Is ketamine (ketamine hydrochloride) a recommended treatment for restless leg syndrome (RLS)?

Ketamine for Restless Legs Syndrome

Ketamine is not a recommended treatment for restless legs syndrome (RLS) and does not appear in any current evidence-based treatment guidelines. The most recent 2025 American Academy of Sleep Medicine clinical practice guideline makes no mention of ketamine as a treatment option for RLS 1.

Evidence-Based First-Line Treatment Recommendations

The current standard of care for RLS prioritizes:

• Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy for adults with RLS, with moderate certainty of evidence 2, 3.

• Iron supplementation should be assessed and addressed first in all patients with clinically significant RLS by checking morning fasting serum ferritin and transferrin saturation 2, 3.

  • IV ferric carboxymaltose is strongly recommended if ferritin ≤75 ng/mL or transferrin saturation <20% 2.
  • Oral ferrous sulfate is conditionally recommended for the same iron parameters 2.

Limited Evidence for Ketamine

While one narrative review from 2023 mentions ketamine as a "lesser known" glutamate NMDA receptor blocking agent that has been used for RLS 4, this represents only anecdotal or case-level evidence, not systematic evaluation. The review explicitly states it covers medications that are not widely accepted as evidence-based treatments for RLS 4.

The American Academy of Sleep Medicine specifically recommends against several medications for RLS including cabergoline (strong recommendation), bupropion, carbamazepine, clonazepam, and valproic acid 2. Ketamine falls into this category of medications lacking sufficient evidence for recommendation.

Appropriate Treatment Algorithm

For patients with moderate to severe RLS who fail first-line therapy:

• Extended-release oxycodone and other low-dose opioids (particularly methadone and buprenorphine) receive conditional recommendations for refractory cases 1.

  • These are particularly useful for treating dopamine agonist-related augmentation 1.
  • Long-term studies show relatively low risks of abuse and only small dose increases over 2-10 years 1.

• Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological alternative 1.

Critical Pitfall to Avoid

Dopamine agonists (pramipexole, ropinirole, rotigotine) are now recommended against for standard use due to the high risk of augmentation—a paradoxical worsening of symptoms with long-term use 1, 2, 3, 5. This represents a major shift from older treatment paradigms.