9 replies to this topic

[StevesPetRat]

Apologies in advance; this thread should be of general interest, but it is, shall we say, inspired by personal experiences. In brief, it's been a rough 15 months. I decided to put any gory details and lengthy symptom lists in spoilers so you can cut to the chase if you like.

Spoiler

Liver damage (thanks, terbinafine ... well, with the assist from ethanol), break up, alcohol withdrawal x 2, benzo withdrawal, job loss, a grueling 2 day job interview near my lowest cognitive point, moving three times, family trying to have me committed, loss of two close relatives and a beloved pet, a nasty virus that left me with some kind of nerve / muscle / heart damage (I think it was maybe an enterovirus; two coworkers also presented with muscle weakness, pain, and fasciculations, GI distress, and lightheadedness, but their symptoms resolved in a week or so), and a "healthy" dose of stachybotrys spores to top things off. After being on this board a while, I know a lot of people go through worse and make less of a big deal of it (of course there are others who make more of less, too), but my point is there's been an objectively large amount of physical and mental stress in the recent past.

Anyway, I'm in a ... temporarily adequate, shall we say ... place now, mentally speaking, though there are some persistent physical and cognitive symptoms that at first seemed unrelated but, upon reflection, actually could all be tied to deficits in cholinergic transmission. And that's the point of this thread.
 
I ran across this paper which suggests an acute trauma may induce chronic changes in acetylcholine expression:
Acute stress facilitates long-lasting changes in cholinergic gene expression
I haven't read the full text, but they imply that the surge in acetycholine that occurs during acute stress (perhaps this is the cause of "life flashing before one's eyes"??) leads to epigenetic changes leaving one in a chronically hyperexcitable state. However, they associate these symptoms with AChE inhibitors, i.e. a surplus of ACh.
 
Now, I dunno about that, but Wikipedia lists the following as anticholinergic side effects:

Spoiler

Possible effects of anticholinergics include:

• Ataxia; loss of coordination
• Decreased mucus production in the nose and throat; consequent dry, sore throat
• Xerostomia or dry-mouth with possible acceleration of dental caries
• Cessation of perspiration; consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
• Increased body temperature
• Pupil dilation (mydriasis); consequent sensitivity to bright light (photophobia)
• Loss of accommodation (loss of focusing ability, blurred vision – cycloplegia)
• Double-vision (diplopia)
• Increased heart rate (tachycardia)
• Tendency to be easily startled
• Urinary retention
• Diminished bowel movement, sometimes ileus (decreases motility via the vagus nerve)
• Increased intraocular pressure; dangerous for people with narrow-angle glaucoma.

Possible effects in the central nervous system resemble those associated with delirium, and may include:

• Confusion
• Disorientation
• Agitation
• Euphoria or dysphoria
• Respiratory depression
• Memory problems
• Inability to concentrate
• Wandering thoughts; inability to sustain a train of thought
• Incoherent speech
• Irritability
• Mental confusion (brain fog)
• Wakeful myoclonic jerking
• Unusual sensitivity to sudden sounds
• Illogical thinking
• Photophobia
• Visual disturbances
  • Periodic flashes of light
  • Periodic changes in visual field
  • Visual snow
  • Restricted or "tunnel vision"
• Visual, auditory, or other sensory hallucinations
  • Warping or waving of surfaces and edges
  • Textured surfaces
  • "Dancing" lines; "spiders", insects; form constants
  • Lifelike objects indistinguishable from reality
  • Phantom smoking
  • Hallucinated presence of people not actually there
• Rarely: seizures, coma, and death
• Orthostatic hypotension (sudden dropping of systolic blood pressure when standing up suddenly) and significantly increased risk of falls in the elderly population

I have all of these (though the mental ones are improving), except no seizures, no full-blown audiovisual hallucinations but only mild disturbances, my orthostatic problem is not really hypotension but POTS (treated with AChEI), and, as far as I can tell, I'm not in a coma or dead. They sorta started mildly a while ago, and became really acute after the virus hit.

