Ideas on Protocols for Testing Higher Rapamycin Doses

[RapAdmin]

A recent twitter post series about a user testing extremely high doses of rapamycin got me thinking about what a better way to test increased doses would actually look like.

Obviously, this would be done working in concert with your doctor, but since this is a new area of medicine that even they are likely to lack too much experience, I think its imperative that the user learn, understand and play a roll in the protocol to be used for testing higher doses. The doctors, the patients and even the researchers are all learning in this area - so we need to work together and share information as much as possible.

In an ideal world we’d work with known rapamycin researchers to try to get funding for a virtual clinical trial (similar to the way the PEARL study is conducted) for dosing of rapamycin in anti-aging where all the blood testing is done by your local LabCorp, but funded by the clinical trial so that the results can be turned into a research paper that we can all learn from.

Lacking a formal clinical trial, the best we can do is have all people doing this type of protocol share their data. Crowdsourcing medical data like this has proven very effective in many situations (see PatientsLikeMe, and others), so this is likely the fastest way to improve dosing knowledge around rapamycin in anti-aging.

My goal here is to get some ideas on “best practices” for users who are interested in testing higher doses of rapamycin (or perhaps even for starting rapamycin for the first time).

Below I’ve gathered the recommendations I’ve seen from researchers and clinicians for this type of thing, and reviewed the data from the few healthy human clinical trials that have been done (and what they look at and track), as well as the PEARL trial, etc. - to get some ideas.

I think there are two approaches to this:

• The basic approach is a “minimal protocol” for where there is more of a strict budget. People can then discuss with their doctor and decide based on their budget what makes the most sense - likely somewhere between “basic” and “ideal”.
• Next is the “cost is no object” approach where you look at what would be the ideal approach to doing this if you have a lot of resources (or a funded clinical trial).

We should try to think about a good protocol for testing new dosage levels to try to push the knowledge base for everyone here. Please - I’d like everyone’s input on this. Many of us will all, at some point, probably want to test increased doses for rapamycin.

We should think about, and discuss with the researchers and clinicians, about the best way to slowly and safety increase rapamycin dosing in a way that captures as much information, and helps us track the true effects on our bodies, and then share this information here so that everyone can learn from each other.

Step 1: Establish a Baseline

Before you make changes its important to understand where you are, so you can measure the differences. So, before you make any changes to a dosing schedule you want to be at a steady state for a while (in terms of medicines, dosages, supplements, etc.) - and check your blood work.

So a starting protocol might be something like this:

1. Stabilize at your existing dose for at least 2 months
2. Evaluate potential health risks for next month or two - do you need a vaccination (in which case you likely want to stop taking rapamycin for a while), is the pandemic still a high risk, etc.
3. Do your blood testing, and make sure you’re healthy (no wounds, injuries, etc):

• Insulin
• CBC (Complete Blood Count)
• CMP (Comprehensive Metabolic Panel)
• Ferritin
• Lipid Panel
• Hemoglobin A1C

Ideally - test peak and trough sirolimus blood levels.
Peak blood levels are approximately 1 hour after dosing, trough blood sirolimus levels are tested the day before you plan to take the next dose - so perhaps day 6 if you are on a weekly schedule, or day 13 if you are on a 2 week schedule. $95 Sirolimus Blood Test, Labcorp Sirolimus Level Test Details.

Ideally; test TREGs (T-cell Regulatory Test) (Test details), Labcorp TREGs test
Test TREGS on the same day you test Trough Sirolimus levels to see if there is significant disruption to your immune system.

Step 2. Dose Increase

1. Discuss with your doctor possible dose increase increments. At lower doses - e.g. 1 to 10mg, a person might want to increase only by 1mg, at higher doses it might make sense to increase the dose by 5mg (e.g. from 10 to 15, or 20 to 25mg)
2. Track blood pressure immediately prior to dosing, and 20 minutes, 40 minute, 1 hour, 2 hours, 4 hours after dose. (I’ve heard some people have spikes in blood pressure - so I’d like to monitor this more)
3. Check self daily after new test for any new side effects / benefits noticeable (we can have a form here on this site for people to easily check off on a regular basis).

Adverse Events / Side Effects (from clinical studies, Mannick paper, etc.):

• Mouth Ulcer / Canker sore
• Headache
• Blood Cholesterol Increase
• Diarrhea
• Dyspepsia (indigestion)
• Fatigue
• Low Density Lipoprotein Increase
• Tongue Ulcer
• Insomnia
• Dry mouth
• Neutropenia - abnormally few neutrophils in the blood, leading to increased susceptibility to infection
• Oral pain
• Conjunctivitis (inflammation/infection around eye)
• Erythema - reddening of the skin / rash / dermatitis
• Limb discomfort
• Paresthesia - burning/ prickling sensation in the body, limbs
• Stomatitis - inflamed or sore mouth
• Thrombocytopenia - low blood platelet count
• Urinary Tract Infection
• Muscle aches or pains

Beneficial Events / Good Effects (The positives you’re seeing): list TBD

• More energy
• Reduction / elimination of soreness or aches/pains
• Better Sleep
  …

Step 3. Redo Blood Tests, Check for variations

1. One week after the new dose, do a new blood test regimen (same blood tests as at baseline). Note any changes in blood variables, and track changes (share on this forum)

