Runner’s High Is Caused by Endocannabinoids, Not Endorphins

Here's Why That Changes Everything.

Research from Harvard University and Johns Hopkins University has rewritten a decades-old assumption about exercise: the euphoric calm known as Runner's High is not caused by endorphins. It's caused by endocannabinoids, the same class of molecules your body was producing long before cannabis entered the picture. A 2021 peer-reviewed study published in Psychoneuroendocrinology (Siebers et al.) helped confirm this in humans for the first time, using a double-blind, randomized design. The findings have quietly significant implications, not just for how we understand exercise, but for how we understand stress, alcohol, and the role of cannabinoids like CBD.

Why the Endorphin Story Was Always Incomplete

Exercise does increase endorphin levels in the bloodstream, and endorphins serve a real purpose: they function as peripheral analgesics, reducing muscle pain during sustained effort. But endorphins are large, hydrophilic peptide molecules that cannot cross the blood-brain barrier. Whatever their role in the body, they are not capable of directly producing the mood changes, euphoria, and anxiety reduction associated with Runner's High.

Endocannabinoids are structurally different. They are small, lipophilic (fat-soluble) molecules that cross the blood-brain barrier readily and act directly on neurons. According to Dr. David Linden of Johns Hopkins, these molecules "promote short-term psychoactive effects such as reduced anxiety and feelings of calm... Exercise has a dramatic antidepressive effect. It blunts the brain's response to physical and emotional stress." In the 2021 Siebers study, 63 healthy participants ran at moderate intensity for 45 minutes. Researchers used the opioid receptor antagonist naltrexone to pharmacologically block endorphin signaling in half the group. The result: blocking opioid receptors did not prevent euphoria or reduced anxiety after running. Endocannabinoid levels, however, rose significantly and were directly associated with those mood effects. A 2023 systematic review of 21 human clinical trials, also by Siebers and colleagues (The Neuroscientist, 2023), found that 14 of 17 studies detected measurable increases in circulating endocannabinoids following acute exercise.

What the Endocannabinoid System Actually Does

The endocannabinoid system (ECS) is a regulatory signaling network present throughout the brain and body, operating via two primary receptor types: CB1, concentrated in the brain and central nervous system, and CB2, found largely in immune tissue and the periphery. Its core function is maintaining homeostasis, the body's capacity to regulate itself under changing conditions.

The ECS influences mood, stress response, sleep, memory consolidation, pain perception, inflammation, immune activity, and appetite. It takes its name from cannabis, because scientists discovered it while investigating how cannabis interacts with the human body. That discovery revealed something remarkable: the body already produces its own cannabinoid-like molecules (called endocannabinoids) that bind to the same receptor system. The first identified was anandamide (AEA), named after the Sanskrit word ananda, meaning bliss, discovered in 1992. The second major endocannabinoid, 2-arachidonoylglycerol (2-AG), was identified in 1995. As Harvard Health has described it, all of us carry tiny cannabis-like molecules in our brains. The cannabis plant, used by humans for thousands of years, works by engaging this ancient biological system that was already there.

What Disrupts the ECS (And What Restores It)

This is where the science becomes particularly relevant. The ECS does not function in isolation; it is directly responsive to the stress system, and that responsiveness goes both ways.

Research published in Neuropsychopharmacology (Morena et al., 2016) established that the ECS plays a central role in regulating the body's response to stress, particularly through the hypothalamic-pituitary-adrenal (HPA) axis. Crucially, chronic stress reduces this capacity. A study at Penn State College of Medicine (Cannabis and Cannabinoid Research, 2023) found that traumatic and chronic stressors actively disrupt ECS function, reducing anandamide levels and impairing the system's ability to regulate anxiety and fear responses. Separate research (Hill et al., 2014) demonstrated that central anandamide levels drop measurably following acute stress, and that this reduction directly predicts anxiety-like behavior. In other words, chronic stress doesn't just make you feel worse. It depletes the very system your body relies on to regulate stress in the first place.

A 2022 systematic review and meta-analysis in Cannabis and Cannabinoid Research (Desai et al., Wayne State University) further confirmed this connection, noting that chronic stress blunts ECS signaling and that disruptions in this system have been linked to anxiety, depression, and PTSD.

Other lifestyle factors affect ECS function as well. Research has shown that acute alcohol exposure measurably reduces anandamide levels (Sloan et al., 2022), and that repeated heavy exposure over time alters CB1 receptor expression and disrupts endocannabinoid-mediated signaling more broadly (Pava & Woodward, 2012). The picture that emerges is a consistent one: the ECS responds to what we put it through. Chronic stress and certain substances deplete endocannabinoid tone, while exercise, particularly moderate-intensity aerobic exercise, robustly restores it.

