Dopamine modifying agents

Turtle said:
I use ropinirol, a dopamine agonist, low dose(4mg) it only works against restless legs and nerve pain (SFN,Raynaud or whatever). No effect on other symptoms. It helps me sleep though.
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Interesting thanks. Yes that’s on the list. Looks to mainly affect D2 (and D2 like) and doesn’t seem to have shown up in any papers or theories posted to the forum. May be interesting looking at a wider search.
 
hotblack said:
Interesting thanks. Yes that’s on the list. Looks to mainly affect D2 (and D2 like) and doesn’t seem to have shown up in any papers or theories posted to the forum. May be interesting looking at a wider search.
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It was used quite a bit for FM alongside gabaergics in the 00's. Maybe still is. Probably gets a mention in Teitelbaum. Best avoided before sea crossings!
 
I’ve been on several of those!

Risperidone did nothing except give me brain fog.

Latuda works great for OCD (what I take it for), but if it has any impact on ME, it’s marginal. I thought it had some minor benefit when I started it, but it’s very possible it was just the downstream effect of not being extremely stressed from OCD all the time.

Methylphenidate has been very helpful with brain fog, avoiding cognitive PEM, and OI, but it doesn’t seem to get at the core of ME. The improvements in brain fog and cognitive PEM threshold may just be because I have ADHD, so the drug probably reduces how much effort it is to concentrate. I’m not sure whether it would help someone who doesn’t have ADHD.
 
I tried low doses of rotigotine for sleep. It gave me a panic attack. My sympathetic system spiked, my pulse rose a lot and it felt like ants in my brain.

I don’t tolerate LDA either, makes me hyper. It seems like my brain prefers depressors over stimulants, my issue seems to be hyperexciteability in the brain, ANS, and vascular system (as in hyper reactive, not stuck in under- or overdrive).

Migraine medication in form of triptanes that causes vasoconstriction in the brain, gave me a similar reaction.

So I’d be careful. But it was an important test for me to figure out what is plausiable in my personal pathology seeing what meds I don’t tolerate - other examples are midodrine, memantine, and normal doses of SSRI.
 
I probably haven't been paying attention so could someone remind me what the possible connection between dopamine and ME is?

Having been given an ADHD diagnosis fairly recently, my experience of the psychostimulants I have been prescribed seems atypical.

In short they did nothing noticeable in improving concentration on tasks and all the supposed "executive dysfunction" that is part of this condition.

One thing that dexamphetamine did albeit briefly was have a slight analgesic effect on the sort of pain that can go with mild ME, the feeling a bit rough but not so much that I would bother to take any painkillers normally. This was interesting but didn't last much beyond a month as I recall and then they stopped doing anything I could gauge as useful (thing I was most aware of was increased thirst, but quite a long time after dose taken, as well as sometimes increased agitation and confusion!)

I find myself wondering whether I am producing enough dopamine for these substances to be useful in shunting it to the right place or stopping reabsorption. Perhaps there is more demand to convert it into noradrenaline or adrenaline or I am lacking the right enzymes to produce it from tyrosine etc. Clearly I don't have the background to understand the neuroscience (though I don't feel particularly confident the psychiatrists in this field do either!)
 
I think one recent thing was this abstract Integrity of Presynaptic Neurons in Long COVID and Relationship to Neuropsychiatric Symptoms which claims to have found a reduction of dopaminergic synapses in some parts of the brain. Hopefully we'll get more information about their methods soon (I think the abstract mentions there will be a forthcoming poster?)

I did a some reading on how we think stimulants work recently and I was thinking of putting it in a thread if people are interested.

It does seem like it's possible for dopamine transmission to be borked and yet stimulants not quite able to unbork it. People with ADHD often find that their stimulants don't work as well during their menstrual cycle (I should find a reference for this, but it happens to me and I had two separate doctors mention it). I assume we give people with parkinsons levodopa (a dopamine precursor) rather than dopamine-releasing stimulants because there is an actual shortage of dopamine there?

Another thing I read is that since amphetamine-type stimulants use the dopamine transporter (to get into the neuron, where they work), and methylphenidate inhibits the dopamine transporter, taking methylphenidate (i.e. ritalin) at the same time as amphetamines (i.e. adderall) reduces the effect of the latter.**

I believe both class of stimulants cause an eventual increase in dopamine transporters though, so if that was the whole problem it would likely fix itself over time.

**I just tried to look up my reference for this but I'm getting snowed in pop sci results so I'll just find it next time I'm going through all the stimulant literature and edit this if I'm misremembering..
 
