“It’s very convincing that significant blood levels can be achieved by bypassing the GI tract . This is important since there is so much inter person variability with the oral route.”
But are we sure that changes in the GI tract brought about by Rapamycin don’t play a role in its systemic effects? Some studies do indicate that, and among others changes in the intestinal microbiome as a result of oral Rapamycin intake have been discussed in research. It is a macrolide antibiotic after all.
If I could ask: how did you sterilise the Rapamycin powder before injecting it intramuscularly, MAC? I don’t mean to sound like a ‘naysayer’ but I’ve read someone ended up in the hospital with a major infection doing a similar thing.
That is approximately correct, I am taking a mega “oral dose” equivalent at < 20 mg IM+IN parenteral.
Pulsed (I assume you mean intermittent) is really to try and offset the side effects of daily dosing, and keeping the trough/AUC level below a therapeutic level, typically < 5ng/L. Taking rapamycin daily, with 62 hr life, the pharmacokinetic balance is tilted to accumulation vs clearance, thus the rise to a high steady state trough level vs clearance dominated in pulse, thus lower trough. One would have to get the daily dosing just right to get a continuous steady state concentration but not trigger dose limiting toxicity. And of course, there is the completely separate question of “what is” the minimum trough/AUC to provide sufficient mTOR1/mTOR2 inhibition to longevity benefits? A very small daily dosing trough level may still not be sufficient; mice studies have shown us the association of levels with longevity benefits.
Are you referring to oral daily? Sirolimus taken daily, even at 1mg/day can easily lead to steady state trough levels above 5ng/L, and trigger side effects.
Intranasal dosing “throughout” the day is still a DAILY systemic dosing protocol, although it does indeed bypass 1st pass metabolism; I think your thought is on the theme of “continuous” vs pulsed dosing. Depending on dose, even daily intranasal can lead to high CNS and/or systemic dosing (part of the dose that doesn’t enter the CNS or get destroyed can enter the systemic pathway). In fact, there is crosstalk between CNS and the systemic periphery (read the intranasal paper…mice given only intranasal also produced a systemic sirolimus signal). But as I have shown, it may not lead to significant side effects depending on dose (pending longer trial duration). We really do not have much of any human data on dosing vs rapamycin crossing the BBB, brain regional tissue concentrations, and pharmacological/symptomatic response. The mouse intranasal study also showed a VERY high brain rapamycin level, and lower systemic level. So how will you even know how to titrate dose when you can only measure systemic sirolimus? You will have NO idea how much is crossing the BBB, and of course, unmeasurable with conventional assays. Much work to be done in translation.
I would think at the trough/AUC levels of my study, based on a previous cancer/rapamycin/brain tissue study (below image/data), and considering the daily dose used in that study, I strongly believe rapamycin has readily crossed the BBB. How much is coming from the IM vs IN route…I do not know.
"Figure 2. Rapamycin Crosses the Blood–Brain Barrier and Blocks mTOR in Tumor Tissue
(A) Rapamycin concentrations in tumor tissue (filled squares) and peripheral blood (empty circles) grouped by rapamycin dose cohorts (2 mg, 5 mg, or 10 mg ORAL daily)."
Notwithstanding the potential benefits of bypassing 1st pass metabolism, the “dose is the poison” still reins. Any drug delivered to some supra-physiological level can fundamentally alter cellular homeostasis.
This is not medical advice.
No sterilization, use of raw powder as received. The sourcing of the powder, partly chosen based on several other forum members who have used this rapamycin without issue
You referring to injection rapamycin or other?
I stated very clearly in my study, what I am doing is potentially very risky, my own calculated risk/reward. This is high wire biohacking.
@MAC , another idea to your IM approach (and perhaps also IN) - might be using Temsirolimus (a rapalog, as you know). Just looking around a bit, it seems that 25mg of Temsirolimus from Wyeth can be purchased for around $700 / 25mg. Not sure if its possible to get shipped from India (refrigeration requirements?). I haven’t researched it at all, other than checking to see if its available. My suspicion is that it would be preferable in terms of product quality (brand name) and manufactured to normal Pharma quality standards (vs DIY from rapamycin powder). Anyway - just a thought, as a way to get a more proven (hopefully safe) rapalog solution.
