When someone has tried multiple antidepressants and still feels stuck in depression, doctors sometimes turn to MAOIs-monoamine oxidase inhibitors. These drugs aren’t the first choice anymore, but for about 1 in 5 people with treatment-resistant depression, they’re the only thing that works. The problem? Combining them with other antidepressants can be deadly if you don’t know what you’re doing.
Why MAOIs Are Still Used
MAOIs like phenelzine (Nardil), tranylcypromine (Parnate), and the selegiline patch (Emsam) were among the first antidepressants developed in the 1950s. They work differently than SSRIs or SNRIs. Instead of blocking serotonin reuptake, they stop the enzyme that breaks down serotonin, norepinephrine, and dopamine. This means more of these mood-lifting chemicals stay active in the brain.That’s why they’re so effective for atypical depression-where people feel heavy, oversleep, crave carbs, and are hypersensitive to rejection. Studies show 40-60% of people with treatment-resistant depression respond to MAOIs when other meds fail. The transdermal patch version, Emsam, is especially helpful because at lower doses (6 mg/24hr), it doesn’t require strict diet changes. About 70% of users on this patch don’t need to avoid aged cheese or tap beer anymore.
The Deadly Risk: Serotonin Syndrome
The biggest danger comes from mixing MAOIs with SSRIs like fluoxetine (Prozac), sertraline (Zoloft), or SNRIs like venlafaxine (Effexor). This combo can trigger serotonin syndrome-a medical emergency. Symptoms include high fever, muscle stiffness, fast heart rate, confusion, seizures, and in severe cases, 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. That’s why the FDA requires a boxed warning: MAOIs and SSRIs must never be taken together. Even worse, fluoxetine sticks around in your system for weeks. You need to wait at least five weeks after stopping fluoxetine before starting an MAOI. For other SSRIs, the wait is 14 days. And if you’re switching from an MAOI to an SSRI, you still need 14 days in between to let your body reset its enzyme activity.
What About Tricyclic Antidepressants (TCAs)?
The rules around TCAs like amitriptyline or nortriptyline are less clear-cut. For decades, doctors were told to avoid combining them with MAOIs entirely. But recent research is changing that view.A 2022 review in PMC found that some patients with severe depression actually respond better when a TCA is added to an MAOI-if done right. The key is timing: the TCA should be started first, or at the same time as the MAOI. Never add an MAOI after a TCA is already running. That’s when serotonin builds up too fast.
And there’s one TCA you must never mix with an MAOI: clomipramine. It’s a strong serotonin reuptake blocker, and combining it with an MAOI raises the risk of serotonin syndrome dramatically. Nortriptyline, on the other hand, has been used safely in combination with phenelzine in clinical trials-with 57% of patients showing major improvement and few side effects.
Safer Alternatives to Avoid
Not all antidepressants are dangerous with MAOIs. Some actually work well together. Here are the ones that are generally considered safe:- Bupropion (Wellbutrin) - It works on dopamine and norepinephrine, not serotonin. No risk of serotonin syndrome.
- Mirtazapine (Remeron) - Boosts norepinephrine and serotonin in a different way. Multiple case studies show it’s safe with MAOIs.
- Trazodone - Used mostly for sleep, it has minimal serotonin reuptake effects. Often paired with MAOIs for insomnia in treatment-resistant cases.
- Nortriptyline - As mentioned, safe when introduced correctly.
Some psychiatrists even add dopaminergic agents like pramipexole (used for Parkinson’s) to help with apathy or lack of motivation in severe depression. These aren’t antidepressants per se, but they can fill gaps when MAOIs alone aren’t enough. The catch? Start low. These drugs can cause nausea or drowsiness, and in rare cases, trigger impulse control issues like gambling or compulsive shopping.
What You Can Safely Combine
You don’t need to stop everything else. Many supportive medications are perfectly safe with MAOIs:- Benzodiazepines (like lorazepam or clonazepam) for anxiety
- Non-benzodiazepine sleep aids like zolpidem (Ambien) or suvorexant (Belsomra)
- Antihistamines like diphenhydramine for allergies or sleep
These don’t interfere with serotonin or cause dangerous spikes in blood pressure. They’re useful tools to manage side effects without increasing risk.
