adult population are as follows:
tension, M=7.00, SD =5.50; depression, M=7.10, SD
=8.40; confusion, M=5.20, SD =4.10; anger, M=6.60,
SD =6.70; fatigue, M=7.30, SD =5.70; vigor, M=20.20,
SD =6.20; and TMD, M=127.00, SD =29.6. The POMS has
been shown to be reliable and valid with internal consistencies
of each mood state, with Cronbach’s alpha values ranging from
.84 to .95 (McNair et al., 1971).
The STAI is a widely used self-report measure that indicates
the experienced intensity of feelings of anxiety. The STAI con-
tains 20 items (e.g., “I am tense”) that assess present levels of
anxiety. Participants were asked to respond to each item on a
Likert-type scale (1 =not at all, 2=somewhat, 3=moder-
ately, 4=very much so). Each of the 20 items (α=.880) were
summed to give a total state anxiety score ranging from 20 to 80
(normative adult population, M=35.20, SD =10.6). Internal
consistencies are high, with Cronbach’s alpha values ranging
from .86 to .95 (Spielberger, 1983).
The PANAS is a validated 20-item questionnaire that
comprises two mood scales: one measuring positive affect
(10 items) and one measuring negative affect (10 items). Each
of the 20 items (α=.857) was rated on a 5-point scale (1 =very
slightly or not at all,2=a little,3=moderately,4=quite a bit,
5=extremely) to indicate the extent to which the participant
felt positive or negative affect during the indicated time frame
(Watson et al., 1988). For the purpose of this study, participants
were asked to respond to the 20 items based on how they felt “at
this moment.” Responses to the items were summed in order to
obtain a total positive affect (adult population, M=31.31, SD
=7.65) and negative affect (adult population M=16.00, SD
=5.90) score, each ranging from 10 to 40 (Crawford & Henry,
2004).
Exercise session. The aerobic exercise session consisted
of a 10-min warm-up at low to moderate intensity (40 to 60%
maximum heart rate [MHR]), followed by 30 min of walking
or running on a treadmill at a moderate intensity (70 to 75%
MHR; 12 to 15 Borg’s Ratings of Perceived Exertion [RPE]),
and then finished with a 5-min walking cool-down. This dura-
tion and intensity of exercise was selected as it has previously
been shown to result in significant elevations in circulating eCB
in regularly healthy individuals (Sparling et al., 2003; Raichlen
et al., 2012). Heart rate and RPE were assessed every 5 min
during the exercise (see Table 2). Standardized scripts were
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Psychobiological Responses to Exercise in PTSD
Table 2
Means and Standard Deviations for Exercise Session Variables
Control PTSD
Variable MSDMSD
Baseline systolic blood pressure (mmHg) 112.00 13.40 102.70 35.70
Baseline diastolic blood pressure (mmHg) 73.20 7.20 69.10 24.00
Average ratings of perceived exertion (RPE) 13.00 0.09 13.00 0.09
Average heart rate (% MHR) 78.90 1.29 76.90 6.00
Treadmill speed (km/h) 7.56 1.29 7.72 3.20
Treadmill incline (% grade) 1.19 0.40 1.00 0.00
Postexercise systolic blood pressure (mmHg) 106.70 12.10 102.80 34.70
Postexercise diastolic blood pressure (mmHg) 73.90 6.70 71.60 24.40
Note. mmHG =millimeters of mercury; km/h =kilometers per hour. MHR =maximum heart rate.
used to explain the exercise session as well as Borg’s Ratings
of Perceived Exertion scale (Borg, 1998).
Endocannabinoid assays. Blood draws were obtained
while participants were seated and samples were collected into
ethyylenediaminetetraacetic acid (EDTA) containing tubes (BD
Vacutainer, K3E EDTA K3). Blood samples were then cen-
trifuged (4 C at 3,500 RPM) within 5 minutes of collection,
separated into aliquots, and frozen at 80 ˚C until eCB and
related biogenic lipid extractions took place. Plasma samples
(0.5 mL each) were then thawed and made up to 15% ethanol,
to which the internal standards, [2H8]-AEA (16.9 pmol) and
[2H8]-2-AG (46.5 pmol) (Cayman Chemicals, Ann Arbor, MI)
were added. Samples were vortexed and centrifuged at 12,000
RPM for 4 min. The resulting supernatant was loaded onto
Bond Elut C18 solid-phase extraction columns (1 mL: Varian
Inc, Lake Forest, CA), which had been conditioned with 1 mL
redistilled ethanol and 3 mL of double distilled water (ddH2O).
The remaining pellet was rinsed with 100 uL of 15% ethanol
and recentrifuged at 12,000 RPM for 3 minutes. The resulting
supernatant was also loaded onto the C18 column. Columns
were washed with 5 mL ddH2O (eluate discarded) followed by
1 mL of ethyl acetate (eluate collected). The ethyl acetate layer
in the resulting eluate was removed and dried under nitrogen.
The samples were resuspended twice in ethyl acetate and dried.
The final samples were resuspended in 30 uL of methanol and
stored at 80 ˚C.
Following preparation, the concentrations of eCBs (AEA and
2-AG), along with related biogenic lipids (PEA, OEA, 2-OG)
were quantified in 5 μl of the methanol extract using stable
isotope-dilution, electrospray ionization liquid chromatogra-
phy/mass spectrometry of the daughter ions (LC-ESI-MS-MS).
Standard curves were generated for 2-AG (10 to 4250 pg/μl),
2-OG (20 to 8,500 pg/μl), AEA (0.2 to 85 pg/μl), OEA (0.3 to
127.5 pg/μl), and PEA (1.2 to 510 pg/μl), and internal standards
[2H8]-AEA (16.9pmol) and [2H8]-2-AG (46.5 pmol).