Where CBD Fits In

CBD (cannabidiol) does not bind strongly to CB1 or CB2 receptors the way THC does. Its mechanism is modulatory rather than direct. Research has identified several relevant pathways. CBD inhibits FAAH (fatty acid amide hydrolase), the enzyme responsible for breaking down anandamide, effectively extending anandamide's active time in the system. A 2023 randomized clinical trial (Translational Psychiatry, Hua et al.) provided the first human, placebo-controlled evidence that CBD increases anandamide levels in individuals with a psychiatric diagnosis. CBD also interacts with TRPV1 receptors and serotonin (5-HT1A) pathways that intersect directly with stress response.

A 2023 systematic review and meta-analysis on CBD and anxiety (Mejia-Mejia et al.) analyzed 316 participants across eight randomized controlled trials and found a substantial effect size for CBD on anxiety outcomes. A 2022 systematic review of RCTs (MDPI) similarly concluded that CBD showed meaningful impact across multiple anxiety disorder subtypes. This research is active and ongoing. CBD is not a treatment or cure, and the field is still establishing therapeutic windows and optimal dosing. But the mechanistic case is scientifically grounded: CBD appears to support ECS function by protecting anandamide from premature degradation and modulating the stress-response pathways that chronic stress disrupts.

Other Ways to Actively Support Your ECS

Exercise is the most reliably documented intervention for raising endocannabinoid tone. A 2024 study in Sports (University of Graz) measured endocannabinoid levels in participants before and after a 60-minute outdoor run and confirmed significant increases in both anandamide and 2-AG, with mood improvements correlating directly with those elevations. Beyond running, research also supports yoga, meditation, heat and cold therapy, healthy social interaction, and dietary omega-3 fatty acids as meaningful inputs to ECS function.

The Bigger Picture

We are, as Harvard Health has noted, at the dawn of an age of discovery of the ECS. What's becoming clear is that this system is not a passive background process. It is a dynamic, responsive network that your lifestyle either supports or erodes. Chronic stress taxes it. Certain substances deplete it. Exercise reliably restores it. And emerging research on CBD offers a mechanistically coherent rationale for its potential role in supporting the same system.

The Runner's High isn't just a reward for effort. It's a window into one of the most important regulatory systems in the human body, and a reminder that the body's capacity for balance is something we actively participate in, every day. So the next time (or first time) you exercise intensely enough to experience a Runner's High, you can thank your ECS for rewarding your efforts with happy feelings.

Sources and Research

Runner's High & Exercise

Siebers M, Biedermann SV, Fuss J. "Exercise-Induced Euphoria and Anxiolysis Do Not Depend on Endogenous Opioids in Humans." Psychoneuroendocrinology. 2021. PMID: 33582575. pubmed.ncbi.nlm.nih.gov/33582575
Siebers M, Biedermann SV, Fuss J. "Do Endocannabinoids Cause the Runner's High? Evidence and Open Questions." The Neuroscientist. 2023. PMID: 35081831. pubmed.ncbi.nlm.nih.gov/35081831
University of Graz. "Investigating Runner's High: Changes in Mood and Endocannabinoid Concentrations after a 60 min Outdoor Run." Sports. 2024. mdpi.com/2075-4663/12/9/232
Fuss J, et al. "A Runner's High Depends on Cannabinoid Receptors in Mice." PNAS. 2015. pubmed.ncbi.nlm.nih.gov/26438875
Desai S, et al. "A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System." Cannabis and Cannabinoid Research. 2022. pmc.ncbi.nlm.nih.gov/articles/PMC9418357

Johns Hopkins & Harvard

Stress & the ECS

Morena M, et al. "Neurobiological Interactions Between Stress and the Endocannabinoid System." Neuropsychopharmacology. 2016. PMID: 26068727.
Lookfong NA, et al. "Potential Utility of Cannabidiol in Stress-Related Disorders." Cannabis and Cannabinoid Research. 2023. pubmed.ncbi.nlm.nih.gov/36409719
Hill MN, et al. "Central Anandamide Deficiency Predicts Stress-Induced Anxiety." PubMed. 2014. PMID: 25004388.

Alcohol & the ECS

Sloan ME, et al. "The Effects of Acute Alcohol Administration on Circulating Endocannabinoid Levels in Humans." 2022. PMID: 36001429. pubmed.ncbi.nlm.nih.gov/36001429
Pava MJ, Woodward JJ. "A Review of the Interactions Between Alcohol and the Endocannabinoid System." Alcohol. 2012. PMID: 22459871. pubmed.ncbi.nlm.nih.gov/22459871
Basavarajappa BS. "Interactions Between Alcohol and the Endocannabinoid System." 2020. PMID: 32056226.

CBD & the ECS

Hua DYH, et al. "Effects of Cannabidiol on Anandamide Levels." Translational Psychiatry. 2023. pmc.ncbi.nlm.nih.gov/articles/PMC10121552
Mejia-Mejia et al. "Therapeutic Potential of Cannabidiol in Anxiety Disorders: A Systematic Review and Meta-Analysis." PubMed. 2024. PMID: 38924898.
Lookfong NA, et al. "Potential Utility of Cannabidiol in Stress-Related Disorders." Cannabis and Cannabinoid Research. 2023.