In Part 1, we looked at how the MAO enzyme breaks down Dopamine in the brain and body, via what we termed the “MAO pathway”. In this part, we consider another pathway by which Dopamine is broken down, via another enzyme called Catechol-O-methyltransferase (COMT).
We mentioned COMT already as being responsible for the last part of the MAO break down pathway, but it can also act directly on Dopamine itself. It not only breaks down Dopamine, but also Adrenaline (as does MAO too) [note, for shorthand, I will be using “Adrenaline” throughout to refer to both Noradrenaline and Adrenaline]. This has important ramifications since another way Dopamine may be used up is via conversion into Adrenaline under stressful conditions.
The Comt Pathway
COMT is an enzyme which degrades/inactivates not only Dopamine, but Noradrenaline and Adrenaline too. It also converts L-Dopa into something other than Dopamine, an issue we will return to do below.
In the Dopamine breakdown pathway, COMT first converts the Dopamine into something called 3-Methoxytyramine, before MAO comes back into the picture, to break this down further in to “MOPAL”. MOPAL is another aldyhyde, and recall that build up of Aldehydes are a problem for folks with PD. MOPAL is then broken down by the Aldehyde Dehydrogenase enzyme into the same final end point of the MAO pathway Homovanillic Acid (HVA), which is excreted in urine.
Slow and fast comt
There are rare genetic disorders in which the body creates too little or too much COMT, with significant impacts on Dopamine supplies. There are also different genetic types, including the so-called Slow and Fast COMT types. These two types remove/inactivate Dopamine and Adrenaline more slowly or more quickly, respectively.
Once again, disruption in the amount of COMT enzyme available or its activity may also occur due to being in chronic stress, and especially due to being stuck in the freeze stress response. Disruption due to chronic stress then mimics the features of these genetic types.
If chronic stress disrupts COMT in the direction of less COMT, or lower COMT activity, it will create features which mimic the Slow COMT type. These types are:
sensitive to stress, anxious, worriers;
sensitive to environment toxins;
sensitive to potentially traumatic events;
poor sleepers, daytime fatigue;
histamine intolerant.
This describes me very well prior to diagnosis.
From this, we can see that if chronic stress causes a reduction in COMT activity, then there is a nasty feedback cycle, as this makes us even less resilient to stress.
The sensitivity to stress is caused by the slow removal of Dopamine and Adrenaline, such that these build up, especially as the Dopamine is readily converted to Adrenaline due to the stress, and the Adrenaline is then slow to be removed. So Slow types tend to stay in stress longer once triggered.
As we have covered here many times before, while the high levels of Dopamine due to slower COMT removal, may be good under calm, relaxed situations, it also means that there is more available to be converted into Adrenaline under stress. Indeed, whenever Dopamine is slow to be removed by other mechanisms, it doesn’t mean we have a lot of it when we are chronically stressed, but that we will be constantly converting it to high levels of Adrenaline,
Slow COMT types have better memory and cognitive functions, however. Fast types, corresponding to higher COMT levels or activity have opposite features to Slow types, i.e. are more resilient to stress at the price of somewhat lower cognitive function. In this case, there is less Dopamine in the calm, relaxed states, but also less to convert into Adrenaline under stress, and the Adrenaline is then also quickly removed, so fast types tend not to stay stressed for so long.
Another feature of the Slow COMT type is rebound effects with supplements, where for the first day or so, a supplement makes you feel much better, but thereafter makes you feel much worse. In particular, it makes you angry, and very irritable. I have experienced this many times myself, especially whenever I’ve tried B12, methylfolate, or vitamin B1.
Suggestions for folks of the Slow type include the following
A low protein diet (especially low in tyrosine and phenylalanine, as these are the precursors of Dopamine, and hence also of Adrenaline), eating regularly and maintaining blood sugar levels, as hunger can also result in the production of Adrenaline. This describes well what I have independently found suits me best, through years of trial and error.
Limit strenuous exercise, as this can generate Adrenaline too. However, vigorous exercise can also burn off Adrenaline, by helping to complete fight or flight stress response cycles. Personally, I have found too vigorous exercise doesn’t suit me.
Take B vitamins which help COMT to work. However, take note of the potential rebound problems covered above.
Engage in stress reduction and management techniques. This allows Dopamine levels to build without converting to Adrenaline, under which circumstances Slow COMT becomes be a positive. Stress reduction has been by far the most important intervention in my own recovery.
COMT and L-DOPA
Many folks with Parkinson’s and other chronic stress related issues have similar profiles to those with a Slow COMT genetic type, as is the case for myself as explored above, albeit the disruption in COMT activity is due to being stuck in a freeze stress response, rather than genetic per se.
Folks with PD are usually supposed to have low Dopamine, so at first glance they would be more like the Fast COMT types, which removes Dopamine more quickly. So we can ask why would the Slow COMT features be more relevant?
Although low COMT activity at first glance would mean we have more Dopamine which would stay around for longer, there are still other pathways for Dopamine breakdown, including not only the MAO pathway, but also via conversion into Adrenaline. The important feature of people with PD is that they are chronically stressed, and hence tend to be constantly converting their Dopamine supplies into Adrenaline. So the lower COMT activity just means more Dopamine available for conversion into Adrenaline, and the longer we then stay stressed due to the slower removal of Adrenaline.
However, COMT inhibitors are a class of pharmaceuticals used for PD, which limit the amount of COMT activity even further. Given the above, why would this be helpful, as it would just exacerbate the Slow COMT profile?
The answer is that the COMT inhibitors are always given alongside L-Dopa drugs, as this makes the L-Dopa work better and extend the “on” times. As mentioned above COMT also breaks down L-Dopa, into something called 3-O-Methyldopa [3-OMD], meaning there is then less L-Dopa available for turning into Dopamine.
If one is reliant on external L-Dopa supplementation for generating Dopamine in the first place, then inhibiting COMT activity also means the L-Dopa lasts longer and is more available. Hence, in some cases, the inhibition of L-Dopa breakdown by COMT may outweigh the exacerbation of the other issues associated with low COMT activity.
In fact, there may be additional benefits of reducing the conversion of L-Dopa in 3-OMD via COMT activity, as 3-OMD itself can cause:
higher levels of dyskinesia;
inhibition of uptake of tyrosine;
competition with L-Dopa for transport across the blood–brain barrier, i.e. making it harder for L-Dopa to get to the brain;
inhibition of dopamine release.