Concentrations of the analytes were determined from stan-
dard curves of the area ratios (standard/analyte) versus the
concentration ratios (standard/analyte); [2H8]-AEA was used
as the standard for AEA, OEA, and PEA while [2H8]-2-AG
was used for 2-AG and 2-OG. The area ratios for all analytes
in all samples were within their respective standard curves.
Data Analysis
We conducted all analyses with SPSS Version 23.0 for Win-
dows. There were no missing data for all outcomes. In or-
der to meet the normality assumption (i.e., Shapiro-Wilk test)
for parametric tests, lipid concentrations were logarithmically
transformed (log10) before we conducted further statistical anal-
yses (repeated-measures ANOVAs). A one-way ANOVA was
used to detect the presence of group differences in baseline vari-
ables. Plasma AEA, PEA, OEA, 2-AG, and 2-OG concentra-
tions, mood states, and pain responses were compared between
and within groups using a series of 2 (group: PTSD and control)
×2 time (pre-, postexercise) mixed-design, repeated measures
ANOVAs. The overall alpha familywise was set at αFW =.05.
Following the presence of significant interaction effects, simple
effects were calculated for all pairwise comparisons (i.e., alpha
pairwise comparison [αpc] =.05) based on Tukey’s honest sig-
nificant difference (HSD) procedures. Cohen’s d(defined as
the difference between means, M1 – M2, divided by the pooled
standard deviation) was used to calculate effect sizes (Cohen,
1988) in order to provide a quantitative measure of the mag-
nitude of the treatment effect (i.e., exercise). Interpretation of
Cohen’s deffect sizes allows for the magnitude of the treatment
effect to be classified as small (d=0.20 to 0.49), moderate (d=
0.50 to 0.79), or large (d0.80). Spearman’s rho correlations
were used to assess associations among pre- to postexercise
changes in mood scores and eCB concentrations.
Results
Endocannabinoid Responses to Exercise
Prior to exercise, there were no significant group differ-
ences in content of AEA, F(1,22) =0.94, p=.345; 2AG,
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Crombie et al.
Figure 1. Endocannabinoid and related lipid responses to aerobic exercise. Data points represent individual participant responses. Dashed lines represent group
means. and =data points for two individuals who met criteria for alcohol abuse based on responses to baseline psychiatric interview. CON =control
group; PTSD =PTSD group; AEA =Anandamide; OEA =oleoylethanolamide; PEA =palmitoylethanolamide; 2AG =2-arachidonoylglycerol; and 2OG =
2-oleoylglycerol.
F(1,22) =1.05, p=.318; OEA, F(1,22) =0.452, p=.509;
PEA, F(1,22) =0.181, p=.675; or 2-OG, F(1,22) =1.97,
p=.175. However, the results indicated there were significant
time effects for 2-AG, F(1,22) =4.34, p=.049; AEA, F(1,22)
=19.28, p<.001; and OEA, F(1,22) =7.32, p=.013, with
the concentrations of lipids increasing significantly from pre-
to postexercise for both groups (see Figure 1). However, results
indicated nonsignificant time effects for PEA, F(1,22) =0.13,
p=.910; and 2-OG, F(1,22) =0.60, p=.256. The group main
effects for AEA, F(1,22) =1.67, p=.209; 2-AG, F(1,22) =
2.04, p=.167; OEA, F(1,22) =0.71, p=.408; PEA, F(1,22)
=1.4, p=.250; and 2-OG, F(1,22) =1.363, p=.256 were
nonsignificant, as were the group ×time interactions for AEA,
F(1,22) =0.34, p=.568; 2-AG, F(1,22) =1.00, p=.327;
OEA, F(1,22) =0.70, p=.411; PEA, F(1,22) =0.55, p=
.468; and 2-OG, F(1,22) =1.25, p=.276. We also computed
effect size calculations to examine the magnitude of the eCB
response for both groups. Between-group effect size calcula-
tions (see Figure 2) indicated that the healthy controls experi-
enced a greater magnitude of change for AEA, 2-AG, and OEA
in comparison to the adults with PTSD.
Mood and Pain Responses to Exercise
The results indicated there were significant (ps=.001 to
.002) time effects for vigor and positive affect, indicating a
significant increase from pre- to postexercise in vigor and pos-
itive affect for both groups (see Table 3). However, the group
main effects and the group ×time interactions for vigor and
positive affect were nonsignificant (ps=.080 to .536). There
were significant (ps=.001 to .050) group ×time interactions
for state anxiety, negative affect, tension, fatigue, confusion,
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Psychobiological Responses to Exercise in PTSD
Figure 2. Effect size changes from pre- to postexercise for the control and posttraumatic stress disorder (PTSD) groups for the two main endocannabinoids:
Anandamide (AEA) and 2-arachidonylglycerol (2-AG), and related biogenic lipids: oleoylethanolamide (OEA), palmitoylethanolamide(PEA), and 2- oleoylglycerol
(2-OG).
and total mood disturbance. Analysis of simple effects indi-
cated that greater reductions in negative mood states occurred
following exercise for the PTSD group in comparison with the
control group. Results also indicated that there was a significant
(p=.001) time effect for pain, with pain decreasing following
exercise in both groups. The group main effect for pain and the
group ×time interaction was nonsignificant (ps=.062 to .429).
Note that the preexercise POMS depression and anger scores
for the control group had standard deviation values of zero, thus
violating the sphericity assumption. As a result, we conducted
independent-samples ttests that compared the mean change
scores for depression and anger between the PTSD and control
groups. Results indicated a significant difference between the
mean change in depression of the two groups, t(20) =3.385,
p=.007, which indicated a significantly greater change in
POMS depression for the PTSD group (M=8.64, SD =8.27),
compared with that of the control group (M=0.18, SD =0.41 ).
In contrast, no significant difference was found,t(20) =1.490,
p=.152, between the change in anger scores for the PTSD
group (M=5.63, SD =11.91) and control group (M=0.27,
SD =0.65). The effect size results are illustrated in Figure 3.