Starrynight said:
I probably haven't been paying attention so could someone remind me what the possible connection between dopamine and ME is?
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For me it is a long process of trying to home in on what fits the overall picture of the disease. Historical information about the symptom pattern and time course makes a problem in the central nervous system a likely candidate. DecodeME principally found gene variants linked to CNS and tracking their expression patterns has led people to think of particular areas and cell groups. That includes hypothalamus, hippocampus nucleus accumbens and there is a particularly strong signal for a neuron type called eccentric medium spiny neurons. I don't know the details but distinct gene expression in neurons tends to point to distinct transmitter use, which includes dopamine and glutamate. Dopamine has been manipulated in the past so potential effects of dopamine modulators on ME/CFS seems of interest.
 
mariovitali said:
If dopamine and/or glutamate regulation were important and had central role we would have known by now. Is this assumption correct ?
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If it were simply a matter of there being too much or too little of one or in ME/CFS maybe but I don't see that as a likely scenario. Despite all the drug development around 5HT it seems that we still have no consensus about the role of 5HT in the diseases they are used for.
 
Jonathan Edwards said:
If it were simply a matter of there being too much or too little of one or in ME/CFS maybe but I don't see that as a likely scenario. Despite all the drug development around 5HT it seems that we still have no consensus about the role of 5HT in the diseases they are used for.
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Once again, I see that you dismiss things quite easily @Jonathan Edwards and I say this very respectfully, as always. If dopamine and glutamate were strictly immune related, I would understand since the immune system is your field. Since dopamine and glutamate are clearly not related only to the immune system but are heavily associated with the nervous system, it would be great to have some references regarding what you wrote about 5HT. In other words, "I don't see that as a scenario" would be more productive to explain why this is so with references.
 
mariovitali said:
In other words, "I don't see that as a scenario" would be more productive to explain why this is so with references.
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I have explained it in detail on the forum over the years and in the review articles I have published with others here or working in the field. If you cannot follow my logic I am sorry, but I don't see any responsibility for providing references for the longstanding debate over 5HT modifying drugs for depression. These days you can get an answer in twenty seconds by Googling. Most people have heard of SSRI's. Half the world have taken them. Most educated people are aware that (a) the original theoretical basis for using them fell into doubt (b) there is debate about how well they actually.
 
mariovitali said:
If dopamine and/or glutamate regulation were important and had central role we would have known by now. Is this assumption correct ?
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Why would we have known by now? I guess a lot hands on ‘central role’ and ‘regulation’ too. I can see ways they could be involved but not necessarily hold a central role, maybe just part of the larger picture in some way.
 
mariovitali said:
it would be great to have some references regarding what you wrote about 5HT.
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It's only a sliver of the story, but you might be interested in this blog post on the history of the serotonin transporter gene (5-HTTLPR), and how a small subfield of probably entirely spurious results formed around it.

Some fun quotes:
The problem isn’t that people studied this. The problem is that the studies came out positive when they shouldn’t have. This was a perfectly fine thing to study before we understood genetics well, but the whole point of studying is that, once you have done 450 studies on something, you should end up with more knowledge than you started with. In this case we ended up with less.
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First, what bothers me isn’t just that people said 5-HTTLPR mattered and it didn’t. It’s that we built whole imaginary edifices, whole castles in the air on top of this idea of 5-HTTLPR mattering. We “figured out” how 5-HTTLPR exerted its effects, what parts of the brain it was active in, what sorts of things it interacted with, how its effects were enhanced or suppressed by the effects of other imaginary depression genes. This isn’t just an explorer coming back from the Orient and claiming there are unicorns there. It’s the explorer describing the life cycle of unicorns, what unicorns eat, all the different subspecies of unicorn, which cuts of unicorn meat are tastiest, and a blow-by-blow account of a wrestling match between unicorns and Bigfoot.
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Second, most studies about 5-HTTLPR served to reinforce all of our earlier preconceptions. Start with the elephant in the room: 5-HTTLPR is a serotonin transporter gene. SSRIs act on the serotonin transporter. If 5-HTTLPR played an important role in depression, we were right to focus on serotonin and extra-right to prescribe SSRIs; in fact, you could think of SSRIs as directly countering a genetic deficiency in depressed people. I don’t have any evidence that the pharmaceutical industry funded 5-HTTLPR studies or pushed 5-HTTLPR. As far as I can tell, they just created a general buzz of excitement around the serotonin transporter, scientists looked there, and then – since crappy science will find whatever it’s looking for – it was appropriately discovered that yes, changes in the serotonin transporter gene caused depression.
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Anyone looking at the cortisol saga in ME/CFS can relate:
But this was just the worst example of a general tendency. Lots of people were already investigating the role of the HPA axis in depression – so lo and behold, it was discovered that 5-HTTLPR affected the HPA axis.
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mariovitali said:
Getting back to dopamine and glutamate, I do believe they are very important. But if they were central we must have had some people getting significantly better by tweaking them.
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I can see the argument for this but it depends on what 'central' means.

