Stockholm Medical Cannabis Conference

Tuning the Endocannabinoid System: Lifestyle Factors and Their Impact on ECS Tone

The Endocannabinoid System (ECS) is a complex biological system in our body composed of endocannabinoids — natural lipid-based neurotransmitters, their receptors, and enzymes involved in the synthesis and degradation of these compounds. It plays a pivotal role in maintaining the body’s homeostasis, regulating a myriad of physiological processes including pain sensation, mood, appetite, sleep, and immune response [1]. Given its widespread influence, it’s no surprise that activities and behaviors can modulate the ECS. This article elucidates different activities and behaviors that affect ECS tone, and their relative importance.

Physical Activity

Regular exercise has been shown to modulate the ECS. A study involving healthy humans found an increase in plasma anandamide (AEA) levels following 30 minutes of moderate-intensity exercise [2]. Similarly, animal studies have found increased AEA levels in the brain following treadmill running [3]. Exercise may therefore be a natural way to enhance the activity of the endocannabinoid system, often referred to as ‘endocannabinoid tone,’ potentially explaining the mood-enhancing effects often associated with regular physical activity.


Dietary factors can also influence ECS tone. Certain nutrients, such as omega-3 fatty acids, have been shown to influence endocannabinoid levels. In animal studies, diets rich in omega-3 led to decreased levels of the endocannabinoids 2-AG and AEA [4]. On the contrary, diets high in fat and sugar can lead to overactivity of the ECS, potentially contributing to obesity and metabolic disorders [5].

Stress and Sleep

Chronic stress and lack of sleep can dysregulate the ECS. Studies have found elevated levels of endocannabinoids in response to stress, indicating an overactive ECS [6]. Sleep deprivation can also increase endocannabinoid levels, which may contribute to the mood and cognitive effects associated with lack of sleep [7].

Social Interaction

Social interaction appears to influence the ECS. Animal studies have shown that social isolation can lead to alterations in the ECS, with isolated animals showing increased AEA levels and decreased 2-AG levels compared to socially housed animals [8]. This suggests that social interaction may be an important regulator of ECS tone.

Alcohol and Substance Use

Substance use, particularly chronic use of cannabis, alcohol, and other drugs, can lead to changes in the ECS. Chronic cannabis use, for instance, can lead to downregulation of CB1 receptors, a key component of the ECS [9]. Alcohol use has also been associated with changes in endocannabinoid levels [10].

The following table provides an overview of these factors and their impact on ECS tone.

*Evidence Grade is based on the strength and volume of existing research, with 1 indicating very low evidence and 5 indicating very high evidence.
Determining the relative importance of these activities and behaviors necessitates a nuanced understanding of the ECS and its role in health and disease. Factors with a high relative importance have been given this classification due to their potential to significantly modulate ECS tone and their association with health conditions linked to ECS dysregulation, such as metabolic disorders and mood disorders.

Physical activity, diet, and stress/sleep were categorized as highly important due to the robust body of research indicating their substantial influence on ECS tone. Regular exercise, a balanced diet, and good sleep hygiene are fundamental pillars of health, and their impact on ECS tone further underscores their importance.

Alcohol and substance use were also classified as highly important due to the potential for chronic substance use to significantly alter ECS function, as shown in numerous studies.

Social interaction was given a medium classification of relative importance. While there is evidence indicating its influence on ECS tone, much of this evidence comes from animal studies, and further research in humans is needed to fully elucidate the extent of its impact.

Understanding how lifestyle factors influence the ECS presents exciting opportunities for the development of interventions and therapeutics. For example, individuals could potentially manipulate their ECS tone through diet or exercise to improve mood or manage chronic pain. However, further research is needed to fully understand the complexities and potential side effects of such interventions. It’s also important to consider that the relationship between lifestyle factors and ECS tone is likely bidirectional and influenced by other physiological processes. Future research should aim to clarify these complex relationships and explore the potential for personalized ECS-based treatments.

Stefan Broselid, Ph.D.
Editor-In-Chief, Aurea Care Medical Science Journal


  1. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006;147(S1):S163-S171.
  2. Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A. Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’. J Exp Biol. 2013;216(2):133-139.
  3. Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, Gass P. A runner’s high depends on cannabinoid receptors in mice. Proc Natl Acad Sci U S A. 2015;112(42):13105-13108.
  4. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011;14(3):345-350.
  5. Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410(6830):822-825.
  6. Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TTY, Gray JM, Hillard CJ, Gorzalka BB, Viau V. Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci U S A. 2010;107(20):9406-9411.
  7. Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, de Wit H, Hillard CJ, Van Cauter E. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. Sleep. 2016;39(3):653-664.
  8. Wei D, Allsop S, Tye K, Piomelli D. Endocannabinoid signaling in the control of social behavior. Trends Neurosci. 2017;40(7):385-396.
  9. Hirvonen J, Goodwin RS, Li CT, Terry GE, Zoghbi SS, Morse C, Pike V, Volkow ND, Huestis MA, Innis RB. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. 2012;17(6):642-649.
  10. Basavarajappa BS. The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism. Mini Rev Med Chem. 2007;7(8):769-779.