N&PD Moderators: Skorpio
Zolpidem possible Cholinergic effects?
Psychedelic Jay
Bluelighter
There is a really strange effect between it and hydroxzine...
It’s like a foogy dreamscape... Very foggy, loopy and floaty...
Limpet_Chicken
Bluelighter
Sekio-well I really have no use whatsoever for all those organophosphate anticholinesterases. Not like I'm a terrorist, or planning to go on the rampage.
Only military agents I can think of that I might find uses for, are the sulfur, nitrogen and oxygen mustards, and the oldfashioned, simple stuff such as chlorine, phosgene, and phosgene oxime. Cl2 and C=O2Cl are most useful. And possibly some of the arsenic compounds.
But the only purpose of nerve agents is to kill people, they aren't 'dual use' compounds like chlorine, phosgene etc., just plain, simple poisons.
And I certainly have no desire to poison myself, and certainly not my neighbors...especially one of my two next door neighbors, who happens to be a very slim blonde lass, with a lovely figure, a hot accent, generally nice person, and I think, somewhere on the autistic spectrum. Seems to have aspie traits, and is in general, fucking hawt
ebola?
Bluelight Crew
Limpet_chicken: he won't kill you with weaponized nerve agents if he thinks you're cute.
ebola
Lightning-Nl
Bluelighter
I apologies, I post shitty responses like this when I'm not thinking. I also do this because it's hard for me to my thoughts on paper.
Anyways, what I really meant was, because Diphenhydramine is binding to AChR's and causes the neurons to greatly slow their firing, the increased firing of neurons that Nicotine causes will be offsetted by the decreased firing caused by the Diphenhydramine. I know that they exert their effects on different subtypes (nicotinic and muscarinic) but the lessened muscarinic activity and the heightened nicotinic activity would explain why they level each other out.
I don't remember if Nicotine actually causes Acetylcholine release, or just agonises the receptors, but in any event, Diphenhydramine lowers cholinergic activity and therefore will stop the motion sickness-like symptoms of too much Nicotine ingestion.
ebola?
Bluelight Crew
For the most part, these are different populations of neurons.
It's the latter.
ebola
Lightning-Nl
Bluelighter
But it's the same system, is it not? They both control similar actions in the body and central nervous system, do they not?
I'm not saying I know this is exact. But Diphenhydramine, I have observed, stops negative effects associated with Nicotine ingestion. Due to the fact that they both work on the same system in the brain, it only makes sense that this would be the reason why Diphenhydramine stops negative effects caused by Nicotine.
Think of this system as a two sided scale. Nicotinic agonism on one side and Muscarinic agonism on the other. When nothing unnatural is inducing a response from either of those systems, the scale is balanced. This is how it "normally" is, thus you feel normal. Now let's picture Nicotine as a weight. You place this weight on one side of the scale, what does this do? It causes the scale to become unbalanced, thus making you feel "not normal." Now let's say that Diphenhydramine is also a weight and it's set on the opposite side of the scale. What does it do? It rebalances the weight.
They may be influencing different sides of the scale, but because this system is on a two demensional axis, this balances it out.
I can't back this up with anything, other than prior knowledge of the inner workings on the central nervous system (e.g because *blank* happens, *blank* MUST happen)
That's what I thought. However, I believe Nicotine also causes ACh release, now that I think about it.
sekio
Bluelight Crew
I don't think it works that way, no. An excess of nicotinic agonism will not cancel out muscarinic agonism/antagonism. As evidenced by the fact that nobody prescribes cigarettes for an atropine overdose (muscarine overdose?)
But they don't; muscarinic and nicotinic ACh are two seperate circuits in the brain. Just like GABA-A versus GABA-B.
I also seem to recall DPH is a muscarinic antagonist. Nicotine is a nicotinic agonist. Your analogy falls short in that regard.
Lightning-Nl
Bluelighter
My enology was actually supposed to have an agonist, and antagonist. Not two agonists. So let me elaborate a bit.
By the two sides I meant the sides were, ones an agonist and the others an antagonist.
Anyways, under the influence right now so aook later to clear up these miaconceptionas.
Lightning-Nl
Bluelighter
Wow I was screwed up....
Anyways, my analogy was only meant to apply to an agonist/antagonist combination. However, since I have researched the subject in more detail, it would appear to me that it depends entirely upon what system the neuron is part of whether or not ACh release will be inhibitory or not. My mistake was believing that ACh agonism is purely excitatory around the body, but from my new understanding, it depends entirely what receptors ACh is agonizing and what system ACh is influencing.
