How to keep dopamine properly away from converting to adrenaline?

[jason30]

Hi all,

Adrenaline plays a big role in my symptoms.
I try to understand how it works and I wonder how to keep dopamine converting properly away from adrenaline (epinephrine)?
Also, is dopamine always converting to adrenaline (epinephrine) or noadrenaline (norepinephrine)?
Both epinephrine and norepinephrine play a role in our body's natural fight-or-flight response to stress.
For me it's important to reduce the fight-flight response as much as possible.

Thanks in advance for thinking along.

 

[drmullin30]

Hi Jason,

The rate limiting factor for COMT to convert dopamine away from epinephrine is to keep the SAMe to SAH ratio high with proper methylation:

"While SAMe activates COMT, SAH inhibits it. SAMe binds the active site on COMT, but SAH binds it more avidly. The rate limiting step in COMT methylation is SAH accumulation, with a resulting low, and thus ineffective, SAMe:SAH ratio. Under normal circumstances, SAH is rapidly converted in to homocysteine, SAH is kept low, the SAMe:SAH ratio is kept high, and COMT can methylate all it wants. However, when Methyl Cycle genomic or nutritional abnormalities result in homocysteine elevation, SAH cannot be cleared to homocysteine (the process backs up), and COMT activity shuts down. Genomically impaired COMT is a problem. Elevated homocysteine/SAH is a problem. Impaired COMT plus elevated homocysteine/SAH is a metabolic disaster. " source: http://www.heartfixer.com/AMRI-Nutr...thyl Transferase and VDR:  Vitamin D Receptor

 

[Snow Leopard]

I'd kindly ask for you to take a step back and reconsider... Emotions and the "fight or flight" response are complex neuropsycho phenomena and cannot (and should not) be reduced to neurotransmitter reductionism like this, the functions of epinephrine, norepinephrine and dopamine are complex based on when, where and how they are secreted as well as what cells they are stimulating.

It is the patterns that matter.

Dopamine and Aderenergic receptors are both Rhodopsin-like G-protein coupled receptors. Adrenergic receptors rely on Gi, Gq or Gs signalling, depending on receptor type, Dopamine receptors also rely on Gi or Gs signalling. This means that meaning stimulation of a D1 receptor has the same intracellular signalling cascade as a Beta 2 adrenergic receptor. What is the difference then? Well cells differentially express the different receptors depending on what they need to be more sensitive to, and the receptor binding kinetics can differ. What does this mean on an organ level? It depends...

So again, it is the patterns that matter, instead of simply saying that adrenaline does one thing and dopamine does another.

The absolute levels themselves are not important - if all the dopamine or epinephrine is doing is being converted back and forth inside a cell, it is of no real consequence.

So my question is, how do you know adrenaline is the problem?

An oversensitive fight or flight response suggests psychological issues such as anxiety, which have their own specific psychological and pharmacological therapies.

 

[Snow Leopard]

The rate limiting factor for COMT to convert dopamine away from epinephrine is to keep the SAMe to SAH ratio high with proper methylation:

COMT (Catechol-O-methyltransferase) deactivates all the catecholamines (including epinephrine). If someone had a hypothetical genetic disease of excessive conversion of dopamine to norepinephrine, inhibiting COMT would likely make things worse (due to excessive accumulation of norepinephrine/epinephrine)

It is Dopamine beta-hydroxylase that catalyses the conversion of dopamine to norepinephrine.

 

[Hip]

Not sure if I can directly answer the question, but in terms of reducing the activity of the sympathetic nervous system (activity which can include the release of adrenaline), spironolactone seems to work. Ref: 1

Clonidine also reduces the sympathetic:

The primary effect of clonidine is to reduce sympathetic activity or “tone.” This lowers BP and often reduces heart rate (HR).

Source: 1

When I tried clonidine 75 mg to 300 mg, I found it would sometimes cause a wave of tiredness lasting around 1 or 2 hours after. But this tiredness would not occur on every occasion taking clonidine.

The similar drug guanfacine, which like clonidine is an alpha 2 adrenergic agonist, should also reduce sympathetic activation.

