New theory about over excitation in highly sensible individuals / ADHD / para-autism.

[dopamimetic]

Hi everyone,

based on the new evidence brought up here about COX-2, interleukin 6 etc. some new theory is forming in my mind.

So there seem to be genetic predispositions for all this stuff, and chronic stress especially in the childhood can trigger things. Because of the sensibility and emotionality, obviously, some people like me are more susceptible to emotional stress, leading to a downward spiral. Very remarkable is that with the glutamate adjusted in the right way, I seem to be able to perform cognitively extremely well with sort of hypermnesia and pronounced ability to understand complex matter as well as to draw conclusions. This can easily become overwhelming and look sorta ADHD-alike and of course any sort of stress / pressure / over excitation exacerbates the things, again a downward spiral. Here the dissociative effects of NMDA antagonists obviously have an independent alleviating effect by helping one to keep distances to the things and act more soberly.
It is so sad that because of prohibition and abuse such overly promising compounds like MXE being not further investigated and researched, with the recent science about Ketamine and its effects on therapy-resistant refractory depression being a truly remarkable exception, as well as its use as an adjunct treatment for pain & the approval of DXM/quinidine for Pseudobulbar Affect.

Maybe because of this, maybe because of a sum of all, ADHD people seem to benefit from NMDA antagonism too, but not all to the same degree so it has been statistically overlooked. Remarkable is that atomoxetine is an NMDA antagonist too and I bet the benefits some get from it are more due to this mechanism than the NRI activity and the latter only leading to side effects. A combined DRI (possibly slight SDRI) & NMDA antagonist without NE activity would be a huge advance.

Seen in this light, the tolerance development of psychostimulants could fit well and be due to different mechanisms as currently thought. As well as the tolerance-abolishing effects of NMDA antagonists for some individuals would make perfect sense. So the acute increase in dopamine is relieving, but gives rise to over excitation, inflammation responses and eventually a worsening of symptoms. Leading to increased dosing on stimulants and/or co-medicating with sedatives ... this has been very pronounced in someone I've met several years ago and where I saw so many similarities in the way she thought, felt, acted etc. to me - she was diagnosed with severe ADHD, had the same adverse reactions to stimulants as well as neuroleptics, was on uber-high doses of d-amphetamine with the obvious adverse effects and smoked pot / used opioids on top of that to get relief. She got messed up obviously & is now off the amphetamine, living with the hell of para-ADHD .... but I guess her can be helped too now with all this great exciting stuff.

So far, I would absolutely love to read your thoughts about all this.
Thanks for any response!

-dopamimetic

 

[dopamimetic]

If my amateur theory is on the right train concerning the link of stress-induced(?) genetically prevalent inflammation leading to raised levels of quinolinic acid and excess glutamatergic neurotransmission, then this would mean that some of us are on kind of an endogenous racteam. Would make perfect sense thinking of the usual response people have to racetams (increased cognition) as well as the pronounced adverse effects a fraction including me has to racetams - exacerbated inner tension, overexcitability & worsened mental / psychiatric symptoms leading to kind of "suicidal" reaction to racetams.
It would also mean that these people should look into glutamate antagonists, and that it is possibly not central about NMDA receptors but it could be more of a NMDA:AMPA imbalance(?). I react overall well to memantine but it also takes some of my drive, energy, motivation etc. especially in regard to social interactions etc. Maybe a combination of medium-high dose memantine AND an AMPA positive allosteric modulator like (s)unifiram could be of great benefit. OR a general glutamate reducing agent like riluzole AND/OR in combination with e.g. sarcosine. OR even a combination of the right doses of memantine & perampanel which could be better adjusted to fit the individual disfunction.

Of course it would be very very nice if something really targeting the cause, be it an interleukin 6 antagonist, a COX-2 inhibitor or whatever would over time normalize everything and leave one with normal cognition and emotions. Then one could even reconsider using a low dose of a racetam to get this (in fact really estimable, if the neuropsychiatric effects just weren't) hyper-cognition without the bad sides... because usually everything that helped me with the emotions also lead to a more or less pronounced unbearable impact on cognition.

 

[Cotcha Yankinov]

Would just like to chime in about the NRI/DRI concepts, thought you might find this interesting. There are actually no dopamine transporters in the pre frontal cortex, the dopamine re-uptake there is handled by the NET. Therefore an NRI increases dopamine in the pre-frontal cortex. https://www.ncbi.nlm.nih.gov/pubmed/2117046 "Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals."

