# Hypercholinergic Depression - Dopamine/Acetylcholine Balance



## mikoy (Aug 12, 2010)

I think that excess acetylcholine may cause depression. Why I think so?

- I have depression with bad responsive to treatment with almost all antidepressants (SSRI, mianserin/mirtazapine, trazodone and other.). But I react well with older drugs like doxepin or amitryptyline. I know that they have a complex mechanism of action, but exclude all the possibilities using - antihistamines (h1,h2), alpha1 antagonists, serotonin reuptake inhibitors, noradrenaline inhibitors, 5-ht2 antagonists. The only thing that remained was muscarinic receptors blockade. I tried to check it out, and take oxybutynin (m1,m2,m3 antagonist), and that was it!

- Physostigmine, a cholinesterase inhibitor which increases acetylcholine levels make people depressed. -> http://www.psychosomaticmedicine.org/cgi/reprint/36/3/248.pdf

Watch out now:

"...We have also reported that methylphenidate (Ritalin®) induced behavioral activation consisting of *increased talkativeness* and *interactions*, as well as increased psychotic symptoms in psychotic patients, *can be antagonized* or prevented by administration of *physostigmine* (9). Similarly, methylphenidate-induced stereotyped
behavior in rats is decreased or prevented by physostigmine (10). Conversely, the anergic syndrome induced by physostigmine is readily reversed by injection of methylphenidate (9)..."

So maybe people who react poorly to dopamine drugs should be added anticholinergic drug to enhance this activity?

Maybe pro-social effects of stimulants in some is blocked by excess of acetylcholine?

-> http://www.ncbi.nlm.nih.gov/pubmed/15857718

Maybe anticholinergic drug may prevent tolerance to stimulants?

Maybe dopamine and anticholinergic drug is that what we are looking for?


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## crayzyMed (Nov 2, 2006)

Yes:
http://www.socialanxietysupport.com...t-antidepressant-effect-of-scopolamine-97134/



> Maybe anticholinergic drug may prevent tolerance to stimulants?


No, Memantine will tough.

Anticholinergics are antidepressive and could be of major help for some ppl.


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## mikoy (Aug 12, 2010)

I took oxybutynin (5mg) a few hours ago... and I have an incredible feeling of calm and control of my body


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## Iwillovercomeanxiety1 (Aug 23, 2010)

Very interesting! I am taking Hyoscyamine which is also an anticholinergic. I'm taking it for my hyperhidrosis. I see that Oxybutyin also can be used for hyperhidrosis but if it works on depression too that I think it would be wise for me to switch over. Can somebody please let me know what the difference is between Oxybutyin and Hyoscyamine? Will Hyoscyamine not possibly work for depression in the same way that Oxybutynin does?


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## mikoy (Aug 12, 2010)

Umm, your drug works stronger than oxybutynin (it's also depends on how much you take it). On wiki writes that this drug antagonises serotonin - that's interesting. Interesting if this drug only antagonises serotonin or all anticholinergics somehow antagonises it. You do not have a sense of peace and a better mood after him? So maybe not for all this drugs has those effects. From today I'm taking anticholinergics with medikinet (ritalin), and I will inform you.

PS. I wonder if anti-depressant effect of wellbutrin has something to do with his antagonizing nicotinic receptors properties. Reportedly there is antidepressant and anxiolytic drug in phase 3 tests that block nicotinic receptors.


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## mikoy (Aug 12, 2010)

Methylphenidate make me more emotional to music, feelings, nice  For sure I have too little dopamine.

"...We report that M1 deficiency leads to elevated dopaminergic transmission in the striatum and significantly increased locomotor activity. M1-deficient mice also have an increased response to the stimulatory effects of amphetamine. Our results provide direct evidence for regulation of dopaminergic transmission by the M1 receptor and are consistent with the idea that M1 dysfunction could be a contributing factor in psychiatric disorders in which altered dopaminergic transmission has been implicated."

http://www.pnas.org/content/98/26/15312.abstract


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## crayzyMed (Nov 2, 2006)

Muscarinic antagonism increases dopamine and can be called a good thing, nicotinic agonism does too (altough oversimplification, some receptors act differendly).

