Exercise increases levels of endocannabinoids in the body

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Many people have experienced reductions in stress, pain and anxiety and sometimes even euphoria after exercise. What’s behind this so-called “runner’s high”?

New research on the neuroscience of exercise may surprise you.

The “runner’s high” has long been attributed to endorphins. These are chemicals produced naturally in the body of humans and other animals after exercise and in response to pain or stress.

However, new research from my lab summarizes nearly two decades of work on this topic. We found that exercise reliably increases levels of the body’s endocannabinoids – which are molecules that work to maintain balance in the brain and body – a process called “homeostasis.” This natural chemical boost may better explain some of the beneficial effects of exercise on brain and body.

I am a neuroscientist at the Wayne State University School of Medicine. My lab studies brain development and mental health, as well as the role of the endocannabinoid system in stress regulation and anxiety disorders in children and adolescents.

This research has implications for everyone who exercises with the aim of reducing stress and should serve as a motivator for those who don’t regularly exercise.

Health benefits of exercise

Several decades of research has shown that exercise is beneficial for physical health. These studies find a consistent link between varying amounts of physical activity and reduced risk of premature death and dozens of chronic health conditions, including diabetes, hypertension, cancer and heart disease.

More recently – over about the past two decades – mounting research shows that exercise is also highly beneficial for mental health. In fact, regular exercise is associated with lower symptoms of anxiety, depression, Parkinson’s disease and other common mental health or neurological problems. Consistent exercise is also linked to better cognitive performance, improved mood, lower stress and higher self-esteem.

It is not yet clear what is behind these mental health boosts. We do know that exercise has a variety of effects on the brain, including raising metabolism and blood flow, promoting the formation of new brain cells – a process called neurogenesis – and increasing the release of several chemicals in the brain.

Some of these chemicals are called neurotrophic factors, such as brain-derived neurotrophic factor. BDNF is intricately involved in brain “plasticity,” or changes in activity of brain cells, including those related to learning and memory.

Scientists have also shown that exercise increases blood levels of endorphins, one of the body’s natural opioids. Opioids are chemicals that work in the brain and have a variety of effects, including helping to relieve pain. Some early research in the 1980s contributed to the long-standing popular belief that this endorphin release is related to the euphoric feeling known as the runner’s high.

However, scientists have long questioned the role of endorphins in the runner’s high sensation, in part because endorphins cannot cross into the brain through the blood-brain barrier, which protects the brain from toxins and pathogens. So endorphins are not likely to be the main driver for the beneficial effects of exercise on mood and mental state.

This is where our research and that of others points to the role of our body’s natural versions of cannabinoids, called endocannabinoids.

The surprising role of endocannabinoids

You may be familiar with cannabinoids such as tetrahydrocannabinol – better known as THC – the psychoactive compound in cannabis (from the Cannabis sativa L. plant) that causes people to feel high. Or you may have heard of cannabidiol, commonly known as CBD, an extract of cannabis that is infused in some foods, medicines, oils and many other products.

But many people do not realize that humans also create their own versions of these chemicals, called endocannabinoids. These are tiny molecules made of lipids – or fats – that circulate in the brain and body; “endo” refers to those produced in the body rather than from a plant or in a lab.

Endocannabinoids work on cannabinoid receptors throughout the brain and body. They cause a variety of effects, including pain relief, reduction of anxiety and stress and enhanced learning and memory. They also affect hunger, inflammation and immune functioning.

Endocannabinoid levels can be influenced by food, time of day, exercise, obesity, injury, inflammation and stress.

It’s worth noting that one should not be tempted to forgo a run or bike ride and resort to smoking or ingesting cannabis instead. Endocannabinoids lack the unwanted effects that come with getting high, such as mental impairment.

Understanding the runner’s high
Studies in humans and in animal models are pointing to endocannabinoids – not endorphins – as the star players in the runner’s high.

These elegant studies demonstrate that when opioid receptors are blocked – in one example by a drug called naltrexone – people still experienced euphoria and reduced pain and anxiety after exercise. On the flip side, the studies showed that blocking the effects of cannabinoid receptors reduced the beneficial effects of exercise on euphoria, pain and anxiety.