Please someone correct me if I'm wrong on any of this, but I thought it was very hard to make a specific DRI because dopamine and norepinephrine are so similar. I don't think any specific DRI's have been developed and it doesn't sound like any will be developed anytime soon, I think most DRI's will have activity at NET as well But we can still antagonize the shit outta NMDA :D

I wouldn't be surprised if elevated interleukins and COX was downstream of something else though. Not that it wouldn't be a therapeutic target however.

 

[yaesutom]

I react like you describe to stimulants (d-amphetamine or d-meth being my favs) its great in the beginning but after a couple hours I need to eat a xanax to kind of chill out... followed by more stimulants. Come to think of it pure d-methamphetamine was probably the best and most useful. Too many bad effects come with it though and a downward spiral always happens. Every Damn Time lol.

What would be great is some kind of new technology which would allow fine control of all parts of the brain, tailored to each individual. Drugs seem too "coarse". I recently read about some kind of injectable technology where they were able to inject something into an animal's brain and this thing would automatically spread out and hook up to the brain in some kind of network. I forget what it was called or where I read it though..

 

[dopamimetic]

Would just like to chime in about the NRI/DRI concepts, thought you might find this interesting. There are actually no dopamine transporters in the pre frontal cortex, the dopamine re-uptake there is handled by the NET. Therefore an NRI increases dopamine in the pre-frontal cortex.

Oh yes, here you're right, I've actually lost this fact when I wrote the posting so well, some people will actually benefit from blocking NET and/or it will improve certain cognitive problems. BUT we should have a NRI that is completely selective for the pre frontal cortex then, as I (and others) strongly feel that norepinephrine is generally bad especially for the overly sensitive / over-excitated / overthinking people amongst us, which I'd bet are common with ADHD. I also speculate that it is responsible for a good part of the stim psychosis and possibly pro-convulsive.

NE & DA are strongly interconnected, yes, and an interesting (and somewhat frustrating) fact is that the preferably autoreceptor-selective a2 agonist Clonidine which lowers NE output & sympathetic tone -> lowering blood pressure, makes a good sleep aid for many including me and has been proposed to use in ADHD to get better sleep after the psychostimulants wear off - seems not only to lower NE but also very much the DA. It somewhat cancels out psychostimulants, as others here have agreed to as well, it's also a good med to use when someone has moderately overdosed on e.g. amphetamine and/or is sleep deprived.

But then again, it does not completely cancel out the DA effect, I've used low-dose clonidine together with stimulants quite often because I find that the overall reduction of side effects is sometimes worth the needed increase of the stimulant dose.. on other days, it makes me too lethargic.

I would love to know the effects of a really pure, really selective a2 auto receptor agonist, as clonidine also targets imidazoline receptors which are said to act possibly anticholinergic (would fit the side effects of higher dose clonidine - dry mouth, miosis, etc. and the opioid folks generally like clonidine - anticholinergics seem to be of benefit in potentiating opioids / helping with the withdrawal)

Also clonidine is not completely selective for the auto receptors, it does affect other adrenoceptors with around 20% the efficacy as well as acting peripherally - leading to clammy hands and feet etc.

Please someone correct me if I'm wrong on any of this, but I thought it was very hard to make a specific DRI because dopamine and norepinephrine are so similar. I don't think any specific DRI's have been developed and it doesn't sound like any will be developed anytime soon, I think most DRI's will have activity at NET as well

I think that this has been said for long time, but showed to be not entirely true. For example, we have Amfonelic Acid, a somewhat interesting compound that's unfortunately also an antibiotic, but absolutely selectively targets DAT.

Also the recently available isopropylphenidate which is not totally selective but much more so than either MPH or EPH, it has a very different overall effect, much much less pronounced peripheral / bodily stimulation but has most of the good cognitive effects. At least whilst combined with memantine, there is few of a rebound at all - and I get this phenomenon very strongly with all stimulants as you describe, yaesutom, it is especially pronounced with EPH (despite that this one is said to be more dopaminergic as MPH - but many agree with the horrible rebound it has) as well as the amphetamines, which is why I avoid the latter. With them, the memantine helps somewhat but it's not nearly as pronounced as with the IPPD.
- Interesting side note, the Russian antioxidant nootropic Emoxypine - which has shown to increase dopamine levels in the brain by an unknown mechanism, I'd speculate by lowering DA (auto)oxidation, also helps in alleviating the rebound & tolerance development to phenidates.

Since I've experienced isopropylphenidate, I really dislike also the MPH. It feels like a caffeine overdose now, mechanical and cold.

