Comment · Thu, March 7, 2013 · Ceretropic
Modafinil Posts
Original post in this thread
MisterYouAreSoDumb · 239 points
Lately this subreddit has been turning into "Modafinil and Me." This is a place to advance our knowledge of all nootropics, not simply beat the latest popular one to death. I understand that many of you have questions about modafinil. However, I assure you that they have all been answered before. The search function works well, please use it before asking basic questions that we have all seen 100 times. I do not want to discourage discussions. However, we should limit those discussions to trying to expand information, not regurgitate what we already know.
* Modafinil is a wakefulness promoting agent.
* Modafinil will not replace dopaminiergic stimulants for ADHD.
* Modafinil will not work for everyone.
* Both enantiomers in racemic modafinil are active.
* R-modafinil is 3 times more active.
* Generics seem to be hit or miss. Some think they are the exact same, other don't...
* Your order will take a while to get here. Don't ask us if this is a normal thing.
* Modafinil increases hypothalamic histamine. This can lead to flush-like symptoms.
* There is a 99.999999% chance that you do not have Steven Johnson's Syndrome. If you did, Reddit is not the place to figure that out.…
What they were answering
Winslow_Strong · 3 points
Indeed. Speaking of oversights, that paper you cited seems to misstate its own conclusions. Their relevant data for dopamine reuptake inhibition are IC50 values of (13, 4, 8.7) for racemic moda, R, and S, respectively. This puts R at more like half the dose of S for 50% inhibition, whereas the factor of 3 is from comparing R to moda, not R to S. So if their data is correct, then they have mistated it in their abstract.
However I find those numbers pretty surprising. I didn't rigorously test microdoses, but I did compare e.g. 75mg armodafinil vs 100mg modafinil on many occasions, self-blinded and didn't find them worlds apart. 75mg armodafinil is not even close to 200mg modafinil in my limited experience at that dose.
So that result seems fishy to me. Do others find a 3x difference in potency in practice between armodafinil and modafinil (we're talking actual pill-weights here)?
I'm no expert in pharmacology, but skimming the wikipedia on IC50 reads: "IC50 values are very dependent on conditions under which they are measured." The paper also mentions cryptically: "[^3 H]DA uptake inhibition is not performed under equilibrium conditions"
Since this was in vitro, maybe the result is not per se portable to in vivo use-conditions?
u/MisterYouAreSoDumb · Ceretropic
Ohh I do not think that 3 times the binding affinity translates directly to 3 times the effects. It's much more complicated than that. Not to mention, modafinil has other mechanisms separate from the DA system. Subjectively I find 75mg R-modafinil similar to 100mg racemic, but without the two step plateau effects. Racemic builds, then dies off a little bit, then build back. That is probably due to the absorption characteristics along with the metabolism of the S enantiomer.
The paper also mentions cryptically: "[3H]DA uptake inhibition is not performed under equilibrium conditions"
Competitive binding is most likely the cause for that.
Since this was in vitro, maybe the result is not per se portable to in vivo use-conditions?
Possible, but unlikely that the mechanism would not manifest itself in vivo as well. Perhaps there are other factors at play in vivo that level out the effects somewhat. But for sure, the S enantiomer is active. It's just less active.
Here is an interesting paper about the crystal and molecular structure of both enantiomers, and their effects. They are postulating that both the S and R enantiomers have the same effects, and their activity is due to the spatial orientation between the diphenyl and amide groups, which are the same in both. That would mean that the subjective difference in effects is solely due to competitive binding and competitive absorption.