Side Effects of Rapamycin (part 2)

As you can see above, in a small survey of rapamycin users done in August, 2022, most people experience no noticeable side effects when dosing in the typical range currently being dosed for anti-aging applications (3mg to 10mg, single dose per week).

The side effects that people do experience are mostly very mild and temporary. Most people continue to take the medication and the problems (e.g. canker sore, small rash) typically go away over a few days with no treatment or minor treatment.

A small percent of people (approx. 3% or so from my estimation) have some side effect significant enough to make them want to stop taking the medication. I’ve also heard of one instance where a person suffered from significant skin rashes so decided to stop the medication quite quickly after initiating it. The side effects seem to be highly personalized and frequently not extremely dose dependent. While the Mannick study of 2014 of a rapalog (acts like rapamycin) saw higher side effect levels at higher dosages, in the experiences from people we’ve seen talked with it seems like the vast majority (95%+) start with lower medication levels, then slowly increase, and may occasionally get mild side effects like a canker sore that goes away - they don’t typically see higher side effect profiles as they ramp up the dose.

I personally have had a single canker sore (technical name aphthous ulcers). It happened early on when I started rapamycin. I think it was when I was at a couple of milligrams (mg) of rapamycin. It started a day after I took the rapamycin, and slowly got better over the next few days. I haven’t had it since (its been nearly two years, and I’m now up to a dose of around 10mg per week, all in one dose. Other people, like Peter Attia, have mentioned occasionally getting canker sores on rapamycin during times of high stress, eg, getting head-butted by your child during play.

Skin rashes are also something I get occasionally which seem highly tied to my rapamycin use. I get a small rash about the size of a quarter on my wrist under where my Fitbit sits. I’ve never had these until I started rapamycin. They come on after I take rapamycin. I use cortisol cream on the rash and it mostly goes away usually within a few days. A few people have reported more persistent and larger rashes developing.

Doctor Green has the largest practice prescribing rapamycin for aging users - with over 700 patients, so he is, theoretically in a good position to have detailed information on the topic of side effects and their frequency and type, if he is keeping detailed records on all his patients throughout the year. Here is a recent note from him (forwarded to me by one of his patients):

From Dr. Alan Green: Five Year Update, October 2021

Increased Risk Bacterial Infection

Five years and 760 patients have revealed that the single major risk of weekly Rapamycin is increased risk of bacterial infection." He suggests having antibiotics (like azithromycin) on hand.

[Note: There is some very significant disagreement about Dr. Green’s above statement, by other medical professionals I’ve talked to with experience with rapamycin. Bacterial infections, and use of antibiotics to treat them, is extremely common in the USA. I found it very hard to get good numbers on the typical percent of a population in the US that get bacterial infections each year, but this document from PEW Trusts suggests that antibiotics in the US are prescribed at a rate of 838 for every 1,000 people (measured in 2015) - which suggests upwards of 84% of Americans (or at least their prescribing doctors) think they have a bacterial infection each year severe enough to require antibiotics. Dr. Green has suggested only 5% to 10% of his patients get bacterial infections in any year, which suggests a much lower than average rate of infection than normal for rapamycin users. Moreover, it is not something that the users of rapamycin that participate in forums suggest is a common issue. So, take this with a grain of salt until more data is provided by Dr. Green.]

Dr. Alan Green has also responded by saying this in an interview in 2017:

What are the side-effects?

The side effects of daily rapamycin are TOTALLY different from the side-effects of weekly rapamycin. Daily rapamycin is used to reduce both mTORC1 and mTORC2. Rapamycin was introduced in 1999 to reduce mTORC2 for organ transplant.

Reduction of mTORC2 has significant side-effects. People can review elsewhere the side effects of reducing mTORC2. Almost all the harmful side-effects of rapamycin use are from lowering mTORC2 and all the beneficial anti-aging effects are from lowering mTORC1.

Weekly rapamycin is designed to lower mTORCl and preserve activity of mTORC2. Dosing interval of one week is based upon the rapamycin half-life of about 65 hours.

It is required to delay the next dose until there is a low blood level of rapamycin so as not to interfere with production of new mTORC2.

There are side effects from reducing MTORC1. The major side-effect of lowering mTORC1 is reducing the activity of the INNATE IMMUNE SYSTEM. The innate immune system is the first line of defense against bacterial infections and it involves neutrophils and macrophages, but not lymphocytes or antibodies. In my practice, everybody is warned of this danger and given a prescription of prophylactic antibiotics, (Z-pak) to have on hand and warned to aggressively treat fever or local signs of bacterial infection. My guess is 5-10% of patients might get a bacterial infection in a year and rapamycin increases the risk of serious bacterial infection. However, bacterial infections respond very well to prompt antibiotics.