Very remarkable is that the IPPD seems to have actually a somewhat lower abuse liability than the more balanced NDRIs. It is less euphoric, but the lack of rebound does most of the trick I'd say. When I dosed too high on it once, it actually made me very tired (! odd for a stimulant but this is how I react to dopamine) but also overflowed by sensory input & somewhat migraine-alike.
There are no numbers afaik yet about it's selectivity though and it could also be possible that it just affects different brain regions / or is much less peripherally acting...?

yaesutom - you might want to look into clonidine potentially as well as memantine, if you're ADHD and/or take stimulants frequently, but as this is more experimental probably many would say that it could have more of unknown 'risks' - the long term use has not really been established afaik, as it is marketed for Alzheimer's and there people will be on it for the rest of their lifetime (ironically it is disputed whether it has a significant effect at all, which I'd bet is because they give it only when it's already too late and too much damage has been done to the neurons... they're still making billions of $$$ with it), but it also was a muscle relaxant (!!) before. I am not the person to really say anything about this, but I strongly feel that memantine poses less risks as some widely used meds like the dopamine antagonists / neuroleptics. Maybe it is equally to the SSRIs, potentially leading to a bit of cloudy mind or a slight withdrawal syndrome - it is not clear yet afaik whether NMDARs up regulate with chronic antagonism or not.

And memantine does not completely block them in therapeutic dosages, it gets displaced when enough glutamate activates the receptor. I think this means less cognitive impact, but unfortunately also limited efficacy in inhibiting over-excitation etc. and is why e.g. methoxetamine works so much better for me. But it could also be about the different binding sites, allosteric, glycine etc. & competitive/non-competitive binding ... that's all so complicated (well, if it wasn't, we wouldn't be able to understand our brain either )

 

[dopamimetic]

3-meo-PCP is helping me with life-long emotional disorders
Medicinal 3-MeO-PCP? daily low dose use? <-- PDD here on bluelight

Then of course (why on earth did they have to go with that shitty vice magazine!?): Interview with a Ketamine Chemist

It's so remarkable that quite a few people (much more than I thought) with life-long mental struggling seem to respond so well to the arylcyclohexylamines / dissociatives ... there are also many reports about MXE & DXM as well ... it seems like everyone reacts differently to the more subtle side effects, with the one preferring 3-MeO-PCP, the other preferring MXE & getting delusional from DXM etc ... but the central anti depressive / relieving / 'healing' effect is shared amongst all. And while the effects may be related to the K antidepressant action (just that K does not work for me, it is relieving as long as it is in the bloodstream but does not have this sustained effect like DXM and 3-MeO-PCP have very pronounced.. MXE is somewhere in between but needs 2-3 doses daily, one at the very least to work).. so I theorize it might actually be that there are TWO related (to glutamate) but indeed different mechanisms with some of us profiting much more from the actual glutamate blockade & the sustained effect being due to the neurons recovering from the chronic over-excitation, and NOT due to the AMPA up-regulation as proposed with K (correct me if I'm wrong of course!)

Initially I thought of them as being ‚mania inducing agents‘ but I was mislead, once more taking a common meaning over without thinking critically enough about it. I have theorized before that most of the mood-stabilizers which are used for bipolar disorder are actually depressing / mood-limiting agents, as they are mostly effective against manic episodes & do not prevent depression … so, here we maybe have indeed anti-depressive agents that are just STRONG, and some people NEED such a strong agent. While in others that are not depressed, or predisposed to (hypo)mania, and when dosed too high, they will lead to mania & things like temporal lobe epilepsy. Things that actually elevate mood aren't liked to see in society (compare psychostimulants : neuroleptics, SDRIs : SSRIs etc). Granted, people do less stupid shit when being sedated to hell, but it's not relieving their terror of mind & it makes them non-productive.

But the anecdotal reports & my own experiences are more than enough for me to truly believe that the common meaning about PCP / the dissociatives is skewed. It’s not totally wrong, but prohibition leads to misthinking about them and overlooking them as truly chemically magic relieving medications.

 

[dopamimetic]

A Story About NMDA Receptor Subunits, and Why SSRIs Impair Cognitive Capacity
The action of antidepressants on the glutamate system: regulation of glutamate release and glutamate receptors.

Sorry for flooding you with information. But this is so exciting & informative.
Could mean that prolonged SSRI use in people who do not actually need them possibly cause lasting glutamate imbalance due to downstream adjusting mechanisms ----> would explain why some (like me) get these withdrawal brain zaps very strongly, that thing increased over the years & every time I withdrew from an SSRI. Memantine alleviates the brain zaps.

 

[marsnd]

Very interesting since I suffer from adhd.