Benicar might also reduce the sympathetic nervous system:

It is possible, however, that olmesartan affects the brain, thereby inhibiting the sympathetic nervous system, at least in part, by reducing oxidative stress in the autonomic nuclei, such as the paraventricular nucleus of the hypothalamus, nucleus tractus solitarus and RVLM.

https://www.nature.com/articles/hr2009160

It's also interesting that panic attacks (which are associated with sympathetic activation and adrenaline release) can be precipitated by administration of either bicarbonate or lactate in people with panic disorder. Ref: 1

And intriguingly, in people who suffer from generalized anxiety disorder (GAD) rather than panic disorder, and who do not normally suffer panic attacks (panic attacks are not normally part of GAD), these GAD people started getting panic attacks when given sodium lactate. Ref: 1

Since lots of ME/CFS patients experience excessive release of lactic acid from physical exertion, I guess it's possible that this lactic acid might go on to cause sympathetic activation.

 

[PatJ]

Adrenaline plays a big role in my symptoms

Here are a couple of posts from other threads on PR:

*Cold; mutaflor probiotic; identifying triggers*
From Basilico on PR:
My husband has had this issue a lot. For him, most of the things that cause the excessive adrenaline issues in some way do so by triggering a vagal nerve response. Also, his MAO system is not very efficient at breaking down adrenaline (which we learned after getting his genetic testing done), so when he gets an adrenaline burst, it lasts much longer than it should.

In terms of dealing with the adrenaline burst after it's already happened/happening, we've not found a magic bullet, but we have come up with a bag of tricks to help deal with it - he does sometimes need to use either Propanalol [or] Xanax works much better for him.

Additionally, we've found that being in a really cold environment (like A/C full blast) seems to prevent it or reduce it pretty quickly. We learned this after one of these attacks sent him to the emergency room, but after sitting in the waiting room which was really cold from excessive A/C, he suddenly felt much better. After that, we've tried experiments with turning the A/C really high in the car or at home, and it seemed to really help.

But probably what we try to focus on the most is preventing it from happening as much as possible by avoiding triggers. For him, there seem to be several triggers that prompt his wonky vagal nerve to trigger an adrenaline attack. His triggers are: low blood sugar, low blood pressure, and needles (so acupuncture was not really successful!).

He still is prone to excessive adrenaline, and it's probably something he'll have to deal with for life, but after taking a really good round of Mutaflor probiotic, a majority of the crazy adrenaline attacks just eventually stopped. He credits the Mutaflor for that, and I think it was likely that the Mutaflor did have a really big impact for him. Since gut flora control neurotransmitters, that's not such a stretch.

Also, certain supplements seem to trigger adrenaline attacks - for him, specifically P5P (B6). I don't know if you are taking any B vitamins, but if you are, you might consider testing them/suspending them to see if anything changes.

*Deep exhalation*
from belgiangirl on PR:
Another trick might help to lower your adrenalin in the body is this once told me by an older GP when I told him about my heart racing thing:
1. Start breath out as extremely slowly as possible, make it the longest outbreath you could ever do, it may take minutes (of course don't get dizzy or don't nearly try to kill yourself ).
2. Then breath in very quickly.
3. Then repeat: breath out extremely slowly ...

Most people's heart rate goes up when breathing in (adrenalin also) and goes down when breathing out.

 

[drmullin30]

Snow Leopard makes a good point. It might not be adrenaline that is causing your anxiety. It can also be caused by high glutamate or as Pat discussed, gut health. I had very high glutamate levels in part due to multiple concussions over my life as well as early childhood trauma and abuse and probably some mercury toxicity. Symptoms included heart palpitations and tachycardia, stimming e.g. rocking, leg shaking and multiple daily panic attacks for years. I was officially diagnosed with panic disorder and OCD.

My genetics also don't help, I have MAO-A several homozygous, MTHFR 1298 homozygous, COMT several homozygous, GAD several homozygous so my physiology was already predisposed to anxiety.

My advice for anxiety is don't listen to anyone who says it's "in your head" or it's psychological. There are times when life should make you anxious and that response is appropriate but if you are anxious all the time or when there are no reasons to be, it's due to physiological processes that are out of whack and your mind will search for external "reasons" for the sensations and then fixate on the thoughts that amplify the response creating a "vicious cycle" or positive feedback loop. The end of that is a full blown panic attack. Take the physical pain and discomfort of anxiety away and your mind will calm on it's own and your "worries" will seem less threatening.

