Periodic reminder: AFAIK (though I didn’t look much) no one has thoroughly investigated whether there’s some small set of molecules, delivered to the brain easily enough, that would have some major regulatory effects resulting in greatly increased cognitive ability. (Feel free to prove me wrong with an example of someone plausibly doing so, i.e. looking hard enough and thinking hard enough that if such a thing was feasible to find and do, then they’d probably have found it—but “surely, surely, surely someone has done so because obviously, right?” is certainly not an accepted proof. And don’t call me Shirley!)
Since 1999 there have been “Doogie” mice that were genetically engineered to overexpress NR2B in their brain, and they were found to have significantly greater cognitive function than their normal counterparts, even performing twice as well on one learning test. No drug AFAIK has been developed that selectively (and safely) enhances NR2B function in the brain, which would best be achieved by a positive allosteric modulator of NR2B, but also no drug company has wanted to or tried to specifically increase general intelligence/IQ in people, and increasing IQ in healthy people is not recognized as treating a disease or even publicly supported. The drug SAGE718 comes close, but it is a pan-NMDA allosteric (which still showed impressive increases in cognitive end-points in its trial) Theoretically, if we try to understand how general intelligence/IQ works in a pharmacological sense, then we should be able to develop drugs that affect IQ. Two ways to do that is investigating the neurological differences between individuals with high IQ and those with average IQ, and mapping out the function of brain regions implicated in IQ e.g. the dorsolateral prefrontal cortex (dlPFC). If part of the differences between high and average IQs is neurotransmitter based and could be emulated with small molecules, then such drugs could be developed. Genomic studies already link common variation in postsynaptic NMDA-complex genes and in nicotinic receptor genes (e.g., CHRNA4) to small differences in cognitive test scores across populations. Likewise, key brain regions like the dlPFC could be positively modulated, e.g. we know persistent‐firing delay cells in the macaque dlPFC rely on slow NMDA-receptor-mediated recurrent excitation, and their activity is mainly gated by acetylcholine acting at both α7 nicotinic and M1 muscarinic receptors. So, positively tuning delay cell firing with a7 and M1 ligands augments your dlPFC. Indeed, electrophysiological and behavioral experiments show that low-dose stimulation or positive-allosteric modulation (PAM) of either receptor subtype enhances delay-period firing and working-memory performance, whereas blockade or excessive stimulation impairs them.
There are in fact drugs, either very recently developed and currently in trials with sound mechanisms as described above that support significant cognitive enhancement, or that have already shown very impressive cognitive improvement in animals and humans in past trials despite not being specifically developed for cognitive enhancement and rather diseases like Alzheimer’s, or conditions like depression, e.g. TAK653 (AMPA PAM), ACD856 (TrkB PAM), Tropisetron (a7 partial agonist), Neboglamine (NMDA Glycine PAM), BPN14770 (PDE4D NAM), SAGE718 (NMDA PAM), TAK071 and AF710B (M1 positive allosterics).
There is a small community of nootropics enthusiasts (r/Nootopics and its discord) that have tried and tested some of these compounds and reported significant cognitive enhancement, with TAK653 increasing IQ by as much as 7 points in relatively decent online IQ tests (e.g. mensa.no, mensa.dk) and also professionally administered tests (that weren’t taken twice to minimize retake effects), and cognitive benchmarks like humanbenchmark.com, as well as the WAIS Digit Span subtest likewise showing improvements. The rationale behind TAK653 (also called “Osavampator”) and AMPA PAMs is that positive-allosteric modulators of AMPA-type glutamate receptors such as TAK653 boost the size and duration of fast excitatory postsynaptic currents without directly opening the channel. That extra depolarization recruits NMDA receptors, calcium influx, and a rapid BDNF-mTOR signaling cascade that produces spine growth and long-term potentiation. In rodents, low-nanomolar brain levels of TAK-653 have been shown to rescue or enhance recognition memory, spatial working memory and attentional accuracy; in a double-blind cross-over Phase-1 study the same compound sped psychomotor responding and stroop task performance in healthy volunteers.