 

[aced126]

Would just like to chime in about the NRI/DRI concepts, thought you might find this interesting. There are actually no dopamine transporters in the pre frontal cortex, the dopamine re-uptake there is handled by the NET. Therefore an NRI increases dopamine in the pre-frontal cortex. https://www.ncbi.nlm.nih.gov/pubmed/2117046 "Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals."

Please someone correct me if I'm wrong on any of this, but I thought it was very hard to make a specific DRI because dopamine and norepinephrine are so similar. I don't think any specific DRI's have been developed and it doesn't sound like any will be developed anytime soon, I think most DRI's will have activity at NET as well But we can still antagonize the shit outta NMDA :D

I wouldn't be surprised if elevated interleukins and COX was downstream of something else though. Not that it wouldn't be a therapeutic target however.

Grave digging this, but several cocaine analogues have been prepared that have a high DA/NET selectivity, or so this paper suggests: http://pubs.acs.org/doi/abs/10.1021/cr9700538?journalCode=chreay. Probably the most common example (in fact this compound is the standard in binding assays, as it is so selective) is WIN-35,428. The paper reports it having a 53.2 NET/DAT IC50 selectivity ratio. Mind you, the Ki values in the paper cannot really be compared to each other for different transporters, because different ligands are used at each transporter, each of which will have differing difficulties to displace from the transporter.

 

[Cotcha Yankinov]

^Thanks for info, I believe I've also since heard about Toparimil (spelling?) a somewhat selective DRI.

 

[aced126]

^Thanks for info, I believe I've also since heard about Toparimil (spelling?) a somewhat selective DRI.

Troparil, yes, that's just the above compound but with a hydrogen instead of fluorine on the aromatic ring. IC50s for troparil, from that paper: 23nM (DAT), 1960nM (SERT), 920nM (NET), making also for very selective DAT inhibiting properties.

 

[Cotcha Yankinov]

Thanks for these corrections I think it was nagelfar that said Troparil/DRIs were dissaponting as far as abuseability. I guess euphoria is no simple matter...

One last thought - it's been hinted that cocaine/methylphenidate are DAT inverse agonists - maybe Troparil is just a normal DRI and hence the low abuseability?

 

[Limpet_Chicken]

Memantine is a true oddball amongst NMDA antagonists, in that its antagonism is voltage-gated as well as the usual ligand-gated ionotropic characteristics of the NMDA receptors. Inhibits excessive glutamatergic activity but only when the presynaptic neuron is sufficiently (that is, excessively) depolarized IIRC. Quite low affinity, but higher than Mg, the ion which naturally blocks the NMDAR ion channel at its resting potential.

Alpha7 nicotinic acetylcholine receptor antagonist, also, which induces an upregulation of this receptor type with continued use. Initial phase of cognitive fogginess, as alpha7 nAChRs are nootropic when activated, by E.G galantamine. Although it synergized perfectly with this drug for me. Regrettably i cannot afford it, got some, trialed it (galantamine) but cannot continue.


Out of curiosity, given that AMPAr-driven action potentials can still induce NMDAR-dependent LTP with memantine, due to its uncompetitive, low affinity and weirdball voltage-gated binding kinetics, how do folks think it might synergize with an AMPAkine.

 

[aced126]

Thanks for these corrections I think it was nagelfar that said Troparil/DRIs were dissaponting as far as abuseability. I guess euphoria is no simple matter...

One last thought - it's been hinted that cocaine/methylphenidate are DAT inverse agonists - maybe Troparil is just a normal DRI and hence the low abuseability?

I'll be starting a thread about this shortly

 

[DotChem]

3C-PEP

Ki (NET) = 1107nM; Ki(DAT) = 0.04nM (about 10,000 more potent than cocaine as DRI)
Ki(NET)/Ki(DAT) ~ 30,000
(older thread on this compound started by @nagelfar..cant dig it up..

 

[Nagelfar]

Grave digging this, but several cocaine analogues have been prepared that have a high DA/NET selectivity, or so this paper suggests: http://pubs.acs.org/doi/abs/10.1021/cr9700538?journalCode=chreay. Probably the most common example (in fact this compound is the standard in binding assays, as it is so selective) is WIN-35,428. The paper reports it having a 53.2 NET/DAT IC50 selectivity ratio. Mind you, the Ki values in the paper cannot really be compared to each other for different transporters, because different ligands are used at each transporter, each of which will have differing difficulties to displace from the transporter.

Iometopane (iodo instead of hydro or fluoro) =

1.26 ± 0.04 (DAT binding)
1.96 ± 0.09 (DA uptake displacement once bound)

4.21 ± 0.3 (SERT binding)
1.74 ± 0.23 (5-HT uptake dis.)

