COMT Inhibitors in Parkinson’s: Tell Me More, Tell Me More

“If the brain were so simple we could understand it, we would be so simple we couldn’t.” Lyall Watson

“The human brain doesn’t come with an instruction manual.” Bill Engvall

Précis: This blog post aims to present an overview of COMT inhibitors in Parkinson’s. A second goal of this blog post is a brief review of the song “Summer Nights” by John Travolta and Olivia Newton-John from the musical Grease (with a repeating refrain of “Tell me more, tell me more“). NOTE: For further information, an additional information entitled “Addendum to COMT Inhibitors in Parkinson’s” has been posted (Click here).

“The human brain is by far the most complex physical object known to us in the entire cosmos.” Owen Gingerich

Introduction: Parkinson’s is a slowly progressing and chronic disorder, ultimately destroying dopamine-producing neurons. The most widely used therapy is some form of Levodopa (L-DOPA) combined with either Carbidopa or Benserazide. Levodopa is converted into dopamine by L-DOPA decarboxylase (DDC). Carbidopa/Benserazide are DCC inhibitors and facilitate the passing of Levodopa from the gut and circulation to the brain.

Typically, over time, there is a wearing-off period for Levodopa where motor and even non-motor symptoms may return between doses. Therefore, there are additional drugs available to prolong the lifetime of Levodopa, specifically, monoamine oxidase B (MAO-B) inhibitors [Selegiline (Zelapar, Eldepryl, Emsam), Rasagiline (Azilect), and Safinamide (Xadago)]. Furthermore, there are Catechol-O-methyltransferase (COMT) inhibitors [Entacapone (Comtan), Tolcapone (Tasmar), and Opicapone (Ongentys)]. Although their end-point is similar, helping preserve Levodopa, the mechanisms for MAO-B and COMT inhibitors are different; thus, this post will only describe the COMT inhibitors.

“Every human brain is both a broadcasting and receiving station for the vibration of thought.” Napoleon Hill

The Path to Taking a COMT Inhibitor: I have noticed a more pronounced “off-on” period with my therapy over the last year. By that, I mean sometimes a rapid drop off, leading to numerous motor defects appearing and then a slower blending up back to normalcy. I recently recounted this occurrence (“Parkinson’s and the Lesson Learned on the Bermuda Railway Trail Walk”).

I just met my new Neurologist (Movement Disorder Specialist). Interestingly, I immediately liked and trusted this physician. She has replaced my Chapel Hill-based Movement Disorder Specialist, which I have had for almost the past decade. I will write about this new experience at some later point. After a lengthy discussion, she recommended I try a COMT inhibitor called Entacapone.

“The human brain is generally regarded as a complex web of adaptations built into the nervous system, even though no one knows how.” Michael Gazzaniga:

Degradation of Levodopa and the Role of COMT Inhibitors: Here are some blogs you may find interesting regarding dopamine science and physiology, including:
“Purple Haze of Parkinson’s: How Dopamine Works” (click here);
“Basal Ganglia, Nigrostriatal Pathway and Parkinson’s” (click here);
“Treating Parkinson’s with Carbidopa/Levodopa” (click here);
“The Complex Role of Neurotransmitters in Parkinson’s” (click here);
“A Graph of Your Daily Level of Exogenous Levodopa” (click here);
“9 Things to Know About Exercise-induced Neuroplasticity in Human Parkinson’s” (click here).

Why does one need a COMT inhibitor? Maybe you have been taking Sinemet for several years, and it is still working but now with more pronounced off-on cycles. You have a few choices. One option is to keep ramping up the Sinemet amount. But even the gold-standard Sinemet has limits, and too much of a good thing is not always helpful. What if you could keep Levodopa to be more available from being degraded? Here enters the MAO-B (not discussed here) and the COMT inhibitors.

COMT converts Levodoa to 3-O-methyldopa (3-OMD), and the process of COMT inhibitors is shown in the schematic below. By blocking COMT, the COMT inhibitors allow more Levodopa to pass through the blood-brain barrier. And it reduces the amount of 3-OMD, which competes with Levodopa for entry into the brain. Thus, taking a COMT inhibitor protects Levodopa from COMT processing. Carbidopa also prevents the conversion of Levodopa to dopamine in the peripheral tissues. COMT metabolizes Levodopa in the intestinal tract. By themselves, COMT inhibitors would serve no real purpose; however, in the presence of Levodopa, they’re relatively effective in reducing the off-on episodes.

There are some side effects of COMT inhibitors. They include diarrhea, nausea, loss of appetite, dyskinesia, hallucinations, orthostatic hypotension, and sleepiness. It also changes the color of your urine.