Some additional symptoms that may be anticholinergic in nature:

Spoiler

• Poor peripheral and skin circulation (cold fingers and toes; I used to be bright as a beet but now pale as a sheet)
• Spinal arthritis (shows up on MRI) and knee / hip pain
• Tinnitus
• Stutter / stammer
• Every one of these growth hormone deficiency symptoms (or at least the ones that don't require a blood test to confirm). As it turns out, growth hormone release is dependent on muscarinic acetylcholine receptors (study picked up from this great thread)
• Sinusitis, possibly, if the effect discussed in that link is somehow due to ACh depletion
• Loss of libido (physically, not mentally, if that makes sense), near-impotence, PE (? can't find a great source for this, but a few "men's health" sites mention it)
• Muscle weakness and pain (connection should be obvious, e.g. as in myasthenia gravis)

There are probably more that other people have, but those are the ones I've got (plus a few other weird things like lumpy adipose tissue - despite being at my lowest weight in 16 years - kidney / adrenal pain, collagen defects - oh wait, that's another HGH thing). Interestingly, as an aside, glaucoma is treated by M3 agonists.

So I've got all these symptoms, and a lot of other people have some or all these symptoms (and some I don't) associated with diverse chronic conditions such as

• CFS/ME
• The morass known as "Adrenal fatigue"
• Post acute benzodiazepine withdrawal
• Chronic Lyme
• Gulf War Syndrome
• PTSD
• MG, Sjogren's, other autoimmune diseases
• More?

Rather than posting 50 studies, just google "stress acetylcholine", and other similar combinations, and you can find various research articles. The gist is that stress floods the brain (not sure about the periphery, but I would imagine there too, since you'd need to be able to flex your muscles) with ACh, which upregulates AChE for a several day period... which somehow messes everything else up indefinitely.

Could it be so simple that so many symptoms of chronic conditions arise as a malfunction of the longest-known neurotransmitter -- a sort of hyperactive sympathetic and anemic parasympathetic nervous system? Or perhaps even stress-induced autoantibodies, a sort of functional myasthenia gravis? I'm guessing no, but still ... cofactors such as B5 are popular in adrenal fatigue treatment, and B1 megadoses have a decent response rate in CFS/ME.

There may be a genetic component. For instance, my mother and her sister have had many of these symptoms since their mid 40s. Of possible relevance, I'm homozygous for COMT V158M, COMT H62H, and MAO-A R297R, which means lots of dopamine with impaired neurotransmitter breakdown. People with that genotype are particularly susceptible to chronic stress. Oopsie.

OK, so IF this mechanism is correct, what are the possible treatment options? Here's what I can think of, in ascending quality:
1) ACh agonists. I don't know if AChR are susceptible to the same downregulation as other receptors, but presumably they are, so this isn't a great option
2) AChE inhibitors. Ditto to 1. Blunt instrument approach
3) Supply abundant precursors, magnesium, thiamine / benfotiamine / sulbutiamine / allithiamine, pantothenic acid / pantethine, and a choline source. Let the body make what it needs. I don't know that this would work, as from personal experience I already get plenty of these in my diet (and furthermore supplement thiamine to make up for possible depletion from booze). Also may lead to downregulation. Nevertheless, I may try a megadose protocol and report back. A doc was able to treat 30% of stutterers with such a protocol.
4) Vagus nerve stimulation may help, if sufficient ACh is actually available
5) Find a way to upregulate / rebalance cholinergic receptors. Not sure exactly how.
6) Increase BDNF to generally restore neuroplasticity. There are a variety of ways to do this. Still, TrKB downregulation is an issue.
7) Restore proper cortisol homeostasis and hopefully the cholinergic system will follow suit.

If anyone knows more about the cholinergic system and stress, please chime in. Any other thoughts or comments are welcome also.

Personally, I think I'm going to finally dig into that pile of NSI-189 that's been sitting around for a couple months really soon.

Edit: added PTSD.

Edited by StevesPetRat, 13 October 2014 - 08:23 AM.

[StevesPetRat]

Oh, also wanted to add:
I wonder what the effects of reactivating the parasympathetic system would be on somebody who has been accustomed to running almost entirely on adrenaline for a long period. Perhaps this could explain the fatigue and depressive side effects seen with NSI-189? If it rapidly remodulates cholinergic transmission, it may take a while for epinephrine and dopamine receptors to upregulate. But that's just wildly irresponsible speculation.

[mindpatch]

Of possible relevance, I'm homozygous for COMT V158M, COMT H62H, and MAO-A R297R, which means lots of dopamine with impaired neurotransmitter breakdown. People with that genotype are particularly susceptible to chronic stress. Oopsie.

