Methylene Blue is fascinating because it has been present in alternative medicine, biohacking, and nootropics forums for decades. It seems everyone in those communities discovers it eventually, thinks it must be a miracle substance, and then either feels nothing or has some initial positive effects that are either placebo or diminish quickly with tolerance.
From the anecdotes I’ve read over the years, very few people continue taking it. They either feel nothing, get some worrying side effects, or the initial effects they experienced (or placebo) disappear after a couple days or weeks. The most positive posts seem to be correlated with people taking a dozen medications and supplements at the same time, so it’s impossible to know what’s causing their experience.
Another ever-popular medication in these communities is Selegiline: Also an MAOI but selective for MAO-B at low doses (warning: it’s easier to reach MAO-A inhibition with repeated dosing, especially sublingual, than many internet sources claim). This one draws in people who are in their “dopamine explains everything” phase of learning neuroscience and think it must be a hack to get “more dopamine”. Again, few people continue it and many are confused about why they end up fatigued or tired while taking it instead of turning into the guy from Limitless. Neuropharmacology isn’t as simple as taking drugs to push neurotransmitter up.
Selegiline was repurposed as an anti-depressant recently, but it’s delivered transdermally and only showed efficacy at levels high enough to be a full MAOI.
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.
> understand that disrupting homeostasis in a durable and meaningful way is actually darn hard to do
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.
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.
> 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.
> 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.
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.
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".
> 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.
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.
From personal experience the right enantiomer at a low dose works longterm without any breaks. It’s not a panacea though. If you’re tired or you don’t have the will power, you’ll still twiddle your thumbs—except you’ll be really into the twiddling.
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).
For some reason people without ADHD really want to make it not a thing, but anyone who actually has it knows these drugs can be life changing
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
Interesting, are you saying you found a difference in efficacy or tolerance? Was it based on enantiopure d-amphetamines or the ratio of d/l-enantiomers?
This isn't always true. Stimulants can -- for a subpopulation, at least -- meaningfully improve focus in ADHD individuals in long-term measurable ways and low risk of side effects. This contrasts starkly to ordinary people, who will quickly build up a tolerance to typical stimulants. The difference is measurable with clinical tests.
> This contrasts starkly to ordinary people, who will quickly build up a tolerance to typical stimulants.
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.
Being downvoted cause they werent paying attention to what the comment above them was saying. The Euphoria WILL always wear off, doesnt mean it doesnt continue to treat symptoms.
Also yes stimulants are the gold standard but I would argue that our metrics for success are bunk
Generally speaking (there are exceptions) ADHD people do not experience euphoria when taking stimulants. I never have, not even the first time. It’s known as the paradoxical reaction.
Some people do develop tolerance, but usually building an off day into the schedule is enough to counter that.
that is absolutely just straight up untrue. Yes excessive stimulant usage depletes magnesium, mostly cause you forget to eat. And yes for both vyvanse and adderall, if your stomach is too acidic it will decrease bioavailability, but neither of things things have anything to do with tolerance, which accrues on a semi-permanent basis every time you take the drug.
The nootropics and biohacking community would benefit most of all by being told repeatedly every time they post online about their “stack” that a good night’s sleep and adequate water intake is more effective for cognitive function than every powder ever put into a pill.
Good sleep and frequent exercise are both amazing. That said, without a good to excellent diet or supplements, exercise can deplete things which in turn compromises sleep and recovery.
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.
SJW inhibits serotonin uptake and also has numerous other targets. It’s a fundamental misunderstanding of the alternative medicine world to consider it safer or more gentle than SSRIs.
Yeah, I thought it was ironic (and a little funny) that people promote it as an SSRI alternative even though it's just a less precise, less regulated SSRI. It's like telling someone to skip their quinine pills and chug a bunch of tonic water instead!
In my experience with hard drugs, the human body has an amazing ability to build tolerance, but in a way that biases against positive effects.
So, for example, a first-time user may consume quantity X of a drug, and get the positive effect Y and negative side-effect Z. An experienced user may consume quantity X and only get a negative side-effect 1/3 or 1/4 Z. But also only get a positive effect of 1/10 Y.
So even though the ratio of Z/X has decreased (less negative side-effect per unit of substance) so has the ratio of Y/X (less positive effect per unit of substance). Most importantly, the ratio of Z/Y has increased (more negative side-effect per "unit" of positive effect).
I find no reason to disbelieve the existence of performance-enhancing chemicals (or mood-enhancing, or anything else). Perhaps Methylene Blue does do what it's fans think it does -- at first.
If you want to get some work done, coffee can really help, Red Bull even more so, and speed even more so. The question is what happens on day 3, week 3, month 3, year 3 of continuous use.
Selegiline is also known as Emsam, the patches reportedly Sam Bankman-Fried was on, alongside ADHD meds. I recall reading how this may have been a large driver of his compulsive risk it all decision making that eventually brought it all down.
Delivery through transdermal patch (Emsam) is different than other presentations of Selegiline, and we don't know the doses he was on. I've heard a low dose of Emsam (6mg) gives a better, more stable dopamine baseline, without getting into MAO-A inhibition that happens at upper doses.
> I've heard a low dose of Emsam (6mg) gives a better, more stable dopamine baseline, without getting into MAO-A inhibition that happens at upper doses.
This is the broscience theory that you find on Internet forums, but it didn’t play out positively in the actual clinical trials. Getting into full MAOI inhibition was necessary for positive effects.
The “more dopamine” theory appeals to people who treat the brain as a simple machine where you’re adjusting levels of different chemicals, but doesn’t really work out in practice. Dopamine is the neurotransmitter du jour in these circles, but mood and mental health are more than one chemical.
Thanks for the info, I was missing an update on this space. If there's no solid, reproducible evidence of cognitive or energy benefits at this level -and full MAO‑A engagement seems necessary for those effects, then that doesn't look good.
About your second paragraph, I agree and I wasn't validating the bro part, just that I read about Emsam once. I guess it's mostly influenced by the popularity of performance enhancers in general, be it wakefulness enhancers, stimulants, etc. People are always trying to find "the edge", without the tradeoff, basically chasing a mirage.
Maybe a neglected topic in this theme has been the acetylcholine pathway. Cobenfy, for example, has been approved for treating negative symptoms of schizophrenia and it's not a classical drug in that space.
From the anecdotes I’ve read over the years, very few people continue taking it. They either feel nothing, get some worrying side effects, or the initial effects they experienced (or placebo) disappear after a couple days or weeks. The most positive posts seem to be correlated with people taking a dozen medications and supplements at the same time, so it’s impossible to know what’s causing their experience.
Another ever-popular medication in these communities is Selegiline: Also an MAOI but selective for MAO-B at low doses (warning: it’s easier to reach MAO-A inhibition with repeated dosing, especially sublingual, than many internet sources claim). This one draws in people who are in their “dopamine explains everything” phase of learning neuroscience and think it must be a hack to get “more dopamine”. Again, few people continue it and many are confused about why they end up fatigued or tired while taking it instead of turning into the guy from Limitless. Neuropharmacology isn’t as simple as taking drugs to push neurotransmitter up.
Selegiline was repurposed as an anti-depressant recently, but it’s delivered transdermally and only showed efficacy at levels high enough to be a full MAOI.