Galantamine (wich inhibits breakdown of acetylcholine) increases dopamine because it acts as a PAM on some nicotinic receptors.


> Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors
> 
> Björn Schilström1, Vladimir B Ivanov1, Charlotte Wiker1 and Torgny H Svensson1
> 
> ...


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## weebeastiebaby (May 15, 2009)

mikoy said:


> I think that excess acetylcholine may cause depression. Why I think so?
> 
> - I have depression with bad responsive to treatment with almost all antidepressants (SSRI, mianserin/mirtazapine, trazodone and other.). But I react well with older drugs like doxepin or amitryptyline. I know that they have a complex mechanism of action, but exclude all the possibilities using - antihistamines (h1,h2), alpha1 antagonists, serotonin reuptake inhibitors, noradrenaline inhibitors, 5-ht2 antagonists. The only thing that remained was muscarinic receptors blockade. I tried to check it out, and take oxybutynin (m1,m2,m3 antagonist), and that was it!
> 
> ...


That is interesting. For me personally, amitryptyline has a definite sedative effect, but actually makes me more anxious. A very unpleasant combination! I respond well to adderall, benzodiazepines, and opiates. There is an interesting book I own called The Edge Effect which explains how different medications effect people in different ways because everyone is "programed" to have differing amounts of serotonin, dopamine, GABA, and acetylcholine. It proposes that when the amount of ones dominant neurotransmitter is depleted, they will suffer from a variety of physical and mental ailments. There is a test in the book to determine your dominant neurotransmitter.


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## mikoy (Aug 12, 2010)

Very interesting article "Cholinergic mechanisms in depression":

http://deepblue.lib.umich.edu/bitstream/2027.42/26059/1/0000133.pdf

"...Substances of abuse, including alcohol, canna-
binoids, barbiturates, opiates, and antimuscarinic
agents, either block the presynaptic release of acetyl-
choline or directly block postsynaptic muscarinic re-
ceptors. Thus, substances of abuse - agents mod-
ulating mood and affect or promoting hedonia - ap-
pear to antagonize cholinergic systems. activate
monoaminergic systems, or, as in the case of the stim-
ulants, both, providing moderate or possible evi-
dence for the cholinergic hypothesis and suggesting
points of study..."

On anticholinergic I have almost the same peace of mind and body like on alcohol. And my senses are stronger - especially touching simple things is very pleasant. I think there is stong link between dopamine-acetylcholine-GABA.


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## LALoner (Dec 3, 2008)

mikoy said:


> Very interesting article "Cholinergic mechanisms in depression":
> 
> http://deepblue.lib.umich.edu/bitstream/2027.42/26059/1/0000133.pdf
> 
> ...


I believe you when you say anticholinergics help your mood. I'm curious if nicotine from smoking hurts your mood since nicotine is prolly the most commonly used cholinergic. If nicotine doesn't hurt your mood may the effect you are feeling is from something other than the direct influence on acetylcholine. Of course you might never have smoked. Anyway, I think it would be interesting to know how nicotine affects someone whose mood is helped by anticholinergics.


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## crayzyMed (Nov 2, 2006)

LALoner said:


> I believe you when you say anticholinergics help your mood. I'm curious if nicotine from smoking hurts your mood since nicotine is prolly the most commonly used cholinergic. If nicotine doesn't hurt your mood may the effect you are feeling is from something other than the direct influence on acetylcholine. Of course you might never have smoked. Anyway, I think it would be interesting to know how nicotine affects someone whose mood is helped by anticholinergics.


Nicotine only acts on the nicotine receptors and facilates dopamine release, anticholinergics that shows the most robust effects in depression act on the muscarinic receptors, basicly you could combine them perfectly with nicotine.

@mikoy
Thats a good link.


