4 ms·

Yeah there's functionally no good solution besides occasional stimulant use and staying off them the rest of the time. I vaguely recall some literature that cla

Yeah there's functionally no good solution besides occasional stimulant use and staying off them the rest of the time. I vaguely recall some literature that claimed many patients had basically no benefit by some period (believe over a year) which matches friends' anecdotal experience. Exceptions exist; they aren't super common. Direct dopamine regulation is just a crappy target for this. TAAR1 agonism may be a better target. 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, but not super well-investigated and noot bros are a little weird here (initial research chose it for a balance between physical work capacity increase vs. cognitive benefits, whereas a cognition-focused analogue might perform better.) HDAC inhibition is vaguely interesting but much too large a target. There are some possibilities to work on, but basically this remains a very unsolved problem, and rhetoric around tolerance often reminds me of the oxycodone "pseudo-addiction" language as much as anything. "Your brain is dopamine-deficient!" No, homeostasis means this probably isn't the case. There may be deficits in signaling but it's not an issue with the concentration of a neurotransmitter.

Aurornis 1y ago
> 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.
- Spivak 1y ago
  > 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.
  - landl0rd 1y ago
    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".
  - DontchaKnowit 1y ago
    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.
    - Aurornis 1y ago
      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.

Aurornis 1y ago

> 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.

Spivak 1y ago
> 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.
- landl0rd 1y ago
  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".
- DontchaKnowit 1y ago
  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.
  - Aurornis 1y ago
    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.