Personally, my experience with pharmaceutical treatments was disastrous. Most of them are addictive, take years to titrate off of and they caused a lot of side effects and in the end they didn't solve the problem and actually made things worse for me. The pharmaceutical companies are not in business for your well being.

I should also tell you that the single most important step in eliminating my anxiety was going gluten free. A three week trial will tell you if it applies to you.

 

[bertiedog]

Anybody tried GABA to help with this problem? I heard a talk last week by William Walsh PhD who said that often GABA was the thing that was missing in these sort of cases.

One interesting thing also was that if you are an under methylator the worst thing you can do is to take folate as that will make you a whole lot worse. Here is a copy of a note that I made during the talk -

Folates enhance reuptake genes which reduce serotonin activity. These genes will work harder with greater activity so you get more of a substance which basically cannot be used by the body because of epigenetics. He was specifically talking about MTHFR SNPs.

Epigenetic means you are born with the problem of being an under methylator and it will be with you for life. On the other hand you are likely to be empathetic, a good listener and neighbour so it isn't all bad.

He has worked with hundreds of patients with problems of anxiety and he said he has seen the folate problem all the time if they start taking it.

I have bought some GABA but its 250 mg have broken it up into 50 mg capsules and tried them a couple of times without any great effect but did feel quite good the other evening and slept well later. I have many of the problem SNPS that don't break down neurotransmitters and definitely have an overactive brain that can be a real problem especially at night. Both my sons are the same so no great surprise there and one of them definitely had ADHD as a child.

Pam

 

[drmullin30]

Hi Pam, I also tried GABA with little success. I read somewhere that it can't pass the blood brain barrier and if it works for you it means that your BBB is compromised.

I think it's important to note that when you say folates are not good for under methylators it's specifically folic acid and for some, folinic acid. L-5-methyltetrahydrofolate is indispensable for me with my MTHFR issues.

 

[bertiedog]

think it's important to note that when you say folates are not good for under methylators it's specifically folic acid and for some, folinic acid. L-5-methyltetrahydrofolate is indispensable for me with my MTHFR issues.

No it was all folate that he was talking about and he said he had seen it 100s of times for the reason stated, ie you get more of a substance your body cannot use due to epigenetic and less serotonin. I am going to try and find some of his videos because he is an expert at dealing with mental health disorders in criminals who virtually all had compromised SNPs and involving dopamine,, serotonin, and glutamate/GABA.

He said that in fact in working with patients who had low GABA, taking the substance DID work for the vast majority.

Pam

 

[bertiedog]

I have just found this and copied a piece from McGill Office for Science and Society -

What we do know is that human’s BBB contains transporters for GABA, implying that GABA can enter/exit the brain through these channels. In mice it was found that GABA was removed from the brain 17 times faster than it entered.

This could explain the conflicting study results. It may not be that GABA cannot enter the brain, but just that it’s removed from it very rapidly.

GABA as a Supplement

Even if it cannot cross the BBB however, GABA could still be affecting your brain.

The enteric nervous system (ENS) is the network of neurons that control your gastrointestinal system. The ENS contains many GABA receptors, and GABA itself, and is connected to the brain through the vagal nerve. It’s been proposed that ingested GABA is able to affect the body even without crossing the BBB through its interactions with the ENS.

We don’t know at this point how GABA is affecting the brain, but we have good evidence that it is. Several studies have shown reductions in markers of stress in patients given dietary GABA.

On their own the success stories from the consumers who buy GABA supplements are meaningless but taken along with the research findings, they may just show that there is something to these supplements.

We’ll need a lot more research to know for sure if GABA supplements are helpful or not. That being said, they are expensive (like most supplements) and if you’re not anxious, experiencing insomnia or very stressed out they’re probably not worth it. There don’t appear to be many side effects or drug interactions, but until more research is done I’d tread carefully.

Pam

 

[drmullin30]

Thanks for the information on GABA Pam.

