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TAK-653 is a highly selective AMPA positive allosteric modulator (PAM), perhaps the most selective tested to date. It is being developed for treatment resistant depression as a less harmful alternative to Ketamine but is yet to enter phase 2 clinical trials . TAK-653, through its increased selectivity, produced greater enhancements to cognition in preclinical studies with less risks for seizure when compared to previous AMPA PAMs . In phase 1 clinical trials, it was well tolerated and didn’t appear to cause any toxic side effects, which is consistent with other AMPA PAMs .
Like other AMPA PAMs , TAK-653 has a study where it enhanced cognition in healthy people . In this study, participants performed better on the stroop test, indicating improved executive function. Piracetam, the first nootropic and AMPA PAM, also improved cognition in healthy people . This mechanism of action appears to extend broadly to most domains of cognition, from visual acuity and memory, to memory of scents, and especially verbal and working memory . As such, TAK-653 has the greatest potential to improve IQ in normal or high functioning subjects due to the relevance of working memory to this measurement. We hope to encourage research by allowing researchers to buy TAK-653.
TAK-653 binds with superior selectivity to the allosteric site of AMPA, which increases endogenous binding of ligands to this receptor, such as glutamate. This increases BDNF release in the hippocampus which is how TAK-653 acted as a functional antidepressant in preclinical studies .
In regards to its nootropic effects, this effect as an AMPA PAM leads to a higher likelihood of information neurons to spike, which results in greater activation of the prefrontal cortex. This also activates the precuneus which normally remains dormant during working tasks , and is associated with consciousness .
The cognition enhancement by TAK-653 coincides with previous ideas surrounding BDNF’s benefits to consolidation, in that they are event and time dependent . Thereby TAK-653, by synchronizing more with homeostatic mechanisms, offers a clear advantage over less selective candidates.
 TAK-653’s selectivity: https://www.nature.com/articles/s41598-021-93888-0
 TAK-653 improves executive function and is well tolerated in healthy people (clinical trial): https://pubmed.ncbi.nlm.nih.gov/36153330/
 TAK-653 demonstrates similar antidepressant effects to ketamine in rats: https://www.sciencedirect.com/science/article/pii/S009130572100188X
 CX516 improves cognition in healthy people (clinical trial): https://www.sciencedirect.com/science/article/abs/pii/S001448869796581X?via%3Dihub
 Piracetam enhances verbal memory in healthy people (clinical trial): https://pubmed.ncbi.nlm.nih.gov/826948/
 Piracetam moderately increases generalized cognition: https://pubmed.ncbi.nlm.nih.gov/785952/
 Piracetam improves EEG readings, consistent with being a cognitive enhancer: https://pubmed.ncbi.nlm.nih.gov/10555876/
 AMPA PAMs activate precuneus when it would otherwise remain dormant during tasks: https://www.sciencedirect.com/science/article/abs/pii/S0091305710004077?via%3Dihub
 Precuneus associated with consciousness: https://academic.oup.com/brain/article/129/3/564/390904?login=false
 BDNF’s time-dependent effects on consolidation: https://pubmed.ncbi.nlm.nih.gov/25218897/
Scientific discussion is purely for educational purposes. This is not medical advice.