Your Brain Quits Before Your Muscles Do
You're deep into a grueling set of leg extensions. Your quads are burning, your heart rate is climbing, and every rep feels harder than the last. Most of us assume it's our muscles that give out first — depleted fuel, accumulated waste products, fibers that simply can't contract anymore. And that's partly true. But a growing body of research points to another culprit: your brain.
Central fatigue — exhaustion originating in the brain and spinal cord rather than the muscles themselves — plays a major role in determining when you hit the wall. Two brain chemicals sit at the heart of this process: dopamine (DA) and noradrenaline (NA), both members of a family called catecholamines. Previous research has established that both influence how long we can keep exercising, but their specific and separate roles have remained unclear — particularly during resistance exercise and across both sexes [1, 2].
A recent study published in the European Journal of Sport Science set out to untangle their distinct contributions, and the results challenge the assumption that feeling fatigued and being fatigued are the same thing [1].
The Study: Isolating Two Brain Chemicals
Researchers at Vrije Universiteit Brussel designed a triple-blinded randomized crossover study — the gold standard for minimizing bias — with eighteen healthy young adults (nine male, nine female). Each participant completed the same test three times on separate visits, performing dynamic leg extensions until complete exhaustion. The only difference between visits was which substance they took beforehand:
- Methylphenidate (MPH): a dopamine reuptake inhibitor, meaning it keeps dopamine active in the brain for longer. (It's worth noting that while MPH primarily targets dopamine, it can also indirectly influence noradrenaline levels in certain brain regions — these aren't perfectly clean manipulations.)
- Reboxetine (REB): a selective noradrenaline reuptake inhibitor that boosts noradrenaline signaling.
- Placebo: lactose tablets as the control.
The researchers tracked everything: how many reps each person completed, how hard they felt the exercise was, their mood, alertness, heart rate, blood lactate, and even the contractile properties of their muscles. This comprehensive approach allowed them to compare what was actually happening in the body against what participants believed was happening.
Dopamine: Boosts Your Mood, Not Your Reps
Participants who received MPH did not perform significantly more leg extensions — just a modest +3.1% increase that fell well short of statistical significance (p = 0.23). Their ratings of perceived exertion were unchanged too. In raw physical terms, elevated dopamine didn't make the muscles work harder or longer.
But the mental picture was strikingly different. With more dopamine circulating in their brains, participants felt more alert and less sleepy both before and after the task. They reported greater vigor and rated their own performance more favorably. After finishing, they perceived the task as less time-consuming and less mentally demanding overall.
Interestingly, despite feeling more alert and vigorous, participants on MPH actually reported higher fatigue on a separate mood scale (p = 0.032). This seemingly contradictory result — feeling simultaneously more energized and more fatigued — highlights just how multidimensional our experience of effort really is. Dopamine appears to boost the "I can do this" feeling while not erasing the body's fatigue signals entirely.
This makes sense given dopamine's known roles. It is deeply involved in maintaining wakefulness, assessing the value of effort, and shaping whether a task feels rewarding or punishing [3]. In effect, dopamine changed the experience of the exercise — making it feel more manageable — without changing the outcome.
Importantly, the researchers note that this result may be context-dependent. The leg extension task was repetitive and monotonous, with no reward or incentive built in. Previous studies have found that dopamine's performance-boosting effects become much more pronounced during prolonged endurance exercise in hot environments, where maintaining central drive and thermoregulation is critical [4, 5]. So dopamine may matter more for an athlete grinding through a marathon in the heat than for someone doing reps in a temperature-controlled gym.
Noradrenaline: Your Muscles Quit, But You Don't Notice
The noradrenaline results were the study's most striking finding. Compared to placebo, participants on REB performed 13.2% fewer leg extensions — a substantial and highly significant decline (p < 0.001). Yet remarkably, they didn't report feeling more fatigued, didn't rate the exercise as harder, and didn't perceive their performance as worse. Their mood was largely unchanged, aside from a modest increase in tension (p = 0.012).
REB also lowered participants' overall perceived task load (p = 0.049) and temporal demand (p < 0.001) — but this is likely a consequence rather than a benefit. Because participants reached exhaustion sooner, they simply spent less time exercising, making the task feel shorter. Meanwhile, their heart rates were significantly elevated (p < 0.001), reflecting genuine physiological strain under the surface.