Some great, well written and cited write ups I would encourage you to read if you have the time:
Very interesting, thanks. I’ve now read most of your links. Obviously I can’t actually evaluate them but they seem intriguing… Especially because IIUC they at least allege positive effects working on different regions of the brain (and contributing to improvements on different sorts of tests), which suggests maybe they can stack.
I take your point that no one’s really trying. Has anyone really tried to really try? For example, has someone who actually knows their stuff tried working out a plausible market plan (e.g. how to deal with regulation), and then tried to get venture capital, for intelligence enhancement? I guess there’s tons of stuff sold as mind enhancing, though presumably it’s mostly useless; and if these are all research chemicals from pharma companies then they’d be hard to sell… Or, has anyone tried a noncommercial (philanthropic, say) angle? Maybe I should talk to the Noo people.
Yeah unfortunately it seems to be the case that no one has really seriously tried (ie invested a lot of resources, on the scale of a large company or a government) to do R&D on significantly increasing IQ in healthy people through drugs, but I won’t get into that here. If you’re interested in this area then I really do recommend to talk with the people at Nootopics. Everychem is the small company that has synthesized most of the drugs I’ve listed and sells them for research (so really they are just research chemicals), but even though this is clearly a grey market, it has attracted…a lot of interest in the community. The user u/sirsadalot is the person who has written the posts I linked and is more knowledgeable than me, so I would suggest talking to him.
Yeah unfortunately it seems to be the case that no one has really seriously tried (ie invested a lot of resources, on the scale of a large company or a government) to do R&D on significantly increasing IQ in healthy people through drugs...
I did a high-level exploration of the field a few years ago. It was rushed and optimized more for getting it out there than rigor and comprehensiveness, but hopefully still a decent starting point.
I personally think you’d wanna first look at the dozens of molecules known to improve one or another aspect of cognition in diseases (e.g. Alzheimer’s and schizophrenia), that were never investigated for mind enhancement in healthy adults.
Given that some of these show very promising effects (and are often literally approved for cognitive enhancement in diseased populations), given that many of the best molecules we have right now were initially also just approved for some pathology (e.g. methylphenidate, amphetamine, modafinil), and given that there is no incentive for the pharmaceutical industry to conduct clinical trials on healthy people (FDA etc. do not recognize healthy enhancement as a valid indication), there seems to even be a sort of overhang of promising molecule candidates that were just never rigorously tested for healthy adult cognitive enhancement.
Thanks. Seems worth looking into more. I googled the first few on your list, and they’re all described as working via some neurotransmitter / receptor type, either agonist / antagonist / reuptake inhibition. Not everything on the list is like that (I recognize gingko biloba as being related to blood flow). But I don’t think these sorts of things would stack at all, or even necessarily help much with someone who isn’t sick / has some big imbalance or whatever.
My hope for something like this existing is a bit more specific. It comes from thinking that there should be small levers with large effects, because natural development probably pulls some such levers which activate specific gene regulatory networks at different points—e.g. first we pull the [baby-type brain lever], then the [5 year old brain lever], etc.
AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not. New pharmaceuticals need to explore more complex chemical spaces, like artificial antibodies. So I think if there was anything simple that has this effect (the way, say, caffeine makes you wake up) we would know.
AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not.
I don’t know anything about pharma research or chemistry, but this smelled off. Asking a bunch of LLMs (o3, 2.5 Pro, 3.7 ET, Grok 3, r1), none of them agree (o3: “no—we are nowhere close… this confuses confuses a genuine slowdown in R&D productivity (Eroom’s law) with chemical or biological exhaustion”, 2.5 Pro: “largely inaccurate and overly pessimistic”, 3.7 ET: “deeply misleading. It fundamentally misunderstands both the state of pharmaceutical research and the nature of small molecule discovery”, etc).
I am no expert but this was pretty much what I heard over and over when working in contact with pharma people around e.g. cheminformatics ML workshops and such. I think it’s well possible that this was meant as shorthand for a more complex “of course there are still tons of molecules that however aren’t even worth the effort of trying to synthesise and test, but all the small (< 100 atoms) candidates that even make sense to try have been explored to death” statement. Like, obviously you can do a bunch of weird small metallorganics I guess but if your reasonable assumption is that all of them are simply going to wreck someone’s kidneys and/or liver that’s not worth pursuing.