While several studies have shown that exercise increases the levels of endocannabinoids circulating in the blood, some have reported inconsistent findings, or that different endocannabinoids produce varying effects. We also don’t know yet if all types of exercise, such as cycling, running or resistance exercise like weightlifting, produce similar results. And it is an open question whether people with and without preexisting health conditions like depression, PTSD or fibromyalgia experience the same endocannabinoid boosts.

To address these questions, an undergraduate student in my lab, Shreya Desai, led a systematic review and meta-analysis of 33 published studies on the impact of exercise on endocannabinoid levels. We compared the effects of an “acute” exercise session – like going for a 30-minute run or cycle – with the effects of “chronic” programs, such as a 10-week running or weightlifting program. We separated them out because different levels and patterns of exertion could have very distinct effects on endocannabinoid responses.

We found that acute exercise consistently boosted endocannabinoid levels across studies. The effects were most consistent for a chemical messenger known as anandamide – the so-called “bliss” molecule, which was named, in part, for its positive effects on mood.

Interestingly, we observed this exercise-related boost in endocannabinoids across different types of exercise, including running, swimming and weightlifting, and across individuals with and without preexisting health conditions.

Although only a few studies looked at intensity and duration of exercise, it appears that moderate levels of exercise intensity – such as cycling or running – are more effective than lower-intensity exercise – like walking at slow speeds or low incline – when it comes to raising endocannabinoid levels. This suggests that it is important to keep your heart rate elevated – that is, between about 70% and 80% of age-adjusted maximum heart rate – for at least 30 minutes to reap the full benefits.

There are still a lot of questions about the links between endocannabinoids and beneficial effects from exercise. For example, we didn’t see consistent effects for how a chronic exercise regimen, such as a six-week cycling program, might affect resting endocannabinoid levels. Likewise, it isn’t yet clear what the minimum amount of exercise is to get a boost in endocannabinoids, and how long these compounds remain elevated after acute exercise.

Despite these open questions, these findings bring researchers one step closer to understanding how exercise benefits brain and body. And they offer an important motivator for making time for exercise during the rush of the holidays.

Funding: Dr. Marusak is funded, in part, by the National Institutes of Mental Health (K01MH119241).


An Overview of the Endocannabinoid System—From Endo to Phytocannabinoids

The endocannabinoid system is defined as a widespread biological lipid system that plays an essential modulatory role in the endocrine, immune, and brain tissue [14,15]. The endocannabinoid pathway includes elementarily G protein-coupled receptors, known as cannabinoid receptors CB1 and CB2 (CB2R), and the endogenous agonists of these receptors, known as endocannabinoids, principally anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG) [16]. It is known that CB1R is predominantly found in the brain (cerebral cortex), whereas CB2R is principally expressed in a number of immune system cells [17].

Considering endocannabinoids, those molecules are synthesized from omega-3 (docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) or omega-6 (arachidonic acid, AA) long-chain polyunsaturated fatty acids (LC-PUFAs) [18]. Anandamide is a molecule generated from N-arachidonoyl phosphatidylethanolamine (NAPE), an AEA membrane precursor, whereas the fatty-acid amide hydrolase (FAAH) catalyzes the hydrolysis of AEA to arachidonic acid and ethanolamine [19].

Although anandamide is a ligand for CB1R, it might interact with non-classic cannabinoid receptors, such as transient receptor potential vanilloid type 1 (TRPV1) or peroxisome proliferator-activated receptors α and γ (PPARα and PPARγ) [20,21]. On the contrary, 2-arachidonoylglycerol, a ligand for both CB1R and CB2R is mainly formed from the degradation of diacylglycerols (DAGs) by diacylglycerol lipases α and β (DAGLα and DAGLβ) and subsequently hydrolyzed by the monoacylglycerol lipase (MAGL) to AA and glycerol [14].

It is worth mentioning that some researchers define an expanded endocannabinoid system as an endocannabinoidome (eCBome)—a complex lipid signaling system composed of more than 100 fatty acid-derived mediators and their receptors, as well as the anabolic and catabolic enzymes of more than 50 proteins. Thus, a vast number of studies reported that eCBome is deeply involved in the control of energy metabolism and its disturbances that may lead to the development of numerous metabolic pathologies [22,23]. Although endocannabinoids constitute a large group of cannabinoids, we may also distinguish two other classes—synthetic cannabinoids and phytocannabinoids—as essential modulators of the endocannabinoid system.

