Combining MAOIs with other antidepressants can be deadly-or it can be life-saving. It all depends on MAOIs, timing, and which drugs you mix. For decades, these older antidepressants were avoided because of scary warnings. But today, they’re making a quiet comeback-not as first-line treatment, but as the last resort for people who’ve tried everything else and still feel trapped in depression.
Why MAOIs Are Still Used
MAOIs, or monoamine oxidase inhibitors, were the first antidepressants ever developed. Iproniazid, the first one, was originally meant to treat tuberculosis. In the 1950s, doctors noticed patients on it started feeling better emotionally. That accidental discovery changed psychiatry.Today, only a handful of MAOIs are still in use: phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), and selegiline (Emsam patch). The patch form, approved by the FDA in 2006, is easier to manage because it doesn’t require strict diet changes at lower doses.
These drugs work differently than SSRIs or SNRIs. Instead of blocking serotonin reuptake, they stop the enzyme that breaks down serotonin, norepinephrine, and dopamine. That means more of these mood-lifting chemicals stay active in the brain.
They’re not for everyone. But for about 20-30% of people with treatment-resistant depression-those who didn’t respond to two or more other antidepressants-MAOIs can be the only thing that works. Studies show response rates of 40-60% in this group, especially for people with atypical depression: extreme fatigue, oversleeping, weight gain, and intense sensitivity to rejection.
The Deadly Risk: Serotonin Syndrome
The biggest danger with MAOIs comes from mixing them with other drugs that raise serotonin. That includes SSRIs like fluoxetine (Prozac), sertraline (Zoloft), and SNRIs like venlafaxine (Effexor). Combining them can trigger serotonin syndrome-a medical emergency.Serotonin syndrome isn’t just nausea or jitteriness. It’s high fever, muscle rigidity, rapid heartbeat, confusion, seizures, and sometimes death. A 1995 study in the Journal of Clinical Psychiatry found that seven out of eight cases where fluoxetine was followed by an MAOI ended in fatality.
The FDA requires a boxed warning on all MAOI labels: Do not use with SSRIs or SNRIs. But the timing matters just as much as the drugs themselves. Fluoxetine sticks around in your system for weeks because its active metabolite, norfluoxetine, lasts up to 15 days. That means you must wait at least five weeks after stopping fluoxetine before starting an MAOI. For other SSRIs, the waiting period is 14 days. The reverse is also true: if you’re coming off an MAOI, you must wait 14 days before starting any SSRI.
What About Tricyclic Antidepressants (TCAs)?
For years, doctors were told to avoid combining MAOIs with TCAs like amitriptyline or clomipramine. The fear was the same: too much serotonin. But recent evidence is changing that.A 2022 review in PMC9680847 found that the risk of serotonin syndrome with MAOI-TCA combinations has been overblown. In fact, some patients with severe treatment-resistant depression have done well on this combo-when done right.
Here’s the catch: you can’t just switch from one to the other. The TCA must be started first-or at the same time-as the MAOI. Starting the MAOI first dramatically increases the risk of side effects. And clomipramine? Still a hard no. It’s too strong on serotonin reuptake and has caused dangerous reactions even in controlled settings.
Nortriptyline, on the other hand, is often the TCA of choice for combination therapy. It’s less serotonergic and has a better safety profile. One 2009 study from the University of Pennsylvania showed 57% of patients with treatment-resistant depression improved on phenelzine plus nortriptyline-with minimal side effects when monitored closely.
Safer Alternatives to Avoid
You don’t have to risk serotonin syndrome to get better. There are antidepressants that can be safely combined with MAOIs because they don’t significantly affect serotonin.- Bupropion (Wellbutrin): Works on dopamine and norepinephrine, not serotonin. It’s one of the safest partners for MAOIs. Many clinicians use it for patients with low energy or lack of motivation.
- Mirtazapine (Remeron): Blocks certain receptors to boost norepinephrine and serotonin-but doesn’t block reuptake like SSRIs. Multiple case reports confirm safe use with MAOIs, especially for sleep and appetite issues.
- Trazodone: Used mostly for sleep, it’s also a mild antidepressant. It doesn’t raise serotonin enough to cause danger with MAOIs.
Even some non-antidepressant drugs can help. Dopamine agonists like pramipexole (used for Parkinson’s) have been successfully added to MAOIs for patients stuck in anhedonia-when nothing brings pleasure anymore. One study at the University of Pennsylvania showed improved motivation and mood in patients who didn’t respond to MAOIs alone.
What About Anxiety and Sleep?
Many people on MAOIs struggle with anxiety or insomnia. The good news? You can safely add medications for these.- Benzodiazepines like lorazepam or clonazepam are fine to use short-term.