Then of course there’s regulatory and research costs, and part of the problem can be simply a classic “Hubbert peak” situation where really it’s the diminishing returns on mining further the configuration space of those molecules that make it impractical.
Fair, though generally I conflated them because if your molecules aren’t small, due to sheer combinatorics the set of the possible candidates becomes exponentially massive. And then the question is “ok but where are we supposed to look, and by which criterion?”.
Thanks. One of the first places I’d look would be hormones, which IIUC don’t count as small molecules? Though maybe natural hormones have already been tried? But I’d wonder about more obscure or risky ones, e.g. ones normally only active in children.
Some would count as small (e.g. cortisol, testosterone). But there’s also protein hormones. Honestly dunno but I expect we’d understand the effects of those kinds of molecules fairly well, if only because almost for all of them there is a condition where you have too little or too much of it providing a natural experiment.
Hm. TBC, the broader category would be “molecule that would activate master regulation of one or more gene regulatory networks related to brain function”, e.g. a hormone but maybe also some other things.
Periodic reminder: AFAIK (though I didn’t look much) no one has thoroughly investigated whether there’s some small set of molecules, delivered to the brain easily enough, that would have some major regulatory effects resulting in greatly increased cognitive ability. (Feel free to prove me wrong with an example of someone plausibly doing so, i.e. looking hard enough and thinking hard enough that if such a thing was feasible to find and do, then they’d probably have found it—but “surely, surely, surely someone has done so because obviously, right?” is certainly not an accepted proof. And don’t call me Shirley!)
I’m simply too busy, but you’re not!
https://www.lesswrong.com/posts/jTiSWHKAtnyA723LE/overview-of-strong-human-intelligence-amplification-methods#Signaling_molecules_for_creative_brains
Since 1999 there have been “Doogie” mice that were genetically engineered to overexpress NR2B in their brain, and they were found to have significantly greater cognitive function than their normal counterparts, even performing twice as well on one learning test.
No drug AFAIK has been developed that selectively (and safely) enhances NR2B function in the brain, which would best be achieved by a positive allosteric modulator of NR2B, but also no drug company has wanted to or tried to specifically increase general intelligence/IQ in people, and increasing IQ in healthy people is not recognized as treating a disease or even publicly supported.
The drug SAGE718 comes close, but it is a pan-NMDA allosteric (which still showed impressive increases in cognitive end-points in its trial)
Theoretically, if we try to understand how general intelligence/IQ works in a pharmacological sense, then we should be able to develop drugs that affect IQ.
Two ways to do that is investigating the neurological differences between individuals with high IQ and those with average IQ, and mapping out the function of brain regions implicated in IQ e.g. the dorsolateral prefrontal cortex (dlPFC).
If part of the differences between high and average IQs is neurotransmitter based and could be emulated with small molecules, then such drugs could be developed. Genomic studies already link common variation in postsynaptic NMDA-complex genes and in nicotinic receptor genes (e.g., CHRNA4) to small differences in cognitive test scores across populations.
Likewise, key brain regions like the dlPFC could be positively modulated, e.g. we know persistent‐firing delay cells in the macaque dlPFC rely on slow NMDA-receptor-mediated recurrent excitation, and their activity is mainly gated by acetylcholine acting at both α7 nicotinic and M1 muscarinic receptors. So, positively tuning delay cell firing with a7 and M1 ligands augments your dlPFC. Indeed, electrophysiological and behavioral experiments show that low-dose stimulation or positive-allosteric modulation (PAM) of either receptor subtype enhances delay-period firing and working-memory performance, whereas blockade or excessive stimulation impairs them.
There are in fact drugs, either very recently developed and currently in trials with sound mechanisms as described above that support significant cognitive enhancement, or that have already shown very impressive cognitive improvement in animals and humans in past trials despite not being specifically developed for cognitive enhancement and rather diseases like Alzheimer’s, or conditions like depression, e.g. TAK653 (AMPA PAM), ACD856 (TrkB PAM), Tropisetron (a7 partial agonist), Neboglamine (NMDA Glycine PAM), BPN14770 (PDE4D NAM), SAGE718 (NMDA PAM), TAK071 and AF710B (M1 positive allosterics).
