Well looking at it from that point of view although I admit my understanding of neuropharmacology is sorely lacking... Are you saying deltaFosB might be a viable target for this idealised motivation enhancement? I guess via the same mechanisms that more typically are known to result in compulsive behaviours that aren't necessarily particularly useful as far as I'm aware? Wouldn't that potentially just increase one's susceptibility to all sorts of more immediately pleasurable avoidance and/or short-term pleasure seeking type behaviours?
On that note though this might be counterintuitive but do you think it's possible that the right balance of partial agonists at an optimal subtype of opioid receptors might be a viable approach? It seems that for one to be able to tolerate stress better one essentially needs to be able to find some kind of reward that makes the suffering worth it, and the human reward system is unavoidably linked to the opioid receptors, which is activated even for rewards that are largely self-generated (ie, from a fairly internal psychological reward event that could be viewed in a variety of ways, not all positive, largely dependent on one's psychological constitution, whether innate or cultivated). All endogenous endorphins are opioids, if I'm not mistaken, thus for an event to have the prospect of a reward, even to convince oneself that it might do, there is going to be some "opioidic" activity... I just spent a bunch of time googling endorphin and dopamine interactions I admit because obviously dopamine is more reliably associated with motivation that results in behavioural changes that actually produce activity whereas even endogenous opioid receptor activation can inhibit this... So dopamine reuptake is broadly enhanced by beta-endorphin-mediated opioid-receptor-agonism (although not reliably everywhere in the brain, just "broadly", again) which intuitively makes sense, given the reward/tendency-to-stop-trying-so-hard, but dopamine also induces endorphin release in itself even prior to the "reward" endorphin dump, thus modulating it's own reuptake sufficiently to keep the hedonic treadmill balanced... I just realised that I'm probably just describing in a kind of simplistic way one of the primary feedback loops that governs "neuronal homeostasis" and keeps us vaguely balanced but generally oscillating between goal-seeking and reward-experiencing behaviours.
Anyway I didn't actually get much insight from the aforementioned googling except to say that dopamine-endorphin interaction is complex.
However - having just thought about that and look at it from a more "upstream" neurotransmitter-oriented perspective that at the level of transcription factors, the right type of partial agonism, selective for the optimal opioid receptor subtypes, whatever they might be, that somehow caps activation just below the threshold of that which would trigger downregulation - oh wait, I just realised I'm describing a Positive Allosteric Modulator...
*googles*
OK, not quite, I'm describing a combined PAM and partial agonist... or am I? Are PAMs already partial agonists by nature?
mOR PAMs are currently the subject of research for pain management, if not motivation enhancement, evidently:
https://jpet.aspetjournals.org/content/385/S3/210
Behind a paywall though so I can't see exactly what's going on but it probably wouldn't mean much to me anyway. So the right PAM/partial opioid agonist combined with, perhaps, another highly selective dopamine receptor PAM - wait - not a positive one, just an allosteric modulator? Oh wait, these things are mentioned in that article I just linked, Neutral Allosteric Ligands. OK so a highly selective mOR NAL and another NAL for dopamine which is selective for whatever subtypes are most affected by beta-endorphin mediated DR enhancement. Or perhaps just a regionally selective DRI if such a compound can exist... actually no, I think that would be more difficult.
Evidently selective dopamine receptor NALs are currently of some interest or at least speculation for treatment - or at least symptom management - of Parkinson's and Schizophrenia, which would seem to indicate that there is at least a theoretical basis for a positive behavioural impact or correcting dysregulation induced by either broad neuronal degradation as in the case of Parkinson's or whatever mechanisms result in Schizophenic dopamine dysfunction:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964653/
(Although that study isn't behavioural, but purely in vitro [in silico?].)
So this answer has ended up more stream-of-consciousness than I originally intended but having thought about it more since we essentially do know that the human motivation/reward mechanism is largely mediated by a balance of opioid and dopamine interactions, I wonder if a simpler route to arriving at the "ideal" cognitive enhancer - and I'm realising now this might be a divergence from whatever the original definition of "enhancement" was in this discussion, but going from the starting point of not inhibiting stress responses but enhancing stress tolerance. which, I think I agree, sounds like a preferable option - could perhaps be as "simple" (hah!) as an optimal calibration of these neurotransmitter systems.
I realise I started talking about endorphins generally and at some point just switched to beta-endorphin alone, also possibly at points I might have mixed up my thinking about brain regions versus receptor subtypes, I can't remember if or how much this matters though, if I ever had any idea.
