It is true. A greater percentage of people in the 0.5 mg daily group experienced adverse events, and they had a higher incidence of the more serious ones including mouth ulcers, which Dr. Green calls the “sine qua non” of rapalog toxicity. In her paper, Mannick also stated that “many of these adverse events are related to the pre-dose (trough) concentrations” and herself pointed out the significance of the higher rate of mouth ulcers in the 0.5 mg daily group. Also, based on the half life, the lowest trough levels are associated with the 5 mg weekly dose. From all of those things, according to doctors and researchers like Green, Attia, and Kaeberlein, the most common dosing protocol for longevity is 5-8 mg weekly.
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46 total adverse events with 5 mg/week and 35 total adverse events with 0.5 mg daily. That’s 24% more.
You cannot claim that
fewest side effects was the 5 mg/wk (everolimus)
when you literally have 24% more total adverse events with 5mg/wk over 0.5 mg daily.
And where are you getting better efficacy with 5 mg/week ?
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There were more SIGNIFICANT adverse events in the 0.5 mg daily group. Consider the full picture. A greater number and percentage of people in the 0.5 mg daily group (22 or 42%) experienced adverse events than in the 5 mg weekly group (20 or 38%) and more importantly, 6 people in the daily group developed mouth sores while only 2 in the weekly group did. Aside from that, I’d just refer to my prior message.
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What do you mean by SIGNFICANT ? Statistically significant or is that just your arbitrary judgement on what you consider significant ?Are mouth sores more “significant” than diarrhea ? (7.5 % with 5 weekly vs 1.9% with 0.5 daily.)
I read your post, no explanation on why you consider one regimen more efficacious than the other.
I listened to Mannick on Master One Thing podcast discussing her previous research and upcoming studies with her new rapalogs. She considers both dosing regimens equal in efficacy and only mentioned more sores with daily dosing. In fact regarding her future studies with TOR101 (similar to rapa), she stated she could go with either daily or weekly regimen. Clearly she didn’t consider the “side effects” of daily significant enough (or less efficacious) to dissuade her from using the daily dosing in future studies.
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How long before we notice the mouth sores or any side effects? I only noticed my gout flaring up so I just drink more water.
Side effects seem very individualized and also dose dependent (generally, higher the dose, the more likely side effects are). Most people report no side effects (and most people also report no obvious benefits… but slowing aging is not something I’d think most of us would notice).
I had one mouth sore at around 5mg/week, once. Never had any issues again even testing as high as 28mg in one dose.
See our polls results here:
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As I said in my first response, Green and Mannick consider mouth sores to be more significant. They also the consider the trough level to be closely linked to the adverse events, and the lowest level is associated with the 5 mg weekly dose. This is why weekly dosing is now the standard for longevity.
And what I actually said was that 5 mg weekly was the most effective dose with the fewest [significant] side effects.
You are free to interpret the Mannick study any way you like.
I think the 0.5 mg daily or similar, more frequent dosing might work better for certain people, despite the higher frequency of mouth sores and the fact that a greater percentage of people in that group had side effects. But the consensus of the medical community is that, generally, weekly is best.
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1.Snowbowl effect is not a part of good science.
2.Don’t confuse biohacking with medical community. The consensus of the ACTUAL medical community is NOT to prescribe rapamycin until we have convincing data from human trials, that includes Attia BTW.
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Are there more side effects with higher peak dosing? @Olafurpall For example, 5 mg one time a week reaching higher peaks than 1 mg EOD. 10 mg two times a month is higher… 20 mg one time a month, etc.
I hate anecdotes like this but Blagosklonny was focusing on higher peak dosing and he got an aggressive cancer according to some early in life.
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Also if you read these forums, there are a lot of reports of skin infections including Kaeberlein himself in people that are weekly dosing. There is a lot that we still don’t know.
I suspect there may need to be a need for periodization in the dosing. For example, a period of loading dose and period of maintenance dosing or no dosing. Some people are already starting to do that, cycling on and off.
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I would point out the Mannick study is over cited and conclusions made from this often exceed what was demonstrated. Ultimately this short duration study has value, in looking at immune response to a vaccine, which certainly is part of aging - but not entirely the same thing.
Jumping on the bandwagon of trough levels, I understand why - it’s because this is what they measured - but it is not in any way logically or pharmacologically the active ingredient in safety or dosing - but instead is a proxy for % of time at a therapeutic level - which is what they should have measured.