Or - to save a little money (
) get the generic version at about $2 / 25mg and have it lab tested:
Also, I’m wondering if sirolimus (injection) may be available at lower cost somewhere:
Also - just wanted to add to this thread, for anyone new to the discussion and/or forums… a previous thread that discusses the whole issue of different rapamycin delivery approaches and rationales. I suspect it was partly due to this earlier discussion that @MAC has begun this new personal testing on rapamycin delivery.
and the related issue of dosing levels: The Key issue of Dosing Levels and Intervals for Best Rapamycin Outcomes
I absolutely think that the change in the microbiome from rapamycin could be significant, but I’m not certain that oral administration of the drug is a necessary factor.
Hi Mac,
It is great that you are doing this pioneering experimenting on IM and IN dosing & delivery for rapamycin. Please continue to keep us posted on your outcomes and observations…!
@Mac, this is an extremely interesting effort in terms of helping push the rapamycin knowledgebase forward, with regard to dosing strategies.
I will continue to study your document, and to watch on the sidelines with great interest. At the same time, I’m wondering how we move this entire area forward faster. It seems what we really need (and I hope your example will help spur this on) is a human clinical study focused on exactly the issues we’ve been discussing around this… dosing methodologies and levels for optimal health and longevity.
The US geroscience academia seems to move extremely slowly. A rapamycin dose / delivery method optimization clinical study would seem to be a perfect type of effort for some international group of researchers focused on aging that is not so ponderously slow (perhaps Singapore?/Brian Kennedy’s group, others?) to get funded by the Hevolution Foundation.
Does anyone else have ideas on how to move this type of effort forward, in a way that gets the geroscience community more on board? Do we have to wait until results come in from the Dog Aging study with rapamycin, or the PEARL study?
How long do you think before Matt publishes data from TRIAD? I plan to remain conservative until I have that.
My hope is that, given @MACs exceptional data collection, this case study will catch the eye of one of the MTOR ‘influencers’.
I sent MK my study, he replied “very interesting, thanks for sharing”
I did ask him about a realistic timeline to get a confirmed Rapamycin signal in the TRIAD project. No response.
To populate the dog intake, baseline markers, and take all the dogs to end of life, based on average intake age of dog and average normal lifespan, you would think at least 5-10 yrs…more?
Even if someone says “awesome, let’s use IM and/or IM delivery instead of oral”…we still need a human RCT trial? Nothing has changed per se. And even if it started today with say 60-65 yr old cohort, would still need what 20+ yrs assuming average lifespan of placebo cohort of 80?
A full on longitudinal longevity study for generic Rapamycin actually triggering is next to nil. Barzali has been trying to get a generic metformin trial going since forever.
I think there is a reason most things are mediated through the digestive system. I’m not saying there’s no reason to use injected pharmaceuticals but it is a step up or out or something. There’s little or no chance for the bodies standard protective mechanisms to weigh in on what’s going to happen with the molecules!
Today post workout, lowest weight I’ve seen on the scale in some time. I weigh out every day after exercise normal routine.
Indications of about 2kg loss in about 6 weeks on this new protocol. The signal may be real.
Tomorrow is injection/snort day!
Do we really know what kind of trough level between doses would be most beneficial?
If this curve applies to lower doses then maybe 14 days between high pulsed doses isn’t enough.
Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated
“The true elimination half-life of sirolimus is approximately 63 h, although the effective half-life is shorter with patients reaching steady state in 5–7 days.”
“bolus doses” = “A single dose of a drug or other substance given over a short period of time.”
“Acute Sirolimus Overdose: A Multicenter Case Series”
“https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874384/pdf/bcp0054-0065.pdf”
“https://www.drugs.com/article/drug-half-life.html”
I have no medical background and have only been researching RAPA for about a month so take what I say below with a big grain of salt! I hope that other who have been researching this much longer than I have will chime in and call BS on anything I have written here.
There are several advantages that I see of maintaining a low-level, constant blood concentration. For example, 1) maintaining a constant, yet not complete, inhibitory pressure on MTOR thereby helping to restore more youthful levels when not activated by eating, stress, etc. 2) avoiding drug resistance over time from higher than necessary dosages and 3) lower side effects by taking the minimum dosage. Exactly what this minimum dosage is for humans is unknown as well as whether it is different for each aging process, area of the body, etc. that we want to target.
Toxicity studies have show that in transplant patients who are not taking cyclosporine that the target steady-state trough range is 12ng/ml to 20 ng/ml. But it is my understanding that these trough levels were selected because they are highly correlated to the AUC for a daily dosing regime and an easily measurable proxy of the AUC, i.e., it is the characteristics of the daily exposure which is really the driver of the toxicities. It’s not clear to me whether its just the AUC that is driving the toxicities or also the Cmax.
