Exercise triggers the release of dozens of chemicals from your brain, muscles, bones, blood vessels, and fat tissue. The list extends far beyond the familiar “endorphins” you may have heard about. Endocannabinoids, stress hormones, signaling proteins called myokines, nitric oxide, growth factors, and even lactate all surge during physical activity, each with distinct roles in how you feel, recover, and adapt over time. The picture researchers have assembled over the past two decades is considerably more complex than a simple “feel-good chemical” story.
The Runner’s High Is Driven by Endocannabinoids, Not Endorphins
For decades, endorphins got all the credit for the euphoria some people feel during sustained exercise. Your body does release beta-endorphin, ACTH, and cortisol during workouts, and the response scales with both intensity and duration.1PubMed. Effects of low- and high-intensity exercise on plasma and cerebrospinal fluid levels of ir-beta-endorphin, ACTH, cortisol, norepinephrine and glucose in the conscious dog But the euphoria itself appears to depend on a different system. In a double-blind study, 63 recreationally active people either ran for 45 minutes at moderate-to-vigorous intensity or walked at low intensity. Half received the opioid blocker naltrexone, which shuts down endorphin signaling, while the other half received a placebo. Blocking opioids did nothing to dampen the euphoria or anxiety reduction that followed running. Meanwhile, blood levels of two endocannabinoids, anandamide and 2-AG, roughly doubled after the run and tracked closely with the mood boost.2PubMed. Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans Endocannabinoids are lipid-based molecules your body produces that bind to many of the same receptors as THC in cannabis. They cross the blood-brain barrier easily, which endorphins largely cannot, making them a far more plausible explanation for why running can feel almost intoxicating.3PubMed Central. Do Endocannabinoids Cause the Runner’s High? Evidence and Open Questions
Endorphins still matter. They contribute to pain modulation during intense effort and play a role in post-exercise well-being more broadly. Exercise also increases the production of endorphins linked to positive mood, and regular physical activity can lower levels of pro-inflammatory cytokines that contribute to depressive symptoms.4PubMed Central. The impact of exercise on depression: how moving makes your brain and body feel better But the classic “endorphin rush” narrative overstates one molecule’s role in what turns out to be a multi-chemical experience.
BDNF and Brain Growth
Brain-derived neurotrophic factor, or BDNF, is a protein that supports the survival of existing neurons and encourages the growth of new ones, particularly in the hippocampus, the brain region involved in learning and memory. Exercise reliably raises it. In mice allowed to run voluntarily for four weeks, hippocampal BDNF protein levels rose significantly compared to sedentary controls.5PubMed Central. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate In humans, a single bout of exercise increased circulating BDNF by about a third on average, and the biggest bump came from vigorous effort sustained for around 40 minutes.6PubMed Central. The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men
BDNF is sometimes called “fertilizer for the brain” in pop-science writing, and that metaphor is roughly accurate. Higher BDNF levels are associated with better cognitive performance, and the exercise-to-BDNF-to-cognition pathway is one of the best-supported explanations for why active people tend to retain sharper memory as they age.
Cortisol and the Stress Hormone Paradox
Cortisol has a bad reputation as “the stress hormone,” so people are sometimes surprised to learn that exercise raises it. But the size and direction of the response depend heavily on intensity. Low-intensity exercise, once you correct for normal daily fluctuations, actually lowers circulating cortisol. Moderate intensity (around 60% of capacity) increases cortisol by roughly 40%, and high intensity (around 80%) raises it by about 83%.7PubMed. Exercise and circulating cortisol levels: the intensity threshold effect
Here is the paradox: that temporary cortisol spike from hard exercise appears to dampen your cortisol response to real-world stressors afterward. In a study where participants exercised at varying intensities and then faced a psychosocial stress task, the cortisol released during exercise was inversely proportional to the cortisol released during the stressor. The harder you exercised, the calmer your stress response was afterward.8PubMed. The effects of exercise intensity on the cortisol response to a subsequent acute psychosocial stressor So the acute cortisol elevation from a workout is not the same thing as chronic stress-driven cortisol. Think of it as a controlled rehearsal that makes your stress system less reactive when it counts.
Time of day adds another layer. The cortisol bump from exercising at midnight is larger than from exercising in the morning or evening, and a rebound suppression of cortisol appears only after that late-night session.9The Journal of Clinical Endocrinology & Metabolism. Cortisol and Growth Hormone Responses to Exercise at Different Times of Day Growth hormone response, by contrast, stays about the same regardless of when you work out.