For example - It appears to me that Nicotinic agonism is entirely excitatory in the ANS, but Muscarinic agonism is entirely inhibitory in the ANS. So this would lead me to believe that an antimuscarinic drug, in combination with a Nicotinic agonist, would cause immense stimulation in the ANS, as the antimuscarinic agent would block most inhibitory influence that muscarinic agonism would have. But, I now believe that this may not be the case for all other parts of the nervous system, right?
The mistake I keep making is the fact that I keep making the assumption that neurotransmitters have the same effect around the entire body (meaning, either entirely excitatory or entirely inhibitory) but it actually depends what kind of neuron they're influencing and in what system the agonism is occurring whether or not they will induce an inhibitory or excitatory response.
Is this the correct way it works?
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Lightning-Nl
Bluelighter
I was thinking about this today and I decided that it was too big of a coincidence that Zolpidem and Ethanol both have Cholinergic effects, and are the only two GABA positive allosteric modulators that, very commonly, induce sleep-walking behaviors. This can't be a coincidence!
So, after doing more research, I found that Nicotinic agonism widely causes Norepinephrine release. I know the body inhibits Norepinephrine release, during REM sleep, to stop the body from acting out movements during a dream. I'm sure there's more to it than just this, but this could be one of the reasons why Zolpidem and Ethanol both cause sleep walking (even though Zolpidem isn't a nAChR agonist persay.)
sekio
Bluelight Crew
I think any drug that disrupts sleep architecture enough can cause sleep-walking. Or at least operating in the "twilight zone" of no memory and no inhibitions.
Lightning-Nl
Bluelighter
If that's the case, then all neuroleptic drugs should have this effect, right?
But if that was the case, why wouldn't antipsychotic drugs cause this? (Although, now that I think about it, antipsychotics don't cause this because they work by decreasing primarily excitatory neurotransmitters, and unlike GABA agonist and modulators, don't affect the inhibitory system much. So antipsychotics don't cause this, probably because there's not enough stimulation there to allow the Central Nervous System to even function all that well, let alone allow you to get up and walk around.)
If Zolpidem disrupts sleep architecture that badly, then why don't they use drugs that promote REM sleep, instead of drugs that just promote Deep Sleep? It seems to me that a Glutamate, Norepinephrine, Serotonin and Histamine antagonist that is also an Orexin and Dopamine agonist would better promote sleep than GABAergics do. Also, an inverse agonist of Glutamate also seems like it would be a preferable drug. Would it not?
ebola?
Bluelight Crew
This is a rare quality in sedatives.
ebola
Lightning-Nl
Bluelighter
Due to the fact that the brain is very much "awake" during REM sleep, it seems to me that it would make sense that a drug that promotes inhibition would suppress REM sleep. Since that's the case, why don't they use very mild stimulants?
I've found that incredibly small doses of Amphetamine is one of the most relaxing things in the world. And it makes me sleep like a baby. In the past, when there have been nights when my legs are especially restless - I've found that taking a fifth or a fourth of a 5MG IR Adderall stops my restless legs almost entirely, and gives me very vivid dreams. On those nights, it's almost as if I skip over deep sleep entirely and go right to REM sleep because my dreams seems to start within minutes of falling asleep. All I seem to have are dreams, and then, I wake up early the next day. But it's not like I've been forced to get up, I wake up because I feel like I've just slept 24 hours
I remember almost all my dreams in full detail when I take 1MG doses (respectively) of Amphetamine right before sleep, and I seems to sleep like a baby.
Is there any pharmacology that would support that?
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checktest
Bluelighter
I'm not sure of the pharmacological effects on sleep specific to amphetamine, but it does seem that sleep wave stages and cycles would certainly be affected by the centrally stimulating releasing drugs.
The rapid onset of dreams sounds like the situation where people have increased recognized number and memory recall of dreams if they wake up early and then proceed to fall back asleep in the early morning. (More of the wake up at 4:30, go back to sleep and dream more heavily sort of deal.) Rather than passing through deep sleep, it appears more that people don't reach the deeper levels of sleep in this period, maybe only proceeding to NREM I or II.
Perhaps there would be a difference on an EEG or MEG in regard to the particular brain wave frequency with that staging. Maybe amphetamine keeps the brain more in the Mu-Alpha (Beta, Gamma or visual cortex stuff?) regions rather than the slow wave Theta and Delta. Especially if you don't enter NREM III on an amphetamine. Or maybe the length of a cycle might be affected, or shorter stages.
