Choline and Depression / Dysregulation from Dissociative Use

[dopamimetic]

In regards to antidepressants I keep reading about trials of scopolamine either alone or as an adjunct. This leads to the conclusion that increased cholinergic / muscarinergic activity can contribute to or cause depression. If this is true, might then continued use of anticholinergic agents cause a downregulation and thus a depressive rebound? If so, will it be transient or potentially long-lasting as with dopamine agonists and post acute withdrawal?

How potent are NMDA antagonists in this regard? I just know that it's said they are have anticholinergic activity, but is it clinically significant in recreational dosages? As specific effects like dry mouth lack completely, one might guess not. Yet might it be enough to cause changes with continued use - I am speaking of months of daily use, and combined with opioids which apparently decrease cholinergic activity too and have read that opioid withdrawal is at least partially caused by cholinergic rebound.

I am struggling with heavy depression and fatigue together with feelings of inner tension probably from heavy dissociative use. As I have used them to fight depression, it was there before and I am somewhat uncertain whether I got an actual worsening or if the previous state does just feel worse when the mood lift from NMDA antagonism fades off rather quickly and throws me back in a matter of hours to a few days and the almost unreal fast way back in just some minutes or even less when take some 2-FDCK. Months off any dissos did not help to any significant degree, neither do SS/NRIs or stimulants. So I always "relapse" to use arylcyclohexylamines which even if I should really be able to sustain their use without physical damage, sooner or later the supplies will be shut down and I am desperately searching for something reliable...

 

[sekio]

Memantine as a sort of methadone-like replacement therapy maybe?

I mean, to be honest this reads to me more like dissociative addiction rather than a generalized depression. I don't see why long term usage of NMDA antagonists wouldn't cause some sort of dependancy, I experienced something similar after periods of heavy dissociative use, but more of an apathy than a depressed mood. For me it lasted no more than a few months.

 

[checktest]

I mean cholinergic rebound is a thing but usually more an acute reaction after some drugs than the same syndrome of dopamine agonist withdrawal. More commonly some tricyclics or antipsychotics, as well as say benztropine. Usually that's more of GI issues/insomnia/agitation (as well as exacerbations of psychosis or say catatonia in some populations.) Let alone the other factors of dirty drugs like some tricyclics (antihistamine and and adrenergic). Seems like there would be more of an extended tricyclic withdrawal if it were along the same lines.

As for inner tension and muscle tension, cholinergics can do that, say overdoing acetylcholinesterase inhibitors. But many drugs in withdrawal can.

As for particular NMDA antagonists at 'recreational doses', well, that seems hard to judge where that lies. Memantine withdrawal is being reviewed because of younger ages, but not really the same. Occasionally destabilization say of anti manic properties in BPD, but a lot came about in people with dementia.

I mean scopolamine did not have the same success that ketamine did. Nor did memantine in depression. Ketamine has some M1 vs say M3 but has a host of other stronger affinities. D2 MOR KOR (of course NMDA), DAT, HCN, a7 (like memantine), so on and so forth

In terms of approved antidepressants, seeing how more muscarinic tricyclics would fare seems interesting relative for judging anticholinergic vs some NMDA effects. Especially since you tried heavy doses of memantine.

'Atypical' depression along hypersomnia and limb heaviness usually reacts better to MAO inhibitors (and adjunct stimulants to some other drugs or multimodal).

Melancholic depression and such usually not the same, even with ketamine, in terms of sustained speedy response

I mean there was a whole period of the adrenergic-cholinergic hypothesis for bipolar disorder.

Agree with ^above though. Drug withdrawal can respond quickly and well to....taking the drug class you are in withdrawal from. (Which aids in staying up 36 hours regularly with acute mood lifts from your other post.) Cycles of addiction can be reinforcing. Co-use of opioids too...

 

[d1nach]

I believe (could be wrong) scopolamine acts like antidepressant rapidly like ketamine possibly due some indirect alteration of cellular signaling, interneurons, and growth factors.

 

[AlphaMethylPhenyl]

Apologies for any missed material...it's way early here.

I don't know...they use adrenergic autoreceptor occupiers for excessive adrenaline from opioid withdrawal. In some cases of ADHD, too. But not for mania.

I know that it remains an enigma in some manner, but bupropion is an NDRI that usually proves more useful for bipolar depression than SSRIs, or at least is given as a mono-therapy for bipolar, whereas SSRIs can be added to mood stabilizers once they are in effect, but by themselves tend to promote some form of mania in those with bipolar disorder.

it's increasing pro-GABAergic activity and decreasing glumatatergic activity that basically explains mood stabilizers--inhibiition of GABA transaminase and the like.

