The Chemistry of Exercise

May is National Mental Health Awareness Month,all the content we bring you this May will be related to psychology, psychiatry, neurology, and/or other mental health adjacent topics.

Disclaimer: this article is not meant to promote exercise as a method of weight loss; instead it is intended to promote exercise for the benefit of mental health and overall quality of life. We will discuss the physical health benefits of exercise briefly, and then expand into the chemistry of exercise and it's evidence-based effects on mental health.

Physiology of Exercise

Before it could ever be proven scientifically, humans understood the benefit of physical activity, as well as the consequences of sedentary lifestyles. Historically, we were hunter gatherers who walked significantly longer distances daily than we do today. Although we know outright that exercise is beneficial, science has struggled to understand exactly how exercise improves our health.

Chemically, the benefits of exercise not only promote healthy adaptations, but also decrease inflammation and age-related metabolic changes. Simply put, exercise increases the expression of genes which are indirectly responsible for signalling responses throughout the body. The changes that occur in our bodies with exercise have shown to improve mental and physical health, while also slowing age-related decline. Given this information, it is fair to say that exercise will keep you younger, healthier, and happier.

It is important to note that physical activity does not impact everyone in exactly the same ways. We know that genetics and environment play a role in the impact of exercise on health, but to what degree is still somewhat a mystery.

Classification of Physical Activities:

• Low-Load Endurance Exercise (Cardio)

  • Mechanical stress is low. Chemical evidence of health benefits are dependent on the duration of activity (endurance). Examples include running, cycling, rowing, swimming, and cross-country skiing.

• High-Load Strength Exercise (Weight Training)

  • High mechanical stress leads to growth of muscle fibers. Examples include weight lifting and other forms of resistance training.

Physical activity can also be classified by setting (occupational, leisure-time, travel, home), quality (frequency, intensity, duration), social context (access to greenspace, facilities, and resources like money and social support), motivation (reasons for undertaking PA) and type of activity (aerobic exercise through yoga to housework and gardening, vs resistance training through weight lifting/strength training)

Extremes: Not Enough, or Too Much?

The World Health Organization (WHO) recommends to adults:

• at least 150 min moderate or 75 min vigorous intensity physical activity per week

• muscle strengthening activities twice a week

• minimize time spent being sedentary/inactive

• similar guidelines exist for those under 18, as well as middle aged individuals
  

It is also worth mentioning that over-exercising can cause harm to the body. Putting excessive stress on the body will interfere with the benefits seen from exercise, while increasing the risk of physical injury substantially. As with anything in this world, moderation is key. We want to aim for exercise that meets, but does not greatly exceed the WHO goal - unless someone is a professional or extreme athlete. Uniquely, professional or extreme athletes have entirely different processes in relation to exercise; similar to how an athlete's resting heart rate is often significantly lower than the majority of the population. An incredible amount of physical activity changes the way our bodies react to exercise. Overall, we should aim to push ourselves, but never to the point of injury.

“While exercise is an effective prescription to promote health, there is no minimum dose, no optimal dose, and no dose without risks or negative consequences.” (1)

Regular exercise at the recommended levels (mentioned above) can reduce lifetime risk of 20+ chronic conditions including coronary heart disease, stroke, type 2 diabetes, some cancers, and obesity. In addition, exercise reduces the severity of mental health concerns, notably depression and anxiety, and potentially dementia as well.

Exercise also has been shown to improve quality of life and overall happiness and satisfaction.

Mental Health Benefits of Exercise: Anxiety and Depression

Potential mechanisms for anxiolytic and antidepressant treatment include extinction training, modification of behavior, distraction theory, and a variety of chemical processes (which we will touch on in a moment). In this section, we'll provide a brief overview of the beneficial impacts of exercise on mental health, specifically in the treatment of anxiety and/or depression.

