Sertraline is not an MAOI. It is a selective serotonin reuptake inhibitor (SSRI), a completely different class of antidepressant. The two drug types work through distinct mechanisms in the brain, carry different side effect profiles, and should never be taken together.
How Sertraline Actually Works
Sertraline, sold under the brand name Zoloft, works by blocking the reabsorption of serotonin back into nerve cells. This leaves more serotonin available in the gaps between neurons, which helps regulate mood. It is a potent and selective inhibitor of serotonin reuptake, with only very weak effects on other brain chemicals like norepinephrine and dopamine.
The FDA has approved sertraline for six conditions: major depressive disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social anxiety disorder, and premenstrual dysphoric disorder. It’s one of the most widely prescribed antidepressants in the world.
How MAOIs Work Differently
MAOIs take a fundamentally different approach. Instead of blocking serotonin reuptake, they disable an enzyme called monoamine oxidase. This enzyme is responsible for breaking down several neurotransmitters, including serotonin, dopamine, norepinephrine, and tyramine. By blocking the enzyme, MAOIs allow all of these chemicals to build up in the brain simultaneously.
The FDA-approved MAOIs include isocarboxazid, phenelzine, selegiline, and tranylcypromine. Some older MAOIs irreversibly shut down the enzyme, meaning the body has to produce entirely new enzyme molecules before normal neurotransmitter breakdown resumes. This is why MAOIs tend to have more serious interactions with foods and other drugs than SSRIs do.
The key distinction: sertraline targets a reuptake pump on one specific neurotransmitter. MAOIs disable a metabolic enzyme that affects multiple neurotransmitters at once. The FDA label for sertraline states explicitly that it “does not inhibit monoamine oxidase.”
Why the Two Should Never Be Combined
Combining sertraline with an MAOI can trigger serotonin syndrome, a potentially life-threatening condition caused by dangerously high serotonin levels. When an MAOI prevents serotonin from being broken down and an SSRI simultaneously prevents it from being reabsorbed, serotonin floods the brain with nowhere to go.
In one published case, a 61-year-old woman who was already taking the MAOI phenelzine received a dose of sertraline. Within three hours, she experienced a dramatic spike in temperature, pulse, and breathing rate, along with muscle rigidity, heavy sweating, shivering, and decreased consciousness. This is a textbook serotonin syndrome reaction, and it developed after just a single dose.
Symptoms of serotonin syndrome can range from mild (agitation, restlessness, rapid heartbeat) to severe (high fever, seizures, loss of consciousness). The combination of an SSRI and an MAOI is one of the most reliable ways to trigger it.
The Required Washout Period
If you’re switching from sertraline to an MAOI or vice versa, a washout period is essential. This gap gives the first medication enough time to fully clear your system before the second one starts working.
The standard guidance is at least 14 days between stopping sertraline and starting an MAOI. The same 14-day gap applies in the other direction: after stopping an MAOI, you should wait at least two weeks before beginning sertraline. Australian prescribing guidelines recommend tapering and stopping sertraline for at least 7 days before starting an MAOI at a low dose, though the FDA label specifies the longer 14-day window. Your prescriber will determine the appropriate timeline based on your situation.
Taking both drugs at the same time, even briefly during a crossover, is not recommended.
Dietary Restrictions: MAOIs vs. Sertraline
One of the most practical differences between these two drug classes is what you can eat while taking them. MAOIs require a strict low-tyramine diet because the same enzyme they block in the brain also breaks down tyramine in the gut. Without that enzyme functioning normally, tyramine from food can build up and cause dangerous spikes in blood pressure.
Foods you’d need to avoid on an MAOI include aged cheeses (cheddar, Parmesan, blue cheese, brie, feta), cured meats (pepperoni, salami, dry sausage, bacon), smoked or processed fish, and fermented or overripe foods. This diet needs to continue for several weeks after stopping the MAOI, since the enzyme takes time to regenerate.
Sertraline carries no dietary restrictions related to tyramine. Because it works on a reuptake pump rather than the monoamine oxidase enzyme, tyramine metabolism is unaffected. This is one of the main reasons SSRIs largely replaced MAOIs as first-line antidepressants: they’re effective for many of the same conditions without requiring patients to overhaul their diet.