But a weekly dose that provides a 20ng/ml trough after 7 days would have a much higher exposure than a constant daily dose that provides 20ng/ml tough all day everyday of the week. Therefore it seems to me that this weekly dose would clearly be more toxic than the constant daily dose.
Also, I’m not sure how relevant the human cancer studies are to establish effectiveness of dosing for prevention purposes. For example, the rodent literature indicates that a much lower blood concentration is required for cancer prevention than inhibition of existing cancer. Of course some cancers will sneak through at the lower blood concentrations and that is possibly where the super high effective doses we are seeing in the mice life span extension studies are coming into play. Recall that something like 95% of all mice die of cancer whereas only 1 in 6 humans do.
This is all a work in progress. Right now my sense is that a dosage that provides a relatively constant blood concentration between 5ng/ml and 15ng/ml might be a good place to start. I think I heard that Blagosklonny’s latest protocol is 2mg/day oral and that would probably get him pretty close to this. I want to read more on MAC’s intrasal administration approach as an alternative to oral as well as do more research and hear from others before moving forward with this concept.
Per my study notes.
Very first full single 0.25mL injection, a large bump developed that was painful (regionally on my injection site leg, and to the touch), which took about a month to dissipate, overlaying ongoing new dosing. In the subsequent weeks, I limited per injection to 0.1mL (total injection volume was split into individual 0.1mL injections spaced apart between both thighs). The 2nd/3rd weeks, the injection sites lingered in terms of residual sting, actually impacted my gait (in combination with the 1st injection large bump which lasted a month); my legs had a stinging feel to them. Per my observations below, it would seem the rapamycin concentration was slowly ramping up as expected without a loading dose (at what we know now is massive dosing) . I was still able to do my daily resistance and aerobic exercise routine, as a reference.
The last few weeks, other than some residual stinging immediately at time of injection, NO lingering pain.
Other than 1st dose bump, NO visible untoward signs of any trauma at the injection site. The bump itself looks totally benign, no discolouration, just a bump in the tissue. Perhaps a small red dot at some sites (blood coming to surface). I did mention in my study notes, blood does aspirate out of some of the injection sites when I withdraw the syringe (not every injection, perhaps 33% of the time). This has NEVER happened with my TRT injections (nor ANY stinging)…so clearly, the DSMO/rapamycin has an entirely different physiological impact on local tissue.
I’ve never done a control DSMO only blank injection to see if the stinging is the DSMO or rapamycin. So I did a 0.1mL DSMO only shot; no stinging, just a tiny rush feeling around the injection site that quickly dissipated.
I took my 5th 15mg/5.8mg IN dose today (feeling fine since last week dose, so onwards). The injections had the characteristic immediate stinging on needle entry…so it’s clearly the rapamycin tissue sensitivity, wow.
But as the weekly doses have progressed, the immediate post injection residual stinging has lessened DRAMATICALLY. Namely, 1st couple of shots, there would be lingering stinging throughout the day/week. As I write this, perhaps 15 minutes have elapsed, I feel next to nothing at injection sites. This was NOT the feeling 1st few doses…they lingered.
Could this be the significantly elevated residual tissue rapamycin I’ve now built (confirmed by huge trough level) now blunting any NEW rapamycin entry? The tissues are fully sensitized already?
New frontiers…it’s both very exciting but I also wonder if/when the hammer is going to fall. Will a single symptomatic DLT emerge? Will it be the underlying biomarkers going south…deeper into anemia and fatigue, gastro, or infection from WBC depression?
Unlike rodents being injected with rapamycin, at least I can share how I feel with the community…a talking lab rat
No sure, I had read that, I meant more with respect to quad muscle strength or local fat etc.
Nothing I can quantify for you. I continued with squat and dead lifts and high speed run treadmill, other than some residual pain, it didn’t stop me from completing my routine. Fully recovered now.
All great questions, but venture to say we don’t know anything about “exactly” what pharmacological/pharmacokinetic dosing protocol results in “human lifespan extension”.
The only thing rodents tell us is more rapamycin = higher lifespan increase, either by increasing oral chow rapamycin OR ip injection. MB’s mantra is “take as much as you can tolerate”, code for MAXIMIZE AUC before DLT? I’m going down this road…
