Ideas on Protocols for Testing Higher Rapamycin Doses

I think the key reason people are wanting to take higher and higher doses of rapamycin is that in the ITP studies, the higher the dose of rapamycin, the longer the life extension effect found in mice. Additionally, numerous people have reported taking very high doses of rapamycin with little in the way of side effects (though this has to be monitored closely with regular blood tests) - so more generally people are testing how their bodies are responding to rapamycin. Most of us experience few if any side effects - so the natural tendency is to see if we can go a little higher and still maintain the same low side effect profile (while also increasing the time period between doses so as to not inhibit mTORC2 - and risk the immune suppression problem that goes with high, ongoing/continual dosing protocols. Search on the forum (top of page search icon) for “higher doses” and you can see many past discussions on this topic.

Here is one example of perhaps the highest dosing I’ve heard of - he seemed to be doing OK until he took a dose near the same time as the vaccination. High Doses of rapamycin by one user.

See below:

Rapamycin Lifespan Improvement given different Doses from the NIA ITP Studies

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Why?

Anyone taking rapermycin know what is their optimum dose is to turn off mTOR1 in their body?

We are all PFA* dosing.

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Yeah but is the higher dosing making a significant difference in comparison to low-moderate ( or just generally taking rapamycin period) dose in terms of lifespan increase outside of the one study? I am just curious how one would even quantify the difference in lifespan in terms of percentages when applied to humans? I mean if its only making lets say a difference of a couple years , I feel like just taking rapamycin in general is enough to increase the lifespan and not really worth spending the money on higher dosing

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For what it’s worth, it’s not clear that mTORC2 inhibition is always “bad.” I recall Dr. Matt Kaeberlein saying this in one of his interviews. For longevity purposes, perhaps there is a sweet spot where a bit of mTORC2 inhibition is actually beneficial.

See for example:

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I am not sure, I think an old peter attia podcast with david sabatini talks about it and Dr. Sabatini said that you really would want intermittent inhibition of MTORC1 and no effects on MTORC2, if i remember it correctly.

It isn’t “just one study” - it is 3 or 4 studies by the ITP, which are themselves a group of studies done at three different labs at the same time - so effectively 9 to 12 studies, that have shown higher doses equal longer lifespan effect (in mice). Plus - many other studies done by many other labs - as outlined in the complete list of rapamycin mouse studies.

So - its over a decade of dozens of studies… pretty robust data.

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Gotcha. I guess what I am asking is the studies done with rapamycin and increase of lifespan, would it make much of a difference if one just practiced general health guidelines(like exercising, eating healthy, routine doctor visits) and take low to moderate dose of rapamycin, in comparison to these really high doses. I imagine too much of anything for the body is going to be consequential down the line( although taking the time period off might negate that). I guess I am just wondering from a lifestyle perspective if taking the high dose is worth the cost financially/ risk of unknown in comparison to just low to moderate dose while doing healthy practices. Its actually part of the reason why I am excited for Dr. Brad Stanfield’s clinical trial with rapamycin and performance as we get to see a combination of both practices put together.
Again, just trying to understand different perspectives, especially since rapamycin is something I will be taking for a long time( if all goes well in terms of my body’s reaction)

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Ah - this is a great question, that nobody has the answer to yet. Definitely a lot more research needs to be done on this topic. As @Joseph mentioned - most of what people are doing right now is PFA dosing - we really don’t know what the right dose is, for ourselves personally and given our own health considerations, or more generally for any group of subgroup of people.

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For members here who have not reviewed an older Attia Interview, listen to #118 aired July 09, 2020, on rapermycin with Lloyd Klickstein. Should give you a good understanding.

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In one of MKs phase one dog trials I believe he compared 0.1 to 0.05mg/kg three times per week. He then settled on the lower 0.15mg once per week for TRIAD which presumably was to minimise side effects and maximise compliance. Does anyone know how the 0.1x3 performed in the initial trial (albeit with a small sample size)?

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“My perspective with new drugs has always been to let someone else be the early adopter / Guinea pig” Well that’s me, the early adopter/Guinea pig. LOL
Sorry folks, at 81 I don’t have time to wait for other early adopters.
I started out at 5 mg/week and started increasing to 10, 15, 20 mg ~ twice monthly. I have been on the 20 mg dose for approx. 3 months. The last 2 doses I took with grapefruit juice before and after.
The only adverse side effects I have experienced so far are a temporary spike in blood pressure, increased cholesterol levels, and an increase in flatulence and loose stools for a few days after the 20 mg dose. ( I am not sure that higher cholesterol levels are a negative thing. I seem to be moving towards the sweet spot of all-cause mortality levels found in this article; Association between low density lipoprotein cholesterol and all-cause mortality: results from the NHANES 1999–2014 | Scientific Reports)

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Is that 20 mg plus grapefruit juice before and after? Or is that the calculated effective dose based on the gfj effect?

