How Exercise Impacts the Endocannabinoid System

What is the Endocannabinoid System?

The endocannabinoid system is a complex cell-signaling system identified in the early 1990s by researchers exploring THC, a well-known cannabinoid.

Cannabinoids are compounds found in cannabis.

The endocannabinoid system plays a role in regulating a range of functions and processes, including: appetite, memory, mood and sleep and is active in your body even if you don’t use cannabis, and plays a key role in maintaining homeostasis throughout the brain and body, including regulating energy metabolism, cognition, sleep, inflammation, and stress responses [1]. 

Although endocannabinoid receptors are widespread, they are most densely located in brain regions that are implicated in stress and emotion regulation, reward processes, fear learning and extinction.

There two main endocannabinoid receptors are:

1. CB1 which are found in the central nervous system
2. CB2 which are mostly found in your peripheral nervous system, especially immune cells

Endocannabinoids can bind to either receptor and its influence is dependent on both the specific receptor it binds to and where the receptor is located. The two most well-studied endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). 

Endocannabinoid concentrations are modified in response to both acute and chronic exposure to stress [2], and disruptions in their signaling are connected to several stress-related diseases, including anxiety, depression, post-traumatic stress disorder, obesity, and diabetes [3].

Due to the critical role in regulating stress responses, the endocannabinoid system has emerged as a promising therapeutic target for the prevention and treatment of stress-related psychopathology [4]. 

Both pharmacologic interventions and administration of low doses of exogenous cannabinoids reduces fear and anxiety-like behaviors, potentiates fear extinction memory recall, and reduces threat response in adults with PTSD [5].

Exercise & Endocannabinoids

There is a growing body of evidence indicating that nonpharmacological approaches—particularly exercise—can boost endocannabinoid signaling.

Traditionally, the euphoric, analgesic, anxiety reducing, and mood-elevating effects of exercise were thought to be facilitated, at least in part, by the endogenous opioid system (i.e., exercise-induced increases in beta-endorphins [6].

This is the runner’s high concept, described as a short-lasting, deeply euphoric state following intense exercise.

Interestingly, recent research has challenged the role of endorphins in facilitating the beneficial effects of exercise. In support of this idea, there’s evidence that endorphins can’t cross the blood-brain barrier [7] and blockage of endorphin signaling doesn’t hinder the post-exercise euphoric effects [8].

In fact, emerging data indicate that the endocannabinoid system plays a crucial role in mediating some of the well documented effects of exercise, including reductions in pain and anxiety, and enhanced cognitive function and mood [9].

Elevations in circulating endocannabinoids may explain some of the reported beneficial effects of exercise on memory and cognitive functioning.

There is also evidence that endocannabinoids may contribute to the motivational or rewarding aspects of exercise through alteration of synaptic activity in reward-related brain regions [10].

The development and worldwide prevalence of neuropathologies such as depression are very alarming, and their prevention has become a considerable issue. Consequently, it’s essential to find new therapeutic targets, which may probably contribute to a reduction in the annual increase of individuals suffering from these diseases among all of the global populations.

Researchers have great hope for the endocannabinoid system and consider it a highly potential preventive and therapeutic approach for both neurological and neurodegenerative pathologies, which might be correlated, at least partially, with physical activity. An important note for future research is that endocannabinoid levels can be measured via blood, which makes them an excellent potential biomarker for tracking the efficacy of exercise interventions.

Does exercise intensity play a role?  Acute vs chronic

Essentially, the majority of research shows that acute exercise causes an increase in anandamide concentrations. This increase in anandamide was observed across modalities (e.g., running, cycling, resistance exercise) as well as, across pre-clinical and clinical studies, including patients with and without pre-existing health conditions (e.g., depression, PTSD).   

However, research also indicates a small but significant increase in 2-arachidonoylglycerol concentrations following acute exercise, with substantial divergency across samples. As far as chronic exercise, endocannabinoid concentrations were inconsistent which may be due to the smaller number of studies examining chronic exercise along with the substantial discrepancy across these studies. 

Essentially, research to date indicates that acute exercise mobilizes endocannabinoids.

Evidence indicates that elevations in endocannabinoids are linked with mood elevations, lower stress, anxiety, and pain, and enhanced cognitive functioning. The observed increase in circulating endocannabinoids following acute exercise may be produced by skeletal muscle given that skeletal muscle expresses enzymes that synthesize endocannabinoids. In addition, exercise has been shown to increase circulating glucocorticoids, which may increase anandamide concentrations in the brain [11].

Circulating concentrations of other biomarkers such as brain-derived neurotrophic factor have also been found to be elevated following acute exercise [12], which may contribute (independently or in conjunction with endocannabinoids) to neuroplastic and antidepressant effects of exercise.

Variation in exercise intensity may explain some of the observed discrepancy in anandamide.

Indeed, several studies report that moderate intensity exercise is associated with greater increases in anandamide as compared with other intensities (see figure below) [5].

 Fig: Proposed increase in AEA and 2-AG concentrations following moderate acute exercise [5]

The idea that optimal endocannabinoid response seems to be at moderate intensity exercise fits with previous data on other outcomes.

