What do we do? MCAS vs withdrawal

[SpinachHands]

We're in a real catch 22 and can't get any medical advice from doctors about this.
We think a lot of my partner's recent issues are probably from MCAS, and it's probably being flared up by their amantadine. They have been trying to taper off but because of horrific withdrawal can only tolerate dropping by 1 or 2mg every few days. They're down from 50mg to 13mg now, but the MCAS is getting worse every day.

They're already on Montelukast, ketotifen, and Cromolyn at pretty much max dose. They can't tolerate any antihistamines they've tried, including compounded ones, and the only MCAS related supplements they can tolerate are vit C and ALA.

We found that electrolytes help the withdrawal a lot, meaning they could go down in larger amounts, but we can't find an electrolyte that doesn't flare their MCAS up worse. We tried Vitassium, bulk unflavoured electrolyte powder, sports drinks, potassium citrate powder and plain potassium and sodium tablets. The latter two have the least impact on MCAS, but also are least effective at helping the withdrawal.

The withdrawal is so bad they get paralysed or start screaming and hitting themselves uncontrollably. The MCAS is so bad they experience unbearable pressure in their head and stomach pain that leaves them crying out for hours. If we taper the amantadine quicker their MCAS will be able to recover quicker, but the withdrawal will be much worse. If they taper slow then withdrawal will be tolerable but the MCAS will keep getting worse. If they could take electrolytes they could taper quicker but every trial of a new electrolyte just messes them up for the whole day where it makes their MCAS worse.


Their long COVID specialist who prescribed all the meds for MCAS is at a loss. I've found another MCAS specialist who is available in a month. The NHS just straight up doesn't treat MCAS. So we have no medical help, and every decision seems to just hurt my partner worse and worse. This is intolerable, and we don't know what to do. Literally, any ideas are welcome- on how we could taper or manage the MCAS or withdrawal better.

 

[SpinachHands]

Forgot to mention they also couldn't tolerate coconut water, and we can't try most electrolytes as they have magnesium in them, which my partner had a really bad reaction to. We think it interacted with their GABA, and anything that messes with their GABA is making the withdrawal worse.

 

[katabasis]

Sounds like you are in a very tough situation. My first instinct is that you might be able to find something to replace the amantadine with which has a similar neurological effect (I'm assuming this is why your partner is taking it) but doesn't cause the mast cell issues.

Amantadine has a lot of different pharmacological mechanisms - it's an NMDA (glutamate) antagonist, it increases extracellular dopamine, it blocks a variety of nicotinic acetylcholine receptors, it's a sigma-1 receptor agonist, and it probably does a bunch of other stuff that we're not necessarily aware of. From what you described, I would speculate that it's a dopamine related issue. Feeling or actually being paralyzed is reminiscent of Parkinsonian (read: low dopamine) symptoms, and withdrawal from dopaminergic drugs like amphetamine often produces intense anxiety, depression, feelings of frustration.

I've always thought dopamine is a factor in ME/CFS spectrum illnesses. I've personally experienced symptoms similar to akathisia (which is a state of dopamine dysregulation caused by antipsychotics, which generally block dopamine receptors), and dopamine agonists like pramipexole have been shown to improve symptoms of fibromyalgia. Potentially you could use a dopaminergic drug, but it's a bit risky because dopamine agonists (like pramipexole) and dopamine releasers like amphetamine both have lots of side effects that I can see being extremely unpleasant for someone with MCAS or ME/CFS. And of course there's no telling whether they might also exacerbate the MCAS in a similar way to amantadine.

I think a compelling alternative would be to use ketamine, which primarily acts as an NMDA antagonist but also has been shown to increase dopamine in the VTA. I've read that it may cause histamine release, but this is not an immunological/anaphylactoid reaction but rather a pharmacological one, which at least theoretically would be prevented if your partner is already taking ketotifen. The major upside is that ketamine has a very short duration (around an hour for the main psychotropic effects) so if there were a bad reaction, it would hopefully resolve fairly quickly. Of course, this is also a downside, as you'd need to dose frequently in order to maintain an effect if it helps. It may also be difficult to acquire ketamine - not sure of its legal status in the UK (pretty easy to get it prescribed in the US).

Another option might be to balance your partner's dopamine responsiveness with anticholinergic drugs. In fact this is a common treatment modality for akathisia. I think a good first option would just be diphenhydramine (Benadryl) - which also happens to be an antihistamine, so it might be more MCAS-safe. And even if it's not treating the withdrawal intrinsically, it causes sedation, which might subjectively help your partner's distress.

Of course, all of this assumes that it's a dopamine issue. If it were a glutamate issue, ketamine could also help, but you might also consider agmatine, or if you can acquire it, gabapentin (which is a alpha-2-delta calcium channel blocker, but NMDA receptors form complexes with this receptor so there's significant coinhibition). Dextromethorphan could also potentially work, and it's also a nicotinic antagonist and sigma-1 agonist like amantadine, but it's notorious for interacting with a ton of different receptors and I suspect that it would probably end up causing a mast cell reaction in someone whose MCAS is so sensitive/severe.

Anyway, hope this helps or is at least food for thought.

Edit: FYI amantadine shouldn't really affect GABA, at least directly. If we're talking about net inhibition of neural activity, it's more a glutamatergic thing. But if you want to go down the GABA path, a benzodiazepine might help, particularly clonazepam because it has some NMDA antagonist properties as well. However you must realize any direct GABAergic treatment is just kicking the can down the road because they are also very habituating, and withdrawal from them will be as bad if not worse. If they don't cause a mast cell issue, this still maybe be preferable since you won't be under a time pressure to complete the withdrawal.

 

[Lara*~]

First thought is Normalyte electrolyte, it’s magnesium free. Other thoughts for electrolyte trials could be high potassium Celtic sea salt, potassium pink cave salt is what I came across, Celtic Sea Salt brand. Are trying other fruit or veggie juices an option? Watermelon and citrus have electrolytes. Salted cucumber. Last thought is fresh salty chicken broth, the boxed stuff would likely trigger mcas.