Associations Between Endocannabinoid and Mood
Responses to Exercise
For the entire sample, there were no significant associations
(ps=.059 to .924) between changes in eCBs and mood re-
sponses following the aerobic exercise session for any of the
aforementioned mood states. However, when data from the
PTSD group alone were analyzed, a significant negative cor-
relation (p =−.611, p=.040) emerged between the change
in negative affect and 2-AG concentrations, indicating greater
reductions in negative affect for individuals with a greater
increase in 2-AG.
Discussion
Our findings from this study indicated that the eCB sys-
tem was activated in adults with PTSD following 30 min of
moderate-intensity aerobic exercise. There were no significant
differences between participants with PTSD and healthy con-
trols; however, the magnitude of the eCB response was greater
among healthy controls compared with participants with PTSD,
which suggests that adults with PTSD may have a blunted eCB
response upon exposure to a physical stressor (i.e., exercise).
Our findings that indicated a significant increase in AEA, 2-AG,
and OEA are in line with a number of previous investigations
that have demonstrated significant increases in circulating eCBs
following exercise. For instance, several studies involving both
humans and animals have consistently reported increased cir-
culating concentrations of eCBs following aerobic (Raichlen
et al., 2012; Sparling et al., 2003; Heyman et al., 2012), resis-
tance (Galdino et al., 2014b), and isometric exercise (Koltyn
et al., 2014). However, almost all of the previous acute exercise
and eCB investigations were conducted in healthy and physi-
cally active male participants. This investigation was novel due
to the fact that it was the first study to examine the eCB response
to exercise in a clinical sample (i.e., PTSD), with a majority of
female participants.
Examining eCB responses to stress in clinical mental health
populations such as people with PTSD is important as results
from several recent investigations have suggested that the eCB
system is a potential target for reducing symptoms and improv-
ing various mental health aspects (e.g., anxiety, depression,
sleep quality; Jetly et al., 2015; Fraser, 2009). In fact, there is
growing consensus based on preclinical and early clinical find-
ings that targeting the eCB system in individuals with PTSD
provides positive outcomes because such treatments could
potentially augment a downregulated eCB system (Papini,
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Crombie et al.
Table 3
Mood and Pain Responses to Exercise
Control PTSD Group Main Effect Time Main Effect Group ×Time
Interaction
Variable MSDMSDFηp2pFηp2pFηp2p
Tensiona16.239 .448 .001 7.285 .267 .014 12.2 .333 .002*
Pre 2.00 1.60 12.10 6.10
Post 2.30 1.60 6.00 4.20
Confusiona22.648 .531 .001 8.364 .295 .009 3.14 .168 .050*
Pre 5.80 5.10 9.00 5.50
Post 1.60 1.20 4.80 2.50
Fatiguea15.529 .437 .001 9.075 .312 .007 4.32 .211 .050*
Pre 2.20 3.00 8.80 6.60
Post 1.20 1.90 3.70 2.40
Vigora3.38 .168 .080 35.72 .591 .001*2.44 .091 .132
Pre 14.30 6.00 8.30 6.60
Post 18.30 5.80 15.10 6.40
TMDa,d 25.164 .557 .001 13.6 .405 .001 8.40 .274 .001*
Pre 92.90 8.80 144.10 35.90
Post 86.80 7.90 107.80 15.50
Negative Affectb12.852 .391 .002 5.625 .22 .028 5.97 .239 .023*
Pre 10.20 0.40 15.60 4.80
Post 10.20 0.60 12.50 2.50
Positive Affectb2.91 .158 .102 12.37 .37 .002*0.40 .001 .536
Pre 30.80 7.80 25.20 11.60
Post 35.50 8.50 28.40 10.00
State Anxietyc39.793 .666 .001 6.503 .245 .019 4.78 .245 .040*
Pre 26.80 4.60 44.80 11.30
Post 26.40 6.10 35.90 6.80
Total Paine7.20 .34 .247 15.53 .429 .001*3.88 .15 .062
Pre 3.25 2.40 1.08 1.60
Post 1.00 1.30 0.33 0.50
Note. PTSD =posttraumatic stress disorder; TMD =total mood disturbance.
aScores were obtained from the Profile of Mood States (POMS) questionnaire. bScores were obtained from the Positive and Negative Affect Schedule (PANAS).
cScores were obtained from the State-Anxiety scale of the State-Trait Anxiety Inventory (STAI). dTMD was derived by adding 100 to the sum of the negative mood
state subscales (i.e., depression, tension, confusion, fatigue, anger) minus the positive mood state subscale (i.e., vigor). ePain was obtained from the McGill Pain
Questionnaire—Short Form (MPQ-SF).
*p<.05.
Sullivan, Hien, Shvil, & Neria, 2015; Berardi et al., 2016). Find-
ings from previous investigations of pharmacological manipula-
tions to the eCB system (Rabinak et al., 2014; Jetly et al., 2015;
Fraser, 2009), combined with the understanding that PTSD is
a chronic stress disorder resulting from an impaired ability to
extinguish fear (a process regulated and dependent on eCB sig-
naling), have bolstered this hypothesis (Marsicano et al., 2002;
Jetly et al., 2015; Fraser, 2009; Bluett et al., 2014). While the
majority of existing evidence supports this idea, recent investi-
gations aimed at examining the possibility of a dysregulated
eCB system in clinical populations have yielded somewhat
equivocal results. For instance, Hill et al. (2013) found that
in a sample of individuals with PTSD stemming from expo-
sure to the September 11, 2001, terrorist attacks, individuals
had lower basal concentrations of 2-AG but no difference in
AEA, compared with trauma-exposed individuals who did not
develop PTSD, whereas Neumeister et al. (2013) found that in-
dividuals with noncombat-related PTSD had lower AEA levels
compared with healthy controls and trauma-exposed individu-
als with PTSD. In addition to lower eCB tone, two other teams
of investigators found that individuals with PTSD had lower
concentrations of eCB-related lipids and fatty acid metabolites
in serum (PEA; Karabatsiakis et al., 2015) and in hair (OEA
and PEA; Wilker et al., 2016), compared with healthy con-
trols. Conversely, in a study that examined individuals who had
been diagnosed with noncombat-related PTSD, Hauer et al.