Phytocannabinoids—Compounds with Dualistic Nature

Cannabis sativa L. has been known for both its healing and psychoactive properties for thousands of years. The first reports of pharmacological usage of cannabis came from ancient China, around ~3000 B.C.E., where it was used in the treatment of such conditions as gout, constipation, or rheumatism. In the Medieval Era, C. sativa was widely used in the treatment of pain, inflammation, vomiting, and fever.

Although the antiepileptic attributes of cannabis were described in the 19th century by Irish physician William O’Shaughnessy, its first use in this pathology was in the Islamic world 100 years prior [24]. Currently, C. sativa is the most popular illicit drug in the world, used by approximately 4% of the global population. Still, it is an object of interest to many researchers around the world due to its large potential as a therapeutic agent [25,26]. Phytocannabinoids are a different group of more than 90 terpenophenolic derivatives produced by C. sativa.

These compounds originate mostly from non-enzymatic reactions of decarboxylation, oxidation, and isomerization of the cannabinoid precursors. In the biosynthesis of phytocannabinoids that occur in C. sativa only three enzymes have an essential significance: cannabinoid acid synthase (CBDA), cannabichromenic acid synthase (CBCA), and tetrahydrocannabinolic acid synthase (THCA). These enzymes are responsible for the conversion of a primary phytocannabinoid precursor—cannabigerolic acid (CBGA)—into final products [27,28].

The most abundant component of C. sativa is tetrahydrocannabinol (THC), which comprises ~17% of the total phytocannabinoid content and is represented by different isomers, including the most well-known—Δ9-THC. It was proven that Δ9-THC has anticonvulsant, neuroprotective, and anti-inflammatory effects, but its psychoactive and addictive properties cause limitations in its clinical usage.

Other phytocannabinoids that may be found in the plant are, for example, cannabidiol (CBD) and cannabinol (CBN) [29,30,31]. The main chemotypes of cannabis preparations are divided into three types: THC predominant (Type I); mixed THC and CBD (Type II, THC and CBD are mixed in 1:1 ratio); and CBD predominant (Type III) [24]. CBD, CBN, and other compounds from this group do not express such psychoactive effects as Δ9-THC [32]. CBD is a much more interesting phytocannabinoid due to its excellent safety profile, and many reported therapeutic effects, especially in the treatment of neurological conditions. Cannabidiol has a very low affinity to cannabinoid receptors.

However, it interacts with other complex signaling systems [25,31]. The recent data showed that mechanisms of CBD action might be associated with many molecular targets, including orphan G protein-coupled receptors, serotonin, adenosine, opioid or PPARγ receptors, as well as transient receptor potential (TRP), glycine or sodium channels. CBD also inhibits FAAH which leads to elevation of AEA concentration in serum. The variety of molecular targets for CBD may be correlated with its influence on many different signaling pathways [33]. Furthermore, CBD interacts with cytochrome P450 isoenzymes which may lead to the altered metabolism of other drugs [34].

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Physical Activity and Its Correlation with the Endocannabinoid System and Neurophysiology
PA and the Endocannabinoid System

Physical activity can be defined as repetitive and planned muscle movements that result in energy disbursement. Some researchers broadly portray PA as an essential, cost-saving, and effective factor in terms of prevention, treatment, and management of numerous pathologies [35]. Although the positive effects of physical exercise in the pathophysiology of various diseases are widely known, the molecular mechanisms are still widely discussed.

However, one of the most probable and examined mechanisms that is changed during PA is the endocannabinoid system. Physical activity was presented as a significant factor that might lead to the activation of the endocannabinoid-signaling pathway, and a clear mutual correlation between them was indicated in several studies. Based on various research, it is worth noting that PA was demonstrated to modulate the ECS in different ways. Several studies conducted on both animal- and human-based models described significant alterations in blood levels of cannabinoid receptors agonists (i.e., AEA and 2-AG) after exercise. In addition to the endocannabinoids mentioned above, OEA and PEA, the analogous endocannabinoid (eCB) compounds that do not act directly on cannabinoid receptors, were also significantly altered during exercise.

