Experiences starting Rapamycin for first time

I’m a new user here, but have been enjoying reading this forum for quite a while. Hope its OK for me to create a new topic for this - couldn’t find an existing topic that really matched.

I’m 53 and been interested in this subject ever since reading David Sinclairs book on anti-aging some years ago. Been researching the subject for quite some time now and was excited to find this forum a year ago and find that Rapamycin is actually a viable option (was well aware of it, but thought it came with all sorts of dangerous side effects…)

I finally managed (with some cajoling of my Doctor to write a prescription) to purchase some Biocon Sirolimus from India (tried for Zydus, but not available currently) and after some hiccups with customs, finally got them.

I have taken just 2 doses of 1mg so far, a week apart (in morning with breakfast of oatmeal). Based on comments here I was not expecting to notice anything, but I definitely did and was wondering if some of these experiences I’ve had are normal.

Both times I had extreme jitteryness on the day taking it - like a high anxiety, yet my heart rate was if anything lower than normal. Plus a strange sense of smell and taste.

These side-effects were gone the next day. I read it can be somewhat ‘stimulatory’, but am glad I started at just 1mg, because I couldn’t handle a higher level of that buzz!

My sleep quality (as recorded by my Garmin) has dramatically improved from the day I started (the jitteryness had no bad effect on sleep). I haven’t been sleeping well for a while now (some challenging personal/family issues am dealing with), with sleep scores from 40 to 70. But straight after first dose my sleep went to averaging 80+ and last night 91 - best score I’ve had in a year or more. No waking up lots of times during the night. Remarkable.
Resting HR also dropped a few points. Went to gym to do weights today and was feeling strongest I can remember.

Really wasn’t expecting such instant effects, and on such a low dose. Does this make sense?

I also take Metformin and venlafaxine (for depression I’ve had for many years), plus a whole set of other stuff like NMN, pterostilbene, reseveratrol, spermidine, bio piperine, plant sterols, fish oil, Vitamin D, DHEA , garlic supplement, folic acid (most of these after tracking my blood indicators on Inside Tracker). Frankly I’ve never noticed ANY effects from the NMN/pterostilbene/reseveratrol combination I’ve been taking for years - either feeling wise or on my metrics (Garmin or blood tests).

Am wondering if I’m getting some sort of interaction effects with other stuff that would give me such strong jitters on just 1mg?

Should I just stay at 1mg for now until this ‘wear’s off’, before going higher?

Any advice appreciated :-).

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Your Metformin will increase the bioavailability of the Rapamycin, but I personally think that is good. I take mine with grapefruit juice and metformin and EVOO to boost the dosage.

Instead of jitteriness, i get a euphoric fatigue. I think everyone can get a random side effect. Improved sleep quality is a big bonus IMHO. Welcome to the club!

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Welcome. I’m a few weeks ahead, re Rapa, but 20 years, re just living.

Basically, we are all guinea pigs in this arena.

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Like you, I’ve read that some people dose in the morning because of the rush they feel.

Regarding raising the dose, I’m not a doctor, but it sounds like your Metformin and your oil supplement are raising your effective dose by increasing bioavailability. Thus, your effective dose at this point is already somewhat higher. Since Rapamycin is a long game, were I in your shoes I might remain at 1mg for a month and then maybe raise to 2mg.

What is your goal dosage? Perhaps do some bioavailability calculations and find out what ingestion it would take to reach that bioavailability number.

Finally, regarding Resveratrol, I’m not sure if you’ve heard the latest but it is unfortunately ineffectual. This podcast with Dr. Richard Miller of ITP gives the deets. The whole thing is worth a listen, but if you don’t have the time or inclination to do so scroll down below the podcast image and there’s a list of all the conversation topics with time stamps. He mentions that the initial resveratrol studies were deeply flawed in their conjectures, were widely misinterpreted, and upon further study have shown no impact on healthy humans. Link: #148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program - Peter Attia

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The newest research coming out says resveratrol may be good for some things in low dosages and have the opposite effects and even deletrious ones at higher dosages. Its a supplement you really have to be informed about as it xould be ineffective or even dangerous.

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Thanks for the response!

Thanks mike666 for the link. Wow - that is a big list of interactions! How on earth do they know/work out that huge list I wonder. I found DHEA on the list - which appears to “increase the level or effect by affecting hepatic/intestinal enzyme CYP3A4”. This is the same mechanism as listed for grapefruit.

I wonder how much difference it makes? e.g. how much does grapefruit increase effective dose by? This same page says bioavailability is 41% in tablet form. That always sounds pretty high to me and would suggest (if I understand this right), that effects of grapefruit/DHEA, etc would be unlikely to do more than doubling the bioavailability and ‘effective dose’.

