Nootropics
"nootropics" are drugs that make you smart or smarter. It is not necessarily a drug. Nootropics are defined as substances or technologies that have neurotrophic or beneficial cognitive effect, whether it improves learning, memory, intelligence, or other cognitive phenomena.
The problem with nootropics is that they are not particularly effective so far. Can we make better smart drugs? Nicotine, dextroamphetamine, and a few others have non-zero impact but the results are not yet congruent with fantasy.
Recursive nootropics
Or "the minimum viable nootropic": a nootropic that makes you smart enough to design a better nootropic.
A "recursive nootropic" would be a nootropic that someone could take and then they subsequently design an even more powerful nootropic that further increases human intelligence or performance. This might sound similar to Aubrey de Grey's "longevity escape velocity" except it's more like "intelligence escape velocity" or the transhumanist concept of "recursive self-improvement".
Microbial nootropics
See a discussion of microbial nootropics at http://gnusha.org/logs/2015-06-22.log for more details.
or page 15 of the following slides http://diyhpl.us/~bryan/irc/2017-02-03-beacon.pdf#page=15
Directed evolution of brain microbes to engineer a nootropic
Intracortical or intracellular parasites should be developed for intelligence enhancement. This could be done through genetic engineering, rational design, machine learning, and directed evolution and selection via bacterial populations in mammalian brains after colonization in brain and psychometric testing for the test function. There were some notes about using neuronal intracellular parasites (like toxoplasma) from the hplusroadmap IRC logs back in 2017 or earlier if you want to go looking for that.
brain parasites (or perhaps intracellular parasites, there are even mitochondrial parasites)
plasmids with BDNF and other neural growth factors
lots of mutagenesis
Selection methods and targets:
Maze solving: infect mice, run mice through mazes, evaluate maze solving performance, recover bacteria from the brains of mice that perform well.
Hippocampus size: infect mice, wait some time, evaluate hippocampus size, recover bacteria from mice that have larger-than-average hippocampus
Sleep: infect mice, observe sleep behavior and patterns, select for microbes that decrease total mouse sleep requirements or decrease the negative effects of sleep deprivation
Besides bacteria, postmortem brains also show evidence of fungi.
Engineering brain parasites for intracellular delivery of therapeutic proteins
Gut microbiome engineering and selection
"Smarty Stools": it may be possible to develop a microbial nootropic confined entirely to the gut using fecal matter donation from high brain growth human infants, interspecies intestinal microbial development, doing multiple rounds of selection based on fetal brain development trajectory or neonatal brain development, followed by eventually returning for treatment in human. Both maternal gut microbial content should be altered (for fetal brain development modulation), as well as newborn gut microbe content (for ongoing brain development).
- maternal gut microbiome and its influence on fetal brain development
- gut microbiome and its influence on early life postfetal brain development
- gut microbiome and its influence on adult brain function, behavior, or learning
Alternative approaches to intelligence enhancement
Other than small molecule supplements, cell therapy, or even gene therapy, there may be surgical options for intelligence enhancement that could be developed with concerted effort.
normobaric oxygen supplementation has been shown to improve scores on psychometric tests.
intracortical injection, infusion or perfusion has been shown to improve certain brain functions. Some of these "direct injection" approaches are on the germline genetic modifications page.
Direct interventions to enhance brain plasticity by transforming the extracellular matrix (ECM) and glycans into a more permissive, juvenile-like state include intrahippocampal or intracortical infusion of chondroitinase ABC (ChABC) to enzymatically digest chondroitin sulfate proteoglycans (CSPGs) in perineuronal nets (PNNs), loosening their restrictive structure, reducing PTPĪ/NgR1-RhoA inhibition, and boosting TrkB/BDNF sensitivity for synaptic remodeling and axonal sprouting; transgenic overexpression of chondroitin 6-O-sulfotransferase (C6ST-1) to elevate the plasticity-favoring 6S/4S chondroitin sulfate ratio while suppressing 4-sulfated CS-A accumulation; Otx2 knockdown or antagonism to prevent glycan-dependent PNN stabilization around parvalbumin interneurons; and expanded glycosyltransferase repertoires (e.g., for N-glycan branching, reduced sialylation via ST8SIA2/4 modulation, or hyaluronan chain shortening) that collectively delay mature ECM condensation. Complementing this permissive environment, interventions boosting axon/dendrite growth drive encompass direct hippocampal BDNF infusion or overexpression to elevate GluA1/2 trafficking, phosphorylate receptors, and increase dentate gyrus dendrite complexity/spine density; Reelin protein supplementation into hippocampus/cortex to enhance ApoER2/VLDLR-Dab1 signaling, NMDAR function, AMPAR insertion, and spine/LTP augmentation; intrahippocampal estradiol or aromatase modulation to cyclically boost CA1 synapse density; and kalirin-7 injection to promote actin-based spine morphogenesis, enabling robust structural plasticity within the remodeled, growth-permissive ECM.
injection of neuronal stem cells or other cell therapies into the brain has been shown to improve memory and learning performance in animal models. Likewise, more recent studies have shown that cortical organoids can be transplanted into animal brains and these animals then go on to show an improvement in learning or memory.
brain-computer interfaces can provide neurotrophic and nootropic effects. The "cognitive pacemaker" concept has been implemented in several research projects and shows, at minimum, an improvement in working memory capacity in aged humanoid adults.
SETI: Search for Exceptional Terrestrial Intelligence
Here I propose a Search for Exceptional Terrestrial Intelligence (SETI) in homage to the Search for Extraterrestrial Intelligence (SETI). This would be a large-scale search for unusual familial cognitive phenotypes related to intelligence, learning, memory, sleep, mathematic ability, reading comprehension, or other cognitive phenotypes of interest. The concept is that there are possibly monogenic changes with single mutations, or a small collection of mutations, or other modifications (such as chromosomal deletions, gain of function, loss of function, copy number variations, etc) that might have a surprisingly strong impact on cognitive phenotype.
Rant about the polygenic trait religion
rant moved to polygenics.
Other
clenbuterol and salbutamol improves immediate verbal recall and delayed recall compared with placebo (ref, ref)
meta-chlorophenyl piperazine improves adaptive tracking test performance (ref)
caffeine improves visual verbal test performance