I think the whole "nootropics" and "biohacking" community would benefit from mandatory introductory reading to understand that disrupting homeostasis in a durable and meaningful way is actually darn hard to do without serious side effects.
This is a huge problem in online ADHD communities, too.
The ADHD subreddits are a constant stream of people having “Wow I feel amazing” reactions after taking their first stimulant dosage, followed a week later by complaints that it “stopped working”. It’s a constant cycle of informing people that the euphoria they experienced was a side effect, not how they’re going to feel for the rest of their life taking a stimulant.
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.
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 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.
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.
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.
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.
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.
My issue was that even with the will power, sleeping and perfect nutrition, etc, my brain physically wouldn’t do it and it was extremely demoralising. Again, not a panacea and if you don’t actually have a condition I think it would be foolish to take (you may feel like you’re doing more but it will likely be at a lower quality).
The feeling of wanting to do productive stuff but being physically unable is hard to describe but it's really not a good feeling and moderate doses of dopamine raising agents really can alleviate it consistently and for the long term
Also yes stimulants are the gold standard but I would argue that our metrics for success are bunk
Some people do develop tolerance, but usually building an off day into the schedule is enough to counter that.
This isn’t really correct.
Everyone builds up tolerance to the euphoric effects. People expecting stimulants to make them happy, motivated, and energized forever are going to be disappointed, ADHD or not.
The concentration enhancing effects are more durable because they’re not re-regulated exactly the same as the euphoric component.
This is the real reason why ADHD people find long term value in stimulants but non-ADHD people do not. They were taking the drug for different reasons.
It’s also possible to overshoot the dose and get to the point where too much drug is counterproductive. This is a common problem for people chasing that euphoria who have doctors who don’t care and keep writing for higher doses. In many patients when the drug “isn’t working” a dose reduction can actually put them back where it’s effective as an ADHD medication.
How do I know? My sleep quality was shot to shit. Tried Mg supplements on a hunch, and got a massive improvement in sleep quality and exercise metrics (I put the latter down to better sleep, not anything in the supplements). I'd tried all the other sleep stuff, no caffeine after 3pm, various GABA modulators, found the somewhat improved sleep quality wasn't worth morning foggyness and lack of motivation, and I didn't like the fog they cause generally (you sleep, but, like alcohol or weed, it's not _clean_ sleep.)
A recent cautionary tale about someone who took St. John's Wort because they didn't want to take antidepressants, then quit the SJW too quickly... which functionally put them into (prolonged, agonizing) SSRI withdrawal.