“The human brain is an incredible pattern-matching machine.” Jeff Bezos

Initial Thoughts on the Effectiveness of a COMT Inhibitor*: My Neurologist told me that based on my frequent activity/exercise pattern, she preferred the COMT inhibitor over the MAO-B inhibitor. For the past few weeks, I have been taking Entacapone (200 mg tablet) with the first three doses of Carbidopa/Levodopa (2.5 tablets of 25 mg/100 mg Carbidopa/Levodopa) of the five doses/day. And the effect of Entacapone is noticeable almost immediately. Transitioning from off-on is much more predictable, not precipitous. It is almost a feeling that maybe I am taking too large of a dose of Carbidopa/Levodopa.

Time will tell. It is not a euphoric feeling. It is still Parkinson’s. And this may be a coincidence, but I scored my lowest 18-hole total for golf last week while using Entacapone to assist my Carbidopa/Levodopa. So far, no noticeable side effects except for the darker-colored urine; however, symptoms may develop with time. To conclude, Entacapone may be an equalizer for my off-on periods.

*Please look over the Medical Disclaimer page on the top menu. Please seek the advice and guidance of your Neurologist before deciding to start a new therapy, such as a COMT inhibitor. This overview introduced one to the topic and described its mode of action. It is not meant to be medical advice.

“Scientific truth is universal, because it is only discovered by the human brain and not made by it, as art is.” Konrad Lorenz

The Musical Movie Grease: Grease was released in 1978. The movie starred Olivia Newton-John and John Travolta. In 2020, Grease was chosen by the Library of Congress for preservation in the United States for being “culturally, historically, or aesthetically significant.” The plot is ‘bad boy’ (Travolta) falls for a ‘good girl’ and a foreign transfer student (Newton-John). It was considered a musical romantic comedy, and it certainly entertained. With the recent passing of Newton-John, there has been a resurgence of shows about her life and showcasing music. There are even TV commercials appearing with her music.

In my opinion, the most notable song from Grease was “Summer Nights,” sung in separate parts of the high school as a duet of sorts by Travolta and Newton-John; total enjoyable nonsense. Their inquisitive friends are attuned and always want more when they sing, “Tell me more, tell me more.” Below is the official video of the song and lyrics.

Summer Nights

Summer loving had me a blast
Summer loving happened so fast
I met a girl crazy for me
Met a boy cute as can be

Summer days drifting away
To-ah! Oh, the summer nights
Well-a, well-a, well-a, huh

Tell me more, tell me more
Did you get very far?
Tell me more, tell me more
Like does he have a car?

Uh huh (doo doo)
Uh huh (doo doo)
Uh huh (doo doo doo doo doo)

She swam by me, she got a cramp
He ran by me, got my suit damp
I saved her life, she nearly drowned
He showed off, splashing around
Summer sun, something’s begun
But ah! Oh, the summer nights
Well-a, well-a, well-a, huh

Tell me more, tell me more
Was it love at first sight?
Tell me more, tell me more
Did she put a fight?

Dow, doobie do, doobie do
Doobie, doobie, doobie
Dow, doobie do, doobie do
Doobie, doobie, doobie, dow

Took her bowling in the Arcade
We went strolling, drank lemonade
We made out under the dock
We stayed up ’til ten o’clock
Summer fling, don’t mean a thing
But ah! Oh, the summer nights
Whoa, whoa, whoa

Tell me more, tell me more
But you don’t gotta brag
Tell me more, tell me more
‘Cause he sounds like a drag

Shoo bop bop, shoo bop bop
Shoo bop bop, shoo bop bop
Shoo bop bop, shoo bop bop
Shoo bop bop, yeah!

He got friendly, holding my hand
Well, she got friendly down in the sand
He was sweet, just turned eighteen
Well, she was good, you know what I mean

Summer heat, boy and girl meet
But ah! Oh, the summer nights
Whoa, whoa, whoa

Tell me more, tell me more
How much dough did he spend?
Tell me more, tell me more
Could she get me a friend?

It turned colder, that’s where it ends
So I told her we’d still be friends
Then we made our true love vow
Wonder what she’s doing now

Summer dreams ripped at the seams
But, oh
Those summer
Nights!
(Tell me more, tell me more, more, more)

Song by John Travolta and Olivia Newton-John

Source: Musixmatch

Songwriters: Jim Jacobs / Warren Casey

“The brain immediately confronts us with its great complexity. The human brain weighs only three to four pounds but contains about 100 billion neurons. Although that extraordinary number is of the same order of magnitude as the number of stars in the Milky Way, it cannot account for the complexity of the brain. The liver probably contains 100 million cells, but 1,000 livers do not add up to a rich inner life.” Gerald Fischbach

Cover Photo Image by Pok Rie from Pixabay