What happens to the biochemistry of grass and exercise?

Dr. Leafly's Nick Jikomes explains the body's signaling system for weed molecules and what happens when your blood gets pumped.

The endocannabinoid system is crucial for maintaining homeostasis (balance). As a result, cannabinoids influence everything from emotions and pain perception to metabolism, prenatal development and the gut microbiome. The plant cannabinoid THC exerts its psychoactive effects via cannabinoid receptors in the brain. These receptors (CB1 receptors) are widely distributed in organs and tissues outside the brain, including the lungs and cardiovascular system. Therefore, we would expect cannabinoids to be related in some way to physical activity and therefore potentially have an impact on exercise performance.

What is known about cannabinoids and physical activity? Let's examine the following questions in three articles:

• Part I: How and why the endocannabinoid system responds to physical activity
• Part II: How THC Affects Exercise Performance and Recovery
• Part III: How body fat and exercise affect THC levels in the body.

How physical activity affects the endocannabinoid system

… it has generally been found that anandamide levels increase acutely after exercise.

The two main endogenous cannabinoids are anandamide and 2-AG. A number of clinical (human) and preclinical (animal) studies conducted since the 2010s have examined how acute (short-term) exercise affects endocannabinoid levels in the body. A 2022 meta-analysis examined these to identify trends in results.

There was wide variation in the results and design of the studies, but in general anandamide levels were found to increase acutely after exercise. This tendency has been observed in various forms of exercise (e.g. running, cycling, strength training) in both animals and humans, as well as in human patients with and without pre-existing conditions (e.g. PTSD, depression). The effects of acute exercise on 2-AG were much less consistent across studies and there were insufficient data to assess the effects of chronic (long-term) exercise on endocannabinoid levels.

In animal studies where biological mechanisms can be studied in detail, both voluntary exercise and consumption of palatable foods have similar effects on the endocannabinoid system. CB1 receptors in the brain are important for reward processing in general, and certain CB1 receptor-containing neurons are critical for everything from the rewarding effects of drugs (including THC) to motivation to exercise. In the case of mice, exercise means cycling – they love it. They also love sugar water.

Given the opportunity, mice spend a lot of time running on wheels and sipping sucrose – it's rewarding for them. Performing both behaviors has been shown to increase the sensitivity of CB1 receptors on certain neurons in the brain. After cycling or consuming sugar, these receptors become more sensitive to cannabinoids – both exogenous cannabinoids (drugs) and endogenous cannabinoids that occur naturally in the brain. This means that both an animal's physical activity and dietary habits can alter its sensitivity to cannabinoids.

Similar to what is commonly observed in humans and other animals, mice experience an acute increase in blood endocannabinoid levels after a running exercise. Human long-distance runners sometimes describe a “runner's high,” a feeling of euphoria, reduced anxiety, and analgesia (pain relief) while running. Something similar can also be observed in mice. Behavioral analysis shows that they experience anxiety and pain relief from wheel running. This “runner's high” effect depends on CB1 receptors in specific neurons in the brain and further illustrates the involvement of the endocannabinoid system in coordinated changes in the brain and body in response to physical activity.

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To learn more details about the connection between exercise and the endocannabinoid system, listen to my conversation with neuroscientist Dr. Matthew Hill to:

Why should an animal's lifestyle – the pattern of behavior it exhibits – lead to changes in its endocannabinoid system, affecting everything from propensity for certain behaviors (exercise) to metabolic changes (hunger, fat accumulation) and experiential changes (anxiety levels ). , pain perception etc.)? How might we think about why animals are wired this way?

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Why the endocannabinoid system may have evolved to coordinate changes in the brain and body

Consider what we've studied before – how increased endocannabinoid levels affect hunger and metabolism on the one hand, and anxiety, fear and pain perception on the other. The metabolic effects of activation of CB1 receptors are generally aimed at motivating animals to find food (short-term hunger) and store energy for later (fat accumulation). An overactive endocannabinoid system is associated with metabolic conditions such as obesity and diabetes. This may be a consequence of what some scientists believe is the CB1 receptor's general, evolved function: to motivate behavior and coordinate physiological changes in favor of energy accumulation (e.g., food intake, fat storage).

