I don't know of outstanding literature on it, but the easiest thing to cite on the eventual inefficacy of methylphenidate is this: https://pubmed.ncbi.nlm.nih.gov/17667478/ Take a glance at table 2, but the headline for the paper is that 2 in 3 of those children had no benefit from medication past 2 years.
You can make solid cases that this should be slower for XR or prodrug formulations like lisdexamfetamine, but the general trend is quite solid.
Amphetamines are TAAR1 agonists, and this is indeed a significant part of their activity, but not the largest. The point is that a higher dose of a selective agent might present a better treatment option. Interestingly methylphenidate, which shows better long-term potential, can block amphetamine's effects on dopamine efflux: https://jpet.aspetjournals.org/article/S0022-3565(24)33772-3...
Of course adjusted patients won't get a rush, but there are two ways this can go: some patients do seem to have ongoing benefits from those stimulants. A large group seem to see a more complete loss in efficacy rather than a loss of euphoria. I picked two studies that presented a more pessimistic view, but most of the literature finds that there is some gradient of the benefit patients retain, and that there's a significant proportion for whom an increased dose is required.
People have speculated on other mechanisms for bromantane's effects, sure, but sigmaergics and the underlying receptors are still not particularly well-understood. This means it's pretty hard to speculate as to whether it's a productive target, unless you're aware of some promising new characterization of its function or promising investigational literature for treating ADHD which I'm not (quite possible).
Noradrenergic drugs can help some types of ADHD, true. I am of the opinion that the tendency to "unify" conditions (also c.f. the conception of "autism spectrum disorder" for a massively heterogeneous and polygenic issue with a correspondingly-wide range of presentations) is a mistake. The fact that some people seem to derive a lot of benefit from atomoxetine while many others don't suggests that it's a colossal mistake to treat these as the same condition.
It's an interesting problem, but I'm convinced the more treatment-resistant/tolerance-prone type of attention deficit that's likely more strongly associated with the dopaminergic system is by no means a solved or easily-solvable problem. In this context, I brought it up because that's what most closely matches with the interest of the biohacker/nootropics bro crowd.
It's hard to find data of this quality for amphetamines but the story is pretty similar over time: https://sci-hub.se/https://link.springer.com/article/10.1007...
You can make solid cases that this should be slower for XR or prodrug formulations like lisdexamfetamine, but the general trend is quite solid.
Amphetamines are TAAR1 agonists, and this is indeed a significant part of their activity, but not the largest. The point is that a higher dose of a selective agent might present a better treatment option. Interestingly methylphenidate, which shows better long-term potential, can block amphetamine's effects on dopamine efflux: https://jpet.aspetjournals.org/article/S0022-3565(24)33772-3...
Of course adjusted patients won't get a rush, but there are two ways this can go: some patients do seem to have ongoing benefits from those stimulants. A large group seem to see a more complete loss in efficacy rather than a loss of euphoria. I picked two studies that presented a more pessimistic view, but most of the literature finds that there is some gradient of the benefit patients retain, and that there's a significant proportion for whom an increased dose is required.
People have speculated on other mechanisms for bromantane's effects, sure, but sigmaergics and the underlying receptors are still not particularly well-understood. This means it's pretty hard to speculate as to whether it's a productive target, unless you're aware of some promising new characterization of its function or promising investigational literature for treating ADHD which I'm not (quite possible).
Noradrenergic drugs can help some types of ADHD, true. I am of the opinion that the tendency to "unify" conditions (also c.f. the conception of "autism spectrum disorder" for a massively heterogeneous and polygenic issue with a correspondingly-wide range of presentations) is a mistake. The fact that some people seem to derive a lot of benefit from atomoxetine while many others don't suggests that it's a colossal mistake to treat these as the same condition.
It's an interesting problem, but I'm convinced the more treatment-resistant/tolerance-prone type of attention deficit that's likely more strongly associated with the dopaminergic system is by no means a solved or easily-solvable problem. In this context, I brought it up because that's what most closely matches with the interest of the biohacker/nootropics bro crowd.