Yes - I did wonder if there could be some unknown substances in the tablets from India. I know someone did an assay on Biocon and there was a peak for an ‘unknown’ other substance. That’s why I wanted to get the Zydus one. That said, lots of people seem to be taking the Biocon one and have seen it used in multiple studies.

Not sure how I could source it from US being based in NZ. Do you have suggestion on how you can do this?

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Hi Kevin, welcome to the forums. Yes - all the things that you are taking are definitely having an effect on the rapamycin, and its levels in your blood. I recommend you study this thread that discusses some of the things that interact with rapamcyin, and you may want to try taking rapamycin one week while pausing these other compounds to get an idea of what the impact / side effects are when you aren’t on those supplements and drugs: Rapamycin Interactions with Other Food, Drinks, Supplements and Drugs

Some other threads that I recommend you read and review:

Here: The Challenge of Predicting Outcomes when Mixing Longevity Therapeutics - How are you thinking about this?
and Here: Combine them all! (Longevity Drugs and Supplements)

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Hi, Kevin –
I saw DHEA on the list, & some other items I take (another vit, as I recall.) However, yes, no indication of the % incr/decr. Grapefruit seems to be the worry – which I stopped more than 20 years ago – as some say it might increase Rapa by 300%.

But remember the list is for those taking daily, higher doses, for organ transplants. I think if we avoid DHEA, etc. a day or two around Rapa, we should be OK.

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Rapamycin has a bioavailability of 10% I believe. Grapefruit juice taken 1-4 hours before can change that to 30%. Other supplements and medications can push that higher. @Agetron measured his blood and was able to get 50%. That would turn 1 mg into 5 mg for effectiveness.

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Exactly… seems the common norm for people to get 3 or 3.5x’s times the multiplication. I have done the Labcorp tests twice checking my Grapefruit Juice addition and I actually get a 5x’s multiplication factor.

I just did a third blood draw and Labcorp test… first my trough (no rapa in me) blood draw… and then my 6mg dose chased down with a cup of fresh squeezed Red Grapefruit (GFJ). Did a blood draw 1.5 hours after juice and dose - all this last Thursday.

I will have my trough results and dose with GFJ results from Labcorp in a few days and will post. I figure it will be a 5x’s increase. We all share our N=1 experiences to at least get some understanding.

My Ph.D. chemist buddy says that how you can get 6mg to turn into 30 mg inside you is (as posted above) that the assumption with medication is you take the dose and get so many mgs out of that dose maybe about 10%. So the 6mg has alot more potential under the right circumstance. So it is assumed under normal digestion you get 6mg . But by changing the chemical reaction in your gut with GFJ that 6mg’s potential opens up to a much higher dose in me and becomes 30mg. That is how he explained it.

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Good question re target dose. I had been thinking of aiming for 20mg fortnightly longer term, based upon reading I’d been doing (based upon normal bioavailability). But I don’t really know what the ideal is. I don’t have access yet to any tests to check blood levels of sirolimus - need to find a way to do this perhaps as I know that appears to be considered the ‘gold’ standard. Any advice on how to calculate the ‘ideal’ target dose welcome. Am certainly going to proceed slowly at the moment based upon initial experiences.

I omitted to mention that I got two epigenetic age tests done - using Elysium’s Health’s Index test. Not really sure how to judge the quality of different epigenetic tests, but their ‘seems’ to be one of the most extensive - they say they check 100,000 sites, where as many of the other check far fewer (myDNAage says they check just 2,000). Also not sure what the difference is between measuring the age of your cheek cells (saliva) vs blood or urine - have read the ‘age’ of different organs/cell types can very greatly.

Anyway, did a test 2 years ago and it showed 48 when I was 50 (2 years younger). Not quite as good as I was hoping, but at least on the right side :-).

After 2 years of resveratrol/NMN, etc I did the same test again and… got 50 when I’m 52 i.e. same result basically. So no change or improvements. None of my other metrics changed either e.g. I’ve been stuck on VO2 Max of 51 for 2-3 years and can’t seem to budge it. I got a laboratory Vo2max test when I was in my early 20s at University once and it came in at 72, was pretty fit back then. But can’t seem to reclaim my youthful fitness. Not that 51 is too bad. Still trying to get close to my previous sub 40 min 10k I used to be able to do. Still along way off.

Of course, am very curious to do it in another year or two after taking Rapamycin and see if this one makes any difference.

Ultimately will be happy to drop all this other stuff - resveratrol and particularly NMN are pretty expensive!

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Wow - thanks for comments DeStrider and Agetron. If normal bioavailabilty is just 10% that makes sense that other things could make a big difference. So that means you don’t really know what effective does your taking unless you use a blood test?