Saying that I guess even having calibrated the stress/motivation/reward balances optimally - while this would surely go a significant way towards enhancing the cognitive baseline of almost everyone but the most genetically and environmentally fortunate who already have peak-optimal functioning motivation and reward systems that just cannot be improved - the next step is actual
enhancement by upstream enhancement of neuroplasticity via something like deltaFosB. An interesting consideration is whether dysregulation (but within the realm of what would typically considered a normally functioning human brain, ie, not with any diagnosable dysfunction such as Schizophrenia or even mild depression or some AD(H)D symptoms) would naturally make someone more resistant to the negative behavioural changes that can arise with deltaFosB activation? Perhaps it would...
Also... obviously this is another feedback loop of the human brain, the interaction between the reward system and deltaFosB, because reinforcing substances themselves induce deltaFosB activation as part of the mechanism of habituation which leads to addiction or at least compulsive use in the face of obviously diminishing rewards and intellectually obvious downsides... would a "fixed" or even just optimal human dopamine and endorphin balance naturally enhance deltaFosB anyway, with intrinsically protective effects against the formation of destructive habits? (Which include, obviously, those with detrimental effects on cognition.) I guess it might do, but given that seemingly already very smart and motivated people are still vulnerable to learning extremely bad habits, it's perhaps not enough if we are looking to truly optimise the functioning of the human brain. Although, perhaps in the shorter term... just the right environment within which induced deltaFosB release can entrench habits of thought which are themselves both protective against bad "habits of thought" and preferential towards good ones could still create some kind of self-reinforcing enhancement within the need to directly induce or otherwise mess with the complexity of directly augmented neuroplasticity.
OK I think I'm out of thoughts for now.
I'll just briefly try to relate some of this to my own experience - tianeptine is known to be a reasonably selective mOR agonist, although it does also have BDNF and AMPA activity. While I think it's fairly widely known by now that the ideas that it doesn't have any abuse potential, and before that the idea that it wasn't even an
opiate opioid, but a SRE, were not accurate - I have no concrete studies to back this up but I think at low enough doses it might well function very similarly to a mOR PAM, given the other activity. Opioids themselves trigger BDNF release, and BDNF increases sensitivity to opioid agonism, thus probably kicking off a part of the loop that ends up suppressing natural endorphin release and subsequent receptor downregulation, so the fact that tianeptine has a direct effect on BDNF likely has a small protective buffer effect against tolerance, in addition to the enhanced neuroplasticity induced from BDNF release it also enhances glutamate activity via AMPA activation, which has actually been studied as possibly suppressing the formation of opioid tolerance:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6847983/ (AMPA Receptor Positive Allosteric Modulators Attenuate Opioid Tolerance and Dependence)
So I guess it's a bit of stretch to say tianeptine itself is a PAM or even an effective PAM because I know it's been shown to be a full agonist, so the AMPA and BDNF activity and their somewhat protective effects against opioid receptor downregulation can be easily overcome,
but it seems to me not to be entirely false that it does have a reduced capacity to induce tolerance if doses are kept strictly below a certain threshold. Anyway I bring this up basically because in my experience tianeptine is cognitively enhancing in a way that other opiates simply aren't and in a way that cannot be accounted for simply by opiate-mediated anxiolysis. It's not perfect though because even with the inhibition and even at low doses I think that full agonism does still have a creeping dysregulating effect and reduced effectiveness, and obviously this stuff is just a kind of interesting accident of design, not something that was exactly planned, so it's not surprising that the relative balances of it's effect on these various systems would still be slightly unbalanced and liable to eventually tip into an unignorable downside.
Oh, while I was trying to find that study linked above I ended up coming across a bunch of research on deltaFosB that was specifically focused on enhanced stress tolerance, so my bad.
That's interesting stuff for sure, I've only been aware of it in the context of drug-induced compulsive behaviours, for whatever reason.
This is turning into a very long post - or has already turned into one - so I won't bother linking any of the exact studies but I remember a few of them mentioned implication of ampakine activity in the, or at least one of, the mechanisms by which deltaFosB mediates neuroplastic enhancement of stress tolerance, which is - I believe - a direct target of most of the well known 'racetam family of nootropics, and something it shares more indirectly (IIRC) with more well studied neurotrophic factors such as BDNF and NGF (I think?) which brings to mind noopept and NSI-189.