Extinction Training

 Because exercise can produce many of the stimuli that are feared by individuals with panic and related disorders, exercise could be viewed as a vehicle for repetitive exposure, thereby decreasing anxiety symptoms related to exercise (e.g., increased heart rate, increased cardiac stroke volume, increased perspiration, elevated respiration rate). (4)

Evidence: Studies have documented significant changes in anxiety sensitivity with repetitive exercise programs. Studies by Broman-Fulks et al. randomly assigned 54 participants with history of severe anxiety to either high-intensity (60–90% maximal heart rate) or low-intensity (below 60% of maximal heart rate) aerobic exercise programs. Results illustrate that high-intensity intervention was associated with significantly greater reductions in anxiety, as compared to the low intensity intervention group. In a second study, Broman-Fulks and Storey compared six sessions of aerobic exercise to a no-exercise comparison condition in 24 participants with a history of severe anxiety. Results once again demonstrated that anxiety sensitivity and likelihood of anxious symptoms decreased significantly in the aerobic exercise condition, with no significant change in the no-exercise group. These studies reinforce that exercise-induced mental health benefits are present with physical activity, and more so present in higher intensity exercise (ex; walking vs. jogging).

Emotional & Behavior Change Theory

Emotional action modification theorizes that the alteration of negative, self-perpetuating behavioral patterns (e.g., avoidance in anxiety, social withdrawal, and inaction in depression) is an incredible and effective therapeutic strategy to mediate psychiatric symptom severity. By doing the exact opposite of what our brain tells us (getting ourselves out of our beds with depression, or taking a walk in a public park with social anxiety), we often reduce anxious responses to the conquered fear. I've heard this before, and I want to emphasize it: do the opposite of what you feel like doing in the throes of mental illness.

Distraction Theory:

Others have proposed that the anxiolytic effects of exercise are due to physical activity serving as a distraction or ‘time-out’ from worries and concerns. Personally, I've always described this as the reason I loved sports such as snowboarding and horseback riding - I always felt as though my mind could not wander, which has been incredibly therapeutic.

Evidence: A study by Bahrke and Morgan found significant reductions in state anxiety following 20 min of exercise (at 70% maximal heart rate), as compared to meditation or rest (non-exercise, mind-wandering activities), suggesting that exercise may be one of several forms of distraction that can decrease anxiety. (4)

The Chemistry, Briefly

Although there are many theorized mechanisms regarding how exercise benefits our health, including neurotransmitter, neuromodulator, and psychological mechanisms - it is not understood to which degree each contributes to health benefits.  In summary, here are multiple reasons why exercise acts as an anxiolytic (relief from anxiety)

Potential chemical mechanisms of change include modulation of neurotransmitter functioning, ANP, BDNF, and modification of behavior. *Don't panic! We'll briefly review each.

Atrial natriuretic peptide (ANP)

ANP is a hormone that is known to possesses anxiolytic (anxiety-relieving) effects, and may be implicated in future anxiety treatment strategies.

Evidence: A landmark study, Ströhle et al. examined the effects of exercise on ANP and response to panic onset: 30 min of 70% of maximum heart rate on a treadmill significantly increased plasma ANP and also reduced anxious response. Importantly, the magnitude of the reduction in anxiety was directly related to plasma levels of ANP. Higher levels of ANP = More profound decrease in anxiety.

Brain derived neurotrophic factor (BDNF) 

Cardio-focused bursts of exercise have been shown to significantly increase BDNF levels and decrease in anxiety symptoms.

Treatment options for anxiety in the future may consider BDNF expression as a method of action.

Studies show that increase in BDNF levels tend to be greater following high aerobic exercise intensity vs. low intensity: In other words, push yourself in your cardio workout, and you'll release more anxious energy. 