Sparling et al. were the first to describe the correlation between acute exercise and higher AEA and 2-AG levels in the blood in human-based models. The elevation of AEA levels may be associated with its acting on peripheral sensory fibers and pain relief as well as the occurrence of “runner’s high” in many regions of the brain, especially in the right anterior lobe and left caudate nucleus [36]. Moreover, the increase in AEA concentration is supposed to be triggered by higher cortisol secretion during acute exercise performance [37,38].

Interestingly, a study by Fuss et al. indicated that exercise-mediated runner’s high might occur due to the interference between physical activity and peripheral CB1 and CB2 receptors, as well as activation of CB1 receptors on forebrain GABAergic (γ-aminobutyric acid) neurons [39]. A large number of studies indicated that moderate and acute physical activity resulted in increased levels of serum concentrations of AEA, OEA, PEA, and 2-AG. Recently, Brellenthin et al. indicated that both AEA and 2-AG circulating levels are significantly higher after exercise, but the increase in AEA is more substantial in the prescribed (approx. 70%–75% max. activity), in comparison to preferred (i.e., self-selected), aerobic exercise [40].

A recent in vivo study conducted by Thompson et al. on mice demonstrated that voluntary physical activity significantly affected circulating endocannabinoid levels differently depending on recent activity and genetic background in comparison to high runner mice (acute PA), which had significantly lower AEA levels. Interestingly, the same study revealed differences in AEA and 2-AG levels between the sexes: males tended to have increased 2-AG levels, whereas AEA levels were higher in females [41].

Recently, Stensson et al. conducted a study on women with fibromyalgia; they indicated that a 15-week person-centered resistance exercise program led to a significant increase in AEA and 2-AG concentration, and therefore might increase muscle strength and provide some neurological alterations, such as analgesia or antidepressant effects [42].

On the contrary, some studies report the constant levels of 2-AG concentration in response to moderate or acute exercises performed by humans [43,44]. Moreover, lower circulating levels of 2-AG after both moderate and preferred physical activity were also demonstrated in some recent research conducted on women with major depressive disorders [11]. Perhaps, alterations in the circulating 2-AG levels depend on the type of physical activity, its intensity, and duration, as well as possible comorbidities. However, further research is necessary to clarify this issue.

It is commonly known that physical activity may also affect the expression of cannabinoid receptors, both CB1R and CB2R. Some studies indicated that chronic exercises might be correlated with the upregulation of CB1R expression and density in mice, most notably in the hippocampus [45,46]. Interestingly, a recent study by Crombie et al. revealed that isometric handgrip exercise for three minutes led to significant alterations in the ECS; not only in higher blood circulating levels of AEA, 2-AG, OEA, and PEA, but also increased expression of cannabinoid receptor type 1, which resulted in significant analgesic effects [47].

It is broadly known that the endocannabinoid system and its signaling pathway might be remarkably involved in the dopamine neurotransmission in synapses at midbrain and striatal sites [48]. Furthermore, the activation of cannabinoid receptor type 1 in GABAergic neurons of the human ventral tegmental area (VTA) in the midbrain may result in disinhibition of VTA dopamine release, involved in reward-directed processes that occur during physical activity (mainly voluntary).

Thus, this demonstrated a significant and promising correlation between the expression of CB1R, GABA, and dopamine [44,49]. Interestingly, Merill et al. using an animal model indicated that ventral tegmental area GABAergic and DAergic cells are able to produce various eCBs, and therefore might be involved in the alterations in the neuronal activity or plasticity in adaptive reward processing or addiction [50].

These studies might be considered, at least partially, as a way to answer the firm doubts concerning the molecular effects of physical activity on the ECS and higher motivation via the reward system. It is worth mentioning, in terms of physical activity, that stimulation of the CB1R at the nerve terminals of neuromuscular junction might lead to the inhibition of acetylcholine (ACh) release and Ca2+ flux that causes decreased muscular tension [35].

Interestingly, there is a lack of findings focused on the interaction between physical activity and phytocannabinoids (e.g., CBD or CBN). Few studies present the action of CBD in muscle recovery by reducing inflammation in the tissue and alleviating pain. However, it underlines the potential usage of phytocannabinoids in the rehabilitation and restoration process after severe physical activity [17,51]. The area of correlation between physical activity and the endocannabinoid system is still unexplored and needs fulfillment by further studies. In addition, novel research should examine the exact mechanism involved in the effect of PA on endocannabinoid signaling, as well as investigate conditions such as the PA type, exercise duration, intensity, age, and sex, which are the most effective in inducing ECS changes.