(2013) reported lower levels of AEA but no difference in
2-AG concentrations in comparison to trauma-exposed and
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Psychobiological Responses to Exercise in PTSD
Figure 3. Effect size changes from pre- to postexercise for the control and posttraumatic stress disorder (PTSD) groups for mood states and pain responses. ±
indicates a small effect size, indicates a medium effect size, and *indicates a large effect size change. Depression, tension, confusion, anger, vigor, and total mood
disturbance (TMD) scores were obtained from the Profile of Mood States (POMS) questionnaire; state-anxiety was obtained from the State-Anxiety Scaleofthe
State-Trait Anxiety Inventory (STAI); positive and negative affect were obtained from the Positive and Negative Affect Schedule (PANAS). TMD was derived by
adding 100 to the sum of the negative mood state subscales (i.e., depression, tension, confusion, fatigue, anger) minus the positive mood state subscale (i.e., vigor).
Pain was measured with the McGill Pain Questionnaire—Short Form (MPQ-SF).
healthy controls without a diagnosis of PTSD (Hauer et al.,
2013).
Given the relatively few number of clinical studies, it is
possible that the equivocal clinical findings (Hill et al., 2013;
Hauer et al., 2013; Neumeister et al., 2013) in studies that have
examined eCB system functioning in PTSD can be explained by
differences in methodology (e.g., type of trauma exposure, type
of stressors). However, arguably one of the most significant lim-
itations that prevents a full understanding of eCB functioning
in PTSD is that previous investigations have solely examined
eCBs under basal conditions. Since the eCB system is a regu-
latory system that responds to stimuli in real time and allows
healthy people to adapt to stress under ideal conditions (Dlu-
gos, Childs, Stuhr, Hillard, & de Wit, 2012; Chouker et al.,
2010), it is necessary to examine the eCB system in response
to various types of stress exposure, rather than just under basal
conditions. In fact, our findings provide the first preliminary
evidence of the eCB response following exposure to a physi-
cal stressor (i.e., exercise) in individuals with PTSD. Although
in our study, circulating eCB levels increased significantly fol-
lowing exercise, effect size calculations suggest that individuals
with PTSD had a blunted eCB response to physical stress (e.g.,
exercise), which provides additional support for eCB system
dysregulation in PTSD.
Consistent with previous research conducted in healthy in-
dividuals (Brellenthin et al., 2017; Koltyn, 2000), our findings
indicate that aerobic exercise was able to elicit improvements
in mood as well as reduce pain in healthy adults. Addition-
ally, the results indicated that aerobic exercise was able to elicit
significant improvements in mood along with reductions in
pain in individuals with PTSD. Specifically, the PTSD group
experienced greater changes in mood following exercise in
comparison to the control group. These greater changes in
mood, however, may be due to the PTSD group having higher
baseline negative mood states and lower positive mood states
prior to exercise than the control group. It is also possible that
the control group may have experienced a floor effect for the
negative mood states and a ceiling effect for the positive mood
states, thus minimizing the magnitude of change scores and
the potential variance in mood outcomes following exercise.
Several previous studies that examined adults with PTSD re-
ported psychological improvements (i.e., reduced depression,
anxiety, stress) and reduced PTSD symptomology (number of
symptoms and symptom severity) following a 3-month exercise
training program (Rosenbaum et al., 2015). The results from
the present study are in line with these previous results but
indicate that adults with PTSD can experience significant psy-
chological improvements following one aerobic exercise ses-
sion; however, further research is needed to document how long
these mood improvements last after the exercise session has
ended.
Additionally, we found a significant positive correlation
among the PTSD group, between the change in negative af-
fect and the change in 2-AG concentrations following exercise,
which indicates that there were greater reductions in negative
affect for individuals with a greater exercise-induced increase
in circulating levels of 2-AG. Likewise, findings from Brellen-
thin and colleagues (2017) suggested that the exercise-induced
increases in eCBs may contribute to positive mood outcomes
following exercise, as changes in 2-AG were found to nega-
Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
Crombie et al.
tively correlate with changes in depression, tension, and to-
tal mood disturbance, while changes in AEA were positively
associated with changes in vigor. Raichlen and colleagues
(2012) also reported a significant positive correlation between
exercise-induced eCBs and positive affect, which offers support
in favor of eCBs playing a role in psychological adaptations fol-
lowing exercise. More research is warranted due to the relatively
few number of investigations in this area.
As expected with a pilot study, there are several limitations
that should be considered when interpreting the results. For
instance, a limitation of this study was a lack of a randomly
assigned control condition. While a randomized controlled trial
design would have strengthened the results, previous research
in our laboratory has not found significant increases in eCBs
following a “quiet-rest” control condition. Another limitation is
that the current study had a small sample size, largely composed
of female participants. However, despite the small sample size,
the current study still found significant mood improvements
and increases in eCB content. Moreover, the fact that a major-
ity of participants in our sample were women is unsurprising
given that PTSD is more common in women compared with
men (Kessler & Chiu, 2005). Another limitation is that drug
consumption was not adequately assessed in this study. Partic-
ipants were screened for drug abuse (according to criteria for
substance abuse given in the Diagnostic and Statistical Manual
for Mental Disorders [4th ed.; DSM-IV; APA, 1994]), and two
participants met criteria for alcohol substance abuse based on
responses they provided during the baseline psychiatric inter-
view (note that we ran analyses with and without these indi-
viduals to see if alcohol abuse influenced the results, but the
results remained the same and are reported with these individ-
uals included in the analyses). We did not, however, collect
specific information about various substance use (e.g., prior to
exercise); thus, we are not able to rule out that certain sub-
stances (e.g., cannabis, alcohol, etc.) used before the exercise
session may have influenced the results. Further research is
needed in this area. Another limitation is that aerobic exercise
was the only exercise stimulus used in this study, so the find-
ings cannot be generalized to other modes of exercise (e.g.,
resistance, isometric), although initial evidence indicates that
these modes can enhance eCB tone in healthy samples (Koltyn
et al., 2014). Lastly, the current study excluded participants
who regularly smoked. Although there is limited clinical data
regarding whether or not nicotine consumption influences basal
eCB levels or the eCB response to exercise (McPartland, Guy, &
DiMarzo, 2014), these results may only be generalizable to the
subsample of patients with PTSD who do not use nicotine (Fu
et al., 2007). Future research examining the psychobiological
responses to exercise in adults with PTSD should not exclude
participants who currently smoke.
