[taeric]

It is frustratingly hard for me to trust most any nootropic discussion nowadays. Without many large random trials, there are as many questions as answers afterwards.

It doesn't help that I'm on Adderall, but if left to my own devices, would absolutely skip it. I'm assuming I benefit in the able to think way from it. Largely the only reason I know I missed a dose is if I find I lose my patience quickly with others.

[nomel]

> Without many large random trials

That, historically, does not work well for neurochemistry. Large random trials are good for an average biological response of profitable chemicals, but it seems there are significant differences in neurochemistry, between people, that these don't capture. If you've ever had a prescription for most anything mental related, like ADHD, depression, etc, there's never just one drug, there's a panel that you just kinda go through until one works for your personal neurochemistry, with some having detrimental side effects for some people.

Unsurprisingly, it seems to be the same with many of these nootropics. I've had several very negative reactions to common nootropics at fractional doses, where others have positive experiences at many times the dose. A few resulted in migraines every day I took it, until I stopped, with one quickly resulting in depression and the only suicidal thoughts of my life, which went aways just as fast as I stopped. One hurt my short term memory so much I couldn't repeat a phone number (a very potent racetam like).

Some nootropics are precursors, which are mostly self regulating/supplements, but there are many out there that very actively poke low level neurochemicals, and your personal response will vary, just as is expected in the regulated drug world.

Min/maxing personal neurochemistry won't come from large random trials.

[Aurornis]

> Unsurprisingly, it seems to be the same with many of these nootropics.

Controlled trials are actually very revealing of the placebo effect, which is a rampant confounded in nootropics communities. When people spend months reading about new nootropics, then a week waiting for it in the mail, then they take their first dose with excitement and anticipation they generally report feeling something.

The nice thing about trials is that they can start separating out this placebo effect.

Several people have done self-trials with different compounds with surprising results. Gwern is perhaps the most famous. Whenever people post about magnesium being a life altering substance or producing profound effects I also point them to his measured magnesium trials where the net effect over time was beginning to trend negative.

One of the myths in nootropics communities is that everything is a matter of neurochemistry and everyone is substantially different. In reality, RCTs are actually great at capturing enough people to see subgroups responding if you have enough people.

One thing most nootropics people don’t acknowledge enough is how often placebo effect appears in RCTs. Perform an RCT for depression and the placebo group will get better. It happens in every study. Give college students Adderall before an exam and they will report performing better, despite no statistical improvement in their grades. Now consider these facts in light of all of the scattered nootropics forum reports from people claiming different substances cured their depression or made them smarter. Not surprisingly, if you check their post history more recent comments will show them off on a new tangent trying a new substance, the old one long forgotten as a short trial that didn’t work out.

[taeric]

I hear what you are saying, but I have a hard time thinking it is an argument against RCTs. Notably, Adderall is a strong counter to this idea. It is clearly effective per all of the tests it has been through. Not surprisingly, it is one of the only ones listed in this website that works. Quite well.

There is an argument that people should treat their own lives as an experiment. Where you track the things you do and see if you can find patterns on mood and productivity and such. If you want to know what generally works, though, there is no counter to effectiveness in RCTs, though?

Put differently, when has evidence ever gone counter to RCTs? Not just are there some questions that an RCT hasn't covered, but times it has been counter to the results?

[nomel]

> Adderall is a strong counter to this idea. It is clearly effective per all of the tests it has been through.

That's a good example, because the statement "clearly effective" is absolutely false, as will be stated by a doctor when they prescribe it to you, and can be found in the documentation that comes with the medication. It is not appropriate or effective for some people, and is detrimental for others (accounts of both are found trivially online).

[taeric]

Adderall has some fairly clear cases where you shouldn't prescribe it, but this is largely not a secret list of "your unique biochemistry means we have no idea whether it will work for you" level of uncertainty. And, at large, this learning has been reinforced by RCTs. Such that I still don't see this as an argument against them?

[nomel]

You misread. I never made an argument against RCT.

> "your unique biochemistry means we have no idea whether it will work for you" level of uncertainty.

If by "work" you mean feeling something happen after you pop some pills, then sure...it's amphetamine.

If by "work" you mean "improved outcome", again, refer to the drugs documentation or are pharmacist, and also observe the existence of ADHD drugs that are not Adderall. The person prescribing it to you will quite literally tell you that it doesn't work for everyone, and go down the list of available drugs until you find something that, in fact "works for you", all entirely based on your personal response to the drug. Those reasons range from ineffectiveness (too high dosage requirement), unacceptable personality changes, to, of course, the rare full psychosis.

Difference in amphetamine response is well documented [1]:

> The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monaminergic function and monoamine system genes.

Ritalin is also ineffective for some, for unidentified reasons [2]:

> The response rates to MPH among adult ADHD patients range from 25 to 78 % in controlled trials (Wilens et al. 2011).

[1] https://pubmed.ncbi.nlm.nih.gov/12716966/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4969350/

[taeric]

If you aren't against RCTs, then I don't think we disagree? Your post certainly makes it sound like you feel there are better ways than RCTs to get an idea of how well things work.

And fair that "work" is not necessarily a binary answer. I think we can easily agree there is no panacea out there. But that doesn't mean you can't make pretty good learning based on the trials.

In common probabilistic game terms, we know that most hands are not as good as pocket aces at hold em. Even if we can say that the aces will not win near 20% of the time.

[Aurornis]

> It doesn't help that I'm on Adderall, but if left to my own devices, would absolutely skip it.

The difference is that you’ve taken it medicinally for years, whereas most nootropics users are early users who are experimenting with high placebo priming.

Stimulant prescriptions have a high churn rate because many people take their first few doses and feel euphoric, then think it’s going to be like that forever. Fast forward a couple years and the fun is long gone so it’s a different story.

Nootropics forums are dominated by posts from people saying “Just took my first dose of $substance and I feel amazing!” which is the least useful measure of how well it will treat someone long term.

[taeric]

Even when I started Adderall, I never felt anything amazing from it. Self reporting mood, as it were, I would think it is not working. It is only that I know I have more patience with things going wrong, that I know it is doing something.

That said, sounds like we are largely in agreement? I have gotten where I assume everything is dominated by noise.