COMT Inhibitors and MAO-B Inhibitors

Indications for Use

COMT and MAO-B inhibitors are used in Parkinson’s disease to enhance and prolong dopaminergic activity. 

COMT inhibitors are used as adjunctive treatment with levodopa in patients with Parkinson’s disease who experience end-of-dose motor fluctuations that are not adequately controlled with levodopa therapy. Tolcapone should not be used as a first line COMT inhibitor due to the risk of fatal, acute liver injury.

MAO-B inhibitors can be used as monotherapy or adjunctive treatment for Parkinson’s disease. MAO-B inhibitors can be used to reduce off time and prolong the clinical response to levodopa. 

Mechanism of Action

Catechol-O-methyltransferase (COMT) inhibitors

COMT inhibitors include tolcapone and entacapone. COMT is the enzyme responsible for the breakdown of levodopa to 3-O-Methyldopa, therefore inhibition of COMT enhances the effects of levodopa.

• Entacapone is a reversible, selective and predominantly peripheral COMT inhibitor.
• Tolcapone is also a reversible COMT inhibitor but has both peripheral and central activity.

MAO-B inhibitors

Selegiline and rasagiline are selective MAO-B inhibitors. MAO-B is involved in the metabolism of dopamine in the brain. Inhibition of MAO-B reduces dopamine breakdown, increasing dopaminergic activity within the striatum and prolonging the effects of levodopa and endogenous dopamine.

At recommended doses, selegiline and rasagiline selectively inhibit MAO-B, so routine dietary tyramine restriction is not generally required. However, higher doses of MAO-B inhibitors may reduce selectivity for MAO-B and increase the risk of adverse reactions. 

By TeachMeSeries Ltd (2026)

Fig 1
Mechanism of Action for Drugs against Parkinson’s Disease

Pharmacokinetics

The following table describes key pharmacokinetic properties of COMT inhibitors and MAO-B inhibitors.

Contraindications

Contraindications vary between individual COMT and MAO-B inhibitors. Hypersensitivity to the individual drug or any of its excipients is a contraindication for all four agents. Contraindications referring to drug interactions are covered in the interactions section. 

COMT inhibitors

Both entacapone and tolcapone are contraindicated in patients with previous neuroleptic malignant syndrome (NMS), non-traumatic rhabdomyolysis and phaeochromocytoma.

Entacapone is contraindicated in patients with:

• Hepatic impairment
• Patients with rare hereditary disorders of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency where the formulation contains sucrose.

Tolcapone has additional important contraindications because of its risk of serious hepatic toxicity; use is contraindicated in liver disease or increased liver enzymes. It is also contraindicated in patients with severe dyskinesia.

MAO-B inhibitors

Selegiline is contraindicated in patients with:

• Active gastric or duodenal ulcer
• Extrapyramidal disorders unrelated to dopamine deficiency

Rasagiline is contraindicated in:

• Severe hepatic impairment

Adverse Effects and Cautions

The adverse effects of COMT and MAO-B inhibitors are largely related to increased dopaminergic activity, particularly when these medicines are used in combination with levodopa. 

Common adverse effects include the following:

• Dyskinesia
• Nausea and vomiting
• Diarrhoea
• Abdominal pain and constipation
• Dizziness and orthostatic hypotension
• Hallucinations, confusion and sleep disturbances
• Somnolence and sudden sleep onset
• Increased sweating
• Fatigue and falls

Impulse-control disorders

Impulse control disorders can occur with dopaminergic drugs. Examples of this behaviour can include gambling, overeating, compulsive buying and sexual excess. 

Withdrawal

Abrupt withdrawal of dopaminergic agents can cause neuroleptic malignant-like syndrome which may include symptoms such as muscular rigidity, hyperpyrexia and psychological changes. Gradual tapering should occur if therapy is to be stopped, and it is vital patients get their medications on time. 

COMT Inhibitors

COMT inhibitors have a lower risk of hallucinations than other drug classes but can cause excessive sleepiness and impulse control disorders. Entacapone and tolcapone can cause harmless reddish-brown/yellow-orange urine discolouration. With entacapone, persistent diarrhoea may indicate colitis.

Importantly tolcapone can cause hepatotoxicity, increases in liver transaminases are recognised, with rare cases of severe hepatocellular injury and potentially fatal acute liver failure.

