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#82
Rapamycin doesn’t significantly cross the BBB. Why would higher doses help? (For sure, if 1% goes through the BBB and you take a mega dose, you’ll get some in the brain, but that will still be 1%.)
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Kaeberlein… Attia all say the same. Hard to get anything across the BBB. And… personally… Blogsklonny might have been wrong about higher doses to achieve this.
Kaeberlein says that lowering inflammation at brain might be enough with the peripheral area of the brain getting benefits.
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I recently came across this study: https://www.researchgate.net/publication/349295206_RapamycinSirolimus_Improves_the_Behavior_of_an_8-Year-_Old_Boy_With_Nonsyndromic_Autism_Spectrum_Disorder
Even though it is for a single person (child) and not a big group, it seems here rapamycin must have passed the BBB sufficiently to induce such a big change especially given the patient was given about 1mg daily continuous (low dose daily).
The only thing I can think of is ASD patients have been shown to have weaker BBB at times which might have helped rapamycin get in, though it might not be the case here, as if the symptoms improved then the BBB should have also gotten stronger so it wouldnt have been a continuous improvement as seen in the study
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Rapamycin need not cross the BBB for it to have an immediate and profound impact on the brain. Note the case of klotho. In the Peter Attia podcast on klotho, his guest, the scientist who conducted klotho studies, discussed the impact of klotho on the brain. Klotho does not cross the BBB. Yet in her studies in mice there is a profound effect of klotho on the brain function within four hours of administration, measurable by rigorous functional tests. The effects are apparently mediated by klotho altering blood factors, platelet activation in particular, which then cross the BBB and affect the brain.
In other words, you don’t need to have a drug/molecule cross the BBB to rapidly and strongly impact the brain, it can do so by modifying other factors which subsequently do cross the BBB and impact the brain. It is possible that rapamycin might work in a similar way, not by directly crossing the BBB, it can modify some other factors and thus affect the brain. Obviously I’m speculating, but the point is that crossing the BBB is not the deciding factor in evaluating the impact of any given molecule on the brain.
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One interesting thing I learned about ketoconazole is that it inhibits P-glycoprotein (P-gp), a key efflux transporter at the BBB. Since sirolimus is a substrate of P-gp, ketoconazole is thought to increase sirolimus penetration into the brain by reducing its efflux. So in addition to ketoconazole’s effects on CYP3A4, it may also aid in raising sirolimus levels in the brain. I’m currently experimenting with a once every 21-day dose of 6mg sirolimus with 200mg ketoconazole (taken two hours prior). I plan to share my results so far in a separate post, but compared to weekly dosing with GFJ+EVOO, the difference is quite remarkable.
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