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## mikoy (Aug 12, 2010)

I've never had a cigarette in my mouth, so simply I don't know. But nicotine work's on nicotinic receptors - anticholinergics block te muscarinic receptors (oxybutynin blocks M1,M2 and M3 - and helps me with my hyperhydrosis). I think acetylcholine alone have no effect on mood, but if it raises to high levels it can block dopamine release. I feel dopaminergic state on anticholinergics - I'm affraid but I think I'm predisposed for pakinson disease in the future (I have high muscle tension, hyperhydrosis, seborrhea - this all exist in parkinson due to acetylcholine increase). What it strange - that on anticholinergics I have better memory and my ADHD is not so strong. I think many of people can have benefits from anticholinergics, but it's unusual to try it in depression (tricyclics have anticholinergic properties but havr also another properties and it's difficult to know if antidepressant effect of this drug is due to it anticholinergic blockade).

And something about nicotinic receptors - I have good responce to wellbutrin that have nicotinic antagonist properties.


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## crayzyMed (Nov 2, 2006)

mikoy said:


> And something about nicotinic receptors - I have good responce to wellbutrin that have nicotinic antagonist properties.


Wellbutrin is a α3β4 nicotinic antagonist, both facilate dopamine release (so agonizing them should be a good thing), i would attribute your response to the NE release.



> I'm affraid but I think I'm predisposed for pakinson disease in the future


We with social anxiety all are, nicotine itself has been shown to protect against parkinson and other neurodegenerative disorders tough, besides that it facilates dopamine and can synergize perfectly with the anticholinergics you are taking.


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## crayzyMed (Nov 2, 2006)

http://www.2shared.com/document/AwWgwZI1/1121.html



> Four testing sessions were performed in random order
> under double-blind conditions during which participants
> received a 15-minute intravenous infusion33 of a
> saline placebo and 3 doses of scopolamine hydrobromide
> ...





> Depression severity decreased markedly during the study.
> The improvements seen, particularly after administration
> of the 4.0-μg/kg dose vs placebo, suggest robust antidepressant
> responses to scopolamine. The effects occurred
> ...





> *The findings reported herein are consistent with the hypothesis
> generated by Janowsky et al68 proposing that hypersensitivity
> of the cholinergic system plays a central
> role in the pathogenesis of mood disorders. **The demonstration
> ...


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## Vini Vidi Vici (Jul 4, 2009)

Huperzine A massively worsened my Depression, Anxiety/SA, OCD, and it made Amph less Effective and worsened my Benzo withdrawal, unless I countered the side effects with Anticholinergics and other Benzos . 

geez------- about 10 seconds ago, I put a capsule of Huperzine in my mouth, intending to do an expiriment. But for the last couple hours, i had this feeling that i should really ask/consult someone, before executing my experiment thingy

so yeah Crazymed i was gonna ask you, but i found this thread, and so like right when i clicked on this thread and read some of the posts i realized how faulty and juvenile and stupid my "expiriment" actually is/seems to be, so i spit out the capsule before swallowing it. 

that last 2 times ive taken Huperzine ( the only 2 times ive ever taken it actually), just 1-3 capsules of like whatever dose it was, = my Depression and Anxiety RAPIDLY worsened to such an extent, i was totally freaked out, and my minor Benzo withdrawal was made a Ton worse and stuff, 

I was/am theorizing that theoretically, Tramadol + Trihexyphenidyl + Huperzine would result in increased alpha-7 Nicotinic receptor agonism, but prevent muscarinic receptor overactivation. ......... the more i think about it, the more incorrect my assumption appears. Besides, a-7 Nicotinic receptors function differently from the other subtypes, .... apparently Nicotine chronic consumption doesnt upregulate a-7, even tho it does upregulate some of the other Nicotinic receptors 

but most of all, for some reason i completely forgot about Nicotine. It was just too obvious........i didnt remember. 1-4mgs Nicotine never seemed to be of any benefit in reducing brain fog caused by Memantine......... which made me think that some other mechanism was involved or something 