MAO-B inhibitors

Excessive sleepiness, hallucinations and impulse control disorders are less likely with oral MAO-B inhibitors compared to dopamine agonists. Selegiline can cause excitement, anxiety and insomnia due to metabolites (amphetamine)

A possible increased risk of melanoma has been reported with the long term and/or high doses of rasagiline.

Interactions

Both COMT inhibitors and MAO-B inhibitors can cause orthostatic hypotension, therefore caution should be taken alongside medicines that can cause orthostatic hypotension such as alpha-blockers. 

Levodopa

When COMT inhibitors and MAO-B inhibitors are prescribed alongside levodopa, levodopa dose reduction may be required due to prolongation of the dopaminergic effect and increased risk of dyskinesias.

• With tolcapone most patients receiving >600 mg levodopa daily may require reduction of levodopa dose by ~30%
• With entacapone the levodopa dose may need to be reduced by about 10–30%
• With selegiline the levodopa dose is reduced by an average of 10-30%
• When rasagiline is added to levodopa, dyskinesia may worsen; reducing the levodopa dose may help manage this adverse effect. 

COMT Inhibitors

COMT inhibitors should not be combined with non-selective MAO inhibitors. Combining a selective MAO-A inhibitor with a selective MAO-B inhibitor is also contraindicated because of the risk associated with excessive monoamine oxidase inhibition, including hypertensive crises and serotonin toxicity.

Both agents may increase exposure to drugs that are metabolised by COMT, such as adrenaline, noradrenaline, dopamine, apomorphine and α-methyldopa.

Due to its affinity to CYP2C9, entacapone may affect warfarin exposure and INR. INR monitoring is recommended when entacapone is initiated in patients receiving warfarin. 

Entacapone can bind to oral iron preparations therefore administration should be separated by 2-3 hours. 

MAO-B Inhibitors

Selective MAO-B inhibitors (selegiline, rasagiline) and MAO-A inhibitors (moclobemide) may be administered with levodopa but not in combination with each other (MAO-B and MAO-A). Excessive MAO inhibition can lead to hypertensive crises or serotonin syndrome.

There is also a risk of serotonin syndrome when MAO-B inhibitors are administered alongside pethidine, tramadol, buprenorphine, antidepressants (including SSRIs, SNRIs, TCAs), St John’s Wort and triptans. 

A minimum 14-day washout period is required between stopping rasagiline and starting an MAO inhibitor, fluoxetine, fluvoxamine or pethidine. 

Fluoxetine has a long half life, therefore a 5 week washout period is recommended prior to starting treatment with rasagiline or selegiline. 

Some combinations, such as with selegiline or rasagiline with pethidine, are contraindicated. 

Other washout periods before starting selegiline are advised by the manufacturers as follows:

• After sertraline: wait at least 2 weeks
• After other SSRIs: wait at least 1 week
• For other interacting medicines: generally allow 5 half-lives of the previous drug.

Before starting an interacting medicine after selegiline: wait at least 14 days after stopping selegiline.

Selegiline is also contraindicated and rasagiline not recommended alongside sympathomimetics, such as nasal and oral decongestants containing ephedrine or pseudoephedrine, due to the risk of hypertension.

When used in combination with levodopa, selegiline is also contraindicated in several conditions, including severe cardiovascular disease, uncontrolled hypertension, hyperthyroidism/thyrotoxicosis, phaeochromocytoma, narrow-angle glaucoma, significant prostatic enlargement with residual urine, tachycardia, arrhythmias, severe angina, psychosis and advanced dementia.

Rasagiline is primarily metabolised by CYP1A2. Potent CYP1A2 inhibitors, such as ciprofloxacin, can increase rasagiline exposure and should therefore be used cautiously. Smoking may induce CYP1A2 and potentially reduce rasagiline concentrations.

References

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
3. Scenario: Confirmed Parkinson’s disease | Management | Parkinson’s disease | CKS | NICE  Accessed 21/09/26
4. Tasmar 100 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 11830  Accessed 21/09/26
5. Entacapone Mylan 200 mg film-coated tablets – Summary of Product Characteristics (SmPC) – (emc) | 8818  Accessed 21/09/26
6. Eldepryl 10mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 6627  Accessed 21/9/26
7. Azilect 1 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) | 74  Accessed 21/9/26
8. BNF Online Accessed 8/10/26