Sertraline is not a MAOI. It belongs to a completely different class of antidepressants called selective serotonin reuptake inhibitors, or SSRIs. The two drug classes work through distinct mechanisms, carry different side effect profiles, and should never be taken together.
How Sertraline Works
Sertraline blocks a protein called the serotonin transporter, which normally pulls serotonin back into nerve cells after it has been released. By blocking this recycling process, sertraline allows serotonin to stay active in the gaps between nerve cells for longer, strengthening its mood-regulating signals. This targeted approach is why the class is called “selective” serotonin reuptake inhibitors: it focuses primarily on serotonin rather than other brain chemicals.
Sertraline is FDA-approved to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, and premenstrual dysphoric disorder. It is sold under the brand name Zoloft.
How MAOIs Work Differently
MAOIs take a fundamentally different approach. Instead of blocking serotonin’s recycling, they block an enzyme called monoamine oxidase that breaks down three neurotransmitters: serotonin, norepinephrine, and dopamine. By stopping this enzyme from doing its job, MAOIs raise levels of all three chemicals in the brain at once. Common MAOIs include phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), and selegiline (Emsam).
This broader mechanism is one reason MAOIs come with more restrictions. People taking MAOIs must follow a low-tyramine diet, avoiding aged cheeses, cured meats, fermented foods, and certain beverages. Tyramine is normally broken down by monoamine oxidase in the gut, so when that enzyme is blocked, tyramine can build up and cause dangerous spikes in blood pressure. Sertraline and other SSRIs carry no such dietary requirement.
Why SSRIs Replaced MAOIs as First-Line Treatment
MAOIs were among the earliest antidepressants available, and they remain effective for some people. But SSRIs like sertraline became the most widely prescribed antidepressants largely because they cause fewer intolerable side effects. The dietary restrictions, drug interactions, and blood pressure risks associated with MAOIs limit their practical usefulness for many patients. SSRIs were specifically developed to maintain antidepressant effectiveness while narrowing the mechanism of action to reduce those burdens.
Why Sertraline and MAOIs Can’t Be Combined
Taking sertraline and a MAOI together is dangerous. Sertraline increases serotonin activity by preventing its reuptake, while MAOIs increase serotonin by preventing its breakdown. Combined, these two mechanisms can flood the brain with serotonin and trigger a condition called serotonin syndrome.
Serotonin syndrome ranges from mild to life-threatening. Early signs include restlessness and tremor, which can progress to confusion, involuntary muscle jerking, and rigidity. In severe cases, it causes dangerously high body temperature. The product labeling for sertraline specifically warns of serious, sometimes fatal reactions when it is used alongside selegiline or other MAOIs.
Required Washout Period When Switching
If you’re transitioning between sertraline and a MAOI in either direction, a drug-free gap is essential. When stopping sertraline before starting a MAOI, the minimum washout period is two weeks. When stopping a MAOI before starting sertraline, a 14-day drug-free period is also necessary to ensure the MAOI has cleared your system. These windows give each medication enough time to leave the body so the two mechanisms don’t overlap.
The washout period varies for other SSRIs. Fluoxetine (Prozac), for instance, requires five to six weeks because it stays in the body much longer than other drugs in the class. The general rule is to wait at least five half-lives of the antidepressant being discontinued before cautiously starting a MAOI.
Quick Comparison: Sertraline vs. MAOIs
- Drug class: Sertraline is an SSRI. MAOIs are a separate, older class.
- Target: Sertraline blocks serotonin reuptake. MAOIs block the enzyme that breaks down serotonin, norepinephrine, and dopamine.
- Dietary restrictions: None for sertraline. MAOIs require a low-tyramine diet.
- Side effect burden: SSRIs are generally better tolerated than MAOIs.
- Combined use: Contraindicated due to serotonin syndrome risk.