Restless legs syndrome (RLS) is driven by a combination of low iron stores in the brain, shifts in dopamine signaling, and genetic predisposition. About 5 to 10 percent of adults experience it, and the underlying cause varies from person to person. For some, it traces back to a single fixable trigger like low iron. For others, several factors stack together.
Your Brain’s Dopamine Drops at Night
The hallmark of RLS is that it gets worse in the evening and at night, and there’s a clear biological reason. Dopamine, the chemical messenger your brain uses to regulate movement and sensation, follows a daily cycle. Levels in the blood peak around 8 a.m. and gradually fall to about 60 percent of that peak between 8 and 10 p.m., hitting their lowest point around 3 a.m. When dopamine drops below a certain threshold, the sensory circuits in your spinal cord lose some of the “volume control” that normally keeps them quiet. The result is that crawling, pulling, or buzzing sensation in your legs that only movement relieves.
Brain imaging studies show that RLS involves more than one region. The thalamus, cerebellum, prefrontal cortex, and areas responsible for processing touch and sensation all show abnormal activity during symptom flares. The sensory cortex itself is measurably thinner in people with RLS, and the white matter pathways that carry sensory signals from the legs show progressive changes tied to how uncomfortable symptoms feel. In short, it’s not “in your head” in the dismissive sense. It’s a real wiring issue in how your brain processes signals from your legs.
Low Iron Is the Most Common Fixable Cause
Iron plays a critical role in dopamine production. When iron levels in the brain drop, dopamine signaling becomes unreliable, and RLS symptoms emerge or worsen. Imaging studies have found reduced iron concentrations in several deep brain structures in people with RLS, even when standard blood tests look normal.
The key number to know is your serum ferritin level. Ferritin measures your body’s iron stores, and RLS experts recommend a threshold of 75 µg/L or higher for people with restless legs. That’s significantly higher than the cutoff most labs flag as “low” (often around 12 to 30 µg/L), which means your doctor might tell you your iron is fine when it’s actually low enough to fuel RLS. If your ferritin is at or below 75 and your iron saturation is under 45 percent, oral iron supplementation taken with vitamin C on an empty stomach is the standard first step. Some people see a dramatic improvement within weeks.
Genetics Play a Major Role
If a parent or sibling has restless legs, your risk goes up substantially. Twin studies estimate that genetics account for 54 to 69 percent of the likelihood of developing RLS. Researchers have identified more than 20 genetic regions linked to the condition, with the strongest signals in genes called MEIS1 and BTBD9. Each of these variants contributes a small amount of risk on its own, but they add up. This explains why RLS often runs in families and why some people develop it without any obvious trigger like low iron or medication use.
Medications That Make It Worse
Several common medications can trigger or intensify restless legs, and many people don’t realize the connection. Antihistamines found in over-the-counter sleep aids (like diphenhydramine) are among the worst offenders. They block dopamine activity in ways that directly aggravate RLS. Melatonin supplements can also worsen symptoms despite being marketed for sleep.
Certain antidepressants, particularly mirtazapine and many SSRIs, are well-known RLS triggers. If your restless legs started or got noticeably worse after beginning a new antidepressant, that connection is worth discussing with your prescriber. Anti-nausea medications that block dopamine receptors can have the same effect.
Caffeine, Alcohol, and Nicotine
All three substances are linked to worse RLS symptoms. High caffeine intake from coffee, tea, cola, or chocolate can increase nervous system excitability in ways that amplify the sensory discomfort. Alcohol disrupts sleep architecture and may interfere with dopamine regulation. Nicotine is a stimulant that can worsen the restless sensation, particularly in the evening. For some people, cutting these out leads to a noticeable improvement on its own. For others, it takes the edge off enough to make other treatments work better.
Pregnancy Is a Common Trigger
About 26 percent of pregnant women develop RLS, making pregnancy one of the most common triggers. Symptoms follow a predictable pattern: they build steadily throughout pregnancy, peak during the seventh and eighth months, and then drop sharply around delivery. One month after giving birth, prevalence falls to about 7 percent, and it settles between 5 and 6 percent by six months postpartum. The likely culprits are the combination of falling iron stores (the baby takes a lot of iron), hormonal shifts, and the natural changes in blood circulation during the third trimester.
Other Medical Conditions Linked to RLS
RLS that appears alongside another health condition is called secondary RLS. The most well-established links include kidney disease (particularly in people on dialysis, where RLS rates can exceed 30 percent), peripheral neuropathy from diabetes or other causes, and anemia. In these cases, the restless legs are a downstream effect of the underlying condition. Treating the root cause, when possible, often improves or resolves the RLS.
Thyroid disorders and vitamin deficiencies beyond iron, particularly magnesium and folate, have also been associated with restless legs. If your symptoms appeared suddenly or worsened without an obvious explanation, a blood panel checking ferritin, iron saturation, thyroid function, and basic vitamin levels is a reasonable starting point.
Why It Only Happens When You’re Still
One of the most frustrating aspects of RLS is that symptoms appear specifically when you sit or lie down and vanish the moment you move. This pattern points to the spinal cord’s role. Normally, your brain sends inhibitory signals down to the spinal cord to quiet sensory input when you’re at rest. In RLS, that top-down suppression is weakened, likely because of the dopamine deficit. Your spinal cord essentially becomes “too loud,” amplifying normal sensory signals from your legs into uncomfortable sensations. Movement temporarily overrides this by flooding the sensory system with new input, which is why walking or stretching brings instant relief, even if it’s only temporary.
Altered blood flow also plays a part. Studies have found that people with RLS show unusual patterns of microcirculation in their leg muscles, with higher blood flow in the morning and lower flow in the evening, a pattern not seen in people without the condition. This reduced evening circulation may contribute to the discomfort that peaks right when you’re trying to fall asleep.