N&PD Moderators: Skorpio
Neurochemicals most intimately involved with cognitive and executive function?
Cotcha Yankinov
Bluelight Crew
Ketamine is promising for treatment refractory depression, you could investigate that. There are clinics that give ketamine therapy around.
There was also some literature I saw on DXM as a fast acting antidepressant as well but I've never been able to find it again.
JohnBoy2000
Bluelighter
dxm - dextromethorphan?
Serotonergic, basically.
Ketamine treatment isn't licensed yet in Europe.
JohnBoy2000
Bluelighter
....which sucks, needless to say.
xbandit07x
Bluelighter
Things that improve executive functioning are Euphoria inducing agents. Thats why its hard to make one that works well and lasts longterm. This is because Executive "focus" doesnt exist. Its just are you high enough to enjoy/partake/put work into something/sit still/care/like/enjoy/do/preform behaviors.
Your IQ and acetylcholine just are whats making you even come on the internet and complain in the first place lol.
You NEED basically Noradrenaline/epinephrine with endorphins/dopamine to have the physical energy to like keep your head alert though and responsive.
JohnBoy2000
Bluelighter
Man, you are hitting the nail on the motherfucking head.
Believe it or not.... well, I guess it's believable but - I previously had delusional depression, where I would use self induced delusions to incite a sense of euphoria/adrenal response.
I kept myself ticking over at base line functioning like that, for.... more than 4 years.
Needless to say, during that time, I lived, comparably to, say, a junkie?
Extreme baseline functionality.
Now - as to where you acquired this information, I'm very curious.
The PhD Beth Murphy, McClean hospital, US, speculated, but did not extrapolate on, NA being "intimately involved" with executive function.
Thus again, your source of this information, I would like to see if possible?
And, to follow up on that - the most suitable drug to alleviate such a condition would be, bupropion?
Noradrenergic based medication.
I tried the dopaminergic, Pramipexole, previously, but it zonked me out. Fatigue inducing.
I only tried it for one day though.
Your assertions would explain entirely, why I was unresponsive to serotonergics, mood stabilizers.
I'm curious as to your points of view on the potential options, medication wise, to treat reduced executive function.
And when I say reduced I mean, unmedicated, basically, a corpse in terms of physical responsiveness etc.
Thus my inquiry as to the potency of agomelatine as a NA DA disinhibitor, it's blockade potency on the 5-HT2c receptor subtype.
I'm assuming, based on your assertions - Brintellix - a serotonergic with a varied mechanism of serotonergic action, may not be applicable?
Just looking at it's pharmacodynamic properties now, it does not seem to affect any receptor subtypes that may indirectly affect NA or DA.
And to follow up on that, clinical trials claiming comparable efficacy of 150 mg bupropion to 300 etc - pharmacologically, how would that make sense?
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JohnBoy2000
Bluelighter
Mmm - and just going on that logic also.
Ketamine, a dissociative - how effective would that be for such a condition?
Cocaine, MDMA, speed, ecstasy etc
Again, going on that logic, may be quite efficacious - for a short term period....
Sustaining a long term intake of them however...?
Was it Sigman Freud who reputedly took cocaine on a daily basis, most of his life?
JohnBoy2000
Bluelighter
Would opioid receptors implicate executive function also?
Euphoria, perhaps?
I've never used recreational drugs so, not exactly sure if opioids do induce euphoria....?
JohnBoy2000
Bluelighter
Pfff - full of damn questions but, quite importantly, so I can explain to my doctor:
What diagnosis would be put on a condition of entirely dissipated executive function, as a result of this neurochemical deficit?
Would it be labelled as "depression", technically?
Cotcha Yankinov
Bluelight Crew
DXM could be functioning as an anti-depressant through other means, for example Sigma 1 receptors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938562/
They try to dose ketamine low to avoid the dissociative (NMDA antagonist) effects - the efficacy of ketamine for depression is probably due to AMPA receptor modulation of a metabolite (HNK) and mTOR induction, while short term NMDA antagonism leads release of monoamines via inhibiton of inhibitory GABAergic neurons.
You can see here NE actually decreases NMDA receptor activation in the PFC https://www.ncbi.nlm.nih.gov/pubmed/7904522
And also that NE leads to a process called LTD in the PFC https://www.ncbi.nlm.nih.gov/pubmed/20434527
You might think about the PFC as communicating information to the limbic (emotional) system, so cognitive thoughts can make you feel abstractly happy or sad depending on what cognitive thoughts are occurring in the cortex, but further in towards the limbic system is where the feelings are actually produced.
