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.
Dw629
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
Very well written and researched post, I’m surprised by the lack of comments.
One small additional note on what you briefly touched upon: neuronal circuitry organized in a more sparse and efficient manner is associated with higher intelligence.
Thus, a drug approach of increasing neuronal connections and dendritic complexity should be paired with an efficient synaptic pruner, perhaps like Rapamycin.
Something else that I recently came across is klotho. A single low dose of klotho administered to aged nonhuman primates enhanced memory, and even more interesting is that a study found that peripheral α-klotho protein fragment administration even in *young* mice was cognitively enhancing, and that it induced cleavage of the NMDAR subunit GluN2B and enhanced NMDAR-dependent synaptic plasticity, which is reminiscent of the “Doogie” mice study. Apparently klotho is already in clinical trials? Though overall, I doubt healthy adult IQ can be significantly increased (on the OOM of >1 SD) through any drug. I agree that the gene editing approach is much more promising. With drugs, one would also have to commit to a chronic regimen of some nootropics cocktail, and effects likely wouldn’t be permanent after you stopped.