Endocannabinoids and exercise

Abstract Exercise induces changes in mental status, particularly analgesia, sedation, anxiolysis, and a sense of wellbeing. The mechanisms underlying these changes remain unknown. Recent findings show that exercise increases serum concentrations of endocannabinoids, suggesting a possible explanation for a number of these changes. This article provides an overview of this emerging field. An exercise induced altered state of consciousness has long been appreciated by endurance athletes. The effect has been well documented in the popular literature and subjected to scientific investigation. In the late 1960s, the psychological changes associated with prolonged physical activity were often described as a “second wind.” A more contemporary label often applied to these exercise induced changes is the “runner’s high.” The runner’s high has been described subjectively as pure happiness, elation, a feeling of unity with one’s self and/or nature, endless peacefulness, inner harmony, boundless energy, and a reduction in pain sensation.5–9 These subjective descriptions are similar to the claims of distorted perception, atypical thought patterns, diminished awareness of one’s surroundings, and intensified introspective understanding of one’s sense of identity and emotional status made by people who describe drug or trance states.

As is the case with all phenomena related to consciousness and its alterations, the runner’s high is a private experience, and the evidence for its existence rests predominantly on verbal report. Scientific inquiry into the phenomenon has been restricted even further because of its ephemeral nature. For example, the runner’s high is not experienced by all runners, and this experience does not occur consistently in runners who have experienced it previously. These observations have left laymen and scientists wondering why and under which conditions the runner’s high occurs, or whether or not it exists at all.

Before the discovery of the opioids, exercise scientists tried to account for the analgesic and euphoric mental states with alterations in the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine). With the discovery and subsequent characterization of the opioid receptor network and endogenous opioid peptides, an entirely different mechanism of action evolved. Soon thereafter, exercise induced changes in psychological functions were often described as being a direct consequence of alterations in endogenous opioid release. However, there are a number of serious problems with the “endorphin hypothesis.” Studies examining the exercise-endorphin connection produced equivocal results, and many of the studies were plagued by methodological confounds. For instance, β endorphin has almost the same amino acid sequence as other members of the pro-opiomelanocortin family such as the adrenocorticotrophic hormone, making cross reactivity to the detecting antibody a serious confound. Also, adrenocorticotrophic hormone is a stress hormone that is known to increase with exercise, compounding the problem. There are also major inconsistencies between the endorphin hypothesis and the physiological and biochemical responses to endurance exercise. For instance, β endorphins bind best to the µ opioid receptor, the endogenous opioid system that mediates the analgesic and euphoric properties of the opiates. However, minimal activation of the same endogenous opioid system is also responsible for the severe respiratory depression, pinpoint pupils, and inhibition of gastrointestinal motility, all of which accompany opiate use. Yet, these effects are not seen in runners. The most limiting factor, however, is that the endorphin hypothesis rests entirely on research measuring endorphins in circulating blood, as ethical reasons preclude the determination of central concentrations of endorphins. Because endorphins are too large to cross the blood-brain barrier, peripheral activation in the systemic circulation cannot be taken as indicative of central effects. In recent years, several prominent endorphin researchers—for example, Dr Huda Akil and Dr Solomon Snyder—have publicly criticised the hypothesis as being “overly simplistic”, being “poorly supported by scientific evidence”, and a “myth perpetrated by pop culture.”

At first glance, it appears that the runner’s high phenomenon is, at present, not a scientific problem because it is built on circumstantial evidence and lacks a plausible mechanistic explanation. However, recent data in our laboratory showed that endurance exercise activates the endocannabinoid system, suggesting a new mechanism underlying exercise induced alterations of mental status. Using trained male college students running on a treadmill or cycling on a stationary bike for 50 minutes at 70–80% of maximum heart rate, we found that exercise of moderate intensity dramatically increased concentrations of anandamide in blood plasma. (Currently, research is underway in our laboratory to explore this finding further by examining the effect of exercise on both serum and cerebrospinal fluid concentrations of endocannabinoids in exercising rats, while also examining several associated alterations of behaviour.) Because activation of the endocannabinoid system reduces pain sensations and alters emotional and cognitive processes, this finding has implication for some of the psychological effects that accompany exercise. Owing to the presence of cannabinoid receptors in muscle, skin, endothelial cells, and lung, this finding also suggests a possible role for the endocannabinoid system in mediating certain physiological responses to exercise. It is important to emphasise that the intention of this paper is not to substitute one neurotransmitter for another and perpetuate the simple reductionist idea of one neurochemical being responsible for a complex variety of psychological processes. Rather, we review the literature on the functional role of the endocannabinoid system as it relates to exercise and call attention to the possibility that the endocannabinoid system may play an important role in the physiological and psychological adaptations to exercise. The review opens unexpected and entirely novel avenues of research in exercise physiology and psychology and is offered on the strength of its heuristic value.