In conclusion, our findings from this study indicated that
adults with and without PTSD reported significant mood im-
provements and reductions in pain following 30 minutes of
moderate-intensity aerobic exercise. In addition, the eCB sys-
tem was activated in adults with and without PTSD. However,
if exercise is to be used as a treatment for improving men-
tal health outcomes among individuals with PTSD due to its
ability to enhance eCB signaling, additional research is war-
ranted as the magnitude of change for eCBs was greater among
healthy controls when compared with adults with PTSD, which
suggests that adults with PTSD may have a blunted eCB re-
sponse to exercise; this would support previous research that
suggested that individuals with PTSD have a dysregulated eCB
system (Hill et al., 2013; Neumeister et al., 2013). However, it
is important to note that exercise is a unique stimulus capable
of inducing physiological stress while at the same time reduc-
ing psychological stress and negative mood states (Gay et al.,
2013; Brellenthin et al., 2017). Moreover, given that the eCB
system is an “on-demand, feedback-regulated” system that al-
lows healthy people to adapt to stress under ideal conditions
(Lutz et al., 2015), there is a critical need to determine the
functionality of the eCB system in response to various types
of stressful stimuli other than just exercise in individuals with
PTSD. These investigations would provide greater insight into
eCB system functionality and potential dysregulation in a PTSD
population. In the absence of this knowledge, the development
of efficacious treatment strategies for PTSD and comorbid men-
tal health disturbances within this underserved population will
likely remain elusive.
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... It is hypothesized that the brain is a source of circulating eCBs, although other organs and tissues can also synthesize and release the eCBs into circulation (14). Consistent with the ECS hypothesis, acute psychological and physical stress-induced increases in circulating eCBs are reported in healthy humans (15)(16)(17)(18)(19). Elevated circulating AEA concentrations are also found in grieving older individuals who are within 1 year of bereavement (20). ...
... In the only previous study of the effects of social disconnection on circulating eCBs, 2-AG concentrations were found to be significantly reduced in healthy individuals after exposure to 520 days of prolonged isolation and confinement (21). These findings are consistent with the preclinical evidence of a hypoactive ECS system in response to chronic stress (9,24), and a blunted 2-AG response in PTSD patients following stress exposure (18,25). ...
... A one-time fasting blood draw at baseline was conducted in all participants between 7:00 and 11:00 a.m. Blood was refrigerated after collection and serum was separated by centrifugation within 60 min and stored in 3 ml aliquots at −80 • C. Serum concentrations of AEA and 2-AG were determined in extracted lipids from serum samples using stable isotope-dilution, liquid chromatography-mass spectrometry quantification methods as described previously (18,20). Cortisol concentrations (µg/dl) were measured in triplicate using 25 µl of the same samples using a radioimmunoassay kit from MP Biomedical (0722110-CF) following manufacturer's instructions. ...
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Background: Loneliness is one of the most distressing grief symptoms and is associated with adverse mental health in bereaved older adults. The endocannabinoid signaling (ECS) system is stress-responsive and circulating endocannabinoid (eCB) concentrations are elevated following bereavement. This study examined the association between loneliness and circulating eCB concentrations in grieving older adults and explored the role of eCBs on the association between baseline loneliness and grief symptom trajectories. Methods: A total of 64 adults [grief with high loneliness: n = 18; grief with low loneliness: n = 26; and healthy comparison (HC): n = 20] completed baseline clinical assessments for the UCLA loneliness scale. In grief participants, longitudinal clinical assessments, including the Inventory of Complicated Grief and 17-item Hamilton Depression Rating scales, were collected over 6 months. Baseline circulating eCB [ N -arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG)] concentrations were quantified in the serum using isotope dilution, liquid chromatography-mass spectrometry; cortisol concentrations were measured in the same samples using radioimmunoassay. Results: Circulating AEA concentrations were higher in severely lonely grieving elders than in HC group; cortisol concentrations were not different among the groups. Cross-sectionally, loneliness scores were positively associated with AEA concentrations in grievers; this finding was not significant after accounting for depressive symptom severity. Grieving individuals who endorsed high loneliness and had higher 2-AG concentrations at baseline showed faster grief symptom resolution. Conclusions: These novel findings suggest that in lonely, bereaved elders, increased circulating eCBs, a reflection of an efficient ECS system, are associated with better adaptation to bereavement. Circulating eCBs as potential moderators and mediators of the loneliness-grief trajectory associations should be investigated.
... 28,29 Rather, emerging data indicate that the eCB system plays a pivotal role in mediating some of the welldocumented effects of exercise, including reductions in pain and anxiety, and improvements in cognitive functioning and mood. 30,31 Indeed, studies suggest a role for eCBs in regulating hippocampal neurogenesis 32,33 ; therefore, elevations in circulating eCBs may explain some of the reported beneficial effects of exercise on memory and cognitive functioning. There is also evidence that eCBs may contribute to the motivational or rewarding aspects of exercise through modulation of synaptic activity in reward-related brain regions. ...