PA and Neurophysiology—Interference with the Endocannabinoid System

The involvement of physical activity in the neurophysiology components, including mood, pain, cognition, and neurogenesis, is indisputable, as indicated in a vast number of studies. Nevertheless, the mutual relationship between physical activity, the endocannabinoid system, and human neurophysiology remains not well discovered and needs proper fulfillment. The molecular alterations in the endocannabinoid signaling triggered by physical activity mentioned above may directly correlate with systemic effects.

Starting with the influence on mood, various types of exercise, both acute and chronic, and ending with resistant and aerobic training, all activate the endocannabinoid signaling and result in significant mood improvements, antidepressant effect, reduced anger, and tension, as well as increased vigor and motivation [35,40,44,52].

Euphoric and analgesic phenomena widely described by athletes that occur during a forced and prolonged physical activity called “runner’s high” are the result of the activity of endorphins, monoamines, and endocannabinoids and their influence on the reward system in the brain [36,53].

Therefore, the “runner’s high” may lead to heavy exercise addiction probably, due to endogenous opioids release, which may be augmented by the ECS [54,55]. On the other hand, the endocannabinoid system is actively involved in the “runner’s high” associated with exercise-induced hypoalgesia. However, the mechanism of this phenomenon is not yet fully understood.

Most of the data describe possible interaction between the ECS and the endogenous opioid system in reducing pain sensitivity associated with physical activity. Studies conducted on healthy individuals revealed that short-time isometric exercise produced a significant analgesic effect, which was associated with increased serum concentrations of AEA, 2-AG, and β-endorphins. Moreover, transiently increased pain thresholds in exercising limbs were observed [47,56,57].

On the contrary, a recent study performed by Hughes et al. showed expanded β-endorphin concentrations, whereas 2-AG remained unchanged during forced resistant exercises [58]. The body of evidence suggests that interplay between PA and ECS may influence cognition processes such as memory and learning and may be associated with the development of adult neurogenesis in some regions of the brain.

The activation of the HPA (hypothalamic–pituitary–adrenal) axis during stressful situations, which physical activity admittedly is, leads to augmented endocannabinoid synthesis in the peripheral blood and, subsequently, increased activation of postsynaptic β-adrenoceptors which facilitate memory consolidation especially during emotional events [49,59]. Furthermore, a recent article by Wang et al. showed that CB1R signaling in glutamatergic neurons, enhanced by treadmill running, played an essential role in memory and learning improvement and resulted in increased synthesis of neurotrophins and spine density of the hippocampal neurons in mice [60]. Many studies indicate a significant influence of PA and ECS on neurogenesis.

Physical activity constitutes a significant factor that leads to enhanced synthesis of BDNF (brain-derived neurotrophic factor), which is a crucial player in the modulation of neurogenesis in the dentate gyrus of hippocampus and subventricular zone. The increased levels of BDNF correlated with expanded AEA and 2-AG levels and CB1R expression within neural progenitor cells. These findings indicate a clear interaction between BDNF and the ECS; what results is the overall promotion of proliferation, regeneration, and viability of neurons [61,62,63]. Interestingly, Heyman et al. showed that intense and prolonged physical activity resulted in enhanced synthesis of BDNF among male cyclists, probably due to elevated circulating levels of endocannabinoids (i.e., AEA among male cyclists).

These findings correlate with neuroplasticity development and antidepressant effect induced by exercise [37]. In summary, the activation of the endocannabinoid system through various types of physical activity may provide a promising influence on neurophysiology aspects. The popularity of physical activity as a cheap, plausible, and effective method of maintaining a healthy lifestyle and prophylaxis of an enormous number of disorders, including neurological, is increasing tremendously worldwide.

Therefore, we believe that more data focused on positive outcomes of different types of exercise may even increase awareness among people and, at least partially, contribute to decreased prevalence of neurological and neurodegenerative conditions. The large number of studies conducted both on animal- and human-based models shows that targeting the ECS by physical activity may provide promising results in the treatment of neurological conditions; they have been gathered and examined and are presented in Table 1.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352563/

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