I see alot of people here have been taking grapefruit juice. So if you want a higher effective dose which is better - using methods (like eating with high fat food, grapefruit, etc) to increase biovailability or just increasing the base dose? Is there any difference/advantage? (aside from lower costs by making same dose go further)

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Many thanks for these links RapAdmin! I hadn’t found some of these in my existing reading on the site! These look like some great info and I’ll read them in detail.

Yes - good point about stopping the other supplements for a while to see what changes. Is beginning to sound like taking some regular blood tests (which I know Dr Green recommends) is key if you really want to know what is going on. Otherwise sounds like the actual dose you’re receiving could be wildly different from the one you think you’re taking…

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I believe the majority on here using GFJ - have a limited amount of rapamycin/sirolimus. Because if you are not on it as a prescription ( I am) it is a pain in the ass to get and then never knowing the quality of what you have - if it has any rapamycin at all. Hence, another reason to do the a Labcorp test to see if your product is real. Taking a smaller amount of pills with GFJ gives me the 20mg to 30 mg that some researchers hint at as ideal if you don’t have side effects. At 8mg with GFJ (40mg) I get diarrhea for 3 days. At 6mg and GFJ… nothing. So I think I have my sweet spot… unless, I were to go intravenous (it is intriguing).

I will get my second GlycanAge test in about 4 weeks - I am almost 65 years - it rated me at 37 years… huge difference and freaked out their CEO and staff as rapamycin was considered dangerous. Now they are having second thoughts on rapa. My TruMe epigenetic methylation test taken 6 months apart has me at 50 and 51 years … 14 years difference - again enough to have the CEO contact me about what I was doing. I explained rapamycin and got… oh. then yes you have done it. Congrats.You are 51 Biologically. My test is accurate.

Will be doing another TruMe test this week when my kit arrives. I have been on 30 mg rapamycin (using the GFJ) since April. Curious to see how my past tests will compare with new ones taking the increased dose these past 7 months.

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If you take grapefruit juice and then your Rapamycin 1-4/hours later, there was a study that determined the bioavailability improved 3X.

Taking Rapamycin with a high fat food increases bioavailability by 0.3X

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Yes, initially I was doing a glass of GFJ an hour before at night and a glass with the dose and a glass the next morning. I finally thought it was too much GFJ and trouble. Kinda made me sick.

Now I buy one fat, ripe Red Grapefuit and slice and hand squeeze it into a glass through a strainer - makes about 1 cup of pure - fresh juice and that is it. I take my pills with the GFJ and I am done. With that method for me - I get a 5x’s multiplication. Let’s see if this holds true when I get my result in a few days.

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I eat a whole pink grapefruit after dinner the night before and then another whole grapefruit 1-4 hours before my Rapamycin. I take 1 g of Metformin the night before. Metformin also increases bioavailability.
The morning of, I drop my tablets in a shot of EVOO and down it goes. I expect my bioavailability is in the 3.5X-5X range (35%-50%) vs. 1X (10%).

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The advantage to not using grapefruit juice or high fat dosage is that you get the standard dose at what someone above suggested is 10% bioavailability. You know what you’re getting and it’s relatively stable dose to dose.

As I have closely read these forums I’ve seen reports of grapefruit juice increasing bioavailability by 3x-7.5x. You don’t know what it will be, as it depends on your biology, the effect of that specific grapefruit juice (some juice leads to largerX some smallerX), and the exact amount of gfj and timing before or with your rapa dosage. Without being extremely precise and testing yourself you can’t be sure what you’re getting rapa-wise.

The advantage of taking rapa with EVOO (extra virgin olive oil) is that the multiplication factor is less than gfj and more reliable.

Another advantage to gfj is that it extends your dosage, as you can take fewer pills for the desired effect. Getting rapa can be a PITA, so extending it makes sense for those who are stretching their pills, or who want giant doses like 12mg, 20mg, 30mg equivalents.

Personally I’ll be steering clear of gfj while I’m satisfied with 6mg weekly with EVOO. Lots of people here using gfj tho.

I agree with rapa-admin that you may want to pause the other supplements for 4-12 weeks and focus on dialing in Rapamycin to your ideal dose. Then add back the ones that you still care about in an orderly fashion to note their effect in combo with rapa on your physiology.

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I’ve had some negative side effects of using grapefruit juice to amp up the absorbability. As you probably know by now through reading, the idea is to inhibit Mtor1 but not Mtor2. that’s why we do a hit and run dose once a week. But if the dose is too high you start inhibiting Mtor2. One of the common side effects of that is canker sores. I got several after taking 8 mg rapamycin and a glass of grapefruit juice. It was hard as heck to get rid of them - I finally did a washout month, went back to 8 mg and no GF juice. And they went away. Soif you take 2 mg dose and GF juice, it’s like taking between 6 and 10 mg.

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