Some people definitely respond to sleep deprivation and cycle-affecting drugs in conditions like Depression. REM interruption seems to have hippocampal-stimulating effects, which likely has to affect the detrimental hippocampal effects of depression. (I.e. The decreased size of the hippocampi in chronically depressed and anxious people.) SSRIs are known to interfere with REM, and MAOIs are known to almost completely reduce REM sleep in the first few months of treatment.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621793/
Large overview of sleep and sleep systems - (REM Cholinergic, Gabamergic effects)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030585/
Orexin effects with d-amphetamine, sleep.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387837/
Sleep states,
Lightning-Nl
Bluelighter
I came back to this thread, because I had another interesting idea.
Nothing is proven, obviously, but is it possible that Zolpidem has DR affinity? I know, probably not, but with the increased arousal that is produced by Zolpidem, and the prescence of psychotic symptoms (hallucinations) - it really makes me wonder if Zolpidem is a Dopamine agonist.
Another thing to consider is the fact that GABAergic activity SUPRESSES monoaminergics activity. If anything, Ambien should be making you sexually inactive, not hard and horny. Apply this to Diphenhydramine for instance. It's a potent antihistamine and anticholinergic drug. Yet, at the right dosages, it increases arousal. Why is this? Well we've come to learn that DPH is also a Dopamine/Norepinephrine/Serotonin reuptake inhibitor. It's affinities for 5ht are in the hundreds, while it's affinities for NE and DA are something like 600+. But it still exists.
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thelonelystoner
Greenlighter
I can't speak in chemistry terms (college freshman) but I am a somewhat frequent user of Ambien, both by itself and in combination with most other drugs, and I have noticed that it has very similar effects as that of high doses of diphenhydramine, promethazine, etc.
The very specific hallucinations I would get when I was 14 and I would take massive doses of Benadryl are the same as the hallucinations I have on very high doses of zolpidem. And, when I take high doses of either zolpidem or an anticholinergic and only those two, I notice this indescribable feeling when I swallow or breathe (not bad, not good, it's just like my nerve endings in certain parts of my body perceive stimulation differently), along with an effect that I could only describe as being a difference in the way I perceive vision but not a difference in my vision. I just get a feeling like everything I see is "fuzzy" even though nothing actually looks different and there isn't any flanging or tracers.
Also worth noting, one time I combined ambien with diphenhydramine and there was a kind of synergy that I can't really explain, but that left me with no doubt that the two substances share some qualities.
Hope my experience is useful for what someone is trying to figure out.
Lightning-Nl
Bluelighter
I think Zolpidem may be antinicotinic rather than antimuscarinic now that I think about it. That would make much more sense, due to neuromuscular relaxing actions, Zopiclone is actually antinicotinic - which is why it gives you such a horrible dry mouth. Ambien does the same thing (at least it can from what I've heard). The difference is, Zopiclone, I believe, has higher affinity for ganglionic type receptors - where as Ambien is probably purely antineuromuscular.
Anyways, due to the very widely documented delirium that is produced by anticholinergic drugs - we know a ton about this kind of hallucinations. Ambien is quite different. Due to the combination of effects that Ambien produces (muscle relaxation that's different than other GABAergics, Hallucinations, Delusions, Dry mouth, Sleep walking, Heightened Libido) I wouldn't be surprised if Zolpidem has some sort of action on Dopamine. Outside of it's indirect effects on Dopamine that heightened GABAa activity has. In fact, due to the effects that Zolpidem produces - I speculate that it may even have affinity for D2 Dopamine receptors.
What do others think about this?
ebola?
Bluelight Crew
There is no evidence for this.
This is very common for gabanergics.
Hence the likelihood of gabanergic action mildly distinct from benzos more parsimoniously explaining its unique effects.
This hasn't been ruled out by binding assays, to my knowledge, but I don't consider its effects-spectrum to lend itself to the hypothesis.
...
I dunno. If zolpidem were an anti-nicotinic, it would block the effects of nicotine in some way. Does it?
ebola
sekio
Bluelight Crew
Considering that 'paradoxical' hallucinations, euphoria, clouded thinking, general Ambien-type behaviour (or a subset) is known in people taking benzos, I don't think that there is a ton of evidence for 'secondary' effects of Z-drugs being responsible for their actions. Besides, zopiclone and friends are not 'old world' drugs - although their behavior in vivo may remain questioned at times, their activity in the human receptorome is fairly well-profiled, since the mid-1980s. Failure to discover its muscarinic/nicotinic affinity would be... unlikely.