36 ± 2.7 (NET binding)
7.51 ± 0.82 (NE uptake)

Lower numbers are higher affinity, so as per the halide-(monohalogen substituted)-phenyltropanes that beats WIN 35,428 (β-CFT) which =

15.7 ± 1.4 (DAT)
22.9 ± 0.4 (DA)

810 ± 59 (SERT)
100 ± 13 (5-HT)

835 ± 45 (NET)
38.6 ± 9.9 (NE)

and definitely beats troparil, the above's para-fluoro group doubles affinity at DAT & SERT as per =

23 ± 5.0 (DAT)
49.8 ± 2.2 (DA)

1962 ± 61 (SERT)
173 ± 13 (5-HT

920 ± 73 (NET)
37.2 ± 5.2 (NE)

...

Some naphthyls, esp. the acyl nortropane, put those to shame (i.e. take WF-23 and demethylate the nitrogen) =

DAT: 0.03 ± 0.01
SERT: 0.23 ± 0.07
NET: 2.05 ± 0.9

...

Of course, talking solely about the ratio between DAT/NET, we got RTI-304:

with DAT/NET ratio is 186.6 in favor of DAT, with only a 0.5 spread in DAT/SERT

RTI-126

DAT/NET = 788
DAT/SERT = 38.3

Want to go really overboard? RTI-143 =

DAT/NET ratio of 9,919 (over nine thousand!)
and a DAT/SERT of under one hundred.

etc.

3C-PEP

Ki (NET) = 1107nM; Ki(DAT) = 0.04nM (about 10,000 more potent than cocaine as DRI)
Ki(NET)/Ki(DAT) ~ 30,000
(older thread on this compound started by @nagelfar..cant dig it up..

Here: 3C-PEP - powerful & selective DA stim, v. close to opioids

WP article

 

[Solipsis]

Pretty weird that wiki describes that 3C-PEP as a recreational drug! Has it ever been found on the market?

I am diagnosed with both a form of autism and ADD... I get Lyrica and Dexamph, but I want to taper and quit the Lyrica, have already started doing that.

Yeah I benefit from dissociatives, but I think many people with mental issues report benefit, because the drugs plain stop a lot of mental activity in its tracks. So if most difficulties with mental issues arise from mental activity of various kinds, seems that dissociation and suspension of mental / cognitive activity will be experienced as temporary relief. That temporary suspension can have protracted benefit perhaps, if it serves as a reset - but it is not a cure, I believe it is a respite.
Lingering effects from dissociatives that take a long time to clear the body can of course also give extra long respite..

For depression that is probably not the whole picture, if 3-MeO-PCP can really wipe your head and lasts a long time but isn't such a great anti-depressant as ketamine, or purportedly MXE. Since LTP effects have been found to be relevant for ketamine, learning effects may be important to cause considerable changes, but an interesting question is whether such learning effects need the dissociative effects for anti-depressant action. How dissociative is low dose ketamine anyway really? Not very much?
Noopept is said to abolish dissociative effects from NMDA antagonists, but I wonder if nootropics with LTP activity might make 3-MeO-PCP an effective anti-depressant? Or is it a particular signal cascade involving glutamatergic receptors from certain hydroxylated arylcyclohexylamines' metabolites, but excluding piperidines which are considered to have different SAR than the simple N-alkyl ACA's?

In any case I have also very recently started adding aniracetam to my regimen again - well still preliminary, not added to actual regimen.. so far promising results, yesterday I thought I had taken all 14 mg Dexamph XR but I had only taken 4 mg accidentally, plus aniracetam, and had good cognitive benefit e.g. when playing the piano and wanting to actually study instead of only free play. I only realized my mistake after the day passed. Can't comment on help with spreaded attention and distractions..

 

[Limpet_Chicken]

Well no, with ketamine at least, the rapid, profound resolution for some people, of depression is mediated via MTOR.

I'm probably somewhat of a different kettle of fish given the post-excitotoxicity but NMDA antagonists whilst they have always been helpful, since the unfortunate..incident, well its like they restore memory and cognitive function. Took some DXM earlier today, as revolting as it is, to help assist with ameliorating opioid WD, and managed to put in a long day at the lab. Still working as it happens

 

[Jonneh]

With ketamine at least, the rapid, profound resolution for some people, of depression is mediated via MTOR.

Interesting. Do you have a source handy for that?

 

[CFC]

Interesting. Do you have a source handy for that?

For example:

http://www.ncbi.nlm.nih.gov/pubmed/21158553

http://www.ncbi.nlm.nih.gov/pubmed/20724638


I wonder if high-dose leucine impacts on the process in any way given its effect on mTOR.