Let us propose that ME/CFS is due to a long term failure of function of eccentric medium spiny neurons in certain sites. Perhaps these neurons have suffered an epigenetic change that makes them unreponsive to certain stimuli. Perhaps that involves a loss of the machinery for maintaining dopamine or glutamate mediated interactions at either dendritic inputs or axonal outputs. Basically the cells become deaf to the relevant transmitter. If you then give drugs that raise or lower levels of the relevant transmitter then you might not see any effect.

You might then say, reasonably that searching drugs that modulate these transmitters was unlikely to get anywhere.

But it might be that a particular drug that altered the turnover of some component of the relevant machinery just happened to lead to the eMSN neurons learning to reverse their epigenetic change and re-establish normal signalling. This might be through a particular receptor subtype which up until now has not been targeted.

An analogy might be the discovery of the benefit of Viagra. In the 1980s people might have thought that they knew more or less what there was to know about phosphodiesterase inhibition. They thought they knew roughly what diseases it would help. But then they thought blocking PDE5 might help angina in a way that other drugs had not.

They turned out to be quite wrong. It was no use for angina but brilliant for something unexpected.
 
Jonathan Edwards said:
Let us propose that ME/CFS is due to a long term failure of function of eccentric medium spiny neurons in certain sites. Perhaps these neurons have suffered an epigenetic change that makes them unreponsive to certain stimuli. Perhaps that involves a loss of the machinery for maintaining dopamine or glutamate mediated interactions at either dendritic inputs or axonal outputs. Basically the cells become deaf to the relevant transmitter. If you then give drugs that raise or lower levels of the relevant transmitter then you might not see any effect.

You might then say, reasonably that searching drugs that modulate these transmitters was unlikely to get anywhere.
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Yes, I understand this hypothesis. I would like to take this hypothesis to an upstream level however and ask : Are eMSNs capable to generate the multitude of symptoms that ME/CFS patients have ? (=alterations of immune, metabolic, and neuromuscular pathways).

Can eMSNs be responsible for ME/CFS patients who cannot tolerate medications? I do not understand how we can infer that this is a possibility.

As previously discussed, I find it extremely frightening that all of the different findings of dysregulations found in ME/CFS patients are being attributed to a single point of failure such as eMSNs and at the same time, several studies are considered worthless.
 
mariovitali said:
Yes, I understand this hypothesis. I would like to take this hypothesis to an upstream level however and ask : Are eMSNs capable to generate the multitude of symptoms that ME/CFS patients have ? (=alterations of immune, metabolic, and neuromuscular pathways).

Can eMSNs be responsible for ME/CFS patients who cannot tolerate medications? I do not understand how we can infer that this is a possibility.

As previously discussed, I find it extremely frightening that all of the different findings of dysregulations found in ME/CFS patients are being attributed to a single point of failure such as eMSNs and at the same time, several studies are considered worthless.
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I could be wrong but looking at eMSNs (or just the highly expressed brain tissues in DecodeMe) is something up stream from all these pathways.

Even if it’s not upstream it’s a solid place to start looking that hasn’t been fished before.
 
mariovitali said:
Are eMSNs capable to generate the multitude of symptoms that ME/CFS patients have ? (=alterations of immune, metabolic, and neuromuscular pathways).
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I think very much so. That to me is the least of our problems. I am more puzzled by why eMSN should fall prey to some post-infective error in maybe less than 1% of people in a lifetime.

People with hypothalamic disease have all sorts of symptoms relating to sleep, fatigue, etc. Other parts of the brain give rise to alterations in pain and sensitivity to stimuli.

But we have not yet found any consistent alterations in immune pathways as far as I know. The puzzle there is that there are symptoms but the peripheral pathways we have access to all seem rather normal.

And although there may be some slight metabolic shifts it is not clear to e that these are not downstream of alterations in activity or diet or artefacts of cohort selection (as Hutan has discussed).

And again, I am not aware of any alterations in neuromuscular pathways other than shifts in ability to do activity that could well reflect sensitivity changes in muscle nociceptors feeding the thalamus and associated basal ganglia.

To my mind there is little doubt that the vast majority of studies in ME/CFS are not so much worthless as evidence that these other aspects of the body are probably much more normal than the investigators would like to claim. Certainly, as an immunologist i am sure that if there is an ongoing immune abnormality, and I think there probably is, it is something that so far we have not been able to identify reliably. Which makes it quite likely to be hidden away in some neural compartment like dorsal root ganglion or subfornical organ.
 
I found the early symptoms of Parkinson's, which, as far as I understood, is a dysregulation of MSNs through a lack of Dopamine resonates with MECFS symptoms quite well.

But of course these symptoms are unspecific and could be caused by a lot of mechanisms.

According to AI they include dysautonomia, constipation, fatique, bad sleep, softening voice, and cognitive impairement
 
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