All i wanna do, is keep the alpha-7 Nicotinic receptors open/agonized ---- im not at all sure what role Choline plays cuz its a partial a-7 agonist, ... ..... and Soy Lecithin supplements never seemed to be of any benefit to me, if they increased Choline in the first place ( i have no idea ) 

if only i could find some diagram of the a-7 receptor, like allosteric binding sites and stuff, and like figure out where specifically Memantine , Tramadol, choline bind and stuff. - Maybe, decreasing Choline would help somehow, cuz then a-7 wouldnt be always blocked or half-agonized 

ive been thinking about this issue thing, for like months , but i dont know why i havent done anything to fix it.... i just kinda Gave up hope because Nicotine didnt work , well and also because im just really lazy, But i must admit that i need to do something to keep the a-7 receptors active regardless of Memantine dosage. A 1mg-per-day Memantine titration would probably work..... I AM making the whole thing way too difficult for myself - but thats what i do with everything.


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## mikoy (Aug 12, 2010)

I've never tried pro acetylcholine drugs, but I'm sure it will worsen my depression. For my the strangest thing is anticholinergic drug calms me more than ritalin :f Ritalin helps my concentration and help a little with hyper-state, but oxybutynin help's with hyper-fast movements, tense, makes my senses stronger, and restore my sense of humor. Strange that it works so strongly...The only thing I fear is that someone will see that I'm on this med - I'm so calm, Like not me - but it's good calmness, not like in antihistamines. A few days ago I have tried mirtazapine 30 mg - and I went to sleep on 1 pm, and sleep to 1 pm next day :f What a ****ty feeling!

I think the best combo will be - anticholinergic and pro dopamine drug, like ritalin, selegiline, wellbutrin or... the best - anticholinergic with dopamine agonist.

A year ago I was on super good state of mind on wellbutrin, ropinirole and anticholinergic.


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## crayzyMed (Nov 2, 2006)

> A year ago I was on super good state of mind on wellbutrin, ropinirole and anticholinergic.


Why did you stop them?


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## Vini Vidi Vici (Jul 4, 2009)

* the Post that formerly existed above this one, has now been deleted ---- because at the time when I wrote it, my Cognitive abilities/functions were severely impaired - due to the ingestion of -- 2mgs of Trihexyphenidyl [a Muscarinic/Nicotinic Antagonist] combined with .5mgs Alprazolam and .25mgs Ropinirole. *

Yes, Trihexyphenidyl strongly enhanced the / positive, beneficial, mood-elevating, somewhat Social Anxiety reducing, of Amphetamine and Caffeine. It appeared....that everything was all good, [ yesterday, when i took the Trihexyphenidyl + Alprazolam + Amph + Caffeine ]. -- I remember going to the computer, and subsequently starting to write a post to this thread. I have no idea how much time I was there, because it seemed all at once, I suddenly woke up from a happyness-coma. 
((This occurrence was Very similiar to those including Klonopin use, like 2 weeks of black-out memories. Except that the black-out was only 3-4 hours i think....))

------

In my *frequently incorrect* opinion, ***Muscarinic Acetylcholine antagonists, definitely have significant potential to treat lotsa stuff, including -- Depression of course, but could also benefit various Anxiety-ish symptoms, and tons of random other stuff. - Then of course, they are obviously significantly effective in reducing Akathisia symptoms (if caused by D2 antagonists).

