Comment · Fri, June 23, 2017 · Ceretropic & Nootropics Depot
Obscure Nootropic "Racetams"; any experiences?
Original post in this thread
Dajaedrogre · 19 points
A small number of points beforehand:
* A similar question was raised at https://www.reddit.com/r/Nootropics/comments/2coqsm/why_dont_we_use_any_of_the_other_racetams/ , but considering that has been 2 years ago, I figured it couldn't hurt asking this question.
* I'm talking about racetams in the broad sense of the word; namely, racetams and racetam-like substances (including "racerams").
* This topic has been tagged as high-risk due that the substances in question have (AFAIK!) no studies demonstrating their safety in humans; in fact, most of them have scant few studies across the board (if at all). Moreover, for the obscure racetams that are actually available to be bought by consumers, it's questionable if the vendors in question have good quality control or not (...which includes ensuring there are no dangerous impurities!).
Presently, the following racetams are fairly well-known in this subreddit and have, at the very least, a decent amount of user experiences:
* Piracetam
* Aniracetam
* Oxiracetam
* Pramiracetam
* Phenlypiracetam
* Coloracetam
* Fasoracetam
The following racetams are not as well-known as the aforementioned, but they do have a (relativ…
What they were answering
iakobos · 2 points
The safety concerns for nefiracetam don't apply for humans. Even long-term studies have shown no toxicity in humans or primates.
Nefiracetam is actually the drug I'm most interested in among the racetams. It appears to be an AMPA positive allosteric modulator, like aniracetam but with better bioavailability. It seems to be effective in treating apathy in some pathological conditions, which suggests that it might be useful for certain types of depression.
u/MisterYouAreSoDumb · Ceretropic & Nootropics Depot
Please do not state that with certainty. The mechanisms behind Nefiracetam's testicular and renal toxicity most certainly do pertain to humans as well. Caution should always be taken with it. If you have some human and primate studies contradicting the risks, please post them.
The reason dogs are more susceptible to the renal toxicity is due to dogs having much lower basal prostaglandin levels than in primates. The lower prostaglandin levels means that nefiracetam's metabolite, M-18, lowered it in dogs to the point of toxicity. Humans will have higher basal prostaglandin levels, so renal toxicity will be LESS likely. That does not mean that there is no risk.
http://www.sciencedirect.com/science/article/pii/S001429990302123X
The testicular toxicity arise from atrophy of seminiferous tubules in the testicles, with multinucleated-giant-cell formation. This arises after 4 weeks of nefiracetam administration. If you can link me a study showing that humans do not have this issue, please do.
http://www.sciencedirect.com/science/article/pii/S0378427403001978
This study showed that nefiracetam's main metabolite, 5-OHN, increases testosterone 6β-hydroxylase activity in the liver. This proves a mechanism, IN HUMANS, for possible lowering of testosterone levels.
The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP) 3A4-mediated testosterone 6β-hydroxylase activity
It seems that CYP3A4 and CYP1A2 are responsible for the formation of 5-hydroxynefiracetam.
http://onlinelibrary.wiley.com/doi/10.1211/0022357011776144/full
Nefiracetam was hydroxylated by human liver microsomes to 5-hydroxynefiracetam (5-OHN). Eadie-Hofstee plots for the formation of 5-OHN suggested substrate activation. The kinetic parameters, apparent Km, Vmax, and Hill coefficient, for the formation of 5-OHN by pooled human liver microsomes were 4012 μM, 2.66 nmol min−1 (mg protein)−1, and 1.65, respectively. The formation of 5-OHN was significantly correlated with cytochrome P450 (CYP) 3A4-mediated testosterone 6β-hydroxylase activity and dextromethorphan N-demethylase activity. The 5-OHN formation was inhibited (94%) by antibody to human CYP3A4/5. The 5-OHN formation was also inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin, but not significantly inhibited by several other P450 inhibitors.
The mechanism exists for both renal toxicity and testicular toxicity in humans. The fact that it has not been observed yet does not mean we should write off the cautions. If I am missing some research that proves the risks are not pertinent to humans, please point me to them. It's been a while since I have done much research on it, so I might have missed something.