Adrenaline, Noradrenaline, and Fat Mobilization
Your adrenal glands pump out epinephrine (adrenaline) and norepinephrine (noradrenaline) as soon as exercise begins. These catecholamines are responsible for the heart-pounding, alert feeling you get during a hard set or a sprint. They increase heart rate, redirect blood flow to muscles, and mobilize fuel from fat stores. In a study using graded epinephrine infusions during low-intensity cycling, progressively higher epinephrine concentrations drove progressively greater rates of fat breakdown, even when insulin was simultaneously rising.10PubMed. Effects of plasma epinephrine on fat metabolism during exercise: interactions with exercise intensity
Catecholamines also have a powerful effect on the immune system during exercise. Epinephrine and norepinephrine drive natural killer (NK) cells out of their reservoirs in the spleen and vascular walls and into the bloodstream. NK cells carry a dense set of receptors that respond to these molecules, and the mobilization tracks directly with exercise intensity. Early research showed that infusing epinephrine alone, without any exercise at all, could mimic the NK cell surge typically seen during a workout.11Trends in Molecular Medicine. Exercise and Natural Killer Cells: An Exercise-Induced Anti-Tumor Reflex This is one reason moderate exercise is associated with better immune surveillance, though the cells retreat from circulation within hours after exercise stops.
Myokines, the Chemical Messages from Muscles
Contracting muscles are not just burning fuel. They secrete hundreds of signaling proteins called myokines, making skeletal muscle one of the body’s largest endocrine organs. The most studied myokine is interleukin-6 (IL-6). During prolonged exercise, IL-6 rises dramatically in the bloodstream, and it is the most abundant myokine released by working muscles.12PubMed Central. Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism IL-6 from muscle behaves differently than IL-6 produced during infection or chronic inflammation. When it comes from exercising muscle, IL-6 stimulates the release of anti-inflammatory cytokines like IL-10 and suppresses the pro-inflammatory cytokine TNF-alpha.13PubMed. The anti-inflammatory effect of exercise It also helps regulate energy metabolism by promoting fat breakdown and glucose uptake in working tissues.14PubMed Central. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?
Another important myokine is irisin, which is cleaved from a protein on the surface of muscle cells during exercise. Irisin travels through the bloodstream to fat tissue, where it stimulates white fat cells to take on characteristics of brown fat cells, a process sometimes called “browning.” Brown fat burns calories to produce heat, so this conversion shifts the body’s energy balance toward greater calorie expenditure.15PubMed Central. Irisin: A Hope in Understanding and Managing Obesity and Metabolic Syndrome Researchers have suggested that irisin may have evolved from the shivering response, where muscle contraction also generates heat, and that the exercise-triggered version essentially co-opts that same pathway.16PubMed Central. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans
A meta-analysis of training studies found that both aerobic and resistance exercise change myokine levels, with no clear winner between the two modes. The size of the change varies across different myokines, though, so the type of exercise you do may shift the myokine profile without dramatically altering the total output.17PubMed Central. Exercise training mode effects on myokine expression in healthy adults: A systematic review with meta-analysis
Nitric Oxide and Blood Vessel Health
When you exercise, blood flows faster through your arteries, and the resulting shear stress on the vessel walls triggers endothelial cells to produce nitric oxide (NO). This gas molecule relaxes the smooth muscle around blood vessels, widening them and lowering blood pressure. The enzyme responsible converts the amino acid L-arginine into NO, which then signals the surrounding muscle cells to relax.18Pulse. Microvascular Function and Exercise Training: Functional Implication of Nitric Oxide Signaling and Ion Channels Regular exercise training amplifies this system by increasing the expression of the enzyme itself.19PubMed Central. Effects of exercise training on nitric oxide, blood pressure and antioxidant enzymes Nitric oxide release isn’t triggered only by shear stress; acetylcholine released at the neuromuscular junction during muscle contraction also contributes.20PubMed. Nitric oxide-mediated metabolic regulation during exercise: effects of training in health and cardiovascular disease
This is one of the main reasons exercise protects cardiovascular health over the long term. The more you exercise, the more efficient your blood vessels become at producing NO on demand, keeping arteries flexible and responsive.
