Addendum to COMT Inhibitors in Parkinson’s

“Too much is never enough.” Mick Jagger

“There’s never enough time to do it right, but there’s always enough time to do it over.” John W. Bergman

Introduction: I left out a few things in the last post regarding catechol-O-methyltransferase (COMT) inhibitors (“COMT Inhibitors in Parkinson’s: Tell Me More, Tell Me More.“) They are included below.

“Understanding why is never enough.” Lucy Freeman

Clinical Evidence for Adjunctive Therapy for COMT Inhibitors in Parkinson’s: In the presence of peripheral decarboxylation inhibition by Carbidopa or Benserazide, the major remaining catabolic pathway for Levodopa is by O-methylation from COMT. COMT inhibitors extend the therapeutic action of Levodopa in patients with both advanced and fluctuating disorder status. Published studies have found that COMT inhibitors increased the daily ‘on’ time by 1-3 hours; likewise, ‘off’ times were reduced significantly. The amount of Carbidopa/Levodopa may have to be reduced due to the increased availability of Levodopa reaching the brain.

“As long as we live there is never enough singing.” Martin Luther

Blood-Brain Barrier, COMT Inhibitors, and Levodopa: The blood-brain barrier is a unique barrier that selectively allows and restricts the entry of substances into the brain. These blood vessels (endothelial cells) are especially attuned to Dopamine and its components. For example, Levodopa is allowed access into the brain, but neither Dopamine nor Carbidopa. Likewise, Entacacapone and Opicapone can not enter, yet Tolcapone gets granted access. See the similarities in many of these compounds. It makes sense that the precursor Levodopa is granted entry. Keeping Dopamine out ensures tight control of this all-important neurotransmitter.

“More and more it’s deliciousness I want but all the time there’s less of it.”.Deborah Landau

Plasma Levels of Levodopa With Entacapone: Recently, I used John Turner’s website entitled “Parkinson’s Measurement” (click here to access the site) to plot the Levodopa levels in my blood plasma. See “A Graph of Your Daily Level of Exogenous Levodopa.”

Looking over the program, I noticed there was Stalevo®, which is Carbidopa, Levodopa, and Entacapone in a single tablet. And it comes in the usual 25/100 mg dose of Carbidopa/Levodopa and the standardized 200 mg Entacapone. So I take it in two tablets, Carbidopa/Levodopa and Entacapone. The diagram below compares a day’s worth of therapy as measured by Levodopa Equivalent Dose (LED, mg) versus time.

The Table above nicely summarizes what Entacapone is doing. In a day, I take five doses of Carbidopa/Levodopa (shown in the top graph and Table). The peaks with each amount go up nicely and down again, which shows how an ‘off-on’ period begins. Now look at the second graph with added Entacapone with Carbidopa/Levodopa. The doses are both broader and higher, showing that more Levodopa is available and implying it lasts longer. The data shown in the Table aptly explains this phenomenon. With the same daily dose of Entacapone, its effect appears substantial. This explains the diminished severity of these ‘off-on’ periods. And this plot is seen in reality as a merging of doses of Carbidopa/Levodopa.

In closing, reducing the COMT-mediated metabolism of Levodopa to 3-O-methyldopa would allow for more Levodopa/dose to reach the blood-brain barrier and to be converted to Dopamine by the dopaminergic neurons.

“There is never enough time to say our last word-the last word of our love, of our desire, faith, remorse, submission, revolt.” Joseph Conrad

References for Your Further Reading:
Regensburger, Martin, Chi Wang Ip, Zacharias Kohl, Christoph Schrader, Peter P. Urban, Jan Kassubek, and Wolfgang H. Jost. “Clinical benefit of MAO-B and COMT inhibition in Parkinson’s disease: practical considerations.” Journal of Neural Transmission (2023): 1-15.

Valkovič, Peter, Ján Benetin, Pavol Blažíček, L’udmila Valkovičová, Karin Gmitterová, and Peter Kukumberg. “Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients.” Parkinsonism & related disorders 11, no. 4 (2005): 253-256.

Yuan, Hong, Zhen-Wen Zhang, Li-Wu Liang, Quan Shen, Xiang-Dang Wang, Su-Mei Ren, Hong-Jie Ma, Shu-Jun Jiao, and Ping Liu. “Treatment strategies for Parkinson’s disease.” Neuroscience bulletin 26, no. 1 (2010): 66.

Finberg, John PM. “Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson’s disease.” Journal of Neural transmission 126, no. 4 (2019): 433-448.

Jost, Wolfgang H., and C. Brück. “Drug interactions in the treatment of Parkinson’s disease.” Journal of Neurology 249 (2002): iii24-iii29.

Kaakkola, Seppo. “Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson’s disease.” Drugs 59 (2000): 1233-1250.

Fabbri, Margherita, Joaquim J. Ferreira, and Olivier Rascol. “COMT Inhibitors in the Management of Parkinson’s Disease.” CNS drugs 36, no. 3 (2022): 261-282.

“No matter how cynical you become, it’s never enough to keep up.” Lily Tomlin

Cover Photo Image by Lars Nissen from Pixabay

5 Replies to “Addendum to COMT Inhibitors in Parkinson’s”

  1. Combinations of Rytary for inactive times with Sinemet/Entacapone for active times have been stable now for 8 months combined with golf for exercise.

    Small Rytary Dose
    6:00 AM Rytary 36.25/145 x2
    9:30 AM Sinemet 25/100 x2
    Entacapone 200 mg
    2:00 PM Sinemet 25/100 x2
    Entacapone 200 mg
    6:30 PM Sinemet 25/100 x2
    Entacapone 200 mg
    10:00 PM Rytary 36.25/145 x4


    1. John. Thanks so much for your note. Sounds like you have adapted well to the lengthening of the ‘on’ period promoted by Entacapone. Good, I’m happy for you. I do feel an elongation of each dose and a smooth landing when ‘off’ arrives, but it’s been ~1 month since starting. So far, no obvious side effects…..Goof luck with. the golf game. Frank


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