On the other hand, the acquired immune system (lymphocytes) is improved as an anti-senescence effect and the risk of viral infection is reduced.

Very high levels of reduction of mTORC1 may cause aphthous stomatitis (canker sores). This is unusual at anti-aging preventive doses.

Aside from increased risk bacterial infections; there are minimal side-effects of weekly rapamycin as used in low doses to prevent age-related disease.

An off-target side effect of rapamycin is it’s an excellent anti-fungal agent. Longstanding cases of nail fungus (onychomycosis) are improved after prolonged treatment.

Different people’s side effect experiences with rapamycin:

Some people see an increase in their lipid level measurements (LDL and triglycerides), especially on higher doses of rapamycin.

I just had labs and my cholesterol readings went up some since I started Rapamycin. See discussion about this on this thread: Rapamycin and Cholesterol Levels? Any impact for you?

There is evidence (see study here) that suggests that even with higher lipid levels, rapamycin still actually decreases risk of cardiovascular disease. There is an ongoing discussion on rapamycin and cardiovascular risk in our forums.

I’ve experienced a development of acne which appears to coincide with my biweekly sirolimus dosing regimens. (from this thread - Rapamycin and Acne)

I had a rash on my scalp. It only bothered me when I put a brush through my hair. It didn’t change the texture, no-one could see it, and it has slowly become less and less. I’m pretty sure it was the Rapa.

I have been taking metformin for 12 years or more and rapamycin (Sirolimus) for the last 6 months or so. I had a couple of bad experiences with Sirolimus when I reached only 2mg (once per week). Most people are on 5mg plus. Some are as high as 20mg/week. My normal insulin level is very low, (2 U/L) and I believe that is why I have a low tolerance for Sirolimus (it sends insulin even lower). So to anyone contemplating using it, I would suggest to have your insulin level checked first and proceed with caution.

I’ve been taking Rapamycin now for a few weeks, I’m up to 8mg every second week. I’ve had an unusually frequent runny nose which is a known side effect, see: https://www.mayoclinic.org/.../side-effects/drg-20068199

I don’t feel it on the day but I don’t feel great the next day, I just feel a little off but not terrible. I also use health trackers both whoop and Garmin so I see my hrv, body battery and RHR all decrease the next day so it correlates. For me anyway

This person below was very light (around 100lbs) and ramped quickly up to a relatively high dose (4mg to 6mg):

Returning symptoms I experienced (up until 3-4 days after taking my dose, some a bit longer):

  • Insomnia - I will be fully awake until 6-7AM in the morning (until 3-4 days after taking my dose).
  • rash on my hand (strangely enough at a place where as a child I had eczema).
  • Itchy minor rash at one of my feet
  • Increased heart rate, at some moments really noticeable.
  • Intense hot flashes/night sweats - I will end up drenched in sweat.
  • Intense coughing at night for a few hours (had this twice, paired with the symptoms above).

Two canker sores over 16 months. Started at 5mg/WK and up to 15mg. Sores were around 8mg but none since going higher.

rapamycin and acne - people’s experiences (discussion)

sirolimus reduced arthritus, and improved heart circulation, but at 4 mg dose I got a severe chest rash or hives 2 days after a dose. It fully cleared up after 14 days on a steroid. I will restart soon on a lower dose and be vigilant.

I have been taking 6 mg rapa once weekly for 2 years with zero side effects.

This person below was trying a very high dose or rapamycin (slowly working his way up from much lower doses) and began to see side effects at 20mg bi-weekly rapamycin with grapefruit juice (effectively around 60mg or 70mg of rapamycin, an extremely high level):

I just completed my second round of using rapamycin bi-weekly at a dose of 20mg with grapefruit juice. At this dosage, I experienced adverse side effects of diarrhea and slow wound healing. I am now doing a washout period of 30 days or more. (source: this post)

This person below ramped up very quickly to very high doses, which is not recommended:

My wife, with early menopause, tried with 3mg every day for 10 days for 2 months in a row. The first round she got a wicked tongue ulcer. 20 days later she did the protocol again and got swollen glands in her armpits - that stayed painful and swollen even after stopping. She also had a very light but discernable period, each month at the 30 day mark. She has stopped given how uncomfortable and swollen the underarms were… (from this discussion thread)

I just started Sirolimus last week and I’m getting very large cysts (acne) on my forehead. Has anyone developed cystic acne as a side effect of taking rapamycin

Yep. That was the main side effect for me. I got a giant red puffy zit somewhere on my body after the dose. I also started on a low dose and got the my first week on 1mg. It’s just our thing I guess