There is a small community of nootropics enthusiasts (r/Nootopics and its discord) that have tried and tested some of these compounds and reported significant cognitive enhancement, with TAK653 increasing IQ by as much as 7 points in relatively decent online IQ tests (e.g. mensa.no, mensa.dk) and also professionally administered tests (that weren’t taken twice to minimize retake effects), and cognitive benchmarks like humanbenchmark.com, as well as the WAIS Digit Span subtest likewise showing improvements. The rationale behind TAK653 (also called “Osavampator”) and AMPA PAMs is that positive-allosteric modulators of AMPA-type glutamate receptors such as TAK653 boost the size and duration of fast excitatory postsynaptic currents without directly opening the channel. That extra depolarization recruits NMDA receptors, calcium influx, and a rapid BDNF-mTOR signaling cascade that produces spine growth and long-term potentiation. In rodents, low-nanomolar brain levels of TAK-653 have been shown to rescue or enhance recognition memory, spatial working memory and attentional accuracy; in a double-blind cross-over Phase-1 study the same compound sped psychomotor responding and stroop task performance in healthy volunteers.
Some great, well written and cited write ups I would encourage you to read if you have the time:
https://www.reddit.com/r/NooTopics/s/9NHUPgxDph
https://www.reddit.com/r/NooTopics/s/4Bh1nnv5sl
https://www.reddit.com/r/NooTopics/s/jsqz2m604o
https://www.reddit.com/r/NooTopics/s/vrT5Ii8MyN
Very interesting, thanks. I’ve now read most of your links. Obviously I can’t actually evaluate them but they seem intriguing… Especially because IIUC they at least allege positive effects working on different regions of the brain (and contributing to improvements on different sorts of tests), which suggests maybe they can stack.
I take your point that no one’s really trying. Has anyone really tried to really try? For example, has someone who actually knows their stuff tried working out a plausible market plan (e.g. how to deal with regulation), and then tried to get venture capital, for intelligence enhancement? I guess there’s tons of stuff sold as mind enhancing, though presumably it’s mostly useless; and if these are all research chemicals from pharma companies then they’d be hard to sell… Or, has anyone tried a noncommercial (philanthropic, say) angle? Maybe I should talk to the Noo people.
Yeah unfortunately it seems to be the case that no one has really seriously tried (ie invested a lot of resources, on the scale of a large company or a government) to do R&D on significantly increasing IQ in healthy people through drugs, but I won’t get into that here.
If you’re interested in this area then I really do recommend to talk with the people at Nootopics.
Everychem is the small company that has synthesized most of the drugs I’ve listed and sells them for research (so really they are just research chemicals), but even though this is clearly a grey market, it has attracted…a lot of interest in the community. The user u/sirsadalot is the person who has written the posts I linked and is more knowledgeable than me, so I would suggest talking to him.
Ok.
Cringe. But,
If anyone is reading this, if Dw629′s claims are true, this is a place where everyone’s dropping the ball for no good reason, so you could have the ball!
Yep… If I find the time/energy I’ll do so.
Thanks for your help!
I did a high-level exploration of the field a few years ago. It was rushed and optimized more for getting it out there than rigor and comprehensiveness, but hopefully still a decent starting point.
I personally think you’d wanna first look at the dozens of molecules known to improve one or another aspect of cognition in diseases (e.g. Alzheimer’s and schizophrenia), that were never investigated for mind enhancement in healthy adults.