So why does too much noradrenaline impair physical output? The mechanism behind this likely relates to what neuroscientists call the inverted-U model [6]. Both dopamine and noradrenaline follow a "Goldilocks" pattern in the brain's prefrontal cortex: too little impairs function, a moderate amount is optimal, and too much causes problems. With noradrenaline pushed beyond the optimal range by REB, the excess likely activated low-affinity receptors (called α1-adrenoceptors) that actually suppress neural firing and reduce the brain's drive to the muscles [1]. On top of this, REB's potent noradrenergic effects also ramp up the peripheral sympathetic nervous system — the body's "fight or flight" response — which may have further compromised the ability to sustain effort.
This finding is consistent with earlier research showing noradrenaline reuptake inhibition impairs both sustained isometric contractions [7] and endurance cycling performance [2]. But this study is the first to demonstrate the same effect during dynamic resistance exercise performed to exhaustion — a scenario that more closely mirrors real-world training.
What This Means for You
The headline takeaway is that fatigue isn't one thing — it's at least two. There's the fatigue you feel (perception, mood, motivation) and the fatigue your body has (actual muscle capacity, motor output). Dopamine shapes the former; noradrenaline shapes the latter. And critically, the two don't always match up.
This has real implications. If your internal sense of effort can become disconnected from your actual physical state, it means you could be pushing too hard without realizing it — or, conversely, quitting too early because the task feels unbearable even though your muscles have more to give. Understanding that brain chemistry mediates this gap is a step toward better fatigue management, though we're still a long way from translating this into practical interventions for everyday athletes.
A few caveats worth keeping in mind: this study tested eighteen young, recreationally active adults on a single, repetitive exercise in a controlled lab setting. The findings may not directly translate to trained athletes, complex multi-joint movements, or competitive sports environments. The drugs used are also pharmacological tools for research, not supplements or performance enhancers — this isn't a blueprint for boosting your next workout. And as the researchers acknowledge, dopamine and noradrenaline don't operate in isolation; other neurotransmitters like serotonin also play important roles in the broader fatigue picture [8].
Still, this study adds an important piece to the puzzle. The next time you're wondering whether to push through that last set or call it quits, remember: the decision isn't just happening in your muscles. It's happening in your brain chemistry — and the signals might not be telling you the whole truth.
References
- Arenales Arauz YL, Mali A, Lathouwers E, et al. "Distinct Roles of Dopamine and Noradrenaline in Physical Fatigue", European Journal of Sport Science 26 (2026) e70119. https://doi.org/10.1002/ejsc.70119
- Klass M, Roelands B, Lévénez M, et al. "Effects of Noradrenaline and Dopamine on Supraspinal Fatigue in Well-Trained Men", Medicine & Science in Sports & Exercise 44 (2012) 2299-2308. https://doi.org/10.1249/mss.0b013e318265f356
- Westbrook A, Braver TS. "Dopamine Does Double Duty in Motivating Cognitive Effort", Neuron 89 (2016) 695-710. https://doi.org/10.1016/j.neuron.2015.12.029
- Roelands B, Hasegawa H, Watson P, et al. "The Effects of Acute Dopamine Reuptake Inhibition on Performance", Medicine & Science in Sports & Exercise 40 (2008) 879-885. https://doi.org/10.1249/mss.0b013e3181659c4d
- Watson P, Hasegawa H, Roelands B, et al. "Acute Dopamine/Noradrenaline Reuptake Inhibition Enhances Human Exercise Performance in Warm, but Not Temperate Conditions", Journal of Physiology 565 (2005) 873-883. https://doi.org/10.1113/jphysiol.2004.079202
- Arnsten AFT. "Stress Signalling Pathways That Impair Prefrontal Cortex Structure and Function", Nature Reviews Neuroscience 10 (2009) 410-422. https://doi.org/10.1038/nrn2648
- Klass M, Duchateau J, Rabec S, Meeusen R, Roelands B. "Noradrenaline Reuptake Inhibition Impairs Cortical Output and Limits Endurance Time", Medicine & Science in Sports & Exercise 48 (2016) 1014-1023. https://doi.org/10.1249/mss.0000000000000879
- Meeusen R, Roelands B. "Fatigue: Is It All Neurochemistry?", European Journal of Sport Science 18 (2018) 37-46. https://doi.org/10.1080/17461391.2017.1296890