Grapefruit juice affect half life?

So grapefruit juice increases bio availability, but does this affect the half life of Rapaymycin?

Any thoughts on ingesting grapefruit for several days after dosing?

IMO, this entire discussion takes place in the wild west of ways to enhance rapamycin when used as a longevity drug.

Grapefruit and some other juices are potent inhibitors of cytochrome CYP3A4 and CYP2C9 isoenzymes. Studies with cancer patients going back to 2009 demonstrated higher blood levels and a reduced rate of breakdown when rapamycin was taken with grapefruit juice. For someone seeking to reduce their weekly dosage of rapamycin by taking it with grapefruit juice, the particulars seem unresolved to me, irrespective of individual differences, which could be large.

I spent some time tracking down the generalized cytochrome inhibition curve for grapefruit juice and it looks like measurable inhibition can occur in an hour or so, peaks around 14 hours, and persists for as long as 48 hours. These numbers have to be taken as averages that might change significantly with dosage, timing, body composition, type of grapefruit, and perhaps diet. Applying grapefruit to rapamycin, other less well validated sources suggest that well-timed consumption of grapefruit juice can increase rapamycin levels anywhere from 3x to 7x. If true, it would seem to me that employing grapefruit juice as a strategy to save money when taking rapamycin may very well work in the individual case but, unless measured, the circulating level of rapamycin will be a crapshoot. Relying on someone else’s reported measurements does not reduce the error term much because we do not know the standard deviation of blood levels based on a distribution of such administrations across a large population, nor have we studied how individual differences in one’s response to grapefruit and/or rapamycin plays into blood levels.

Taking the other side of this, many cancer patients have done well taking less rapamycin and grapefruit juice in combination. Unfortunately, the timing and amounts have mostly taken place in various non-standardized ways.


Well to start, taking rapamycin is a crapshoot if you are not a kidney transplant patient. No one, no one, knows the proper dose of rapamycin to take at any age to increase the human lifespan. This information might not be available for decades. The general guideline I accept is that older people need to take more than younger people. The general premise from Dr. Blagosklonny is to take doses that are just high enough not to cause unacceptable side effects. This is easy for me. If the dose is too high, then I will get diarrhea. Then I have to back off.

I think it is legitimate to use grapefruit juice to save money for some people.
Again, as per dosing, the lists of people on this forum, celebrities, doctors, educators, etc.
that publish their dosage regimen, it is all over the place as to the amount and frequency in which they are taking it.


There seems to be a widespread assumption that grapefruit juice’s inhibition of CYP3A4 enzyme of the cytochrome P450 system is, if taking rapamycin, equivalent to simply taking a higher dose of rapamycin. The discussion and debate centers on the magnitude of the dosage leverage and how to achieve optimal timing between consuming rapamycin and grapefruit juice.

In making this assumption, we are also assuming that there are no other material mechanisms of action – toward or untoward – that would alter the nature or magnitude of rapamycin’s biochemical impact.

What evidence tells us these assumptions are correct? Compelling evidence would come from a randomized case controlled study examining relevant endpoints of rapamycin when administered in various doses with and without the co-administration of grapefruit.

A lesser form of evidence could come from a clinical/theoretical explanation of the full process of rapamycin’s metabolism under the two conditions of administration.

Another lesser form of evidence, and one admitting to potentially many further unexamined issues, would be reports of individual blood tests noting higher rapamycin concentration for a given dose when also consuming grapefruit juice.

I seem to recall other cases in which cytochrome inhibition results in a higher blood level of a drug but that this higher level does not function in the same way as the intended design of the drug. Perhaps we have a biomedical chemist in the group who can unpack this issue.


I have what might be a partial answer to the question I raised above. I put the question to GPT-4 and received this response. I omitted all of the expected and framing responses and have pasted in the portion of the response most relevant to the question.

Are there examples in which the inhibition of cytochrome, such as when consuming grapefruit juice results not only in an increased blood level of a medication but also causes the medication to have a different effect?

. . . Active Metabolites: For some drugs, the metabolism by CYP3A4 produces active metabolites with distinct pharmacological effects. Inhibition of this metabolism could decrease the formation of these active metabolites, potentially reducing the drug’s overall efficacy or altering its effect profile. However, specific examples where this leads to a qualitatively different effect, rather than just a variation in efficacy or side effect profile, are less common and would depend on the unique pharmacology of the drug and its metabolites.

My takeaway from this GPT-4 response it that there are mechanisms by which a drug could have an altered response profile in the presence of grapefruit juice but that this kind of outcome is less likely than the outcome of seeing an increased or decreased magnitude of effect. The response did note that the magnitude of effect is sometimes unpredictable and can allow a drug to reach dangerous levels.

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Not an assumption… there have been studies. See this thread: Improve Bioavailability of Rapamycin (2)

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Thank you for this @RapAdmin. The link you referenced took me to a U of Chicago discussion paper addressing the leveragability aspect of a broader 2012 study. That study may be posted elsewhere but I’ll post the link to the publication below for convenience if nothing else. Even though the participants were cancer patients, the dose levels were for designed for them, the primary endpoints were AUM and tolerability, and there were no endpoints of direct relevance to the potential effects of rapamycin on longevity, it is worth reading as additional evidence informing the question I raised. When I get time, I’ll see if additional phases to this study were published or perhaps you are aware of related experimental research with endpoints closer to longevity goals.

There have really only been a couple of clinical studies with rapamycin (or rapalogs… e.g. everolimus) in longevity-related applications, the Joan Mannick studies done as part of her ResTOR Bio startup effort… targeting immune system function: mTOR inhibition improves immune function in the elderly - PubMed

Since rapamycin is a generic medication, there is no financial incentive to do clinical trials with it now.