Evidence: A notable study, Broman-Fulks et al. randomly assigned 54 participants with high levels of anxiety sensitivity to either six 20-min high-intensity (60–90% maximal heart rate) or a low-intensity (below 60% of maximal heart rate) aerobic exercise program. (4) The high-intensity intervention was associated with significantly greater reductions in anxiety sensitivity compared with the low intensity intervention. In a second study, Broman-Fulks and Storey compared six sessions of aerobic exercise to a no-exercise comparison condition in 24 participants with high anxiety sensitivity. When comparing exercise vs. no exercise, Anxiety symptoms decreased significantly in the cardio exercise condition, with no significant change in the control (no exercise) group. (4)

Endorphins - Less Important Than We Thought?

Endorphins are well-know to be endogenous (existing naturally within our bodies) peptide molecules that act as opioid receptor agonists. If this sounds complicated: think of endorphins as the "natural oxycodone" within our bodies, as endorphins bind to the same receptors, and were thought to contribute to exercise euphoria. However, the significance of endorphins as it relates to anxiety reduction has recently come into question.

Evidence: Various studies have demonstrated that periods of exercise result in decreased anxiety, regardless of whether participants were administered naltrexone, an opioid receptor-blocking medication, or placebo. In other words, the effects of endorphins were completely removed in the naltrexone group, which then allows researchers to understand the importance of endorphins, or lack thereof, in regards to exercise-mediated anxiety relief.

Findings show that β-endorphin is released into the bloodstream during stress/exercise. However, there is not much evidence that β-endorphin crosses the blood–brain barrier during or after exercise, and is therefore unlikely to directly influence anxiety or mood.

Neurotransmitter Affects

Serotonin and Norepinephrine

Animal studies have demonstrated that exercise produces similar alterations the serotonergic [28–31] and noradrenergic systems [32–36], which underlie pharmacologic treatments for depression and anxiety. For example, treadmill running appears to increase free tryptophan in the blood, thereby causing tryptophan (the precursor to serotonin) to enter the brain at an increased rate, resulting in increased serotonin production.

Exercise may also affect noradrenergic neurotransmission, which has been implicated in the etiology of panic disorder [32–36]. Support for this hypothesis comes from studies showing that increased physical activity in rats is associated with increased noradrenaline turnover in the mediobasal hypothalamus, which appears to cause a downregulation of α2-adrenergic receptors [41,42]. To our knowledge, this finding in rats has not yet been translated to humans

Dopamine and Glutamate (Not Yet Proven)

One theory is adenosine effects on dopamine and glutamate. Adenosine A1 and A2A receptors, the receptors responsible for controlling neurotransmission, are implicated in anxiety etiology. In rat populations, there is evidence that exercise has an effect on adenosine- modulated dopamine and glutamate levels. This may be significant in the future, but these studies have yet to be replicated in humans.

GABA-A (Unique Implications)

It has been theorized that exercise may reduce anxious behavior by increasing GABA concentrations, thereby down-regulating GABA-A receptors in the brain.

Evidence: Studies performed in rats found that voluntary exercise on a running wheel, but not forced treadmill exercise, increased open-field voluntary physical activity and decreased other anxiety-related behaviors with a corresponding GABA-A downregulation.**

• I found this particularly incredible; it may be a foundation for the idea that "forcing yourself" to exercise or being forced to by another, will not produce the same anxiolytic effects as choosing to exercise would produce. Keep this in mind next time your friends try to force to out on a run, or to the gym!
  

The most significant human studies regarding anxiolytic effects of GABA downregulation were conducted by by Streeter et al. and specifically study the effects of Yoga. Results determined that A 12-week yoga intervention produced greater anxiolytic effects and increases in acute thalamic GABA levels than a metabolically matched walking intervention, suggesting that the GABA-mediated anxiolytic effects may be Yoga-specific. This illustrates that GABA mediated anxiolytic effects may be dependent on the type of activity, and/or the willfulness behind the activity.

**Both activity wheel exercise and treadmill exercise resulted in increased GABA levels, suggesting that the decreases in anxiety behavior resulted from chronic downregulation of GABAA receptors and not acute increases in GABA. (4)

So then... is Exercise Medicine?

Yes! The benefits of exercise and physical activity, as well as associated risks of over or under exertion, can absolutely be compared with that of a drug. Exactly how we can regulate exercise and utilize this information to create treatment strategies, however, is still to be determined.