 

This interests me.  I've seen mentioned before folks here citing their genetic predispositions through genetic tests, one of which was, I think, 23andme.com.  Then someone mentioned that has turned into a scam site. 

 

To me, that's where people should start if they want to gain insight into how to improve their overall function, or correct for their own congenital weaknesses.  In my case, I was diagnosed with ADHD as a teen with concurrent depression, and was on SSRI's for years.  I think this actually hurt me, downregulating my dopaminergic system, which, if that system genetically started relatively weaker, means that SSRIs were the absolute worst thing I could have taken.

 

 The treatment protocol with meds has, up till now, been a haphazard shotgun approach...or it lacks precision.  "oh, you feel depressed?  Here, have some anti-depressants." 

If there are certain types of ADHD and depression or cognitive dysfunction that a very specific root cause genetically, then wouldn't it make sense to have a tailored approach to treatment?  If through testing you determine you have a particular gene over or underexpression, it would be most efficacious to develop a treatment protocol that dealt with individual variation. 

 

There are lots and lots of threads here talking about the latest and greatest supplements and research chemicals to fix us.  To me it would seem like there needs to be postings and thinking on how to identify and properly treat very specific genetic problems. 

[StevesPetRat]

The treatment protocol with meds has, up till now, been a haphazard shotgun approach...or it lacks precision.  "oh, you feel depressed?  Here, have some anti-depressants." 
If there are certain types of ADHD and depression or cognitive dysfunction that a very specific root cause genetically, then wouldn't it make sense to have a tailored approach to treatment?  If through testing you determine you have a particular gene over or underexpression, it would be most efficacious to develop a treatment protocol that dealt with individual variation.

Yes, I totally agree. I think 23andme is still pretty reliable, though if I had the money I'd buy one or 2 more tests just to make sure the results were consistent. The gene results really turned on the lightbulb as to my poor response to Adderall when I "suddenly developed" ADD out of nowhere after a bout of Epstein-Barr virus (a half dose kept me awake in a manic state for three days, woo!). Some integrative practitioners use gene testing to tailor treatments, but it's hardly mainstream yet. And it may very well take a generation before it catches on.

[mindpatch]

I'd forgotten I'd responded to this.  Although I don't quite have the constellation of symptoms that you do, and what I've experienced doesn't quite match the symptom profile of an anticholinergic syndrome, my problems with severe anxiety and anhedonia came on rather suddenly when I was undergoing quite a lot of physical stress.  

 

continue to give us updates. 

[factsmachine]

After being prescribed Orphenadrine for my car accident last week, the first dose gave all of the symptoms of anticholigernic crap such as delusions.
It's been 24 hours and the pill is a 12 hour extended release. Should I just keep waiting or will this problem fix itself?
I was doing excellent with verbal cognition, memory and everything even anxiety, mood and socially but then 1 pill of this and I feel so... dumb and zombified, not clear headed. Terrible, atleast the unpleasant delusions went away.. after I slept for the full day, that is.
all because they didn't want to prescribe something more abusable. They didn't order X rays. And they also said there is a shortage of codeine promethazine cough syrup, or they would give me it (I have job interviews and i have a cold) I found out my pharmacy has it in stock..
She also gave me an anticholigernic nasal spray at the same time. I didn't even turn in the prescription because I was smart enough to know that orphenadrine was already an ache inhibitor.

[StevesPetRat]

After being prescribed Orphenadrine for my car accident last week, the first dose gave all of the symptoms of anticholigernic crap such as delusions.
It's been 24 hours and the pill is a 12 hour extended release. Should I just keep waiting or will this problem fix itself?
...
She also gave me an anticholigernic nasal spray at the same time. I didn't even turn in the prescription because I was smart enough to know that orphenadrine was already an ache inhibitor.

It has a long half life, but it's an anticholigernic rather than an AChEi, so when it finally wears off you should be OK. Give it another day or 2.

[Irishdude]

I think we are in a similar place. Did you find a solution?

[lourdaud]

IME there may be some truth to this. Coluracetam and galantamine seem to help.

[gamesguru]

Stress also contributes to cytokine and interleukin disruptions.  Blueberries, ginseng, bacopa, shilajit, galantamine, zinc and many other common supplements have the dual effect of lowering cytokines and raising acetylcholine.  Perhaps in your case one of them would quite helpful?