In addition, we propose to reconceptualise the runner’s high into a set of behavioural phenomena that can be, at least to a large extent, subjected to scientific scrutiny. Traditionally, the runner’s high has been operationally defined as a “euphoric sensation experienced during running, usually unexpected, in which the runner feels a heightened sense of well being, enhanced appreciation of nature, and transcendence of barriers of time and space”(Pargman et al3 p 342). It is obvious that such a broad definition, in conjunction with the extensive use of esoteric language, does not qualify as an operational definition that can be used to derive testable hypotheses. We propose instead a more limited operational definition of the runner’s high centred mostly on observable behaviours such as analgesia, sedation (post-exercise calm), anxiolysis, and a sense of wellbeing. This definition has a number of advantages. Firstly, there is a large body of scientific literature documenting that exercise suppresses pain, induces sedation, reduces stress, and elevates mood. Secondly, because these effects are directly measurable, the operational definition allows the formulation of empirical predictions and the testing of specific hypotheses. Moreover, data from animal research can be recruited to elucidate the phenomena, as exercise in rodents has been shown to increase tolerance of pain (hot plate or tail flick tests), induce sedation (open field test), and produce anxiolysis (elevated plus maze).

THE ENDOCANNABINOID HYPOTHESIS

Endocannabinoid receptors and their endogenous ligands have been identified.To date, two cannabinoid receptor subtypes have been cloned. The CB1 receptor is located in the central nervous system, and it is more densely concentrated on the membranes of neurones located in the cortex, hippocampus, basal ganglia, amygdala, hypothalamus, and cerebellum.CB1 receptors are also found in several peripheral sites, including the peripheral nervous system. The CB2 receptor, on the other hand, is located mainly in peripheral tissue. Both the CB1 and CB2 receptors are coupled to Gi/o proteins. Thus cannabinoid receptors inhibit adenylate cyclase and, thereby, depending on the cell type, either inhibit voltage gated calcium channels or activate potassium channels. Thus, with respect to the nervous system, the general effect of CB1 activation is neuronal inhibition, which does not apply to CB2 receptors, as they are mainly expressed on immune cells. There is also an ongoing hypothesis in the field that there may exist an additional cannabinoid receptor, tentatively named CB3. Although the existence of a CB3 receptor is currently hypothetical, it may be of interest as some of the effects reported in this review might turn out not to be accounted for by CB1 and CB2 receptors.

Two naturally occurring ligands, which are members of a small family of fatty acid derivatives, have been identified for CB1 and CB2 receptors. Anandamide is one ligand, and it exhibits a higher affinity for the CB1 receptor subtype than CB2. A second ligand, sn-2-arachidonylglycerol (2-AG), has been identified more recently. Although the two endocannabinoids are found in the systemic circulation at equal concentrations, the concentration of 2-AG is about 200 times higher than that of anandamide in the brain.34 Anandamide and 2-AG have different biosynthetic pathways and may be produced under different conditions.34 However, the sites of anandamide and 2-AG production in brain and peripheral tissues are not known. Because endocannabinoids are lipids that are rapidly eliminated from extracellular space, it is generally assumed that production sites are located in close proximity to their attending cannabinergic receptors. More importantly, the environmental stimuli responsible for the production and release of endocannabinoids are also unknown, making it difficult to assess the physiological and behavioural functions of anandamide and 2-AG.

