Mirtazapine is not an MAOI. It belongs to a completely different class of antidepressants called NaSSAs (noradrenergic and specific serotonergic agents). The distinction matters because mirtazapine and MAOIs work through unrelated mechanisms, and combining them is dangerous.
How Mirtazapine Actually Works
Mirtazapine, sold under the brand name Remeron, increases levels of both serotonin and norepinephrine in the brain, but it does so in an unusual way. Rather than blocking the reabsorption of these chemicals (like SSRIs or SNRIs do), mirtazapine blocks a specific type of receptor called the alpha-2 adrenergic receptor. These receptors normally act as a brake on the release of serotonin and norepinephrine. By blocking that brake, mirtazapine allows more of both chemicals to flow.
It also directly affects several serotonin receptor subtypes, which contributes to its antidepressant effect and explains some of its side effect profile, including sedation and appetite stimulation. Under newer classification systems, it’s formally categorized as a “serotonin, norepinephrine receptor antagonist.”
How MAOIs Work Differently
MAOIs take an entirely different approach. Monoamine oxidase is an enzyme that breaks down serotonin, norepinephrine, and dopamine after they’ve been used. MAOIs block that enzyme, so these brain chemicals stick around longer and accumulate to higher levels. It’s the difference between opening the faucet wider (what mirtazapine does) and plugging the drain (what MAOIs do).
Only four MAOIs are currently available in the United States:
- Isocarboxazid (Marplan), approved for major depressive disorder
- Phenelzine (Nardil), approved for treatment-resistant depression, panic disorder, and social anxiety disorder
- Tranylcypromine (Parnate), approved for major depressive disorder
- Selegiline (Emsam), approved for major depressive disorder and as an add-on treatment for Parkinson’s disease
Mirtazapine is not on this list and does not inhibit monoamine oxidase.
Why the Two Should Never Be Combined
Even though mirtazapine isn’t an MAOI, combining the two is explicitly contraindicated by the FDA. The reason is serotonin syndrome, a potentially life-threatening reaction that occurs when too much serotonin builds up in the nervous system. MAOIs prevent serotonin from being broken down while mirtazapine boosts serotonin release. Together, the effect can push serotonin to dangerous levels.
Serotonin syndrome typically produces three clusters of symptoms: mental status changes (agitation, confusion, anxiety), autonomic instability (rapid heart rate, sweating, high blood pressure, vomiting, diarrhea), and neuromuscular problems (muscle rigidity, tremor, exaggerated reflexes). In severe cases, body temperature can spike above 106°F, and complications can include seizures, kidney failure, and respiratory failure. The combination of an MAOI with a serotonergic drug like mirtazapine carries the highest risk for the most severe form of this reaction.
The 14-Day Washout Rule
If you’re switching between mirtazapine and an MAOI in either direction, the FDA requires a minimum gap of 14 days. That means at least 14 days must pass after stopping an MAOI before starting mirtazapine, and at least 14 days must pass after stopping mirtazapine before starting an MAOI. This waiting period gives your body enough time to fully clear the first medication so the two drugs never overlap in your system.
This rule also applies to less obvious MAOIs. The antibiotic linezolid and intravenous methylene blue (a dye sometimes used in medical procedures) both have MAOI activity and carry the same interaction risk with mirtazapine.
Where the Confusion Comes From
The question likely comes up because mirtazapine, like MAOIs, increases serotonin and norepinephrine activity. Both drug classes treat depression, and both carry warnings about serotonin syndrome. From the outside, that can make them look related. But the mechanism is fundamentally different. MAOIs stop the breakdown of brain chemicals. Mirtazapine blocks receptors that regulate their release. They arrive at a loosely similar destination through completely different routes, and that’s precisely why stacking them is so dangerous: two independent systems both pushing serotonin levels higher at the same time.