Prior research comparing effects of intensity, commonly report enhanced improvements in mood and cognitive performance, reductions in stress, and greater neurobiological reward response after moderate intensity compared with low or high intensity exercise [13].

Research to date shows no consistent effects of chronic exercise on endocannabinoid concentrations. It is not clear if chronic exercise can regulate basal endocannabinoid concentrations or endocannabinoid responses to acute stress.

The training status of a person may also play a role in modifying endocannabinoid responses. Initial evidence indicates more physically active individuals may demonstrate a more robust anandamide response to exercise as compared with those with low physical activity.

In addition, endocannabinoid 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 endocannabinoid system, sleep restriction, psychotropic medications, oral contraceptives, menstrual stage, recent cannabis or alcohol use, injury or inflammation, or racial/ethnic background [5].

Future research needs

Endocannabinoid research is in its infancy and there are many gaps that need to be addressed to gain a more robust understanding of this system and how it interacts with exercise.

Here are some future research needs:

• Characterize endocannabinoid system functioning at baseline and responses to exercise in various patient or risk groups (e.g., trauma-exposed, first-degree relative with depression), which may inform the pathophysiology of these disorders or inform exercise interventions.
• Standardize the duration, timing of measurements and exercise, time-of-day, fed state (e.g., fasted or standard breakfast)
• Ask participants to refrain from exercising or refrain from using substances such as alcohol and/or cannabis before the session.
• Identify the most effective modalities and durations of exercise for enhancing endocannabinoid concentrations. Most research to date were done using primarily aerobic exercise.
• Examine the impact of exercise on children and adolescents. Thus, the observed effects of acute exercise on endocannabinoids in adults may not generalize to younger populations.
• Examine the role of endorphins, BDNF, or other signaling systems in mediating or moderating acute exercise effects either in isolation from or in conjunction with the endocannabinoid system.

Exercise may be a potent nonpharmacological intervention for a variety of stress-related disorders that could benefit from elevations in endocannabinoids and associated effects on mood, stress, anxiety, pain, cognitive functioning, inflammation, sleep, and appetite.

In addition, exercise may be helpful in conditions associated with a hyperactive endocannabinoid system such as diabetes, obesity, and inflammation.

Given that the endocannabinoid 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 endocannabinoid system stress reactivity in those at risk for psychopathology [9]. 

Therefore, the ability of exercise to increase endocannabinoid signaling may have significant benefits for the management of stress-related disorders.

Summary

It’s clear from research that acute exercise activates the endocannabinoid system and increases circulating concentrations of endocannabinoids.

Provided that disruptions in endocannabinoid signaling are linked to several stress-related diseases (e.g., anxiety, depression, PTSD, obesity, and diabetes) exercise is a promising nonpharmacological approach for the prevention and treatment of stress-related psychopathology through its potential impacts on endocannabinoid signaling

You can learn more about marijuana’s effects on athletic performance, hormones, inflammation & cardiovascular system here.


References:

1.    Kesner, A.J. and D.M. Lovinger, Cannabinoids, Endocannabinoids and Sleep. Front Mol Neurosci, 2020. 13: p. 125.
2.    deRoon-Cassini, T.A., et al., Meet Your Stress Management Professionals: The Endocannabinoids. Trends Mol Med, 2020. 26(10): p. 953-968.
3.    Charytoniuk, T., et al., Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders? Int J Mol Sci, 2020. 21(12).
4.    Mayo, L.M., et al., Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation? Biol Psychiatry, 2022. 91(3): p. 262-272.
5.    Desai, S., et al., A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System. Cannabis Cannabinoid Res, 2021.
6.    Morgan, W.P., Affective beneficence of vigorous physical activity. Med Sci Sports Exerc, 1985. 17(1): p. 94-100.
7.    Pardridge, W.M., D. Triguero, and J.L. Buciak, Beta-endorphin chimeric peptides: transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain. Endocrinology, 1990. 126(2): p. 977-84.
8.    Koltyn, K.F., et al., Mechanisms of exercise-induced hypoalgesia. J Pain, 2014. 15(12): p. 1294-1304.
9.    Crombie, K.M., et al., Psychobiological Responses to Aerobic Exercise in Individuals With Posttraumatic Stress Disorder. J Trauma Stress, 2018. 31(1): p. 134-145.
10.    Dubreucq, S., et al., Ventral tegmental area cannabinoid type-1 receptors control voluntary exercise performance. Biol Psychiatry, 2013. 73(9): p. 895-903.
11.    Hill, M.N., et al., Endogenous cannabinoid signaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus, 2010. 20(4): p. 513-23.
12.    Heyman, E., et al., Intense exercise increases circulating endocannabinoid and BDNF levels in humans--possible implications for reward and depression. Psychoneuroendocrinology, 2012. 37(6): p. 844-51.
13.    Nakagawa, T., et al., Regular Moderate- to Vigorous-Intensity Physical Activity Rather Than Walking Is Associated with Enhanced Cognitive Functions and Mental Health in Young Adults. Int J Environ Res Public Health, 2020. 17(2).