As in, maladaptive daydreaming disorder? I think you really stand a lot to gain from mindfulness meditation. Over-activation of a network called the Default Mode Network is implicated in ruminating depression, and mindfulness has shown efficacy for ruminating depression that has correlated with decreased activity of the default mode network.
LSD's effects have been correlated to deactivation of the default mode network, and its hypothesized that this would be a therapeutic route for depression https://www.ncbi.nlm.nih.gov/pubmed/26979587
"What diagnosis would be put on a condition of entirely dissipated executive function, as a result of this neurochemical deficit?"
I think its important to look beyond just the receptors and neurotransmitters. Just because boosting NE helps depression doesn't necessarily mean there was an NE deficit in the first place. The issue is more likely to do with cell physiology and neuroplasticity. I believe things like maladaptive daydreaming disorder can really mess up neuroplasticity, and its really important to address the circuitry with mindfulness meditation, or neurofeedback if you wish.
Limpet_Chicken
Bluelighter
With opioids (assuming no secondary modes of action such as for instance, the serotonergic effects of pethidine (meperidine in the US) and stimulant properties (although a lot of its due to the metabolite norpethidine, while its also a convulsant in excess. the SRA/SNRA effects of tramadol (ick!! grosshooorrrkkhsphlegmrrghghthptoooie!) it depends on the dose. Of course at very high doses they simply cause unconsciousness, if not in true overdose, simply knocking the subject out cold. Lol done that..ahem..ahem..once or twice now and then
High doses insufficient to knock the subject out cause an initial rush upon intravenous use, the rush is absent in the case of oral and rectal use, whilst there is with some opioids at least an almost-rush-ish with the drug quickly causing a strong warm glowing sensation and euphoria. More warmth than is felt usually (for me) when the same drug is used rectally (allowing similarly for quick absorption but less so than IM) And nodding off. Sub-nodding high doses tend towards facilitating laziness, but they can be nice for reading, and keeping attention focused on noncritical tasks. I love to take a solid whack of morphine and get the computer fired up, so I can start worming through pubmed, like a maggot, wriggling and munching its way deep within a juicy piece of rotting flesh. Instead of having a crappy attention span generally speaking (although its good for things I WANT to read, like the things I find on pubmed, unless something actively disrupts the maintainence of attention) where scientific study is concerned I just love to eat it up, breakfast, elevenses, lunch (if I ate lunch habitually), tea and supper plus midnight snacks whenever I wake up during the day)
Medium doses I find, when its not too sedating to leave the improvement in focus, motivation to focus and once focused and busy with one's task at hand, helps get into the rhythm of things, as can smaller doses. Microdoses seem to do the opposite. Whether thats just to do with being moreish, or selectively binding high-affinity Gs-coupled excitatory MORs resulting in unpleasant sensations, antsyness etc, similar to how nano-dose naltrexone works only with a MOR agonist rather than an anagonist I do not know.
And then there are...extreme f****ng well oddities like the intermediate in synthesis of desomorphine, alpha-chloromorphide, which whilst claimed to be '10x the strength of morphine' on wikipedia it is....well it is capable of the alleviation of withdrawal from a Mu-opioid receptor agonist to which the subject is habituated in the physical capacity. However its action is primarily psychostimulant yet without cardiovascular push. It is very different from a dopamine receptor agonist, such as pramipexole or piribedil, it is closer to the classical psychostimulants, amphetamine, the various ritalinate esters, although what it reminded me of most was desoxypipradrol, in that it was mentally right in there, but at the same time, itwas both possessed of subtlety and with the trait of very little cardiovascular pushyness (in the case of desoxypipradrol, in the case of alpha-chloromorphide however it is completely absent. It is a most peculiar drug, very smooth stimulating effects at all but too high a dose, in which case it seems to cause myoclonic twitching of the distal extremities, not sure quite what to make of it really. And I do not intend on pushing it too far, I.e above the level at which the twitching an slight tremor began, there were no unpleasant psychic phenomena attening this, it seemed purely to be a somatic complaint. However since agonists of the delta-1 opioid rceptors can be seizurogenic, and I am myself already prone to seizures, taking chlormethiazole as my control and termination med. I have myoclonic seizures, which turn into atonic ones an then often, for a time back into myoclonic although less severe in the tertiary phase if it decides to return in myoclonic form. I think it highly probable that alpha-chloromorphide is an agonist at one or both DOR subtypesl due both to its behaviour in vivo (human[oid] and the fact that in the morphine-habituated subject (murine model) heroin switches from being a MOR agonist to mixed MOR-DOR2 agonist, might prefer DOR, can't recall specific Ki values, and 6-MAM is apparently a selectivev DOR2 agonist.