- Non-benzodiazepine sleep aids like zolpidem (Ambien) or eszopiclone (Lunesta) don’t interact dangerously.
- Antihistamines like hydroxyzine can help with anxiety without raising serotonin risk.
These aren’t just theoretical-they’re used in real clinical practice. The key is avoiding anything that blocks serotonin reuptake. Stick to the safe list, and you can manage symptoms without risking your life.
Dietary Restrictions Still Matter
Even with the patch form, dietary rules aren’t gone. Tyramine-a compound in aged, fermented, or spoiled foods-can cause a dangerous spike in blood pressure when MAOIs are active.Avoid:
- Aged cheeses (Parmesan, blue cheese, cheddar-over 20mg tyramine per 100g)
- Tap beer and home-brewed beer (over 10mg per 100ml)
- Fermented sausages like salami or pepperoni (over 100mg per 100g)
- Soy sauce, miso, and fermented tofu
- Overripe bananas, avocados, and fava beans
The Emsam patch at 6mg/24hr lowers this risk significantly-many users don’t need to change their diet. But at higher doses (9mg or 12mg), the restrictions return. And you must keep avoiding these foods for two weeks after stopping the MAOI, because your body needs time to rebuild the enzyme that breaks down tyramine.
Stopping MAOIs Isn’t Simple
Quitting MAOIs cold turkey is a bad idea. Withdrawal isn’t like quitting caffeine. It’s intense.Studies show up to 71% of people experience sleep problems, 68% get headaches, 62% feel restless, and 55% get flu-like symptoms. Tingling or burning skin? That’s common too.
The fix? Taper slowly. Most doctors recommend reducing the dose over 2-4 weeks. Never stop abruptly, even if you feel fine. Your brain has adapted to having more neurotransmitters around. Removing the drug too fast leaves you with a chemical vacuum.
Who Should Prescribe MAOIs?
Not every doctor feels comfortable with MAOIs. A 2019 study found only 32% of psychiatry residents felt trained enough to manage them. That’s why many patients are stuck in a loop of failed treatments-they’re not being offered the right option.If you’ve tried at least two antidepressants and still feel hopeless, ask for a referral to a psychiatrist who specializes in treatment-resistant depression. They’re more likely to know how to use MAOIs safely. Some clinics now offer MAOI “starter programs” with close monitoring, dietary counseling, and follow-up visits every week for the first month.
The Future of MAOIs
Newer versions are being tested. Selective MAO-B inhibitors (like selegiline) are being studied for depression, not just Parkinson’s. And early research at Yale is looking at combining MAOIs with ketamine for rapid relief in suicidal depression.But for now, the most powerful tool we have for treatment-resistant depression is still the old-school MAOI-if used with precision. It’s not about fear. It’s about knowledge. Timing. And knowing which drugs play nice together.
For the 15-20% of people who’ve tried everything else, MAOIs aren’t a last resort. They’re the only shot left. And with the right approach, that shot can save lives.
Can I take an SSRI after stopping an MAOI?
Yes-but only after waiting at least 14 days. If you were on fluoxetine (Prozac), you must wait five weeks because its active metabolite sticks around much longer. Never start an SSRI sooner than recommended. The risk of serotonin syndrome is real and potentially fatal.
Is it safe to combine MAOIs with bupropion?
Yes. Bupropion (Wellbutrin) doesn’t affect serotonin reuptake-it targets dopamine and norepinephrine instead. It’s one of the safest antidepressants to combine with MAOIs and is often used for low energy, lack of motivation, or smoking cessation alongside MAOI therapy.
Why can’t I eat aged cheese while on MAOIs?
Aged cheese contains tyramine, a compound that normally gets broken down by the monoamine oxidase enzyme. When MAOIs block that enzyme, tyramine builds up and causes a sudden, dangerous spike in blood pressure. This can lead to stroke, heart attack, or death. Avoid all aged, fermented, or spoiled foods during treatment and for two weeks after stopping.
Can I take melatonin with an MAOI?
Yes. Melatonin is a natural hormone that regulates sleep and doesn’t interact with serotonin or monoamine oxidase. It’s safe to use with MAOIs for insomnia or jet lag. Just avoid high doses unless advised by your doctor.
Are MAOIs still prescribed today?
Yes, but only for treatment-resistant depression-typically after two or more other antidepressants have failed. About 5-10% of depression specialists regularly prescribe them. The transdermal patch (Emsam) is becoming more popular because it reduces dietary restrictions at lower doses.
What’s the biggest mistake people make with MAOIs?
Trying to switch quickly between antidepressants without waiting the required washout period. People often think, “I feel worse on this drug, so I’ll just start the new one tomorrow.” That’s how serotonin syndrome happens. Always follow the 14-day (or 5-week for fluoxetine) rule. Your life depends on it.