If you haven’t already, listen to the Joan Mannick podcast that Kristen Kaupi did:



Thank you for this. I’ll look at it. Specifically, I was asking about relevant endpoints comparing the 5-6 mg./week consensus target for longevity with lower doses leveraged by grapefruit juice.

I agree that is it difficult to secure funding in this situation. Larry Page, Sergey Brin, Jeff Bezos, Larry Ellison, and others are funding longevity research but, so far, their interests have not aligned with middle-class access. This is not to say they would not respond favorably to a proposal for a small budget study of the kind we are discussing. For those on LinkedIn, I see a Longevity Research Foundation that might be approached with ideas informally on LinkedIn. The Longer Life Foundation apparently funds small proposals. I see others but don’t know much about any of them. Perhaps this group could be instrumental in starting a small funding group.


Thanks. I had been taking grapefruit juice 1 hr before, but based on your information, it sounds like taking juice or eating a grapefruit 12 hours before makes more sense.

So far from what I read 4 hours after consuming grapefruit juice is the most potent. The half life is 12 hours. Tomorrow I’ll take 2mg at 4 hours after the GFJ and see if I get the diarrhoea and flatulent like last week. Next week I’ll go back to 6mg after GFJ.

Go to point 30.

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I believe 1-4 hours is the sweet spot. After 4 hours the effects of GFJ on Rapa absorption drop off a cliff.


@desertshores is absolutely correct in regard to what dose and what frequency. We know what Dr. Alan Green has been doing and we at least know a bit about the safety of that regimen. I’d also suggest that having MTORC1 inhibition for a prolonged period might put individuals at risk of truly being immunosuppressed, and if they get a serious bacterial infection both having little usual warning of this, and once profoundly unwell, have less chance of survival and response to therapy.
Having had over 25 years in the ER, I’ve treated a lot of septic individuals on immunosuppressants. They are uniformly sicker and have worse outcomes. I however have never seen someone solely on Rapamycin present in this fashion (probably because it is still relatively rare, or the individual doesn’t disclose).
Working a little bit backwards from what Dr. Green has been doing, I’d guess most of his patients are having ~35% of the time under pretty reasonable MTORC1 inhibition and 65% in recovery. Single doses of Rapamycin in the range we might use - e.g. 5-7 mg probably run on a half life of ~35 hrs +/-. Daily regular doses end up running in the mid 60’s hrs.
The pharmacokinetics obviously matter, and in a given individual, especially as we push the doses higher, they may well end up tending toward running a longer half life, which I think needs to be accounted for in dosing interval.
My approach for the time being is to measure a level at 20 hrs post dose, and once solidly in the therapeutic range (if for neurocognitive decline then heading higher range 12-18 ng/mL) then do both a 20 hr and 92 hr (72 hrs post initial test) levels so that we can calculate the half life in that patient, then we can start sorting out a sensible interval of dosing frequency to make sure the person isn’t continually under MTORC1 inhibition.
This would be my thought about this on a safety basis - and adding Grapefruit adds another unknown into this. The one rule of trying to live longer and biohack is to not accidentally off yourself while doing so! I worry that without significant thought and monitoring, throwing an unknown in dosing of a medication like rapamycin, which has very real risks, if done wrong, could put an individual at unexpected risk.
Not giving medical advice - just detailing my thought process of how I approach this, having sadly spent a fair bit of time having formal education with pharmacology and pharmacokinetics.


This made me a little nervous. But I assume that this is only a concern when you are pushing to find your own individual upper limits on dosing while of course watching for any side effects. In that case, I don’t think that I would be using grapefruit juice.

No risk no gain. Just pay attention to your body. If you got too much you’ll just get a diarrhoea.

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I’d be concerned about diarrhea being your signal of whether you are continually under MTORC1 inhibition. I don’t think we have data of that being sensitive or specific. If you are taking Rapamycin, it’s important to be aware there can be bad things that occur, and the pharmacology matters. Not that one can’t take with Grapefruit Juice - it’s just that you’d actually want to measure what happened in your situation, and modify dosing and intervals based upon your personal pharmokinetics if you choose to do this. That would be my caution. Again - don’t harm yourself while trying to live longer. Some impacts may not be evident immediately, but the risk of continual MTORC1 inhibition would seem much more likely when adding things to impact metabolism/absorption of a drug and then not monitoring to understand exactly what is occurring.


When I took 6mg last week one hour after 240ml GFJ… Let’s just say the first 2 days I had the runs. Previous 2 weeks earlier I took 6mg without GFJ and no runs. Tomorrow I’ll take 2mg with GFJ and see how I go.

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So much is not understood about dosing. But, I agree suppressing mTORC1 for long periods is likely to expose one to undesirable effects.

Those of us who take rapamycin, but also want to build muscle have a little paradox to overcome. Life extension or muscle gain?

Leucine is an mTORC1 activator. Exercise is an mTORC1 activator.

As a believer in the unproven modulation theory; that it is better to modulate mTORC1 than to suppress it for long periods. I take the precaution of not taking the amino acid leucine, a primary protein synthesis activator on the day I take rapamycin, but I do take it on the days that I go to the gym. I believe (no proof) that mTOR1C1 will recover within a few days after taking rapamycin. Going to the gym and doing resistance training is also going to help prevent suppression of mTORC1 for too long of a period.

Several members of the forum, who take rapamycin but also exercise regularly have been taking relatively high doses of rapamycin weekly with no ill effects.


When I was digging through the research on my own, I found a better than average paper that supported the 4/14/48 hour cytochrome inhibition timing. Based on that, I passed the information on the other day. The consensus in this group seems to be for faster activation and effective duration closer to 24 hours. Using GPT-4 and Gemini-Advanced, I see similar consensus around the 4-hour peak, all of course noting potentially wide inter-individual variance.

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