Lactate as a Brain Signal
Lactate used to be dismissed as metabolic waste, the stuff that makes your muscles burn. That view has been overhauled. Lactate produced during exercise crosses into the brain, where it serves two roles. First, it provides direct fuel for neurons when their energy demands spike. Brain cells called astrocytes take up glucose and break it down into lactate, which is then shuttled to neighboring neurons for energy, a process that becomes especially important during intense neural activity.21PubMed Central. The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule
Second, lactate acts as a signaling molecule in its own right, binding to specific receptors and triggering gene expression involved in forming new blood vessels in the brain and strengthening synaptic connections. Researchers now view exercise-induced lactate as a key part of how physical activity reshapes brain function, not just a leftover from anaerobic metabolism.22PubMed Central. Lactate-induced metabolic signaling is the potential mechanism for reshaping the brain function – role of physical exercise
Signals from Bones and the Heart
Muscles are not the only tissue sending chemical messages during exercise. Bones release osteocalcin, a hormone whose circulating levels roughly double during aerobic exercise. Osteocalcin travels to muscle fibers and promotes their uptake of glucose and fatty acids, helping fuel continued effort. In older mice, giving exogenous osteocalcin restored exercise capacity to levels seen in young animals, suggesting it is central to maintaining physical fitness with age.23PubMed Central. Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise Osteocalcin levels plummet early in adulthood across mice, monkeys, and humans, which may partly explain why exercise capacity naturally declines with age.24Cell Metabolism. Mediating the Bone-Muscle Crosstalk in Exercise
The heart gets in on the action too. Atrial natriuretic peptide (ANP), a hormone produced by heart muscle when the atrial walls are stretched, rises during exercise. The dominant stimulus for ANP release is the increased blood volume returning to the heart during physical effort.25PubMed Central. Involvement of the atrial natriuretic peptide in cardiovascular pathophysiology and its relationship with exercise ANP promotes sodium excretion through the kidneys and lowers blood pressure, but it also stimulates fat breakdown. During repeated bouts of endurance exercise, ANP contributes to fat mobilization independently of the catecholamine pathway.26PubMed. Atrial natriuretic peptide stimulates lipid mobilization during repeated bouts of endurance exercise
Cathepsin B and the Muscle-to-Brain Highway
One of the more surprising discoveries in exercise science is that a protein originally known for its role in cellular cleanup, cathepsin B, acts as a muscle-to-brain messenger. Running increases cathepsin B secretion from muscle, and the protein enters the bloodstream and reaches the hippocampus. In humans, changes in cathepsin B levels correlated with both fitness and hippocampus-dependent memory.27PubMed Central. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function In mice, knocking down muscle-derived cathepsin B partially reversed the improvements in hippocampal neurogenesis and memory that treadmill running normally produces.28PubMed Central. Myokine Cathepsin B as a Key Muscle-Brain Axis Regulator Mediates Treadmill-Running-Induced Hippocampal Neurogenesis and Cognitive Improvement in Mice
Intriguingly, long-term exercise training in middle-aged men actually lowered resting cathepsin B and BDNF levels, with both inversely correlated with weekly exercise hours. The researchers interpreted this not as a loss of benefit but as a sign that well-trained bodies become more efficient in their signaling, requiring less baseline output to maintain cognitive gains.29PubMed Central. Long-term exercise training improves memory in middle-aged men and modulates peripheral levels of BDNF and Cathepsin B
VEGF and Building New Blood Vessels
Vascular endothelial growth factor (VEGF) is another exercise-responsive chemical that works on a longer time scale. Rather than producing an immediate mood or energy effect, VEGF drives the growth of new capillaries in muscle tissue, a process called angiogenesis. In trained mice, capillary density in deep muscle regions increased by about 59%, but this adaptation was completely absent in mice genetically engineered to lack VEGF in their muscle fibers.30PubMed Central. Myocyte vascular endothelial growth factor is required for exercise-induced skeletal muscle angiogenesis Without muscle-cell-produced VEGF, the improvements in running speed and endurance that normally accompany training were also blocked.31PubMed Central. Skeletal myofiber VEGF is essential for the exercise training response in adult mice This means the blood supply infrastructure your muscles build in response to regular training is directly dependent on this single growth factor.
Extracellular Vesicles, the Body’s Postal System
Beyond individual molecules floating freely in the bloodstream, exercise also increases the release of tiny membrane-enclosed packages called extracellular vesicles (EVs), especially exosomes. These are essentially parcels of cargo, containing small RNA molecules called microRNAs along with proteins and other bioactive material, that one tissue sends to another.32PubMed. Aerobic exercise training regulates serum extracellular vesicle miRNAs linked to obesity to promote their beneficial effects in mice Exercise-derived exosomes carry specific microRNAs that influence signaling pathways in bone, muscle, and fat tissue, coordinating metabolism and tissue remodeling across the body.33PubMed. Exercise-derived exosomes mediate crosstalk between skeletal muscle, adipose tissue, and bone: mechanisms of inter-organ communication and tissue adaptation The microRNA content of these vesicles varies depending on exercise type, frequency, and intensity.34PubMed Central. Exercise‑induced extracellular vesicle microRNA regulates physiological function
This is a relatively new area of research, but it is reshaping how scientists think about why exercise has such wide-ranging effects on organs that are not directly involved in physical movement. A workout in your legs may be sending molecular instructions to your liver, brain, and immune cells via these circulating packages.
Why Men and Women Release Different Chemical Profiles
The chemical response to exercise is not identical across sexes. A large genetic analysis found that while the raw expression levels of most myokines do not differ much between men and women, nearly all of the cross-tissue signaling effects of myokines operate in a sex-specific or hormone-dependent way, with estradiol playing a particularly prominent role.35PubMed Central. Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones
In practical terms, this means the same workout can produce different downstream effects depending on your hormonal environment. In adults with obesity, daily physical activity was an independent driver of certain myokine levels in women but not in men.36PubMed Central. Sex-specific associations between regular exercise habits and serum myokine levels in adults with obesity After a bout of high-intensity interval exercise, men showed greater upregulation of growth and repair mediators in muscle, while women showed broader suppression of inflammatory and chemotactic factors. Basally, women had higher levels of growth-associated cytokines and repair signals, while men started with higher levels of pro-inflammatory cytokines.37PubMed. Sex-specific cytokine and signaling responses to acute high-intensity interval exercise in recreationally active young adults These differences do not mean exercise is better for one sex. They mean the body uses different chemical strategies to achieve similar adaptations, and research that ignores sex may miss important variation in how people respond to training.