... eCB tone or response to stress may also be affected by fasted state, last meal timing and content, recent exercise, circadian timing of exercise, BMI, sex, gender, pre-existing health conditions, genetic variance in the eCB system (e.g., FAAH, CNR1), sleep restriction, psychotropic medications, oral contraceptives, menstrual stage, recent cannabis or alcohol use, injury or inflammation, or racial/ethnic background. 30,[65][66][67][68][69][70][71][72][73] Future studies should characterize eCB system functioning at baseline and responses to exercise in various patient or risk groups (e.g., trauma-exposed, firstdegree relative with depression), which may inform the pathophysiology of these disorders or inform exercise interventions. Future studies should also standardize the duration, timing of measurements and exercise, time-of-day, fed state (e.g., fasted or standard breakfast), and ask participants to refrain from exercising or using substances (e.g., cannabis, alcohol) before the session. ...
... Given that the eCB system responds to stimuli (i.e., stressors), and due to the fact that exercise is a form of physical stress, administering an acute bout of exercise may be useful for probing eCB system stress reactivity in those at risk for psychopathology. 30 Furthermore, eCB signaling is considered to be critical for fear extinction learning and recall, and prior studies indicate that individuals with stress-related disorders (e.g., PTSD) have impaired fear extinction learning and/or recall. 83 Therefore, the ability of exercise to augment eCB signaling may have significant benefits for the management of stress-related disorders, for example, as an adjunct to extinction-based exposure therapy. ...
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Introduction: The endocannabinoid (eCB) system plays a key role in maintaining homeostasis, including the regulation of metabolism and stress responses. Chronic stress may blunt eCB signaling, and disruptions in eCB signaling have been linked to stress-related psychiatric disorders and physical health conditions, including anxiety, depression, post-traumatic stress disorder (PTSD), diabetes, and obesity. Pharmacological and nonpharmacological behavioral interventions (e.g., exercise) that target the eCB system may be promising therapeutic approaches for the prevention and treatment of stress-related diseases. In this study, we perform a systematic review and the first meta-analysis to examine the impact of exercise on circulating eCB concentrations. Materials and Methods: We performed a review of the MEDLINE (PubMed) database for original articles examining the impact of exercise on eCBs in humans and animal models. A total of 262 articles were screened for initial inclusion. Results: Thirty-three articles (reporting on 57 samples) were included in the systematic review and 10 were included in the meta-analysis. The majority of samples that measured anandamide (AEA) showed a significant increase in AEA concentrations following acute exercise (74.4%), whereas effects on 2-arachidonoylglycerol (2-AG) were inconsistent. The meta-analysis, however, revealed a consistent increase in both AEA and 2-AG following acute exercise across modalities (e.g., running, cycling), species (e.g., humans, mice), and in those with and without pre-existing health conditions (e.g., PTSD, depression). There was substantial heterogeneity in the magnitude of the effect across studies, which may relate to exercise intensity, physical fitness, timing of measurement, and/or fasted state. Effects of chronic exercise were inconsistent. Conclusions: Potential interpretations and implications of exercise-induced mobilization of eCBs are discussed, including refilling of energy stores and mediating analgesic and mood elevating effects of exercise. We also offer recommendations for future work and discuss therapeutic implications for exercise in the prevention and treatment of stress-related psychopathology.
... Importantly, these findings indicate that high endocannabinoid tone in the peritraumatic period is associated with increased risk for the development of non-remitting PTSD, rather than reduced risk as originally hypothesized based upon studies showing that circulating endocannabinoids are lower in individuals with chronic PTSD [19,37] and that an increase is associated with improved symptoms [38]. Additionally, a wealth of preclinical literature supports the notion that reduced endocannabinoid tone mirrors the symptoms of chronic PTSD [14][15][16]. ...
... The lack of associations in the current study between PTSD symptoms and circulating 2-AG concentrations measured concurrently is contrary to findings that those with chronic PTSD have lower [19] or higher [46] circulating 2-AG concentrations as well as less robust recruitment of 2-AG in response to psychological or physical stress [38,50]. It is possible that 2-AG has a more significant role in chronic stress management such that depletion of 2-AG after sustained periods of stress, such as having chronic PTSD, creates a vulnerability to ongoing stress. ...
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The endocannabinoid signaling system (ECSS) regulates fear and anxiety. While ECSS hypoactivity can contribute to symptoms of established post-traumatic stress disorder (PTSD), the role of the ECSS in PTSD development following trauma is unknown. A prospective, longitudinal cohort study of 170 individuals (47% non-Hispanic Caucasian and 70% male) treated at a level 1 trauma center for traumatic injury was carried out. PTSD symptom assessments and blood were obtained during hospitalization and at follow-up (6–8 months post injury). Serum concentrations of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were determined at both time points and selected genetic polymorphisms in endocannabinoid genes, including rs324420 in fatty acid amide hydrolase, were assessed. For the entire sample, serum concentrations of AEA at hospitalization were significantly higher in those diagnosed with PTSD at follow-up (p = 0.030). Serum concentrations of 2-AG were significantly, positively correlated with PTSD symptom severity at follow-up only in minorities (p = 0.014). Minority participants (mostly Black/African American) also demonstrated significant, negative correlations between serum AEA concentrations and PTSD symptom severity both measured at hospitalization (p = 0.015). The A/A genotype at rs324420 was associated with significantly higher PTSD symptom severity (p = 0.025) and occurred exclusively in the Black participants. Collectively, these results are contrary to our hypothesis and find positive associations between circulating endocannabinoids and risk for PTSD. Minority status is an important modulator of the association between endocannabinoids and risk for PTSD, suggesting that the ECSS contributes to risk most significantly in these individuals and the contextual factors related to these findings should be further explored.