Given that some of these show very promising effects (and are often literally approved for cognitive enhancement in diseased populations), given that many of the best molecules we have right now were initially also just approved for some pathology (e.g. methylphenidate, amphetamine, modafinil), and given that there is no incentive for the pharmaceutical industry to conduct clinical trials on healthy people (FDA etc. do not recognize healthy enhancement as a valid indication), there seems to even be a sort of overhang of promising molecule candidates that were just never rigorously tested for healthy adult cognitive enhancement.
https://forum.effectivealtruism.org/posts/hGY3eErGzEef7Ck64/mind-enhancement-cause-exploration
Appendix C includes a list of ‘almost deployable’ candidates:
Amantadine, Amisulpride, Amphetamine (incl. dexamphetamine, levoamphetamine) Aripiprazole. Armodafinil, Atomoxetine, Brexiprazole, Bupropion Carbidopa-levodopa, Clonidine, Desvenlaflaxine, Donepezil, Duloxetine, Entacapone, Folic acid, Galantamine, Gingko Biloba, Guanfacine, Istradefylline, Ketamine, Lisdexamphetamine, Memantine, Methamphetamine, Methylphenidate (incl. dexmethylphenidate), Modafinil, Opicapone, Piracetam, Pitolisant, Pramipexole, Rasagiline, Reboxetine, Rivastigmine, Ropinirole, Rotigotine, Safinamide, Selegiline, Sodium oxybate, Tacrine, Tolcapone, Venlafaxine, Viloxazine, Vortioxetine
Thanks. Seems worth looking into more. I googled the first few on your list, and they’re all described as working via some neurotransmitter / receptor type, either agonist / antagonist / reuptake inhibition. Not everything on the list is like that (I recognize gingko biloba as being related to blood flow). But I don’t think these sorts of things would stack at all, or even necessarily help much with someone who isn’t sick / has some big imbalance or whatever.
My hope for something like this existing is a bit more specific. It comes from thinking that there should be small levers with large effects, because natural development probably pulls some such levers which activate specific gene regulatory networks at different points—e.g. first we pull the [baby-type brain lever], then the [5 year old brain lever], etc.
AFAIK pharmaceutical research is kind of at an impasse because virtually all the small molecules that are easily delivered and have any chance to do anything have been tested and are either found useful or not. New pharmaceuticals need to explore more complex chemical spaces, like artificial antibodies. So I think if there was anything simple that has this effect (the way, say, caffeine makes you wake up) we would know.
I don’t know anything about pharma research or chemistry, but this smelled off. Asking a bunch of LLMs (o3, 2.5 Pro, 3.7 ET, Grok 3, r1), none of them agree (o3: “no—we are nowhere close… this confuses confuses a genuine slowdown in R&D productivity (Eroom’s law) with chemical or biological exhaustion”, 2.5 Pro: “largely inaccurate and overly pessimistic”, 3.7 ET: “deeply misleading. It fundamentally misunderstands both the state of pharmaceutical research and the nature of small molecule discovery”, etc).
Maybe you meant something more nuanced?
I am no expert but this was pretty much what I heard over and over when working in contact with pharma people around e.g. cheminformatics ML workshops and such. I think it’s well possible that this was meant as shorthand for a more complex “of course there are still tons of molecules that however aren’t even worth the effort of trying to synthesise and test, but all the small (< 100 atoms) candidates that even make sense to try have been explored to death” statement. Like, obviously you can do a bunch of weird small metallorganics I guess but if your reasonable assumption is that all of them are simply going to wreck someone’s kidneys and/or liver that’s not worth pursuing.
Then of course there’s regulatory and research costs, and part of the problem can be simply a classic “Hubbert peak” situation where really it’s the diminishing returns on mining further the configuration space of those molecules that make it impractical.
That’s unexpected and interesting, thanks.
Perhaps you misread the OP as saying “small molecules” rather than “small set of molecules”.
Fair, though generally I conflated them because if your molecules aren’t small, due to sheer combinatorics the set of the possible candidates becomes exponentially massive. And then the question is “ok but where are we supposed to look, and by which criterion?”.
Thanks. One of the first places I’d look would be hormones, which IIUC don’t count as small molecules? Though maybe natural hormones have already been tried? But I’d wonder about more obscure or risky ones, e.g. ones normally only active in children.
Some would count as small (e.g. cortisol, testosterone). But there’s also protein hormones. Honestly dunno but I expect we’d understand the effects of those kinds of molecules fairly well, if only because almost for all of them there is a condition where you have too little or too much of it providing a natural experiment.
Hm. TBC, the broader category would be “molecule that would activate master regulation of one or more gene regulatory networks related to brain function”, e.g. a hormone but maybe also some other things.