What You Must Avoid
Beyond SSRIs, SNRIs, and clomipramine, here’s what else can be dangerous:- Over-the-counter cough medicines with dextromethorphan (like Robitussin DM)
- St. John’s Wort - a herbal supplement that acts like an SSRI
- Illicit drugs like MDMA, cocaine, or amphetamines
- Tyramine-rich foods - aged cheeses, cured meats, tap beer, soy sauce, fermented foods
Tyramine is the reason MAOIs come with dietary warnings. Normally, your body breaks it down with monoamine oxidase. But if that enzyme is blocked by an MAOI, tyramine builds up and causes a sudden, dangerous spike in blood pressure. That’s why you need to avoid foods with more than 20 mg of tyramine per 100g. Even after stopping an MAOI, you should keep avoiding these foods for two weeks.
How to Switch Safely
Switching from one antidepressant to an MAOI isn’t a quick swap. It’s a careful, step-by-step process:- Stop your current antidepressant.
- Wait the full washout period: 5 weeks for fluoxetine, 14 days for others.
- Start the MAOI at the lowest dose.
- Wait at least 2 weeks before adding any other antidepressant.
- If adding a TCA like nortriptyline, start it after the MAOI is stable.
- Never combine MAOIs with SSRIs, SNRIs, or clomipramine.
Stopping an MAOI suddenly is just as risky. People report restlessness (62%), upset stomach (48%), tingling (37%), flu-like symptoms (55%), sleep problems (71%), and headaches (68%). Always taper slowly-over 2 to 4 weeks-under medical supervision.
Who Should Use MAOIs?
MAOIs aren’t for everyone. They’re for people who’ve tried at least two other classes of antidepressants and still aren’t improving. That’s about 20-30% of people with depression. Only 5-10% of psychiatrists regularly prescribe them today, partly because training is lacking. Only 32% of psychiatry residents feel confident managing MAOI interactions.But for those who’ve been through years of failed treatments, MAOIs can be life-changing. Dr. Alan Frazer put it plainly: “For the 15-20% of patients with truly refractory depression, MAOIs remain the most effective pharmacological option we have.”
The key isn’t avoiding MAOIs-it’s using them wisely. With the right knowledge, timing, and monitoring, these once-feared drugs can offer hope where nothing else could.
Can I take an SSRI after stopping an MAOI?
Yes, but you must wait at least 14 days after stopping the MAOI before starting an SSRI. For fluoxetine (Prozac), you need to wait 5 weeks because it and its active metabolite stay in your system much longer. Starting an SSRI too soon can trigger serotonin syndrome, which can be fatal.
Is it safe to combine MAOIs with bupropion?
Yes. Bupropion (Wellbutrin) doesn’t affect serotonin reuptake-it works on dopamine and norepinephrine. Multiple clinical sources, including the Psychotropical commentary and Dr. Kenneth Heilman, confirm it’s one of the safest antidepressants to combine with MAOIs. It’s often used to help with low energy or lack of motivation in treatment-resistant depression.
Why is clomipramine dangerous with MAOIs?
Clomipramine is a tricyclic antidepressant with very strong serotonin reuptake inhibition. When combined with an MAOI-which prevents serotonin breakdown-it causes serotonin to flood the brain too quickly. This dramatically increases the risk of serotonin syndrome. Unlike nortriptyline, which has weaker serotonergic effects, clomipramine should never be used with an MAOI under any circumstances.
Do I need to avoid cheese forever if I take an MAOI?
No. You only need to avoid high-tyramine foods-like aged cheeses, cured meats, and tap beer-while taking the MAOI and for two weeks after stopping it. The transdermal selegiline patch (Emsam) at the lowest dose (6 mg/24hr) doesn’t require dietary restrictions at all. About 70% of users on this patch can eat normally without risk.
What happens if I stop an MAOI suddenly?
Abruptly stopping an MAOI can cause withdrawal symptoms like restlessness (62% of cases), upset stomach (48%), tingling or burning sensations (37%), flu-like symptoms (55%), sleep problems (71%), and headaches (68%). Always taper off slowly over 2 to 4 weeks under a doctor’s supervision to avoid these effects.
Are MAOIs still used today?
Yes. While they’re not first-line treatment, MAOIs are still prescribed for treatment-resistant depression, especially when other drugs have failed. The transdermal selegiline patch is becoming more popular because it has fewer dietary restrictions. About 5-10% of psychiatrists regularly use them, and research shows they’re the most effective option for about 1 in 5 people with severe, stubborn depression.