Noopept is known to be a releaser of both the aforementioned NFs and I think some others - in my experience it's actually not especially enhancing, at least in the acute phase of effects - in the context of what I just said that sensitization to endogenous opioid activity is perhaps an explanation for this. Actually as far as a "partial enhancer" I think it perhaps occupies a different fragment of the same spectrum of one possible approach to a theoretical "ideal enhancement" mediated primarily by modulation of the opioid and dopamine systems as tianeptine does - I think it is a "wellbeing enhancer", in a fairly subtle way, but it lacks the motivational aspect that tianeptine seems to possess, presumably due to the absence of opioid activity and second-order (presumed) dopamine release - actually it would surely be more correct to say that the balance of neural effects is weighted towards being demotivational, in a pleasant way.
NSI-189 is really not well understood yet, AFAIK, but also neutrophic factor release is (I think probably) one of the most important elements of it's mechanism of action. NSI-189 IME is NOT demotivational in the same way as noopept is - although neither is it especially motivational, or directly motivational - but in my experience it IS wellbeing enhancing in a very similar way, and with fewer downsides than noopept. Noopept directly modulates AMPA activity whereas (I think!) NSI-189 perhaps doesn't directly, but perhaps has some kind of downstream AMPA impact from whatever other activity it has. I thought I read somewhere a while back that NSI-189 also acts as some kind of cortisol inhibitor, but I could have totally made that up because I haven't been able to find anything about this since... but both noopept and NSI-189, IME, have a smoothing effect on blunt dopaminergic stimulants - mitigating both some of the negatives during the acute phase of dopamine-fuelled stimulation (anxiety, overstimulation, peripheral effects), AND most of the negatives of the dopamine crash in the aftermath - AND, in fact, and this is far more true for NSI-189 than it is noopept, in mitigating the anhedonia of stimulant overuse, and possibly even the PAWS of opioidergic dysregulation from opioid overuse. I haven't tried it in the acute phase of opioid withdrawal, and actually never even thought to, because it is not particularly reinforcing, I have to think about it to remember what it actually feels like to be on it, which is itself a pretty interesting phenomenon, I think...
All the substances I just mentioned are inconsistent both in terms of the people who report positive effects however, and even in properly controlled scientific studies, although I don't believe either has been directly studied for PAWS anhedonia, so they are obviously far from the "ideal" enhancer, but with the exception of NSI-189 which is a bit of an outlier due to the lack of clarity about it's mechanism - but which, honestly, I include because my perception of it is as a kind of Noopept 2.0 - all these substances share some of the neurotransmitter involvement spectrum with deltaFosB, primarily through AMPA but perhaps via other less clear mechanisms.
I was going to say something about Phenylpiracetam which is another interesting substance to me on the topic of cognitive enhancement, being basically Piracetam but an undeniably effective dopaminergic stimulant, but without the negatives of amphetamines, for example, or other classes of more "hard" stimulants, and is essentially a DRI with some strangely divergent effects on different dopamine receptor subtypes, unless this has since been disproven while it has a tolerance curve like nothing else which seemingly cannot be overcome with just ramping up the dose, perhaps some kind of ceiling effect even although I haven't tested this and wouldn't advise it - still upregulates D3 or D5 or something while downregulating most of the rest of them. I can't think exactly where it fits in to whatever picture it is I'm trying to paint now though except as dopamine agonism seemingly done well, assuming only 1 dose a week or something. Being a racetam there is also AMPA involvement though.
OK haha, think I'm out of words for now... oh, I could say something about modafinil probably, although actually I'm not entirely convinced modafinil is at all "enhancing" anymore, I think it's potentially a glorified orexin-inhibiting atypical dopaminergic, which maybe applies to all the eugeroics. Obviously it is a highly effective eugeroic, but alertness is not itself necessarily an "enhancement" although it is very easy to mistake for one and having used armodafinil for a very long time, perhaps more regularly than any other substance I've ever done, I think I'm reasonably qualified to say this... if not quite as much as an actual scientific study. Oh, I know the eugeroics have been shown to enhance working memory as well, which is, I guess, a very specific kind of enhancement but still not necessarily an indicator of any kind of global or sustainably improved ability to learn. The tolerance curve is amazingly shallow, I'll give it that... but actually I think it might well have many of the downsides of more traditional stimulants, just ones that manifest over a far, far longer timescale.