Research on cannabinoid induced analgesia has made use of a variety of noxious stimuli, and it has become clear that different types of tissue damage (mechanical, thermal, chemical, etc) differentially activate the endocannabinoid system.14,19 The finding that there are particular types of pain against which cannabinoids are particularly effective may provide fresh insights into the sport specificity of the runner’s high. It is curious that an “exercise high”, similar to the one experienced by long distance runners, should not occur in athletic activities involving brief physical exertion, such as sprinting and weightlifting, or in sports requiring changes in pace and workload such as track, soccer, football, tennis, basketball, etc. Further testing should resolve the issue whether these activities engage the endocannabinoid system. Yet, there is also no reference to a “swimmer’s high” in the literature, although it is a rhythmic and repetitive activity producing a particular pain concentration at a specific heart rate. Bearing on this problem, evidence is accumulating that cannabinoids induce analgesia by acting through CB1 receptors located in skin.17,19,41 This mechanism might suggest that painful stimuli to the skin are particularly potent in activating endocannabinoid antinociception. Unlike other rhythmic endurance activities such as swimming, running is a weight bearing sport in which the feet must absorb the “pounding of the pavement.” We are not arguing that moderate intensity long distance swimming fails to activate the endocannabinoid system. Rather, an endurance activity of this nature may not stimulate endocannabinoid release to as great an extent as running. It is also important to mention with regard to the runner’s high that cannabinoids produce neither the respiratory depression, meiosis, or strong inhibition of gastrointestinal motility associated with opiates and opioids. This is because there are few CB1 receptors in the brainstem42 and, apparently, the large intestine.

Peripheral effects

Activation of the endocannabinoid system may also participate in other adaptive responses to exercise. For instance, anandamide acts as a vasodilator and produces hypotension76–78 and may thus facilitate blood flow during exercise. Although the distribution of CB1 receptors in smooth muscle and endothelial cells suggests that the vasorelaxant effects of anandamide are mediated through CB1 or CB2 receptors, recent experiments79 have intimated a prominent role of vanilloid receptors in the vasodilatory effects of these endocannabinoids. Finally, cannabinoids affect the respiratory system. Although studies have reported bidirectional control of airway responsiveness, in general, endocannabinoids and exogenous cannabinoids act as bronchodilators.17 Consequently, a possible role for the endocannabinoid system could be to facilitate breathing during exercise.

CONCLUSIONS To date, a sound neural mechanism for the well known beneficial effects of exercise on mental health has yet to be proposed. Recent findings show that exercise increases serum concentrations of endocannabinoids, a result suggestive of a new possible explanation for a number of these changes. Further research is necessary to characterise the precise nature of this endocannabinoid response to exercise, specifically the relative importance of factors such as the nature of the activity, exercise duration, exercise intensity, sex, and age. In addition, animal models can be used to identify the production and binding sites of endocannabinoids as well as their functional role in exercise.

The cannabinoids produce psychological states that closely parallel several experiences described as being related to the runner’s high. Compared with the opioid analgesics, the analgesia produced by the endocannabinoid system is more consistent with exercise induced analgesia. Activation of the endocannabinoid system also produces sedation, anxiolysis, a sense of wellbeing, reduced attentional capacity, impaired working memory ability, and difficulty in time estimation. This behavioural profile is similar to the psychological experiences reported by long distance runners. Considerable research is needed to clarify to what extent the endocannabinoid system might be responsible for the exercise induced changes in mental status. Nevertheless, a significant upregulation of serum concentrations of endocannabinoids has recently been reported in endurance athletes, and studies are underway to explore this further in laboratory animals.

The close interaction of endocannabinoids with dopamine shows that they have a function in the brain’s reward system and therefore possibly addiction. The endocannabinoid system is also implicated in the control of motor activity mediated through the basal ganglia, and central activation of anandamide in freely moving rats has been demonstrated.63 Finally, the endocannabinoid system mediates peripheral effects such as vasodilation and bronchodilation that may play a contributory role in the body’s response to exercise.

This article is intended to provide an overview of the emerging field of the endocannabinoid-exercise interaction. The list of topics was necessarily selective, but it is offered in the hope that researchers of diverse backgrounds will use the review to conduct empirical tests of its premises. We suggest that the “endocannabinoid hypothesis” is a feasible alternative to the endorphin hypothesis and should be subjected to further empirical tests.

SOURCE ARTICLE :

https://bjsm.bmj.com/content/38/5/536

http://dx.doi.org/10.1136/bjsm.2004.011718

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