Comment by Aurornis | Hacker News Reader

Comment by Aurornis | Hacker News Reader

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> Yeah there's functionally no good solution besides occasional stimulant use and staying off them the rest of the time.

This is literally the misunderstanding I was talking about.

The startup euphoric effects are a side effect, not the main ADHD therapeutic function. This is the confusion that leads people off track, especially when they’re prescribed too high of a starting dose.

Taking the stimulant every day and acknowledging that it’s not supposed to be euphoric is the only way to use them for actual ADHD treatment. The attention-enhancing effects largely remain.

This is also where the “stimulant medications affect ADHD people differently” myth comes from. The real reason is that the ADHD patient has taken the med for years and doesn’t get a stimulant rush when taking it. The college student who borrows the fully-titrated dose from their friend is speeding around because they are stimulant naive.

> Direct dopamine regulation is just a crappy target for this. TAAR1 agonism may be a better target.

Amphetamine (Adderall) is a TAAR1 ligand. Guanfacine (non-stimulant ADHD medication) is as well.

> I've heard some sketchy reports that things in the class of bromantane might be good options, as it acts to epigenetically upregulate dopamine synthesis rather than altering clearance,

Bromantane is thought to upregulate expression of some genes related to dopamine, but it also might have some effects on the sigma receptor, act on a potassium channel, and it does have some dopamine reuptake inhibition though the exact amount is up for debate.

Anyway, people often equate ADHD and dopamine, but norepinephrine is actually the common thread among all ADHD medications. Like you said, there’s a lot of “dopamine deficiency” broscience on the internet that doesn’t really match the science.

> This is also where the “stimulant medications affect ADHD people differently” myth comes from

This doesn't seem right, the effect people talk about isn't a non-ADHD person taking adderall and going off the wall— it's someone with ADHD taking a stimulant, even a pretty high dose, for the first time and it having very little effect outside of a mild calm and focus.

It very well might be a myth that this is related to my ADHD and it's caused by something else weird with my body but I can vouch for this experience. I was offered a 30mg adderall at a party and it didn't do much of anything for me except I felt "normal." No euphoria, just kinda sleepy, but I could think about stuff and my brain wouldn't hurt after a while which was nice.

Has this been characterized in literature to any significant extent? This isn't a "challenging" question btw, I hear it repeated but wonder to what extent it's actually true vs. people's later perceptions coloring it and/or odd internal perception. The latter I think is possible because I've read anecdotes from people who say they don't feel much, yet they go from demotivated to get up and do something to sudden motivation to do lots of different things besides what they got up to do, which reads to me as overshooting the mark in terms of effect if not in matching patient's expectations of "how it should feel".

In my experience people are VERY bad at evaluating how they are affected by amphetamines. Ive given many people amphetamines and the response is usually "I dont feel anything at all" meanwhile, their pupils are huge, theyre tapping all their feet and fingers, and theyre hyper focusing on some minute detail of something without even realizing it.

Exactly. This is an extremely common phenomenon among several drug classes.

The part about feeling “normal” is a common report, as people misinterpret the temporary good feeling as how they think everyone else must feel all the time.

> it's someone with ADHD taking a stimulant, even a pretty high dose, for the first time and it having very little effect outside of a mild calm and focus.

Subjective self-evaluation of drug effects is a fascinating topic. It’s a common theme in drug use for people to self-report effects that differ from what other people observe.

For example, benzodiazepine users will commonly report that benzos don’t inebriate them, they just make them feel “normal” while outside observers can clearly see that the person is impaired. In abusers, this phenomenon of false sense of sobriety is a known problem and leads people to drive cars and do other things they’re clearly incapable of doing while drugged, all while believing they’re perfectly sober.

Even with SSRIs, doctors and family members around the patient will report dramatic improvements while patients own self-rating of their condition stays low for a long time. Others can visibly see the improvement in the patient before the patient acknowledges it.

Cocaine and stimulant abusers will often think they feel “normal” or “calm and focused” while talking a mile a minute or doing things like hyper focusing on minutia. My friends who work in an ER have some stories.

What I’m getting at is that it’s common for first-time stimulant users to interpret the euphoria, confidence, and connectedness as a feeling of being “normal”.

The “this is how normal people must feel” thought is a common report from people taking several classes of drugs for the first time and experiencing the brief euphoriant effect that temporarily silences anxieties, dysphoria, worries, and replaces it with a false sense of positivity. Add on top of this the placebo effect that comes from all of us having heard the “ADHD people react differently” and it translates to first-time users interpreting the effect differently.

> but norepinephrine is actually the common thread among all ADHD medications

Anecdata, but my ADHD (and depression!) didn't significantly improve until I was on both lisdexamfetamine and buproprion. Both drugs lift production of both neurotransmitters, but they "specialize" in dopamine and norepinephrine, respectively.

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.

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.

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