Lamotrigine is not an MAOI. It belongs to a completely different drug class called phenyltriazine anticonvulsants, and it works through a different mechanism than monoamine oxidase inhibitors. The confusion likely comes from the fact that both lamotrigine and some MAOIs are used to treat mood disorders, but the two medications are pharmacologically distinct.
How Lamotrigine Actually Works
Lamotrigine stabilizes electrical activity in the brain by blocking voltage-gated sodium channels on nerve cells. This prevents neurons from firing too rapidly and reduces the release of excitatory brain chemicals, particularly glutamate and aspartate. There is also evidence it interacts with calcium channels, which may broaden its effects. Notably, research has not shown that lamotrigine has significant direct effects on serotonin, norepinephrine, or dopamine, the three neurotransmitters that MAOIs target.
The FDA has approved lamotrigine for two main purposes: treating several types of epilepsy (including partial-onset seizures and generalized seizures) and maintenance treatment of bipolar I disorder to delay mood episodes. In bipolar disorder, it is primarily used to prevent depressive episodes rather than to treat acute mania.
How MAOIs Work Differently
MAOIs block the enzyme monoamine oxidase, which normally breaks down serotonin, norepinephrine, and dopamine in the brain. By disabling this enzyme, MAOIs cause these neurotransmitters to accumulate, lifting mood. The classic MAOIs still on the market are phenelzine, tranylcypromine, and isocarboxazid, all of which irreversibly shut down both forms of the enzyme (MAO-A and MAO-B). Selegiline and moclobemide are newer, more selective versions that target only one form or bind reversibly.
One of the most recognizable features of classic MAOIs is the strict low-tyramine diet they require. Because the enzyme they block also processes tyramine (a compound found in aged cheeses, cured meats, and fermented foods), eating these foods while on an MAOI can cause a dangerous spike in blood pressure. Lamotrigine carries no such dietary restriction.
Why the Two Sometimes Get Confused
There is a small grain of truth behind the question. In laboratory studies, lamotrigine did inhibit monoamine oxidase activity in isolated tissue samples. One clinical study also found that six weeks of lamotrigine treatment significantly decreased MAO-B activity measured in blood platelets of people with bipolar depression. That finding raised the possibility that mild MAO-B inhibition might partly contribute to lamotrigine’s mood benefits.
However, follow-up research painted a different picture. When scientists gave lamotrigine to live animals and then measured MAO activity directly in brain tissue, they found no meaningful reduction in MAO-A and only minimal reduction in MAO-B. The explanation is that lamotrigine’s interaction with monoamine oxidase is competitive and highly reversible, meaning the drug binds weakly and lets go quickly. In a living brain, this interaction is too brief and too weak to meaningfully change how serotonin, norepinephrine, or dopamine are processed. Researchers concluded that altered monoamine metabolism in the body is unlikely to account for lamotrigine’s antidepressant effects in bipolar disorder.
In short, lamotrigine can technically interact with the MAO enzyme in a test tube, but the effect is so fleeting that it does not function as an MAOI in any clinically relevant way.
Practical Differences That Matter
The distinction between lamotrigine and MAOIs has real consequences for daily life. If you take lamotrigine, you do not need to follow a low-tyramine diet. You also face a very different set of drug interaction concerns. MAOIs are notorious for dangerous interactions with a long list of medications, including many common cold medicines, certain pain relievers, and most other antidepressants. Lamotrigine’s interaction profile is narrower and centers mostly on other anticonvulsants and hormonal contraceptives.
Lamotrigine is processed in the liver through a pathway called glucuronidation, primarily by enzymes known as UGT1A4 and UGT2B7. This is completely different from the enzyme system MAOIs affect. The most important drug interaction to know about is with valproate (another mood stabilizer and anticonvulsant), which slows lamotrigine’s breakdown and can roughly double its blood levels. Hormonal contraceptives can also alter lamotrigine levels, and lamotrigine can reduce contraceptive effectiveness in return.
The side effect profiles also differ. Lamotrigine’s most serious risk is a rare but potentially severe skin rash that is minimized by starting at a low dose and increasing slowly. MAOIs carry the risk of hypertensive crisis from food or drug interactions, along with a different set of common side effects like dizziness, weight gain, and sleep disruption.
Both Treat Bipolar Disorder, but in Different Roles
The overlap that likely drives this question is that both lamotrigine and MAOIs can be part of bipolar disorder treatment. Lamotrigine is FDA-approved specifically for bipolar I maintenance, where it excels at preventing depressive episodes. MAOIs are sometimes used off-label for bipolar or treatment-resistant depression, though they are rarely a first-line choice because of their dietary and drug interaction demands.
If you are comparing the two because a provider suggested switching or adding one, it helps to know they work through entirely separate pathways and are not interchangeable. Lamotrigine targets neuronal excitability through sodium channels, while MAOIs boost monoamine neurotransmitter levels by blocking the enzyme that degrades them. Being on lamotrigine does not mean you are taking an MAOI, and the precautions for each are different.