For most wildlife, it may be adaptive to feed in the presence of abundant food sources, as food often becomes scarce in the future. Feast in preparation for a famine.

When it comes to anxiety, pain perception, and fear memory, an overactive endocannabinoid system is associated with lower anxiety, reduced pain perception, and weaker fear memory. While lower levels of fear, pain, and fear sound like a good thing, it can be deadly for wildlife. Imagine a mouse that doesn't become anxious when it smells a cat nearby, or remember the last place it was attacked by a cat. Life may become less stressful moment by moment, but it probably won't last long.

Why would excessively high endocannabinoid levels, resulting in an overactive endocannabinoid system, tend to drive this pattern of biological effects – metabolic changes that promote energy accumulation, along with various experiential changes (reduced anxiety, etc.)? It may seem strange until you consider it in terms of the ecological contexts in which animals must survive.

After a physically demanding hunt, you naturally want a good meal.

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Imagine again that you are a wild mouse. You are well-fed and plump and have a supply of food in your den. Times are good. What is your best option for survival? Stay home, clean yourself and take a nap? Or venture out from the safety of the nest and risk death at the hands of predators? The answer is clear: rest and digest.

Now imagine a time of famine. You are running out of food and your fat reserves are depleted. The only way to survive is to search for more food. Will you be motivated to do this if you are extremely anxious and afraid of predators? Of course not. A risky foraging adventure is a much better option for survival than starving in the comfort of your own home. Animals are predisposed to be more adventurous, less fearful and more willing to take risks in times of energy scarcity.

Why would levels of an endogenous cannabinoid like anandamide generally be higher after exercise? The body may sense that its energy stores are being depleted – you are burning calories and may soon need more. For most of human prehistory, much like a wild mouse, this would have meant being motivated to venture outside the safety of one's home. This is only possible if you are not gripped by fear and anxiety.

For most of human evolution, we basically had to exercise to eat – and exercise (hunting, foraging) to accumulate calories. It makes sense that humans and other animals have evolved biological mechanisms that prepare their bodies to use and store energy after engaging in the physical activities necessary to obtain food. After a physically demanding hunt, you naturally want a good meal.

This perspective also begins to understand the modern health problems that are widespread among people who have never faced the threat of hunger.

Ancient biology, modern health problems

Thinking about biology in an ecological-evolutionary context can help understand modern, “civilizational” problems. For example, today people are increasingly suffering from metabolic disorders (e.g. obesity, diabetes) and are experiencing an increase in mental health problems such as anxiety. Could these things be related?

Today there is an almost unlimited supply of calories available. These calories provide the body with a strong tendency to accumulate fat reserves and prepare us for the next famine – a famine that will no longer occur. We are in constant rest and digest mode. On an evolutionary time scale, we created civilization yesterday. But our behavior is influenced by biological systems that have evolved over millions of years. Our biology hasn't had time to fully adapt to the hyper-new, rapidly changing environment we invented.

Since life-threatening food shortages never motivate us to venture back into a dangerous wilderness, we are ready to imagine new fears and anxieties. Many of our mental health problems may be at least partly due to the convenience of modern life. There is more room for new fears when you are not faced with the threat of impending famine.

Our modern environment has also given us the opportunity to alter our endocannabinoid system in new ways through the intentional use of exogenous cannabinoids such as THC. If the endocannabinoid system helps regulate our biology in response to physical activity, can plant cannabinoids like THC influence things like exercise performance? This will be the topic of the next article in this series.

Read the other two articles in this content series:

• Part II: How THC affects the lungs, cardiovascular system and exercise performance
• Part III: How exercise and body fat affect blood THC levels