Currently I take Kava Kava specifically for the reason that it helps with GABA and glutamate and it's worked extremely well and worked much better for me than GABA supplements. This information is from a paper I found by Beverly Yates:
"Kava is thought to provide anxiety relief without mediation via the benzodiazepine binding site on the GABA(A) receptor complex. A study using mice demonstrated statistically significant dose-dependent improvement in anxiety behaviors. Another study with cats showed that Kava may promote anxiolysis without causing sedation via selective action on limbic structures in the brain. Kava extract also exhibited neuroprotective activity, which was probably mediated by its constituents methysticin and dihydromethysticin. Pyrones constituents have been noted for their inhibition of noradrenaline uptake. Kava seems to facilitate GABA transmission. "

I remember studying some of Bill Walsh's material when I was first learning about methylation. He has many great videos up on youtube. However, including methylfolate as a problematic supplement for under methylators seems counter-intuitive since it's a methyl donor. I also have several SNPs on my TPH (tryptophan hydroxylase) gene so I have trouble making serotonin. At one point I was on SSRIs for anxiety and depression. I always considered myself to be undermethylated as I had all of the symptoms he talks about but some of the overmethylated symptoms as well.

Lately though, I'm becoming less convinced that there is such a thing as an over or under methylator and that there's simply a spectrum methylation cycle defects and effects that are mediated by genetics and epigenetics and there are a lot of potential treatment conflicts between them.

I have been on the Advanced Methylation Protocol (Feddd's Protocol) for almost a year and I take 35 mg (35,000 mcg) per day of L-methylfolate and all of my symptoms are in remission. That protocol includes b12, carnitine, (the deadlock quartet), TMG etc. Greg at b12oils.com stresses the importance of riboflavin, molybdenum and other co-factors as well which I also take. So maybe that's the key for folates to work is that you have to address as much of the cycle as you can.

I also agree with you that the gut is hugely important which could be why I am so much better on a paleo diet. I have never been able to take probiotics though, they always made my symptoms worse. Could be that I just can't find the right blend. I've been thinking about trying a customized probiotic like this: https://www.thryveinside.com/ but I already spend too much on supplements.

 

[percyval577]

@jason30 Selenium could be helpful:
Low selenium diet increases the dopamine turnover in prefrontal cortex of rat Castano et al 1997

Low selenium diet affects monoamine turnover differentially ... Castano et al 1993, from the abstract

The most striking result was the increase of dopamine turnover (63%) and 3-methoxytyramine turnover (55%) in substantia nigra between control and experimental animals.

On the other hand, no changes were found in the turnover rate of dopamine and its metabolites in the striatum. Likewise, no changes were found in noradrenaline turnover in substantia nigra.

In the striatum, there was a significant increase of serotonin turnover versus no change for 5-hydroxy-3-indoleacetic acid. However, in the substantia nigra, serotonin turnover did not show significant changes, whereas 5-hydroxy-3-indoleacetic acid turnover decreased. At the same time, glutathione peroxidase activity significantly decreased in both structures after selenium-deficient diets.

These results suggest that a selenium-deficient diet for a short period of time decreases brain protection, principally in the substantia nigra, against oxidative damage.

(link to be found at the other linked page)​

Furthermore VitE might be of help:
Effects of short period of vitamin E-deficient diet ... Castano 1993, from the abstract:

The levels and turnover of dopamine increased and the levels of serotonin decreased in both structures whereas serotonin turnover decreased only in striatum.

No change was found in the turnover rate of noradrenaline between control and experimental animals.

However, the most striking result was the increase of dopamine turnover found in substantia nigra. This dopamine increase was accompanied by an increase in 3-methoxytyramine turnover which seems to indicate an increase in dopamine release after vitamin E deficiency.

The present study indicates that the nigrostriatal dopamine neurons are susceptible to the deficiency of vitamin E. Moreover, these data suggest that substantia nigra may be more susceptible to damage from vitamin E deficiency than striatum.

@Judee

 

[percyval577]

@bertiedog Thank you for the information on GABA. I have read that it crosses very poorly the BBB (though the BBB might be comprised sometimes). A mechanism I thought on myself were that under supplementation less GABA would be needed to be built in the periphery, thereby increasing the built up in the CNS.

@bertiedog @jason30 I take GABA with taurine, or even with additional tyrosine, in the latter case I use a mixture with 6:6:1. Here I wonder if GABA + taurine does fascilitate nice dopamine function, and preventing a conversion into norepinephren, a quite speculative question though. GABA is high in the basal ganglia (where DA is high too). Taurine has it name from he Taurus, when in the caudatus of the Bull much taurine had been found.

 

[percyval577]

@Judee tagging you here now as tag above doesn´twork.