I'm generally enthusiastic about nootropics, and more broadly about using pharmaceuticals (and other "external" stimuli) to affect the mind in various ways. However, I'm also concerned about the risk that such stimuli might have unknown negative long-term side effects. As a result, I would generally be hesitant to use or promote substances that are not both fairly well-tested, and have been around for a fairly long time, even if those substances have interesting short-term pharmacological profiles. I'm sure many other people are in a similar position.

However, I don't actually know what the baseline likelihood is that a new drug has negative long-term side effects, and I have not been able to find this statistic. This seems very relevant to pharmacology research, neurochemistry research, and the ethics of human trials, so I would be somewhat surprised if this information has not been compiled somewhere. Do you know where to find it?

I could make the question more specific like this (for example): when a new drug is discovered, what is the likelihood that it will later be discovered to have substantial negative side effects upon moderate but regular long-term use, conditional on there being no noteworthy negative short-term effects, and conditional on it not being chemically similar to any other drug that is known to have negative side effects under the same conditions? By "substantial negative side effect" I mean something like "a noteworthy negative effect that persists once the drug has been entirely metabolized, and that is not easily reversed". I would count things like "an increased risk of developing serious medical condition X" or "a permanent decrease in cognitive capacity Y", but not things like "a buildup of tolerance that induces a nasty withdrawal" (assuming there are no further issues after that).

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I don't have an answer for the actual question you're asking (baseline side effects), however I would like to offer my experiences with nootropics. A number of years ago, I went through a phase where I tried a large variety of nootropics, including doing some basic psychometric tests on a daily basis (Stroop test, dual n-back, etc). 

It's remarkably hard to find a test that measures cognitive ability and is immune to practice effects, but I figured some testing was better than just subjective assessments of how I felt.

In all my testing, I only found a very, very small handful of drugs that had any measurable effect:

  • Caffeine helped significantly (or rather, not having caffeine hurt, since I was consuming a lot of caffeine on a regular basis).
  • Modafinil / Armodafinil was amazing. I had to stop taking it though because I eventually developed an allergic reaction. If you try this, get an actual prescription for it rather than trying to buy it from a sketchy offshore pharmacy
  • Alcohol had a much longer negative effect than I would have thought. If I drank on Monday night, I could still see the effects on Tuesday night, and I didn't rebound until Wednesday. This was for even moderate drinking (i.e., 1 cocktail).

Everything else I tried (*-racetam with and without choline, L-theanine, etc) had no measurable effects. I suspect nicotine might have had a measurable effect, but I wasn't willing to risk dependence. 


Finally, I would suggest that nootropics are mostly small scale optimizations compared to the benefit you'll see from eating healthy, exercising, getting enough sleep, and maintaining a healthy body weight. If you haven't optimized these, take care of that first and you'll get a much bigger result from your efforts. 

I would say the mind is complex and multifaceted and interconnected enough that the odds of any given psychoactive drug having long term negative side effects beyond the intended one, at least in some proportion of those taking it, should be close to 100%.  Once I asked my doctor whether something could be a side effect of an over-the-counter medicine, and his response was, "In the right patient, any drug can have any effect." Not literally true, but a good heuristic.

I was prescribed modafinil from 2012-2016 for a sleep disorder no one could identify. It's probably the only reason I was able to keep my job and my relationship (now marriage), or was able to safely drive. The only side effect I noticed was some increased moodiness.

Unfortunately the extra energy and focus also masked other underlying issues and symptoms. Until I went off the medication I didn't realize I'd been in a state of depression, possibly since as far back as 2007. Because it happened so gradually, and because I'd been able to function day to day, I didn't notice that I'd pretty much stopped having emotions, that my reaction times were slower, and that my senses and memory and thinking were dulled (it got bad enough that several times I and others thought I might have had a stroke). It's taken years of therapy (and later, bupropion) to function normally again. 

None of that was a chemical side effect of modafinil in the way you're asking about, but if I had been thinking psychologically instead of pharmacologically I could have better identified what was going on and avoided years of suffering (my own and my wife's).

My point is: even if you have no adverse biological reactions to something, the medium and long term effects of a psychoactive substance have a good chance of being dominated by second-order effects resulting from how changes in your thinking affect how you live and experience your life, in ways that are extremely hard to predict and very individually variable. And because those things can change who you become and not just how you think, they will tend to last long after you stop taking the substance.