.... -- Do the risks outweigh the benefits? There should be large variations in the response to Muscarinic Acetylcholine Antagonists. Definitely it could benefit some patients suffering from diminished effectiveness of Methylphenidate and Amphetamine*** , due to tolerance, or a genetically predisposed excess of Acetylcholine activity/ect. --- Specifically of Interest, is the connection between pesticide poisoning/ingestion/exposure and occurrence of ADD/ADHD. http://www.medscape.com/viewarticle/721892

---- actually the more i learn about it, the more Interesting it becomes......... I always thought *NMDA/Glutamate* and *Dopamine* imbalances were the primary causative factors in ADD/ADHD, Depression , Anhedonia, and almost any other Mental Illness/condition. /// I definitely have complete tunnel vision sometimes..... cuz I was only basing my conclusions/hypothesis on the information I knew at that time. Then when I tried different Meds/drugs (which I believed would help my condition)..... they failed, or produced sub-par results. I want to see the whole picture ...-

If an Individual is suffering from Nerve Agent/Organophoshate poisoning, you could shoot him with a Tranquilliser gun (loaded with a balanced/unselective Muscarinic antagonist, such as Atropine) , the specific individual would probably feel somewhat better. ~~ (I wonder though, what the symptoms of residual Nicotinic overactivation would be.....)  **** At least the victim wouldn't have to endure the torturous effects of excessive Muscarinic activation, [ I think the worst ones might be the Akathisia/Restlessness, Decreased mood, ... but then again, Twitching uncrontrollably, ect., would also not be cool]

I find the current subject of this thread, like indescribably Awesome ---- Excess Acetylcholine activity/unbalanced receptor expression, appears to be an obvious possible factor contributing to symptoms of tons of stuff, definetly Depression and ADD/ADHD,

this would be a horrible pesticide to accidentally eat or something....... http://toxsci.oxfordjournals.org/content/82/2/545.full

$$ - i must return to finish post, not done yet, $$
--------------

post = finished . [ looking back on this post, which was written a couple weeks ago from this present date, i cant help but notice that most of what i write seems to have no real intrinsic point/contribution to the actual thread........but is it a good thing to randomly vocalize stuff if Ive spent years saying nothing --- or is it counterproductive, [talking to much about meaningless stuff, makes me feel like Im destroying my credibility] ??


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## mikoy (Aug 12, 2010)

The only things that bothers me with anticholinergic -> abnormal coordination, numbness and increased seborrhea...


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## JohnG (Sep 3, 2010)

mikoy said:


> The only things that bothers me with anticholinergic -> abnormal coordination, numbness and increased seborrhea...


From what I know, dopamine has a inhibitory role to ACth. For example in Parkinson where dopamine is depleted a lot of Acth is released causing trembling and so.

So cholinergic deplete dopamine, as I saw with a log term use of piracetam and choline for 1 year. But Acth is very important for cognition, so I don't think that anti-acth meds can be a log term solution..

For example, wellbutrin after a month deleted my short memory, blocking the nicotine receptors.. even if my depression and ADHD where improved, but was not a good deal. I prefere to use a choline\nicotine source with a dopaminergic to balance the Acth activity.

New ADHD meds in stage II, are ONLY alfa-7-nicotine receptor agonist, so blocking it I think is not good.


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## crayzyMed (Nov 2, 2006)

I just remember that i was free of social anxiety when i was accidently tripping on diphyndramine, that and dopamine releasers are the only thing that help my anxiety, dopamine release in reward related area's is of no benefit for me, anticholinergics and dopamine releasers cause the most "widespread" dopamine increase and they seem to succesfully target whatever brainarae is involved in my issues.


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## mikoy (Aug 12, 2010)

Yes I think I'm the same as you - methylphenidate don't work on me, and I haven't tried adderall - but I think it will work like anticholinergics for me. I'm almost SAD free on anticholinergics, but it's not all - I'm free of my ADHD and more calm (I can drive my car like professional driver). The only thing that bothers me is more risky behavior on anticholinergic


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## JohnG (Sep 3, 2010)

mikoy said:


> Yes I think I'm the same as you - methylphenidate don't work on me, and I haven't tried adderall - but I think it will work like anticholinergics for me. I'm almost SAD free on anticholinergics, but it's not all - I'm free of my ADHD and more calm (I can drive my car like professional driver). The only thing that bothers me is more risky behavior on anticholinergic


The same for me, but with cholinergics. :roll


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## mikoy (Aug 12, 2010)

This shows that people are different


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## crayzyMed (Nov 2, 2006)

mikoy said:


> Yes I think I'm the same as you - methylphenidate don't work on me, and I haven't tried adderall - but I think it will work like anticholinergics for me. I'm almost SAD free on anticholinergics, but it's not all - I'm free of my ADHD and more calm (I can drive my car like professional driver). *The only thing that bothers me is more risky behavior on anticholinergic *


I hope that wont be too bad for me, i'm allready crazy enough at the moment:b.