I couldn't see how acetylcholline can be so excessive as to cause depression. For the ionotropic part, acetylcholline can provide some measure of happiness. Aceylchollinesterase inhibitors are used for dementias and are otherwise known as nootropics, I thought. Perhaps that's partly how bupropion fights mania, though, as it is an antagonist of some nicotinic subtypes, to my knowledge. But that would be a straight guess.

If there would be rebound, for the nicotinic subunits it wouldn't be acute, as they aren't GPCRs and I thought GPCR agonists generally lead to faster tolerance but also faster reduciton of tolerance. Ionotropics, the opposite, Look at how benzos have such an extreme discontinuation syndrome.

I'd think ketamine more addictive for DRI and mu activating properties than by NMDA antagonist rebound. Ketamine is a dirty player.

Muscarinics don't have any recreation to speak of. Just useful for acute physical sicknesses mostly.

Yeah I'd be concerned with not just your brain, but perhaps more so early-onish, your bladder.

 

[polymath]

The M5 muscarinic receptor actually has pro-dopaminergic effects in the reward circuitry of the brain. Choosing an anticholinergic with as little affinity as possible to that receptor would probably be good when used as an antidepressant.

 

[AlphaMethylPhenyl]

Ah, guess you learn something every day.

 

[polymath]

Blocking the M5 receptors, or deleting them from the genes of a rodent, reduces the stimulant effects of cocaine. Maybe this is one reason why orphenadrine-like anticholinergics don't have much stimulant-like effects despite being dopamine reuptake inhibitors.

Discovery, synthesis and characterization of a highly mAChR selective M5 orthosteric antagonist, VU0488130 (ML381): a novel molecular probe

Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs or M[1] -M[5] ), M[5] is the least explored and understood due to a lack of mAChR subtype selective ligands. We recently performed a high-throughput functional screen and identified ...

www.ncbi.nlm.nih.gov

Numerous studies have suggested that subtype-selective muscarinic acetylcholine receptor (mAChR) antagonists may provide novel approaches to treat a number of central nervous system (CNS) disorders;[1–7] however, the majority of existing antagonists are not selective for specific mAChR subtypes, forcing the field to rely on biochemical and or genetic approaches to discern therapeutic potential.[1–7] Of the central mAChRs, M5 expression is the lowest (<2% ), and M5 is predominantly localized to dopaminergic neurons originating in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA).[4–10] Studies with M5−/− mice have confirmed the hypothesis that M5 modulates dopaminergic neurotransmission and that M5 functions in addiction/reward mechanisms, with M5−/− mice displaying reduced cocaine place preference and self-administration without affecting food intake.[4–10] Further biochemical studies with M5-targeted antisense oligonucleotides, or scopolamine, infused into the VTA have recapitulated the genetic findings,[11,12] strongly suggesting that selective M5 inhibition may provide a novel therapeutic approach for the treatment of addiction.[1–12]

 

[dopamimetic]

Have to try memantine again. Such a misery that the arylcyclohexylamines aren't better studied yet and I personally don't have the tools nor expertise yet to do so ... I am craving something so much like a life-long H addict his shot, and it's not plain dissociation, it's not dopamine, it's not ... anything isolable. That cuddly-muddly friendly positive intelligent energy on the beginning of a lower dose (2F)-O-PCM trip.

Might be a problem that it's not a few days or weeks but month as you say @sekio but still, I've gone through this multiple times and still craving the hell out. Still no words about the seemingly unlimited creativity in this mode. The sudden utter change from introverted nerd to the person I want to be. All my money has gone to government for shitty legal cases of RCs and other related stuff. It's so frustrating. Will move to another country where living is cheaper and access to university more easy. Have to learn a new language for that. And will need a shitload of dissos again. Oh my. xD

 

[polymath]

Deletion of the M5 receptor or blocking it with an antagonist attenuates morphine reward and physical dependence but doesn't prevent the analgesic effect:

Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia - PubMed

Little is known about the physiological roles of the M5 muscarinic receptor, the last member of the muscarinic receptor family (M1-M5) to be cloned. In the brain, the M5 receptor subtype is preferentially expressed by dopaminergic neurons of the substantia nigra and the ventral tegmental area...

www.ncbi.nlm.nih.gov

This is likely to be the reason why scopolamine is found to slow down morphine tolerance development in this 1999 article:

Attenuation of morphine tolerance and dependence in scopolamine-treated rats - PubMed

Morphine tolerance and dependence were investigated in scopolamine-treated rats. The results showed that scopolamine treatment (up to 2 mg/kg) did not affect basal line or morphine-induced latency in the tail-flick test but significantly increased the escape latency in the Morris water-maze...

www.ncbi.nlm.nih.gov

 

[Nagelfar]

Deletion of the M5 receptor or blocking it with an antagonist attenuates morphine reward and physical dependence but doesn't prevent the analgesic effect:

Am more personally interested in parsing reward from dependence ;^P (meaning withdrawal)