“Exercise might be best understood as a drug with powerful benefits, especially for cardiovascular health. As with any potent drug, establishing the safe and effective dose range is critically important—an inadequately low dose may not confer full benefits, whereas an excessive dose may produce adverse effects that outweigh its benefits." (4)

Conclusion Exercise is most likely to benefit mental and physical health when used as an adjunct to a healthy lifestyle. Regarding mental health, exercise can be used concomitantly (simultaneously) with psychotherapy, such as CBT (cognitive behavior therapy), or pharmacotherapy (medication) to maximize potential anxiolytic effects. Regarding physical health, pay close attention to diet, nutrition, and daily activities. It may seem silly, but increasing the amount of whole foods in the diet, avoiding processed foods, and maintaining optimal vitamin levels, can all significantly contribute to all areas of health.

My fellow Depression sufferers have heard the dreaded advice: "Have you tried exercising?"

Instead of (metaphorically) ripping the head off the inconsiderate a**hole minimizing the severity of your mental illness- think about it. Have you? I hate to say it, but physical activity on a regular basis is actually one of the easiest, most beneficial, and least costly treatment options available to just about everyone. You may actually be able to cure, or improve depressive episodes through regular exercise. ...Don't shoot the messenger; blame the science!

The Future: With an expanded understanding of the aforementioned chemical mechanisms of anxiety relief, we can potentially maximize the mental health benefits of exercise in healthy individuals. Additionally, we can potentially develop pharmacological interventions that provide similar benefits to those who cannot exercise due to age, illness, or disability. Imagine your Grandma has severe depression; we most likely should not set her up on a stationary bike to break a sweat and beat the blues. Alternative methods of mental health treatment are necessary, but the chemical information we learned about could greatly influence future treatment options.

Limitations of Studies: First, I'd like to mention that interventions among these studies are limited, with most studying the effects of treadmill walking/running. However, studies have also suggested anxiety reduction through Tai-Chi and Yoga. By studying various forms of exercise in the future, we hope to learn more about how certain activities impact the body vs. other activities. In terms of limitations regarding study results: many exercise induced health benefits (ex: reduced risk of diabetes, cancers, and age-related mental decline) manifest over time frames of months, years and decades. Therefore, it is important to understand the long term health changes associated with exercise interventions. The studies we mentioned throughout this article observe patients for several weeks at a time, but in order to understand the full impact of exercise on health, we need to increase the length of clinical trials, or preform longitudinal studies (following the subjects for extended periods of time) to assess these proposed benefits.

Lastly, I'd like to propose a question for thought. Feel free to reply in the comments!

*your answer does not have to be complicated, based in chemistry, or provable with today's science.

THINK: How can we mimic the physiology of exercise to create drug treatments OR therapeutic treatment modalities in the future?

Resources:

1. Eissenberg JC. Working Out: The Molecular Biology of Exercise. Mo Med. 2022 Jul-Aug;119(4):379-384. PMID: 36118818; PMCID: PMC9462916.

2. Kelly RS, Kelly MP, Kelly P. Metabolomics, physical activity, exercise and health: A review of the current evidence. Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165936. doi: 10.1016/j.bbadis.2020.165936. Epub 2020 Aug 19. PMID: 32827647; PMCID: PMC7680392.

3. Nieman DC, Pence BD. Exercise immunology: Future directions. J Sport Health Sci. 2020 Sep;9(5):432-445. doi: 10.1016/j.jshs.2019.12.003. Epub 2019 Dec 30. PMID: 32928447; PMCID: PMC7498623.

4. DeBoer LB, Powers MB, Utschig AC, Otto MW, Smits JA. Exploring exercise as an avenue for the treatment of anxiety disorders. Expert Rev Neurother. 2012 Aug;12(8):1011-22. doi: 10.1586/ern.12.73. PMID: 23002943; PMCID: PMC3501262.