In most cases, yes, naltrexone can be taken alongside common antidepressants like SSRIs and SNRIs. In fact, one FDA-approved medication (Contrave) deliberately combines naltrexone with the antidepressant bupropion. That said, the combination isn’t completely free of considerations. Naltrexone can affect how your liver processes certain antidepressants, and one class of antidepressants, MAO inhibitors, is a hard contraindication when paired with naltrexone-containing medications.
Why These Medications Are Often Prescribed Together
Naltrexone is primarily used to treat alcohol use disorder and opioid dependence by blocking opioid receptors in the brain. Since depression frequently coexists with substance use disorders, many people taking naltrexone are also on an antidepressant. The two medications work through different brain systems, which is why they can generally coexist without directly interfering with each other.
There’s also growing clinical interest in using low-dose naltrexone (typically 1 to 5 mg, far below the standard 50 mg dose) as an add-on for people whose depression hasn’t fully responded to antidepressants alone. A small randomized trial of 12 adults with major depressive disorder found that adding 1 mg of naltrexone twice daily to existing antidepressant regimens produced meaningful improvements in depression scores over three weeks compared to placebo. The results were statistically significant on some measures, though the study was small and designed as a proof-of-concept. Larger trials are still needed to confirm the effect.
The FDA-Approved Combination: Naltrexone Plus Bupropion
The clearest evidence that naltrexone and an antidepressant can work together safely comes from Contrave, approved by the FDA in 2014 for chronic weight management. It combines 32 mg of naltrexone with 360 mg of bupropion daily (at the full maintenance dose), and went through the full safety review process required for FDA approval. This combination is specifically indicated for adults with a BMI of 30 or higher, or 27 or higher with weight-related health conditions. The dose is gradually increased over three weeks to reduce side effects, starting with one tablet per day and building to two tablets twice daily.
Bupropion is notable here because unlike many other antidepressants, it doesn’t increase the sedative effects of alcohol or cause the psychomotor impairment seen with SSRIs or tricyclic antidepressants. Reports of serious neuropsychiatric side effects when bupropion is combined with naltrexone are very rare.
How Naltrexone Affects Liver Metabolism
One area that deserves attention is how naltrexone interacts with your liver’s drug-processing enzymes. A study using human liver tissue found that naltrexone significantly inhibits three key enzymes responsible for metabolizing many common medications: CYP3A4 (inhibited by about 38%), CYP2C9 (inhibited by about 37%), and CYP2D6 (inhibited by about 32%). CYP2C9 and CYP2D6 were particularly sensitive, showing reduced activity even at very low concentrations of naltrexone.
This matters because many antidepressants rely on these same enzymes to be broken down and cleared from your body. Several SSRIs and SNRIs are metabolized through CYP2D6, and tricyclic antidepressants depend heavily on both CYP2D6 and CYP2C9. When naltrexone slows these enzymes down, antidepressant levels in your bloodstream could rise higher than expected. In practice, this doesn’t mean the combination is unsafe, but it does mean your prescriber may need to monitor you more closely or adjust doses, especially if you’re on a tricyclic antidepressant or an SSRI that relies heavily on CYP2D6 processing.
The One Clear Contraindication: MAO Inhibitors
The one antidepressant class that should not be combined with naltrexone-containing medications is monoamine oxidase inhibitors (MAOIs). This includes older antidepressants like phenelzine and tranylcypromine. The risk is a potentially dangerous reaction involving confusion, agitation, extremely high blood pressure, high body temperature, and severe seizures.
If you’re switching between an MAOI and a naltrexone-containing medication in either direction, a minimum 14-day washout period is required. This means stopping one medication completely and waiting two full weeks before starting the other.
Serotonin Syndrome Risk
Serotonin syndrome occurs when too much serotonin accumulates in the brain, causing symptoms that range from mild (shivering, diarrhea) to life-threatening (high fever, seizures, irregular heartbeat). The FDA has flagged this as a risk when opioid-related medications are taken with serotonergic drugs like SSRIs, SNRIs, and certain migraine medications. Naltrexone appeared in the FDA’s adverse event database in connection with serotonin syndrome cases, though it was listed among many opioid-related drugs and the reports involved patients on multiple serotonergic medications simultaneously.
The practical risk of serotonin syndrome from naltrexone specifically is considered low because naltrexone blocks opioid receptors rather than activating them. Still, symptoms to watch for include restlessness, rapid heartbeat, muscle twitching, loss of coordination, and fever, particularly in the first days after starting a new medication or changing a dose.
What the Combination Feels Like Day to Day
When people take naltrexone alongside an antidepressant, the most commonly reported side effects overlap with what each drug causes individually: nausea, headache, dizziness, and trouble sleeping. Nausea tends to be more pronounced in the first week or two and often fades as your body adjusts. Starting at a lower naltrexone dose and increasing gradually, as the Contrave dosing schedule does, helps reduce early side effects.
One subtler effect worth knowing about: naltrexone blocks the brain’s natural opioid system, which plays a role in the feeling of reward and pleasure. Research has shown that naltrexone can partially blunt the mood-lifting effects of placebo treatments by blocking opioid signaling in brain regions involved in predicting positive outcomes. For some people, this translates to a sense of emotional flatness or reduced ability to feel pleasure, particularly in the early weeks. If your antidepressant was working well and you notice this shift after adding naltrexone, it’s worth discussing with your prescriber rather than assuming the antidepressant stopped working.
Practical Considerations
If you’re already on an antidepressant and considering naltrexone (or vice versa), a few things are worth keeping in mind. First, the type of antidepressant matters. SSRIs, SNRIs, and bupropion are the most commonly combined with naltrexone in clinical practice, and the safety profile for these combinations is the most well-documented. Tricyclic antidepressants require more caution because of the liver enzyme overlap and because they can worsen alcohol-related sedation. MAOIs are off the table entirely.
Second, the dose of naltrexone matters. Standard-dose naltrexone (50 mg daily for alcohol dependence) and low-dose naltrexone (1 to 5 mg) have different profiles. The liver enzyme inhibition data was measured at concentrations relevant to the standard dose, so low-dose naltrexone likely produces smaller metabolic effects, though specific interaction studies at low doses are limited.
Third, if you’re taking naltrexone for alcohol or opioid dependence while also managing depression, both conditions need active treatment. Untreated depression is one of the strongest predictors of relapse in substance use disorders, so the question isn’t really whether to combine these medications but how to do it safely, with appropriate monitoring and dose adjustments as needed.