2. Calculate Levine Phenotypic age using spreadsheet (see attached below)

Spreadsheet I downloaded from Mike Lustgarten’s website for calculating your Levine Phenotypic Age:
3ba41-dnamphenoage_gen-1.xls (31.5 KB)

[KERRY_BELL]

I have been taking rapa for 4 years. Was Dr. Green’s 2nd. patient. Have experimeted with higher doses in all time frames. 75 yo., male Currently take 20 mg every 14 days. No problems so far. I use the Grapefruit Juice Protocol as suggested by Dr. Thieummeur to save money. The reason Dr.Blagosklonny and Green use this dose is that there have been studies where at higher doses the rapa can get past the blood/brain barrier to directly inhibit the Tor signal in the Hippocampus. There is a belief that the Hippocampus regulates ageing. There is very little rapa in your system at the end of 14 days before next dose. My Phenotypic Age is 60.

[RapAdmin]

Hi Van, sounds like that protocol is working for you. You’ve been taking rapamycin for a long time. One of the issues seen in mice that has not yet been seen in humans is the risk of cataracts. how are your eyes - any issues?

Also - have you seen any side effects at all over the past 4 years that you think might have been linked to rapamycin?

[RapAdmin]

Here is some feedback on the “Testing Higher Rapamycin Doses Protocol” from a doctor:

there seems to be pharmacodynamic justification for higher doses, but just realize that you are going even further into the realm of untested and experimental therapy as you escalate the dose. My perspective with new drugs has always been to let someone else be the early adopter / Guinea pig, and while I realize that all of us who take rapamycin are kind of in that category, at least there is a body of collective experience that suggests safety. Do we even have six months let alone a year of case reports of people taking the high doses of rapa? That said, since this is the rapa group, my suggestion for those of you determined to experiment would be very gradual escalation and periodic bloodwork.

and some feedback from another person (not a doctor):

Any sign of a drop in lymphocytes or an increase in CRP or other inflammatory markers is a big red flag that dose is too high. And IGF1 should not fall too far below normal range.

Doses for aging should not be immunosuppressive, and should not be high enough to be disrupting the balance of cytokines (so-called “sirolimus-induced inflammatory syndrome”). They should not be dropping IGF1 to a level that could cause wasting diseases. My 2 cents.

It has been documented in certain cases that rapamycin can induce a significant inflammatory attack on the body. The term for it is “Sirolimus-Induced Inflammatory Syndrome”. This paper explores why it happens and the mechanisms involved.

[KERRY_BELL]

I follow the lead of Dr. Mikhail Blagosklonny who knows more about rapa dosing than all of us combined.
He is currently taking 20 mg. twice a month without side-effects. I have the same dosing schedule for the last 4 months without incident. Knowing that we are all different, Dr. B recommends everyone be under the care and guidance of a physician.

[Maveric78]

Bringing back an old thread… Feels like the average dosage on the forum is trending upwards? (Still keen to know people’s mg/kg!)

If I recall correctly the (mostly mild) side effects of 20mg per week reported in the Mannick trial still weren’t that much higher than placebo?

[约瑟夫]

FWIW…The only way to know what “your” personal blood level dose would be is the measure. As I have stated in an another posting;
Base draw
Take dose
30 minute draw
1 hour draw
2 hour draw
3 hours draw
4 hours draw
At $95.00 per draw/test the cost would add up.
A base to 8 hours, $1,000.00{$95 x 10] Try to negotiate a lower cost with the lab running testing.

[RapAdmin]

Yes - but I suspect the number of people who would want to spend the day hanging out in the LabCorp or Quest office doing blood draws is pretty small. Plus - you would ideally want to do this at different dosing levels - say 10mg, 20mg, 40mg, etc.

It would be interesting to have a clinical trial / study done on this type of model in healthy people of different ages (e.g. age 30, 40, 50, 60, 70). I wonder if this type of information would be more generalizable to the broader healthy population…

[Guywholikessleep]

So why are people wanting to take higher and higher doses of rapamycin? I am wondering if you really are seeing any addition benefit by taking these higher doses in comparison to just taking rapamycin in general. I mean we do not want MTORC2 inhibition and I am wondering on top of rapamycin a lot of people on the forum are generally practicing good lifestyle practices that may influence some of the results they are seeing while on rapamycin. Now, I am a believer in rapamycin and like the data that comes out ( I am trying to stay unbiased and objective) but I see a lot of people on the forum combining so many supplements and different lifestyle approaches that its hard to single out what is actually being effective for them. I also see a lot of people constantly looking at research articles and trying the next “new” longevity thing and it almost seems like its done in a anxious fever. I just am curious why people are trying to up their doses to higher levels? I am just trying to understand others logic in this, especially since I am so young and havent felt the impacts of aging yet.

[RapAdmin]

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

[约瑟夫]

Why?

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

We are all PFA* dosing.

• Plucked From Air

[Guywholikessleep]

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

[brandy111]

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:

Increased TORC2 signaling promotes age-related decline in CD4 T cell...

[Guywholikessleep]

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.

[RapAdmin]

@Guywholikessleep

( or just generally taking rapamycin period) dose in terms of lifespan increase outside of the one study?

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.

[Guywholikessleep]

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)

[RapAdmin]

@Guywholikessleep

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.

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.

[约瑟夫]

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.

#118 – Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging

[Maveric78]

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)?

[desertshores]

“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)