Exercise and Euphoria

Why Do I Feel High After Working Out?

When we exercise or follow a training fitness program, it is believed that the pituitary gland in the brain releases endorphins that block pain receptors named opioid receptors leading to a state of euphoria and a reduction in anxiety levels (anxiolytic effect).

However, a study reported that the sense of well-being (euphoria) after exercise referred to as the “runner’s high”, is not associated with the release of endorphins and their binding to opioid receptors. The authors show that endogenous cannabis-like substances named endocannabinoids that are released by neurons could be the ones responsible for this effect [1].

To validate their hypothesis, the authors of the study used inhibitors of opioid receptors in exercising individuals and showed that the state of euphoria is also observed in these individuals.

These results suggest that endorphins are not responsible for the well-being sensation in exercising individuals. However, although they reported a significant increase of endocannabinoids in the plasma, they did not show their direct involvement in this process.

Exercise has also been shown to stimulate the release of Serotonin, a known neurotransmitter that induces mood changes including anxiolytic effects which may also contribute to the sense of euphoria after exercise.

What Are Endorphins?

Endorphins are a group of endogenous opioids that include alpha-endorphin, beta-endorphin, and gamma-endorphin characterized by their capacity to bind and block opioid receptors. However, the roles of alpha-endorphin and gamma-endorphin are unknown. Beta-endorphin blockade of opioid receptors results in two main effects on the nervous system:

  • Effect on the peripheral nervous system that leads to the inhibition of the secretion of the neurotransmitter named Substance P, responsible of pain. Substance P mediated pain is due to substance P binding to its receptor called neurokinin type 1 found on the surface of most tissues and organs’ cells.  
  • Effect on the central nervous system by inducing dopamine which secretion is blocked by the neurotransmitter gamma-aminobutyric acid (GABA).

What Are Endocannabinoids?

Endocannabinoids are fatty acid neurotransmitters that are synthesized and released by the neurons’ synapses. Endocannabinoids include anandamide (AEA) and 2-arachidonoglycerol (2-AG) which bind to specific receptors named cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2).

CB1 is found in the central nervous system and specifically in the cortex, hippocampus, basal ganglia, amygdala, hypothalamus, and cerebellum, while CB2 is found in the peripheral nervous system.

Due to their high level of release in the plasma of exercising individuals, it was suggested that endocannabinoids are also involved in initiating the euphoric effect of exercising [2][3].

What is Serotonin?

Serotonin, also known as 5-hydroxytryptamine or 5-HT, is a neurotransmitter that modulates mood, cognition, learning, memory, depression, anxiety, social phobia, schizophrenia, obsessive‐compulsive, panic disorders, and numerous physiological processes such as vomiting and vasoconstriction. 

It is mainly found in the enteric nervous system (gut nervous system), the brainstem, and specific cells in the tongue and skin [4].

How Are Endorphins Activated?

The beta-endorphin precursor beta-lipotropin, ACTH (Adrenocorticotropin hormone), and neuropeptides are synthesized and stored in the pituitary gland in the form of proopiomelanocortin (POMC).

Physiological and psychological changes, such as pain and exercise, stimulate the release of CRH (corticotropin-releasing hormone) by the hypothalamus that instructs the pituitary gland to cleave POMC.

POMC cleavage leads to the production of beta-lipotropin, ACTH (Adrenocorticotropin hormone), and neuropeptides.  Beta-lipotropin is then cleaved to generate beta-endorphin which is released by the pituitary gland [5].

How Are Endocannabinoids Activated?

Physiological and psychological changes, such as pain and exercise, result in the activation of postsynaptic activities of metabotropic glutamate receptors that initiate the synthesis (metabolism) and release of endocannabinoids [6]. Metabotropic glutamate receptors are receptors that are stimulated by the binding of neurotransmitters (e.g., glutamate and amino acids) resulting in the initiation of metabolic reactions.

How is Serotonin Activated?

Serotonin is produced by serotonergic neurons and enterochromaffin cells from its precursor amino acid L-tryptophan and stored in the enteric nervous system (gut nervous system), the brainstem, specific cells in the tongue and skin, and blood platelets [7].

Physiological and psychological changes, such as cognitive changes and exercise, induce nerves impulses that trigger the release of serotonin is into the synapses, where it binds to the serotonin receptors that transduce an extracellular signal along neurons [8].


The sense of euphoria (Runner’s high) after exercising is proposed to be due to endorphins and neurotransmitters such as endocannabinoids and serotonin. However, further studies challenged the involvement of endorphins in triggering euphoria, and therefore, further studies are needed to clarify this controversy.

Moreover, although endocannabinoids levels in the plasma are increased following exercise, it is not known if the euphoric state is due to their increase, and thus, further studies are also needed to clarify this point.

However, whether this state of well-being is due to endorphins, endocannabinoids, or serotonin, it is very clear that exercising is the key. This is not surprising as exercise has also been shown to reduce stress, anxiety, and depression and improve the function of the cardiovascular and nervous systems among other beneficial effects to the body and mental health.


[1] Siebers, M., Biedermann, S.V., Bindila, L., Lutz, B. and Fuss, J., 2021. Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans. Psychoneuroendocrinology126, p.105173.

[2] Tantimonaco, M., Ceci, R., Sabatini, S., Catani, M.V., Rossi, A., Gasperi, V. and Maccarrone, M., 2014. Physical activity and the endocannabinoid system: an overview. Cellular and molecular life sciences71(14), pp.2681-2698.

[3] Dietrich, A. and McDaniel, W.F., 2004. Endocannabinoids and exercise. British journal of sports medicine38(5), pp.536-541.

[4] Mohammad‐Zadeh, L.F., Moses, L. and Gwaltney‐Brant, S.M., 2008. Serotonin: a review. Journal of veterinary pharmacology and therapeutics31(3), pp.187-199.

[5] Smyth, D.G., 2016. 60 YEARS OF POMC: Lipotropin and beta-endorphin: A perspective. Journal of molecular endocrinology56(4), pp.T13-T25.

[6] Rezayof, A. and Hashemizadeh, S., 2016. Critical Role of Cannabinoid CB1 Receptors in Nicotine Reward and Addiction. In Neuropathology of Drug Addictions and Substance Misuse (pp. 158-167). Academic Press.

[7] Berger, M., Gray, J.A. and Roth, B.L., 2009. The expanded biology of serotonin. Annual review of medicine60, pp.355-366.

Albert, P.R. and Tiberi, M., 2001. Receptor signaling and structure: insights from serotonin-1 receptors. Trends in Endocrinology & Metabolism12(10), pp.453-460.

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