Metaxalone Side Effects: What to Expect and When to Call Your Doctor

Metaxalone (Skelaxin) is generally considered one of the better-tolerated muscle relaxants available — it's often cited as the least sedating option in its class. But like all medications, it carries side effect risks you should understand before starting treatment. This guide covers what most patients experience, what's rare but serious, and when to pick up the phone and call your doctor.

Common Side Effects of Metaxalone

The most frequently reported side effects of Metaxalone are related to its central nervous system (CNS) depressant effects. These are generally mild and tend to be dose-dependent:

• Drowsiness. The most common complaint. Even though Metaxalone causes less sedation than cyclobenzaprine, drowsiness is still possible — especially if you take it with food or with other CNS depressants.
• Dizziness. Can occur, particularly when standing up quickly (orthostatic hypotension). Avoid activities requiring balance and coordination until you know how Metaxalone affects you.
• Headache. Reported in some patients, typically mild.
• Nervousness or irritability. Some patients report feeling anxious or on edge, particularly early in treatment.
• Nausea. Stomach upset and nausea are common, particularly when the medication is first started. Taking it with food may help — but note that food also increases absorption and can intensify CNS effects.
• Vomiting and GI upset. Related to the nausea; usually resolves once the body adjusts to the medication.

The Food Effect: Why What You Eat Matters

One of Metaxalone's quirks is that taking it with food significantly increases how much of the drug your body absorbs. This means a dose taken with a full meal delivers more metaxalone to your bloodstream than the same dose taken on an empty stomach. The result: taking Metaxalone with food can enhance CNS depression, making you more drowsy or dizzy than expected.

The key advice from prescribers: be consistent. If you start taking it with food, continue taking it with food. If you take it on an empty stomach, keep doing that. Switching back and forth can cause unpredictable changes in the medication's effect.

Serious Side Effects: When to Call Your Doctor Immediately

While rare, certain serious side effects can occur with Metaxalone. Know these warning signs:

Serotonin Syndrome

This is the most important serious risk with Metaxalone. Serotonin syndrome is a potentially life-threatening condition that can occur when Metaxalone is taken with other medications that increase serotonin levels — such as SSRIs (like fluoxetine or sertraline), SNRIs, TCAs, triptans, MAO inhibitors, tramadol, or fentanyl.

Seek emergency care immediately if you experience:

• Agitation, hallucinations, or confusion
• Fast or irregular heartbeat
• High fever, excessive sweating
• Muscle stiffness, twitching, or loss of coordination
• Nausea, vomiting, or diarrhea appearing suddenly after starting Metaxalone with another medication

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CNS Depression and Respiratory Depression

Taking Metaxalone with other CNS depressants — including alcohol, benzodiazepines (like Xanax or Valium), opioid pain medications, or sleep aids — can intensify CNS depression. In severe cases, this can cause respiratory depression (dangerously slow or shallow breathing). Never mix Metaxalone with alcohol or other sedating medications without your doctor's explicit guidance.

Severe Allergic Reaction (Anaphylaxis)

Anaphylactoid reactions have been reported with Metaxalone. Symptoms include rash, itching, swelling of the lips, face, or tongue, and difficulty breathing. If you experience these symptoms, stop taking the medication and seek emergency help immediately.

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Liver Effects (Rare)

Jaundice (yellowing of the skin or eyes) has been reported rarely with Metaxalone. This is why Metaxalone is contraindicated in patients with severe liver disease and why periodic liver function monitoring is recommended for patients with existing liver conditions. If you notice yellowing of your skin or eyes, or very dark urine, contact your doctor promptly.

Special Populations: Extra Caution Needed

• Elderly patients are especially susceptible to CNS effects from Metaxalone. Use with caution and consider starting at a lower dose if your doctor agrees.
• Patients with liver or kidney disease should not take Metaxalone if their condition is severe. Mild-to-moderate impairment requires caution and monitoring.
• Patients with anemia (especially hemolytic anemia) should not take Metaxalone. Inform your doctor of any history of anemia.

Practical Safety Tips

• Don't drive or operate heavy machinery until you know how Metaxalone affects you
• Avoid alcohol while taking Metaxalone — it intensifies CNS depression
• Be consistent about taking it with or without food to avoid unpredictable dosing effects
• Tell all of your healthcare providers (including dentists) that you're taking Metaxalone
• Report any unusual lab results to your doctor — Metaxalone can cause a false-positive Benedict's test (a urine glucose test); use a glucose-specific test instead

Bottom Line

Most patients tolerate Metaxalone well. Common side effects like drowsiness and nausea are manageable, and Metaxalone's low sedation profile makes it a popular choice for active patients. The most important safety concern is serotonin syndrome risk when combined with other serotonergic drugs. For a complete list of drug interactions to watch out for, see our companion guide: Metaxalone Drug Interactions: What to Avoid.