Had a surreal experience. I go see a dermatologist due to a few skin tags that happened in the last year. She looks at them carefully and immediately asks the question: were you on any kind of immunosuppressant? (Rapamycin isn’t mentioned in any of my health records). She said immunosuppressants like cyclosporine can cause the fat gland outgrowths (skin tags) like the one I have on my front head. Luckily they’re benign. As mentioned earlier, I’m very pleased with the improvement in my creatinine/eGFR and fatty liver. On the downside, I believe immunosuppression with 6mg/once a week dose is real (despite having unchanged WBC numbers) and the human life extension benefits with continuous use haven’t been demonstrated. I always liked how Rapamycin made my face a tad younger and more fresh 🙂 I probably won’t take it for the foreseeable future due to a conflict with another drug I’m taking.

I have the exact same skin tags in the exact same place. 5mg rapamycin once a week.

Anyone feel flu/cold achy symptoms the day after taking their very first does? I started yesterday w on 3gms…
There’s an association between rapamycin and interstitial disease of the lungs… keep an eye on it. Seems to be reversible when you stop the medication.

Independently, Matt Kaeberlein, Director, Healthy Aging and Longevity Research Institute University of Washington, and one of the leaders of the Dog Aging Project (studying rapamycin in dog aging) suggests this:

Here are the side effects seen with the rapalog (a drug almost identical to rapamycin) Everolimus (RAD001, Novartis Afinitor) in the famous Mannick 2014 clinical trial (with elderly but healthy people, dosed weekly) where it was shown to improve aging immune systems in people.

Interestingly, they reported only 1 serious adverse event in the study:

Only one severe adverse event was assessed as related to RAD001: mouth ulcers in a subject treated with 20 mg weekly RAD001.

If you are taking rapamycin, please add your own side effects experience by clicking on the “Reply” button and add in your comments below:

After my weekly rapamycin dose on Sunday, a workout during the first few days of the cycle will give me muscle soreness for 3 or 4 days. Identical workouts done later in the cycle recover within a day or 2. It seems that rapa delays recovery from intense exercise.

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Hi, I’ve gotten my Rapamycin via Dr. Green. No mouth sores, but unfortunately have gotten 2 skin infections in 8 months. Both have required antibiotics (had to go to urgent care since Z-pak didn’t seem too effective). Have been taking 6mg/week, but have decided to switch to 6mg every 2 weeks to give opportunity for drug to completely clear from system. My logic around this point a as follows:

  1. Would rather space the doses and keep the max higher rather than lowering the weekly dose.
  2. If we think of Rapamycin as a fasting mimetic (I realize that isn’t entirely true), it makes sense to cycle between fasting (low MTOR, low immunity) and higher MTOR and higher immunity. Much of the benefit of fasting comes from the refeeding phase where MTOR rises and immune system and other cells are regenerated post the apoptosis/autophagy of the fasting state.
  3. I noticed in my infections that bubbles of clear liquid formed on my skin. No pus, which means no dead neutrophils. This means neutrophils were inactive and and probably NK cells as well. Basically my innate immune system was out of commission. This might be Ok temporarily but is not something that should be a “normal” situation. NK cell activity is important for cancer prevention.
  4. I also take metformin (not for diabetes), curcumin, and a bunch of other supplements daily. These should also be lowering MTOR, if only indirectly. Hence, the 6mg/weekly may have been lowering my MTOR too much.

Would appreciate any feedback or thoughts.

I hsve not had the opportunity yet to discuss with Dr. Green, though I read somewhere that he’s now taking a larger dose bi-weekly, and Dr. Blagosklonny is presumably taking 20mg bi-weekly (which seems like a huge dose to me).

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Did they culture the skin infection each time and if so, did they tell you what bacteria was responsible? (Usually it’s staph, but just curious if it was MRSA or some other more rare bacteria such as pseudomonas, etc). What antibiotic(s) did you have to take to clear the infections?

Also, as I pointed out on another thread, since you mentioned you take a bunch of other supplements, I wonder if any of these inhibit the liver enzyme cytochrome p450 3A4, which is responsible for metabolizing rapamycin (if so, you’d actually be getting a higher dose than 6mg and raising your risk of immunosuppression and other side effects).

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Hi, welcome to the site, and thanks for posting about this situation. The more we share, the more we can all learn.

You mentioned:

I’m just curious - as part of Dr. Green’s standard recommendations to patients, does he ever recommend “rapamycin vacations” to be sure that any mTORC2 inhibition that may be taking place, goes away?

There are no studies around this issue - so I would understand if he doesn’t, but other doctors (e.g. Dr. Attia) does take the breaks from rapamycin for this reason, and I’m wondering if this might be an example of a reason why the breaks might be a good idea.