The trough levels are simply a proxy for time at a therapeutic level where mTORC1 is highly inhibited. If you had patients maintained at 0.1, 0.4, and 0.8 troughs by microdosing - there would almost certainly be absolutely no difference between them – as all would likely have essentially no activity in any fashion - beneficial or harmful. None would be active - as the trough is not the active ingredient. Treating it as such is a misunderstanding of pharmacology.
I appreciate that this is a standard measure in pharmacology, and understand why they did this. It would be more precise, and meaningful to have assessed the % of time in a therapeutic level on a weekly basis. That logically is the active ingredient, and also would relate to risk of adverse outcomes and benefits.
I see no situation in which I would care what the trough is, as it is a less precise way to look at what the real issue is - how strongly inhibited is mTORC1 and for what % of the time. That being said, my approach will result in a low trough before repeat dosing.
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This is a great question. The answer is, it depends. Taking very high single doses, instead of spreading the same dose throughout a week or few, comes with certain risks. While rapamycin is generally very safe, the risk of side effects increase with higher doses. The high peak levels seen when taking a lot in a single dose will increase the risk of certain rare side effects. There are individuals that are susceptible to strange side effects, and for those people, a high single dose could be risky. Note that this is not comon. I’ve seen a ton of anecdotes on rapamycin and know of only one case where an individual got a serious adverse reaction right after taking a single high dose of rapamycin, which required a visit to the ER. That individual supposedly did not have adverse reactions to lower doses, so this is a case where high peak levels might have been causing negative effects. This is why one should always ramp up the doses slowly and start small and increase it a little bit every week or few to see if one tolerates it.
On the other hand, chronic mTORC inhibition by rapamycin does tend to inhibit mTORC2, which causes side effects like impaired insulin sensitivity and elevated blood lipids. This can be largly avoided by intermittent dosing, but taking a large dose every one or two weeks can often prevent this effect almost completely, while the same dose spread out into more frequent smaller doses will inhibit mTORC2 and cause more side effects. In this respect, intermittent doses have less adverse effects, despite higher peak levels.
Overall we have a case where the dose makes the poison and overall for most people the side effects are likely minimized with intermittent doses (every one or two weeks) as opposed to chronic daily or every other day doses. People just need to be careful and ramp up the doses slowly to test their tolerance levels.
Regarding Blagosklonny, the reason he was focusing on higher peak dosing is, if I recall, the idea that higher peak levels are necessary for rapamycin to cross the blood-brain barrier. I think this is one reason he eventually stopped taking rapamycin weekly and started taking double the dose every two weeks instead. I doubt this dosing strategy had anything to do with him getting cancer.
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Can you please elaborate on what this means? Do you mean that you were able to get a physician to write you a script for Sirolimus using Push Health, and then said prescription can be sent electronically to CostPlusDrugs?
Yes, I do not use CostPlusDrugs.
The prescription was sent electronically to the pharmacy of my choice.
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Well that’s very good to know. Under what kind of premise did you request Sirolimus if I may? Were you upfront about what you wanted it for?
I had a PharmD, Henry Dunklau, contact me from MidTown Express Pharmacy in Nashville, TN. Their number is 615.320.8410 and website is www.midtownexpresspharmacy.com
He has coated tablets of Rapamycin 2 mg x 30 for $90 or 2 mg x 90 for $240.
Yes, they need an Rx - but he can send them to 43 states - cannot send to CA, OK, Kansas, Arkansas, SC, WV or NH.
Seems like this could be a good U.S. based resource for some folks!
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how do you buy from india? Any reputable sources? Or for that matter, any sources. On brazil medications are usually very cheap, 1/5 of US price, yet rapamicyn (60 pills 1mg) cost 600 dollars as generic companies do not produce them (even though the patent expired long ago).
See the information on this page, about importing, and pricing and list of reliable India pharmacies: How to Get Rapamycin, Where to get a Prescription
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Recommend both apple pharmaceuticals and Shivansh trade!
Just create a Indianmart account and then start quoting and you will then get quite a response from the many pharmaceutical companies in India!
Payment is easy via wise.com and product quality is good as well! You can negotiate the best possible price as well!
I got some some discounts!
Yeah I don’t love rapamycin becoming more mainstream before there is enough acceptance in the medical community that it can be prescribed freely.
A clampdown on the gray market before the traditional medical world accepts it would make things difficult.
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