MAO-B and COMT Inhibitors: What They Add to Levodopa

MAO-B inhibitors and COMT inhibitors do not treat Parkinson’s directly. They protect dopamine from being broken down — in the brain, or before it gets there. That is why they are almost always discussed alongside levodopa rather than instead of it, and why their side effects often look like too much levodopa.

MAO-B inhibitors: selegiline, rasagiline, safinamide

Monoamine oxidase B is one of the enzymes that clears dopamine inside the brain. Blocking it leaves more dopamine available at the synapse for longer.

These can be used two ways. Early, alone, they give a modest symptomatic benefit that may postpone the need for levodopa in mild disease. Later, added to levodopa, they can reduce “off” time. The effect size is modest in both roles — useful, not transformative, and no MAO-B inhibitor has been shown to slow the underlying disease despite considerable effort to demonstrate it.

Safinamide additionally affects glutamate transmission; whether that adds anything clinically beyond its MAO-B action is not settled.

Two practical cautions. First, combinations with certain antidepressants and with some opioids — notably pethidine/meperidine and tramadol — carry a serotonin syndrome warning, so every prescriber and pharmacist needs the full list of what you take. Second, selegiline is metabolised to amphetamine derivatives, which can disturb sleep if taken late in the day.

COMT inhibitors: entacapone, opicapone, tolcapone

Catechol-O-methyltransferase breaks levodopa down in the bloodstream before it reaches the brain. Blocking it means more of each dose arrives.

This has a direct consequence: a COMT inhibitor does nothing on its own. It has no effect unless it is taken with levodopa, because it works on levodopa. Entacapone is taken with each levodopa dose; opicapone is once daily. Adding one typically extends how long each levodopa dose lasts rather than making the peak stronger.

Tolcapone is more potent but is rarely used, because it carries a risk of serious liver injury and requires scheduled liver monitoring.

Why adding one can make things worse before better

If a COMT or MAO-B inhibitor is doing its job, more dopamine is reaching the receptors from the same levodopa dose. The usual first sign is increased dyskinesia — the involuntary writhing movements that come from too much stimulation, not too little. This is expected, and the answer is usually to reduce the levodopa dose rather than abandon the addition. It is worth knowing in advance, because it can otherwise read as the disease worsening.

Entacapone commonly turns urine a harmless orange-brown, and can cause diarrhoea that sometimes appears weeks after starting.

Questions worth asking

• Are we adding this to extend each dose, or to reduce off time overall?
• Does my levodopa dose need to come down at the same time?
• If I get more involuntary movement, is that expected here — and what do I do?
• Does this interact with anything else I take, including painkillers and antidepressants?

Sources

• NINDS — Parkinson’s Disease (National Institute of Neurological Disorders and Stroke, NIH)
• Parkinson’s Foundation — Prescribed Medications
• FDA Drugs@FDA — approved prescribing information, including the tolcapone liver warning

This is general information, not medical advice. Do not start, stop or change any Parkinson’s medication without talking to the doctor who prescribes it.