Comment · Fri, April 19, 2013 · Ceretropic
Modafinil Tolerance: Possible Modes of Action
Original post in this thread
cretan_bull · 59 points
I've recently started taking Modafinil for its nootropic and eugeroic effects; and was interested in anecdotal reports that long-term use leads to tolerance and decrease, or cessation of effectiveness.
A Google search for "modafinil tolerance" produces many dozens of blog posts, forum comments etc., of people reporting building tolerance or wondering how to reduce the effects of tolerance.
However, searches of PubMed or Google Scholar do not produce any substantive results on the matter. I have been unable to find any publications mentioning tolerance, except to say it is "well tolerated" toxicologically.
As a practical matter, I am interested in the following question:
Is this tolerance effect real? If so, under what conditions does it appear and can it be mitigated by appropriate dosing; supplementation with other drugs; or otherwise?
At this point, I would like to mention that I do not have a background in pharmacology, only that I have spent a few hours researching and synthesising the literatur…
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Direct reply to the original post — see the thread post above.
u/MisterYouAreSoDumb · Ceretropic
I can 100% confirm that the CYP3A4 induction from modafinil is substantial. At least it is for me. If I take modafinil in the morning, then take a substance that is metabolized by CYP3A4 (i.e. kratom), then the effects are drastically diminished. If I do the same thing, but take black pepper and grapefruit juice before the kratom, the effects become strong again. So I know CYP3A4 is definitely being induced a significant amount.
Is that what is causing the tolerance buildup? Perhaps it's playing a big role. However, receptor down-regulation could be a factor as well. I think the short term tolerance is CYP450 related, and long term tolerance is receptor related.
Using milk thistle is one option, but I'd go with the black pepper extract and grapefruit juice myself. I know that does a good job of inhibiting CYP3A4 for 5-7 days.