Do bupropion (Wellbutrin) and buspirone (Buspar) cause restless legs syndrome?

Does Wellbutrin (Bupropion) or Buspar (Buspirone) Cause Restless Legs Syndrome?

Bupropion (Wellbutrin) does not cause RLS and may actually improve symptoms, while buspirone (Buspar) has been reported to cause RLS in rare postmarketing cases.

Bupropion (Wellbutrin) and RLS

Evidence Against Causation

• The 2025 AASM guidelines specifically recommend against using bupropion for RLS treatment, but this recommendation is based on lack of efficacy data rather than evidence of harm or causation. 1
• Bupropion is notably absent from lists of medications that exacerbate or induce RLS in major guidelines, unlike serotonergic antidepressants which are consistently flagged as problematic. 2

Evidence of Potential Benefit

• A randomized controlled trial demonstrated that bupropion 150 mg daily significantly improved RLS symptoms compared to placebo at 3 weeks (10.8-point vs 6.0-point reduction in IRLS scores, p=0.016). 3
• A head-to-head trial comparing bupropion 300 mg daily to ropinirole and iron showed that bupropion reduced RLS severity, though less effectively than ropinirole. 4
• Multiple case reports document complete resolution of RLS symptoms within days of starting bupropion, including cases where RLS was induced by other antidepressants. 5, 6
• A systematic review concluded that "bupropion may reduce restless legs syndrome symptoms, at least in the short term." 7

Mechanism

• Bupropion's dopamine and norepinephrine reuptake inhibition likely explains its beneficial effect, as it enhances dopaminergic transmission—the opposite mechanism of RLS-inducing medications. 8

Clinical Recommendation for Bupropion

• Bupropion is an excellent choice when an antidepressant is needed in patients with existing RLS, as it does not worsen symptoms and may provide therapeutic benefit. 3, 8

Buspirone (Buspar) and RLS

Evidence of Causation

• The FDA label for buspirone explicitly lists "restless leg syndrome" and "akathisia" as adverse events reported in postmarketing surveillance. 9
• The label notes that "a syndrome of restlessness, appearing shortly after initiation of treatment, has been reported in some small fraction of buspirone-treated patients," which may represent akathisia or dopaminergic effects. 9

Mechanism

• Buspirone binds to central dopamine receptors, and the FDA label raises concerns about its potential to cause "acute and chronic changes in dopamine-mediated neurological function" including akathisia, which can mimic or trigger RLS. 9
• The restlessness syndrome associated with buspirone may be attributable to dopaminergic effects or increased central noradrenergic activity. 9

Clinical Recommendation for Buspirone

• While RLS with buspirone is rare, clinicians should monitor for new-onset restlessness or leg discomfort when initiating therapy, particularly in patients with RLS risk factors. 9
• If RLS symptoms emerge after starting buspirone, consider discontinuation or switching to an alternative anxiolytic. 2

Key Clinical Pitfalls

• Do not confuse akathisia with RLS—both cause restlessness, but akathisia is a generalized motor restlessness without the circadian pattern or sensory component characteristic of RLS. 9
• When evaluating new RLS symptoms in patients on psychiatric medications, systematically review all agents: serotonergic antidepressants (SSRIs, SNRIs), dopamine antagonists (antipsychotics, metoclopramide), and antihistamines are far more common culprits than bupropion or buspirone. 2, 10
• If a patient with depression and RLS requires antidepressant therapy, bupropion should be strongly preferred over serotonergic agents. 3, 8