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Matt discussed it in this podcast. The results were good - especially on heart function, which I think was the primary endpoint they were looking at. Below is the paper that resulted from it, and the podcast where they discussed the results:

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It’s 20 mg Rapamycin + grapefruit juice.

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Hi desertshores. From my reading of the literature, the grapefruit juice inhibits the intestinal CYP3A4 enzyme, thereby increasing absorption of the sirolimus from the gut. Therefore, the grapefruit juice taken after your dose would not be expected to help absorption much.

For what it’s worth, here’s my current biweekly protocol: one whole grapefruit with dinner ~12 hrs prior to dosing, and another grapefruit ~1 hr prior to dosing in the morning (as well as 500 mg metformin and ~1/4 teaspoon of black pepper for potentially more CYP3A4 enzyme inhibition). I take the sirolimus tablets with two small avocados (as a source of fat) in an attempt to further boost the rapamycin levels. There’s more discussion on this topic in the forum thread titled “Improve Bioavailability of Rapamycin (pt 2).”

By the way, thank you so much to RapAdmin for creating this wonderful website! :pray: Your efforts are much appreciated!

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Yes, actually I drink “Florida Naturals” Ruby Red grapefruit juice quite often because I like it. I make sure I drink about 6 - 8 oz the day before, the day I take Rapamycin and the day after. I don’t know the efficacy of the brand I am drinking so I just make sure I have a fair amount in my system. Previously I used to take olive oil with it. I am currently subscribing to the high peak dose protocol and take Rapamycin on an empty stomach and wash it down with some grapefruit juice. Fats lower the peak and spread the time it takes to exit the system. (At least that’s my understanding. I am a retired electrical engineer and my understanding of biology is limited.)
After taking metformin for over 20 years, I have stopped taking it. I believe it is an option for people younger than me. “Metformin Impairs Exercise Training-Related Improvements In Older Adults”
I might suggest checking out Michael Lustgarten, Ph.D. on Youtube

He plans on living forever and has excellent videos on most biomarkers and tries to find the sweet spot for all-cause mortality risks.

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Just to make sure I understand, you’re taking equivalent to something like 60mg+ of rapamycin by taking 20mg with GFJ? Is that right?

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Desertshores, you may not have seen my post in the other thread regarding optimizing peak dose (Cmax), so I’ll post it for you here.

Taking sirolimus with high-fat food has opposite effects on the Cmax (peak dose in the blood), depending on whether you’re taking the Oral Solution or Tablets.

"Food effects: In 22 healthy volunteers receiving Rapamune Oral Solution, a high-fat meal (861.8 kcal, 54.9% kcal from fat) altered the bioavailability characteristics of sirolimus. Compared with fasting, a 34% decrease in the peak blood sirolimus concentration (Cmax), a 3.5-fold increase in the time-to-peak concentration (tmax), and a 35% increase in total exposure (AUC) was observed.

After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, tmax, and AUC showed increases of 65%, 32%, and 23%, respectively."

So, depending on whether you’re taking the Oral Solution or Tablets, taking it with fat will lower or increase the peak dose, respectively.

Regarding the source of the grapefruit juice, the authors of the research study actually found one of the store bought brands didn’t actually contain the active compounds which are necessary to result in the increased rapamycin absorption. From the article: “Interestingly, different grapefruit juice formulations appear to vary in inhibitory potency and therefore, in consultation with the Florida Department of Citrus, we employed a frozen concentrate product that was tested for furanocoumarin levels prior to delivery of each batch.”

Just to take that variable out of the equation, I use actual grapefruits rather than relying on store-bought juice which may have different processing methods, pasteurization, etc.

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Thanks. Yes, I know the grapefruit juice I drink is problematic, but as I said: I like it. I really don’t like eating grapefruit. That is why I am taking a 20 mg dose. If my grapefruit juice amplifies the dose so much the better, if not, I am still okay.
If you have any insight on what dosage is needed to have some sirolimus cross the blood-brain barrier in a significant way, I would appreciate the info. Right now I am looking for a quick peak spike.

“Sirolimus was absorbed more slowly when administered after a high-fat meal than when administered after fasting, as shown by statistically significant reductions in peak concentration (Cmax) and the ratio of Cmax to the area under the curve (AUC), and lengthening of the time to peak concentration” The effect of a high-fat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin) - PubMed

mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer’s Disease

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FWIW…

“Drug transport across the blood–brain barrier”

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