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## zodiac55 (Mar 12, 2010)

great to hear that galantamine has DA-releasing action... other choline-esterase inhibitors (even epimedium ) have always been really helpful for music performance and feats of dexterity (playin improv piano for 4 hours at a time haha X)) just cuz of keeping more of the fuel around -- it's a noticeable difference -- but I've always disliked their anti-dopaminergic effects downstream.

another big HMMM for galantamine.


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## mikoy (Aug 12, 2010)

http://scienceblog.com/601/nicotine-antagonist-relieves-depression-in-children-with-tourettes/

but, why?... 

"In a report published this summer in the journal Molecular Psychiatry, the USF researchers suggest that many newer, more selective antidepressants such as Prozac work, in part, by inactivating nicotine receptors in the brain. These receptors appear to be overstimulated by the biochemical messenger acetylcholine in patients who are depressed."

Hmm, maybe my good responce to wellbutrin and not methylphenidate is by nicotinic receptor antagonist properties of bupropion. I will try fluoxetine and find it.

Memantine is nicotinic antagonist too.

Is mecamylamine available in US? I'm not sure it available in europe. I would like to try it.


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## JohnG (Sep 3, 2010)

After an year of use of piracetam, that is supposed to increase the Ach receptor expressions, I can definitely say that my depression is worst.. but stabilized my mood in a good way (less irritable, less mood swing) with some little help for cognition too.


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## mikoy (Aug 12, 2010)

"It is clear that both anxiety and depression are related to smoking behavior in human subjects [9]. Consistent with a role for nAChRs in regulation of anxiety-like behavior, *mice lacking either the α4 subunit or the α7 subunit show less anxiety-like behaviors *[122, 142]. With respect to depression-like behavior, *β2 KO mice do not respond to classical and atypical antidepressants*, emphasizing the relationship between the cholinergic and the monoaminergic systems in mood disorders [143-145]. Interestingly, these mice are also less immobile in the forced swim and tail suspension tests at baseline, suggesting that β2* nAChRs may normally have a role in regulating mood."


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## mikoy (Aug 12, 2010)

Blah, I can't tolerate methylphenidate - too much nervousness. I like calming effect from anticholinergic, just like pure (without noradrenaline) dopamine or something like this - my senses are stronger, sensitive - to music, touch etc.


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## Jdwca123 (Feb 24, 2014)

*Strange...*

What I find strange is I initially had the opposite reaction. Sorry for the TLR aspect:

I'm a 40 year old male with what appears to be some sort of acetylcholine dysregulation. I first contracted symptoms 15 years ago which were both constant tacycardia, severe depression, nonstop anxiety and a 'revved' feeling which 
I assumed was adrenaline.

Long story short no serotenergic psychotropic medications resolved the tachycardia nor any of the mental symptoms. I tried everything until I discovered phosphatidylserine complex (ethanolamine and choline) addressed nearly all the symptoms: slowed my heart down reasonably, gave me clarity and I was able to go back to work.

Fast forward 10 years later or about 3 weeks ago i came down with a chest infection and took a Z-pac. The third night of use I was overcome by a panic attack and all of my old symptoms returned. The phosphatidyl serine complex no longer slowed down my heart and my panic returned. However, if I do not take it at all during the day things are worse.

Sorry for the long winded reply, but: any idea what could be happening here? Im really suffering and don't understand this paradoxical reaction.


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## mikoy (Aug 12, 2010)

Have no idea.

ethanolamine and choline is cholinergic and z-pac is anticholinergic? People are different so there are other reactions to the same substances.


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