Endocannabinoid and Mood Responses to Exercise in Adults with Varying Activity Levels : Medicine & Science in Sports & Exercise

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Endocannabinoid and Mood Responses to Exercise in Adults with Varying Activity Levels


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Medicine & Science in Sports & Exercise 49(8):p 1688-1696, August 2017. | DOI: 10.1249/MSS.0000000000001276
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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 primary 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 regulation (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 responses to exercise as well as exercise behaviors are dependent 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 regulate 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 in positive affect in a small sample of recreationally fit individuals (41). Other than this preliminary investigation, the relationship between eCB and mood outcomes after exercise in humans remains largely unexplored. In addition, the aforementioned 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 individuals 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 varying levels of physical activity (inactive/low, moderate, and high). A secondary objective of this study was to characterize mood and eCB responses to preferred exercise, which in some instances has been shown to elicit greater mood improvements than prescribed exercise (38,55).


Study Participants

A power analysis (G*Power 3.1) was conducted to determine 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 participants (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 medium 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 participants 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, moderate, 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 Institutional Review Board.


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 activity 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 based on the 2008 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 min·wk−1 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 α = 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 Anxiety 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 consistencies are high, ranging from α = 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 administered before and after exercise on preferred and prescribed exercise days.

Commitment to Exercise Scale

For exploratory purposes, the eight-item Commitment to Exercise Scale (CES) was administered to assess participants’ psychological commitment 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 pathological relationship with exercise. For example, items inquire 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 α = 0.90). Composite scores from the CES range 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.


Participants completed three experimental sessions. Sessions 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 provided 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˙O2 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˙O2max), followed by 45 min at 70%–75% estimated V˙O2max (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 previously been shown to result in significant elevations in circulating 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 duration. When they indicated they had completed their session, participants finished with a 5-min walking cooldown. Heart rate and RPE were assessed every 5 min during exercise. 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 exercise. 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 −80°C. After preparation, AEA and 2-AG as well as related biogenic lipids, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), were quantified using isotope dilution, atmospheric 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 activity group and condition changes in eCB and mood states from pre- to postexercise. The overall alpha family-wise was set at αFW = 0.05. Simple effects were calculated based on significant interaction effects. Pearson’s r correlation 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.


Participant characteristics

Thirty-six men and women with a mean age of 21 ± 4 yr were recruited for this study. There were no significant differences between groups for age, body mass index, or trait anxiety (P > 0.05). There were significant group differences for estimated V˙O2max (F2,33 = 7.31, P < 0.01), exercise commitment scores (F2,33 = 15.97, P < 0.001), and amount of time spent in MVPA (F2,33 = 31.72, P < 0.001). Pairwise comparisons indicated that estimated V˙O2max and exercise commitment were significantly lower (P < 0.01) in the low activity group compared with the moderate and high activity groups. Self-reported MVPA minutes were significantly different (P < 0.05) between all three activity groups (see Table 1), and MVPA was significantly correlated with estimated V˙O2max (r = 0.57, P < 0.001). Average preexercise concentrations in AEA were inversely associated with MVPA (r = −0.33, P = 0.05) but not estimated V˙O2max (r = −0.05, P = 0.77). No significant associations were found between baseline lipid concentrations and other variables.

Preferred and prescribed condition characteristics

In the prescribed condition, there were significant group differences for treadmill speed (F2,33 = 5.75, P < 0.01). Pairwise comparisons indicated that the low activity group had slower treadmill speeds (P < 0.01) than the high activity group. There were no group differences for RPE in either the prescribed or the preferred conditions (P > 0.05), although there was a significant condition difference for estimated exercise intensity such that participants elected to exercise at a relatively higher percentage of their estimated V˙O2max in the preferred compared with the prescribed condition (F1,33 = 7.74, P < 0.01). In the preferred condition, there were significant group differences for preferred duration (F2,33 = 5.47, P < 0.01) and treadmill speed (F2,33 = 23.69, P < 0.001). Pairwise comparisons indicated that the high activity group exercised for significantly longer durations (P < 0.05) than the low and moderate groups, and the low activity group selected significantly slower treadmill speeds (P < 0.001) than the moderate and high groups. There were no significant differences in the timing of blood draws between groups or between conditions (P > 0.05) (see Table 2).

