Smokers are more likely to have restless legs syndrome than non-smokers, according to a meta-analysis of 30 studies covering 364,744 people. But when the same researchers used a genetic technique designed to test cause and effect, that link disappeared — suggesting cigarettes themselves may not be to blame after all.
The study, published in the Journal of Global Health, pooled data from 108,678 smokers and 256,066 non-smokers across three decades of observational research, then layered on a Mendelian randomization analysis to probe whether the association reflected a true causal effect or something else entirely.
A Real Association, an Uncertain Cause
Restless legs syndrome (RLS) causes an uncomfortable, often irresistible urge to move the legs, typically worsening in the evening and interfering with sleep. It affects an estimated 3% to 10% of adults in Western populations, and researchers have long debated why smokers seem to report it more often than nonsmokers.
The meta-analysis confirmed the pattern: pooling results across the 30 included studies, smoking was associated with meaningfully higher odds of having RLS. That part of the analysis lines up with decades of smaller studies that hinted at a smoking-RLS connection, often attributed to nicotine's effects on dopamine signaling — the same neurotransmitter system implicated in RLS itself.
The twist came from the Mendelian randomization component. This method uses genetic variants known to influence smoking behavior as stand-ins, or "instruments," for lifetime smoking exposure. Because genetic variants are assigned randomly at conception, largely independent of lifestyle or environment, the technique sidesteps the confounding that plagues typical observational research — the tendency of smokers to also differ from nonsmokers in stress levels, sleep habits, alcohol use, socioeconomic status, and dozens of other RLS-relevant factors. When the researchers applied this genetic approach, they found no evidence that smoking causally increases RLS risk.
Why a Real-World Link Might Not Be Causal
The gap between the two findings points toward confounding rather than direct biological cause. People who smoke are statistically more likely to also experience chronic stress, poorer sleep quality, iron deficiency, and other conditions independently linked to RLS. Any of these shared risk factors, rather than nicotine or tobacco smoke itself, could be driving the observational association.
It is also possible that people with undiagnosed RLS or other sleep disturbances are more likely to smoke in the first place, perhaps self-medicating restlessness or anxiety — a form of reverse causation that observational studies struggle to rule out but that genetic instruments are specifically designed to detect and exclude.
The authors note that Mendelian randomization has its own limitations, including the assumption that the genetic variants used as instruments affect RLS risk only through their effect on smoking. If any of those variants influence RLS through some other, unmeasured pathway, the null result could understate a true but smaller causal effect. Still, the divergence between the two analytic approaches is itself informative, and consistent with a growing pattern in sleep research where genetically informed methods overturn associations that looked solid in conventional cohort studies.
What This Means for Patients
For people with restless legs syndrome who smoke, this study is not a green light to keep smoking — tobacco use carries well-established risks to cardiovascular and pulmonary health regardless of its relationship to RLS. But it does suggest that quitting smoking alone may not resolve restless legs symptoms for everyone, and that clinicians should keep looking for other contributors, particularly iron deficiency, which remains one of the most treatable and evidence-backed causes of RLS.
The findings also illustrate why patients should be cautious about single studies claiming a lifestyle factor "causes" a sleep disorder. Observational associations, even large and consistent ones, can reflect shared risk factors rather than direct cause and effect. Discussing the full picture — sleep habits, iron status, medications, and other chronic conditions — with a sleep specialist remains the most reliable path to identifying what is actually driving an individual's symptoms.