... Therefore, it was not surprising that AEA and OEA were both responsive to aerobic exercise of maximal intensity in the present study, also considering that they share similar metabolic pathways 50 . However, Crombie and colleagues (2018) documented that not only AEA, OEA, but also 2-AG concentrations greatly increased following 30 min of moderate running in healthy adults, females in majority 51 . The increase of AEA levels after aerobic exercise could be due to the decrease of the major AEA degradation enzyme (fatty acid amide hydrolase) as shown in a middle-aged female cohort 52 . ...
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The extended endocannabinoid system, also termed endocannabinoidome, participates in multiple metabolic functions in health and disease. Physical activity can both have an acute and chronic impact on endocannabinoid mediators, as does diet. In this crossover randomized controlled study, we investigated the influence of diet on the peripheral response to acute maximal aerobic exercise in a sample of active adult women (n = 7) with no underlying metabolic conditions. We compared the impact of 7-day standardized Mediterranean diet (MedDiet) and control diet inspired by Canadian macronutrient intake (CanDiet) on endocannabinoidome and short-chain fatty acid metabolites post maximal aerobic exercise. Overall, plasmatic endocannabinoids, their congeners and some polyunsaturated fatty acids increased significantly post maximal aerobic exercise upon cessation of exercise and recovered their initial values within 1 h after exercise. Most N-acylethanolamines and polyunsaturated fatty acids increased directly after exercise when the participants had consumed the MedDiet, but not when they had consumed the CanDiet. This impact was different for monoacylglycerol endocannabinoid congeners, which in most cases reacted similarly to acute exercise while on the MedDiet or the CanDiet. Fecal microbiota was only minimally affected by the diet in this cohort. This study demonstrates that endocannabinoidome mediators respond to acute maximal aerobic exercise in a way that is dependent on the diet consumed in the week prior to exercise.
... Recent studies highlight the impact of exercise on the prevention and treatment of different psychopathological abnormalities and several epidemiological studies have shown significant cross-sectional correlations between mental health and exercise [94]. Similarly, many animal [72,80] and human studies [21,31,33,8] have confirmed the positive effects of exercise on brain health. In other words, regular physical activity and an active lifestyle are effective ways to improve physiological and mental health [1,23,35]. ...
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Posttraumatic stress disorder (PTSD) is an anxiety disorder that occurs following exposure to somatic or psychotic trauma. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. However, the role of exercise on acquired PTSD-like phenotype was not examined. The present study investigated the effects of prior moderate treadmill exercise on anxiety-like behaviors, serum corticosterone and BDNF levels, hippocampal BDNF and mRNA expression of apoptotic - related proteins in the single prolonged stress (SPS) as an animal model of PTSD in rats. Male and female rats underwent a regular treadmill exercise regimen (4 weeks, 5 days per week). Following the exercise, rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min and ether anesthesia), and then they were kept undisturbed for 14 days. After testing anxiety-like behaviours in the elevated plus maze, the levels of corticosterone and BDNF in serum and BDNF and apoptosis markers (Bax, Bcl-2, and Caspase) in hippocampus were measured. Sedentary male and female SPS rats significantly (Ps ranging <0.05 to <0.0001) exhibited increased anxiety levels in the elevated plus maze, enhanced serum corticosterone, reduced serum and hippocampal BDNF and enhanced hippocampal apoptosis than the corresponding control group. Prior exercise significantly (Ps ranging <0.05 to <0.001) alleviated all SPS-induced behavioral and biochemical alterations as compared with the sedentary SPS rats. There were no significant differences in serum and hippocampal BDNF and serum corticosterone levels and apoptotic markers between male and female rats in all of groups. Our findings strongly support that short term prior exercise training can prevent the harmful effects of traumatic events, and the resulting trauma-related disorders in both sexes.
... The RPE is a widely used, easy and valid measure to describe physical activity intensity as it strongly correlates with heart rate and blood lactate (Scherr et al., 2013). The RPE is already used in PTSD samples (Rosenbaum, Sherrington, et al., 2015) and the moderate intensity of 60-70% of someone's maximal heart rate is comparable to a RPE score between 12 and 15 (Crombie, Brellenthin, Hillard, & Koltyn, 2018). The heart rate and RPE scales will be used to control for the intensity during the first and second week of treatment at home (online). ...
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Background: New intensive trauma-focused treatment (TFT) programmes that incorporate physical activity have been developed for people with post-traumatic stress disorder (PTSD). However, the unique contribution of physical activity within these intensive TFT programmes has never been investigated in a controlled manner. Objectives: This randomized controlled trial will investigate the effectiveness of physical activity added to an intensive TFT programme. In addition, the study aims to investigate the underlying mechanisms of the effects of physical activity on the change in PTSD symptoms. Methods: Individuals with PTSD (N = 120) will be randomly allocated to two conditions: a physical activity or a non-physical active control condition. All participants will receive the same intensive TFT lasting eight days within two consecutive weeks, in which daily prolonged exposure and EMDR therapy sessions, and psycho-education are combined. The amount of physical activity will differ per condition. While the physical activity condition induces daily physical activities with moderate intensity, in the non-physical active control condition no physical activity is prescribed; but instead, a controlled mixture of guided (creative) tasks is performed. The two primary outcome measures are change in PTSD symptoms from pre- to post-treatment and at six months follow-up, measured with the Clinician-Administered PTSD Scale (CAPS-5), and the PTSD Checklist for DSM-5 (PCL-5). Additionally, self-reported sleep problems, depressive symptoms, emotion regulation, dissociation symptoms and anxiety sensitivity will be measured as potential underlying mechanisms. Conclusions: This study will contribute to the research field of augmentation strategies for PTSD treatment by investigating the effectiveness of physical activity added to intensive TFT. Trial registration: This trial is registered in the Netherlands Trial Register (Trial NL9120).
