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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
1. I didn’t notice any difference.
2. It’s really messy, as in it (semi permanently) stains your counter tops blue if you so much as let a fraction of a drop land somewhere, including the dehydrated dust. I ended up buying some lab glassware cleaner to help clean it up.
3. It temporarily stains your teeth blue. It also turns your urine blue/green, but that’s no big deal as long as you’re expecting it.
That said, I also didn’t experience any negative effects that I could perceive.
Doesn't it also turn your internal organs blue/green?
Not concerning per se... but concerning.
One of the claims against this company is that they were preventing other companies from getting their hands on generic thalidomide, because they didn't want competitors to do research that might uncover similar analogs.
(I'm also not convinced that the results for methylene blue are especially promising or unique, but that's another matter :P)
> Then you realize: methylene blue can't be patented and it's manufacture is no secret
This isn’t an impediment at all. There are numerous examples of old, simple drugs being repurposed for new conditions at different doses or different delivery mechanisms with very high price tags attached.
Selegiline is one such example. It was repurposed for depression as a transdermal patch and very high prices.
If methylene blue worked for the conditions claimed, it would be used clinically. The myth that big pharma is ignoring a compound that works doesn’t hold water.
There's plenty of research done on things which can't be patented or used to turn a profit in some way. People do research on diet, exercise, vitamins, and pharmaceuticals which are now generic like aspirin etc. just to name a few off the top of my head.
There's also public funding available for research which isn't intended to make money for any particular corporation.
Methylene blue turns your urine blue. How does someone conduct a double-blind studies with a substance that very clearly indicates whether or not you are taking it?
Another issue is it's hard to get grant money to run studies in general. What would the goal of the study be? What would it measure?
And generally speaking, when you are looking to treat something in a double-blind test, the control isn't placebo, it's the standard treatment.
It's a tricky enough problem that when double blind studies have been done, the control will generally simply have a lower dose of methylene blue rather than no dose.
Do you you think that everybody is cynical and is motivated by dollars? Since it is an inexpensive, readily available compound, what prevents biohackers from doing a small scale (say, N=100) double blind trial against some relatively inert compound that makes your pee blue?
A close cousin to this claim is the old chestnut, "A tinkerer invented a carburetor that allows any care to get over 100 mpg, but then the oil companies bought out and buried the patent!"
There are no "promising results": there is placebo effects, survivorship bias and snake-oil peddlers.
Also, overdoses on methylene blue, apparently: https://x.com/iAnonPatriot/status/1887232439770087608
For %99.999999 of the population looking like this and being as physically fit without drugs in their 70's is impossible.
I would much prefer to take testosterone to look like RFK and be as physically capable as he is then age naturally like all of the 70+ year old people I know. Most of them have trouble pulling themselves out of a pool
Yes
> For %99.999999 of the population looking like this and being as physically fit without drugs in their 70's is impossible.
Incorrect
> I would much prefer to take testosterone to look like RFK and be as physically capable as he is then age naturally like all of the 70+ year old people I know.
Sure
> Most of them have trouble pulling themselves out of a pool
Incorrect
Being in the top 5% of healthy people for your age bracket should be table-stakes and we definitely do not have much of that.
Do say more. Nursing some achilles tendonitis on one leg right now.
Tendon stretches 2x a day with resistance bands. First thing in the morning and night before bed.
3 sets of ~30 - start light and move up. I just got a set of rubber bands off amazon for ~$25
Vitamin C - take at night
Collagen supplement - I just got the powder and I mix it in water - take at night with the vitamin C
Peptides TB-500
BCP-157
GHK-Cu
Ask chatgpt about how much sterile water to mix with the peptides and for a dosing chart
Peptides can be injected subq in belly fat or closer to the injury in the calf - don't inject into the tendon. GHK-Cu is also going to help your skin look good so a little bonus.
Recommend doing the band workouts, vitamin c and collagen for a month to gauge progress. You can move on to the peptides after that, lots of people don't like shots so would recommend starting with the less invasive parts of the plan and scale accordingly.
took 3 months but I went from getting out of bed and having to hop around for 2 hours until the tendon warmed up to getting out of bed and no pain. Its still not 100% but I can jog lightly now and do heavy calf raises without issue. Alternative was surgery.
Note: my tendon did not rupture, that's a whole other ball game where surgery is pretty much a must.
For your consideration, I just ran across Dr. Keith Baar of UC Davis via Tim Ferriss' podcast: https://www.youtube.com/watch?v=BnFzjcPTSsc
He is recommending isometrics for tendon health, which is something I'm also going to incorporate.
Nice going.
As a habitual liar the pendulum of doubt swung to “presume bullshit” with junior a long time ago.
Regardless, I don't understand why biohackers are often obsessed with things like methylene blue when targeted modulators usually exist. If someone is obsessed with "mitochondrial function" I'd expect him to look at methoxatin or something along those lines before something as broadly active as methylene blue. If someone wants MAO inhibition pharmaceutical options are probably better in terms of controllable isoform affinity. I don't see any reason to prefer something less well-studied for MAO inhibition over e.g. rasagiline or moclobemide.
Whether you’d get caught or not is a separate matter, but don’t assume that it’s legal without checking local laws.
Interesting, so buying prescription medication from abroad (and without a prescription of course) is not illegal as long as it isnt a narcotic?
Because these are usually ordered from overseas companies that aren't governed by U.S. regulations, they're in the clear. Because it's not actually illegal for you to buy it, you're in the clear.
N.B. some "nootropics" are still controlled substances. For example, modafinil is I believe schedule IV so you technically could be prosecuted though it's unlikely.
I don’t knot that steroids is a good example to support your case. Anabolic steroids are classified as Schedule III controlled substances under the Controlled Substances Act (CSA) in the United States.
Thanks, ha ha.
That's 5X what is considered a safe dose.
Up to 2mg/kg/day is considered safe. Double that with care. But they were dosing every hour for days!
That triggered my "uh-oh" alarm.
Anyone familiar with MAO inhibitors as a psych med, know that they can have really serious side effects, when you eat certain things (like chocolate or caffeine). It can kill you[0].
However, I guess that this stuff doesn't have those side effects.
[0] https://www.ncbi.nlm.nih.gov/books/NBK539848/#:~:text=MAOIs%...
I had heard chocolate and coffee, but I have no personal experience.
I’m not sure what penis pumps have to do with the quality of his research, they’re a legitimate medical device used in patients with erectile dysfunction. [1]
An hour is a significant time investment. Not linking to your sources increases the bar for verifying claims high enough that it's suspicious to not do so.
I can't verify your claims about dosage. I can investigate the claims made in this article. If you want to strengthen your argument and ensure you aren't walking yourself down a path based on nothing but other people's ability to weave a narrative, you should seek out stronger sources for topics you care about.