eCB and mood responses to exercise

The results indicated that there were significant time effects for 2-AG (F1,33 = 24.46, P < 0.001) and PEA (F1,33 = 17.59, P < 0.001), with the concentrations of both lipids increasing significantly from pre- to postexercise. There were also significant condition–time interactions for AEA (F1,33 = 5.12, P < 0.05) and OEA (F1,33 = 7.04, P < 0.05). AEA and OEA increased significantly after both exercise conditions; however, analysis of simple effects indicated that postexercise plasma concentrations of AEA (F1,33 = 4.47, P < 0.05) and OEA (F1,33 = 10.04, P < 0.01) were greater in the prescribed compared with the preferred condition. There were no main effects or interactions for activity group for any eCB or lipid responses to either preferred or prescribed exercise (P > 0.05), and effect size estimates (η2) for group–time interactions were small (AEA = 0.015, PEA = 0.020, OEA = 0.019, 2-AG = 0.039) (see Fig. 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 exercises in the low, moderate, and high active groups as well as the overall sample. *Significant main effect of time for 2-AG and PEA (P < 0.001). ‡Significant condition–time interaction for AEA and OEA (P < 0.05). 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.

The results indicated that there were significant decreases in tension (F1,33 = 4.1, P < 0.05), depression (F1,33 = 8.09, P < 0.01), anger (F1,33 = 5.51, P < 0.05), and increases in vigor (F1,33 = 23.84, P < 0.001) after both exercise conditions. There were significant condition–time interactions for confusion (F1,33 = 4.39, P < 0.05), total mood disturbance (F1,33 = 5.03, P < 0.05), and state anxiety (F1,33 = 5.45, P < 0.05), and analysis of simple effects indicated that reductions in confusion (F1,33 = 10.19, P < 0.01), total mood disturbance (F1,33 = 18.14, P < 0.001), and state anxiety (F1,33 = 6.55, P < 0.05) occurred in the preferred but not the prescribed condition (P = 0.26–0.65). There were no significant main effects or interactions for activity group for any mood state responses to either preferred or prescribed exercise (P > 0.05), and effect size estimates (η2) 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).

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 (P < 0.05). ‡Significant condition–time interaction (P < 0.05), 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.
Sample characteristics.
Exercise session characteristics.

Associations between eCB and mood responses to exercise

In the preferred condition, changes in 2-AG were negatively associated with changes in tension (r = −0.59, P < 0.01), depression (r = −0.45, P < 0.01), and total mood disturbance scores (r = −0.40, P < 0.05) after exercise. In the prescribed condition, changes in AEA were associated with changes in vigor (r = 0.37, P < 0.05).


eCB responses to exercise

Aerobic exercise was found to activate the eCB system, which agrees with previous work conducted in humans (23,42,50). There were significant 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 exercise 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 insufficiently 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 increase in 2-AG was related to its circadian rhythm while it was approaching this midday peak, it remains plausible that 2-AG responded to exercise because it increased approximately 28% and 55% from baseline in the preferred and prescribed conditions, respectively.

The current investigation also found that there were significant 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-acylethanolamines, 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 been routinely explored with regard to psychological outcomes, 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 properties 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 differences 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 active men compared with the sedentary men. The authors speculated that the effect of IL-6 on fatty acid amide hydrolase activity was a metabolic adaptation that occurred to negotiate the repeatedly increased eCB concentrations that 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˙O2max 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 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˙O2max × duration in minutes) in the prescribed versus the preferred condition, and these findings did not differ between groups. The greater amount of total work (and thus greater physical stress) may simply explain the differential AEA and OEA responses. However, although total 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˙O2max 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 indicated 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 increase 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 shown to significantly reduce voluntary 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 contributes specifically to the motivational aspects of wheel running possibly through eCB and GABA interactions influencing 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 condition, it is interesting that baseline AEA levels were inversely associated with self-reported MVPA but were not significantly associated with V˙O2max, although MVPA and V˙O2max 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., improved 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 individuals 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 significantly 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 surrounding exercise, and there was little evidence suggesting that this sample exhibited a pathological relationship with exercise.

Mood responses to exercise

Acute aerobic exercise, whether preferred or prescribed, was able to elicit improvements in several mood states, including reductions in tension, depression, and anger, and increases in vigor. Preferred 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 nonsignificant (P values from 0.14 to 0.53). Furthermore, in both conditions, preexercise values for mood disturbance and state anxiety were below published norms for a young adult population (51,52). It has also been suggested that allowing individuals 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 participation 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 tension, 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 associated 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 mobilized 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 influential 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 participants, although mood states and AEA were not directly correlated in that study.

In the broader literature, eCB dysfunction has been associated with several psychiatric conditions, including major depressive disorder, posttraumatic stress disorder, and substance 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 depressive 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 between inflammation and the brain may underlie the etiology of depression, suggesting that the ability to regulate inflammatory processes could be instrumental in lowering the risk of depression or other stress-related psychological disorders (37). Moving forward, it will be important to determine 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 elicited 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 declare. 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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