Article
Background Little is known about the acute affective response to physical activity in people with depression, which may have implications for acute symptom management and may also be a mechanism that explains the antidepressant effects of physical activity. This study aimed to quantitatively synthesize existing research on the acute affective response to physical activity in people with depression. Methods Five online databases were searched to July 2021 to identify studies that examined pre-post changes in affective states following a bout of moderate-to-vigorous physical activity in people with depression. The affective response to physical activity was synthesized using a random-effects meta-analysis with a robust variance estimator. Results A total of 18 studies were included in the meta-analysis. Results showed that people with depression experienced a favourable affective response following an acute bout of physical activity (SMD = 0.585, 95% confidence interval = [0.456, 0.714], 95% prediction interval = [−0.079, 1.249]). Moderator analysis indicated this effect was consistent across different types of affective states, exercise conditions, and participant characteristics. Additionally, results were robust to changes in the study protocol and publication bias. Limitations Only within-person pre-post changes in affective responses were examined. No comparisons were made with control conditions. Conclusion Acute bouts of physical activity can significantly improve affective states in people with depression. Future research should examine the effect of physical activity on affective states in non-experimental settings and examine whether the affective response to physical activity is a predictor of the long-term antidepressant effects of physical activity interventions.
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The runner’s high is an ephemeral feeling some humans experience during and after endurance exercise. Recent evidence in mice suggests that a runner’s high depends on the release of endocannabinoids (eCBs) during exercise. However, little is known under what circumstances eCBs are released during exercise in humans. This systematic review sampled all data from clinical trials in humans on eCB levels following exercise from the discovery of eCBs until April 20, 2021. PubMed/NCBI, Ovid MEDLINE, and Cochrane library were searched systematically and reviewed following the PRISMA guidelines. From 278 records, 21 met the inclusion criteria. After acute exercise, 14 of 17 studies detected an increase in eCBs. In contrast, after a period of long-term endurance exercise, four articles described a decrease in eCBs. Even though several studies demonstrated an association between eCB levels and features of the runner’s high, reliable proof of the involvement of eCBs in the runner’s high in humans has not yet been achieved due to methodological hurdles. In this review, we suggest how to advance the study of the influence of eCBs on the beneficial effects of exercise and provide recommendations on how endocannabinoid release is most likely to occur under laboratory conditions.
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The endocannabinoid system is known to be involved in mechanisms relevant to PTSD aetiology and maintenance, though this understanding is mostly based on animal models of the disorder. Here we review how human paradigms can successfully translate animal findings to human subjects, with the view that substantially increased insight into the effect of endocannabinoid signalling on stress responding, emotional and intrusive memories, and fear extinction can be gained using modern paradigms and methods for assessing the state of the endocannabinoid system in PTSD.
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Aim: This study examined the effect of aerobic exercise with and without blood flow restriction on exercise-induced hypoalgesia and endogenous opioid and endocannabinoid systems. Methodology: In a randomised crossover design, pain-free individuals performed 20 min of cycling in four experimental trials: 1) Low intensity aerobic exercise (LI-AE) at 40% V̇O2max; 2) LI-AE with low pressure BFR (BFR40); 3) LI-AE with high pressure BFR (BFR80); and 4) High intensity aerobic exercise (HI-AE) 70% V̇O2max. Pressure pain thresholds (PPT) were assessed before and 5 min post-exercise. Circulating concentrations of beta-endorphin and 2-arachidonoylglycerol were assessed before and 10 min post-exercise. Results: In the exercising legs, post-exercise PPTs were increased following BFR40 and BFR80 compared to LI-AE (23-32% vs 1-2%, respectively). Post-exercise PPTs were comparable to HI-AE (17-20%) with BFR40 and greater with BFR80 (30-32%). Both BFR80 and HI-AE triggered comparable systemic hypoalgesia in remote areas of the body (26-28% vs 19-21%). Post-exercise circulating beta-endorphin concentration was increased following BFR40 (11%) and HI-AE (14%, with the greatest change observed following BFR80 (29%). Post-exercise circulating 2-arachidonoylglycerol concentration was increased following BFR40 (22%) and BFR80 (20%), with the greatest change observed following HI-AE (57%). Conclusion: Addition of BFR to LI-AE can trigger both local and systemic hypoalgesia that is not observed follow LI-AE alone and activate endogenous opioid and endocannabinoid systems of pain inhibition. Compared to HI-AE, local and systemic hypoalgesia following LI-AE with high pressure BFR is greater and comparable, respectively. LI-AE with BFR may help pain management in load compromised individuals.
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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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Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients.
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The endocannabinoid system has been implicated in the regulation of the stress response, fear memory formation, and inflammatory processes. Posttraumatic stress disorder (PTSD) can result from exposure to extreme stress and is characterized by strong, associative memories for the traumatic events experienced. Furthermore, an elevated physical disease risk has been observed in PTSD, likely to be mediated by inflammatory processes. Therefore, altered endocannabinoid regulation can be expected in individuals with PTSD. However, attempts to assess PTSD-associated differences in the endocannabinoid system from human blood samples have provided inconsistent results, possibly due to fluctuating levels of endocannabinoids. In hair, these neuromodulators are accumulated over time and thus give access to a more stable and reliable assessment.
Chapter
The purpose of this chapter is to provide an introduction to the mechanisms for the regulation of endocannabinoid signaling through CB1 cannabinoid receptors in the central nervous system. The processes involved in the synthesis and degradation of the two most well-studied endocannabinoids, 2-arachidonoylglycerol and N-arachidonylethanolamine are outlined along with information regarding the regulation of the proteins involved. Signaling mechanisms and pharmacology of the CB1 cannabinoid receptor are outlined, as is the paradigm of endocannabinoid/CB1 receptor regulation of neurotransmitter release. The reader is encouraged to appreciate the importance of the endocannabinoid/CB1 receptor signaling system in the regulation of synaptic activity in the brain.
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The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.