Did you take rapamycin for the entire 8 months straight? (even when you had the infection) - of did you stop when you got the infections? How many months did you go between infections?

No - unfortunately no culture was taken. I was prescribed Cephalexim (which presumably is better for skin infections). The infections weren’t major (though I acted quickly). My concern is that I don’t want to be taking antibiotics every few months (not to mention that the associated diarrhea isn’t too much fun). More importantly, I also think that a permanently weakened innate immune system isn’t a good situation to be in.

Will look into the liver enzyme processing issue you mention and check my supplements. That could be a contributing factor if it’s effectively giving me a higher Rapamycin dose.

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BTW - I did take Rapamycin for all 8 months but took a couple of weeks off each time I had an infection to ensure it cleared up. I thought the first infection was a fluke, but when I got a second one it seemed clear it was Rapa related. Particularly as I’ve NEVER gotten a skin infection before.

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I haven’t had a chance to discuss with Dr. Green. I’m scheduling a follow up with him and will discuss then. I did hear about taking breaks from Rapa in one of Peter Attila’s podcasts. I think it makes sense logically for the reasons I mentioned in my original post. My 2 infections came in the last 3 months (so the first 5 months I had no noticeable side effects, though my triglycerides did shoot up around the 3rd month, but we’re back to normal by the 5th month).

However as you state, we really don’t have clinical trials that would give us an answer on this issue. As Matt Kaeberlein has pointed out, we desperately need human trials with Rapamycin as an anti-aging medication.

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I just wonder if you actually had skin infections to begin with, and if the rashes would have healed/resolved without the cephalexin. The lack of pus likely indicated that these were microvesicles rather than pustules, which would suggest either a contact dermatitis (allergic or irritant) or another eczema-type rash and not a bacterial infection at all. If it’s recurred in the exact same place, had clear small blisters and was painful, it may have even been herpes (HSV-1 OR 2) which also spontaneously resolves. Primary care providers aren’t very good with rashes and often misdiagnose tthem, which I can’t blame them because they have to deal with such a wide variety of problems. If/when this happens again, I’d insist they take a culture (very easy to do) to find out if indeed this is a skin infection (impetigo) vs something completely different.

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Interesting question. I get rash (small quarter-sized rash) on my wrist (under my Fitbit band) since I’ve gone up to the 8mg/10 mg a week dosing. This hasn’t been a big issue for me - I just used cortisol cream and it mostly heals - until my next dose.

I never had these before I got on the higher doses of rapamycin.

And - to add - it looks like it would classify as contact dermatitis:

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Good points. I don’t believe it’s herpes since I’ve never had it, nor have I ever had this type of rash/infection before. The infections weren’t terribly painful either. Getting a culture done is definitely a good idea. Will request one of it happens again.

I’ll look into using cortisol cream if it happens again. I only used a antibiotic ointment, but that didn’t seem to do much.

Funny - I tried an antibiotic cream too, and when that failed I went to cortisol cream and it worked.

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Great point, I had similar skin situations with aaa21usa
I am in late 20s, immune system is fine, but also developed big pimple without pus after taking rapamycin
I thought it was an infection, but it didn’t resolve well after 1 week oral antibiotic treatment
I agree your suspect that it may be a dermatitis or rash

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Am in my 4th week of 4mg Sirolimus. (will eventually ramp up to 6mg). On the very first day (within 6 hours of taking) I had a canker sore appear in my mouth. I never get them, so I’m sure it was the med. I treated it by dabbing with Listerine on a q-tip several times a day. It went away before the week was out and I have had no further occurrence.

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I just recently started rapa. Wanted to titrate slowly so started with 2mg first week. Next day got canker sores, which I never get. They started to fade on their own but still present enough that I took 3mg the following week instead of the planned 4mg. That brought on a new burst of canker sores.

Is there an accepted method for dealing with rapamycin-triggered canker sores?

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I’ve not seen any people commenting on any special protocol to deal with canker sores. Mine just went away over a few days. And I never had any problems again. I started at 1mg, and slowly increased each week by 1mg. I might have paused the increases for a week when I got my canker sore.

Anyone else have any strategies that worked with canker sores?

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I use Kanka – it instantly numbs the sore and creates a protective film that helps prevent it from further irritation. Note I haven’t had any aphthous ulcers since starting rapa 3.5 months ago, I just get them occasionally after eating chocolate.

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https://www.walmart.com/ip/Kanka-Maximum-Strength-Mouth-Pain-Liquid-0-33-Oz/10319968

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I’m still getting a canker sore about every other week, and I started rapa 3 months ago, slowly ramping up, now at 3mg with grapefruit juice weekly. If the sore is still there, I delay the next dose until it is gone. I’ll try Kanka.

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