And do not DOR agonists induce DA efflux?
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Limpet_Chicken
Bluelighter
And what is maladaptive daydreaming disorder?
xbandit07x
Bluelighter
First of all none of us understand the science.
Yes Opiods/Dopamine/noradrenaline all three are needed. Do you think athletes are known for being smart? No but they have intense pain/norepinephrine/focus Dopamine activation abilities.
Acetylcholine is inversely proportional to Dopamine.
Meaning those headachey nootropics are creating brain fog to some.
To address this future, WHAT do you imagine as executive functioning? I'm sure you CAN use your brain to think and understand things fine as it is.
What you CANT do is generate effort or energy to utilize the duration or meaning of looking and spending time with things to your brain.
Norepinephrine lacking would make you be sedated by just Dopamine and endorphins and no Dopamine but high norepinephrine will make you not focus but have the brain energy to focus on many things in general.
What sources? Just remember the first day you tried Amphetamines. You know those release pleasure center neurons right? There's no magic focus.
Remember anytime you liked what you were doing in life, you enjoyed it and did it well,
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JohnBoy2000
Bluelighter
Once again - you are hitting the nail right on head, fren.
But when I said "sources", I was referring to, links to academic research papers, chapters in books (I have Foundations in neuropharmacology by steven stahl downloaded).
Because, what you're saying makes complete sense.
Complete sense.
And corresponds exactly to my experiences with these drugs thus far.
And also to what I outlined regarding the use of self induced delusions, inciting an adrenal response - gives energy, allowed me to focus, read, do things etc.
However, you explore various topics such as acetylcholine being inversely proportional to dopamine...
These are areas of neuropharmacology I have no understanding of.
Naturally, I wish very much to gain an understanding of them.
But lack the focus (energy),to spend time reading through books to find the key information buried somewhere within etc.
So if I were to be directed to their source, directly - that would be super fantastic.
In the absence of this, for the time being - perhaps you could elucidate me further...
You mention lack of norepinephrine leads to.... high dopamine/endorphans - in turn leading to sedation?
So - I should be looking for an exclusive norepinephrine implicating drug??
Reboxetine?
NE heavy tricyclics?
Lavish me in your wisdom, fren.
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xbandit07x
Bluelighter
That's why when your ADD meds make you tired or you aren't calm on them, you goofed it.
Can you even imagine focusing not calm?
xbandit07x
Bluelighter
by seeing acetylcholine and Dopamine are inversely proportional, we Know why the acetylcholine products don't seem to help.
It Does not lead to high Dopamine/endorphins to lack noradrenaline. Just theoretically if you had that you'd be sedated.
Like mostly opioids can put you into a very happy but sedated/motivationless state.
But things like adderall typically overshoot Noradrenaline and quickly anything pleasurable that helped you from day 1 is vastly too low to work with those noradrenaline levels being that high.
Realistically and naturally neurotransmitters are low from brain fog/health problems ranging from gut to intestinal to metals. Our mutations and genetic stuff too. Lots of it's fixable but pharmaceutical meds are meant not to work. They make them to try and turn one switch and hope you can build off that "help" in the brain.
Stuff like Amphetamines were created before pharmacy was doing that in 1910s, when they tried to make the most syntheticly effected mood boost possible.
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JohnBoy2000
Bluelighter
JohnBoy2000
Bluelighter
So - regarding executive function.
What drugs exactly would you suggest??
Dopaminergics like pramipexole?
NE heavy drugs etc?
Would the dopamine implication of wellbutrin be a hindrance to alleviating cognitive impairment where, paradoxically the other side to the drug, norepinephrine enhancement, assists with it?
xbandit07x
Bluelighter
Drugs that cure whatever reason you aren't keeping your head up and calmly existing to work with information/tasks.
Marijuana, Dexedrine, or opiates combined with supplements like Sam e, b12, correct b9, tons of b6. That works for me but if you have anxiety or are helplessly addicted eh.
JohnBoy2000
Bluelighter
Are you suggesting that adderall could be beneficial, where methylphenidate was not??
I don't know respective mechanisms of action so....
xbandit07x
Bluelighter
No norepinephrine enhancement alone normally fails with people that have the energy to come on the internet anyway already. I'm sure some people out there can respond well to Wellbutrin I won't try it because I really do not want to switch to that format of Drug.
For a primary norepinephrine drug to help youd have to be somebody that atleast lazily watches tv or something.
