Can buspirone (Buspar) cause restless‑leg syndrome, and what is the recommended evaluation and management for a patient who develops restless‑leg symptoms while taking it?

Buspirone and Restless Legs Syndrome

Buspirone (Buspar) can cause restless leg syndrome, though this is a rare adverse effect documented in postmarketing surveillance. If a patient develops restless leg symptoms while taking buspirone, discontinue the medication immediately and initiate appropriate RLS treatment based on the 2025 AASM guidelines.

Evidence for Buspirone-Induced RLS

The FDA drug label for buspirone explicitly lists restless leg syndrome as a rare postmarketing adverse event 1. Additionally, the label describes a "syndrome of restlessness appearing shortly after initiation of treatment" that may represent akathisia related to buspirone's dopaminergic effects 1. This mechanism is biologically plausible since buspirone binds to central dopamine receptors, and dopaminergic dysfunction is implicated in RLS pathophysiology.

Key Clinical Distinction

It's critical to differentiate between:

• True RLS: Urge to move legs at rest, worse in evening/night, relieved by movement
• Drug-induced akathisia: Inner restlessness that occurs shortly after drug initiation, not necessarily confined to legs or evening hours

Both can occur with buspirone, but the temporal relationship (onset after starting buspirone) and resolution after discontinuation strongly suggest drug causation.

Immediate Management Algorithm

Step 1: Confirm RLS Diagnosis

• Verify the four essential diagnostic criteria: urge to move legs, worsening at rest, relief with movement, circadian pattern (worse evening/night)
• Rule out RLS mimics: neuropathy, nocturnal leg cramps, positional discomfort, akathisia 2

Step 2: Discontinue Buspirone

• Stop buspirone immediately – this is the definitive treatment for drug-induced RLS 3
• Monitor for symptom resolution over 1-2 weeks
• If anxiety symptoms require ongoing treatment, select an alternative anxiolytic that does not exacerbate RLS

Step 3: Check Iron Status

While awaiting buspirone washout, obtain:

• Serum ferritin (target >75 ng/mL for RLS patients)
• Transferrin saturation (target >20%)

This is essential because iron deficiency commonly coexists with or exacerbates RLS 2.

Treatment if RLS Persists After Buspirone Discontinuation

If symptoms continue beyond 2-3 weeks after stopping buspirone, treat as primary RLS:

First-Line Options (Strong Recommendations)

For patients with low iron stores:

• IV ferric carboxymaltose if ferritin <75 ng/mL and transferrin saturation <20% 2
• This addresses a fundamental pathophysiologic mechanism

For symptomatic pharmacologic treatment:

• Gabapentin 300-1800 mg/day (strong recommendation, moderate certainty) 2
• Pregabalin 150-450 mg/day (strong recommendation, moderate certainty) 2
• Gabapentin enacarbil 600-1200 mg/day (strong recommendation, moderate certainty) 2

These alpha-2-delta ligands are now preferred over dopamine agonists as first-line therapy because they avoid the risk of augmentation (worsening of RLS symptoms with long-term dopaminergic treatment).

Second-Line Options

If alpha-2-delta ligands are ineffective or not tolerated:

• Oral ferrous sulfate if iron stores are suboptimal 2
• Extended-release oxycodone or other opioids (conditional recommendation) 2

Avoid Dopamine Agonists as Standard Treatment

The 2025 AASM guidelines suggest against standard use of pramipexole, ropinirole, and rotigotine due to augmentation risk with long-term use 2. These may only be considered for short-term use in patients who prioritize immediate symptom relief over long-term adverse effects 2.

Important Caveats

Antidepressant considerations: If the patient requires ongoing psychiatric treatment, be aware that:

• Most antidepressants do NOT reliably cause or worsen RLS despite common clinical belief 4
• Mirtazapine may be associated with higher RLS rates 5
• Bupropion may actually reduce RLS symptoms 2, 5 and is specifically mentioned in AASM guidelines as ineffective for treating RLS but not as causing it
• Sertraline, fluoxetine, and trazodone appear relatively safe 5

Buspirone-specific mechanism: The restlessness syndrome with buspirone may reflect either increased noradrenergic activity or dopaminergic effects (akathisia) 1. This dual mechanism explains why some patients experience restlessness that doesn't fully meet RLS criteria.

Timeline expectations: Drug-induced RLS typically resolves within days to weeks after discontinuing the offending agent 3. If symptoms persist beyond 3-4 weeks, consider that buspirone may have unmasked underlying primary RLS rather than causing it de novo.