It seems there are many potential contributing factors when it comes to apthous ulcers…
From chatgpt
Aphthous ulcers (also called canker sores) are small, painful lesions that occur inside the mouth. Their exact cause is not fully understood, but several causal and contributing factors have been identified:
Certain food additives (e.g., sodium lauryl sulfate in toothpaste)
Allergens like chocolate, coffee, nuts, strawberries, or gluten
6. Infections
Viral infections (though aphthous ulcers are not caused by herpes)
Secondary bacterial infection may worsen the lesion
7. Genetic Predisposition
Family history increases risk
8. Systemic Diseases
Celiac disease
Crohn’s disease
Ulcerative colitis
HIV/AIDS
9. Medications
NSAIDs
Beta-blockers
Chemotherapy drugs
If aphthous ulcers are frequent, persistent, or unusually severe, it may indicate an underlying systemic issue that should be evaluated by a healthcare provider.
[Immune dysregulation linked to several triggers may facilitate the development of RAS. The roles of the immune system and inflammatory processes have been confirmed in recent large-scale bioinformatics analyses (14,15). It is known that a Th1-type hyperimmune response favors the appearance of inflammatory reactions that precede ulcerations (Fig. 1) (16,17). In addition, genetic risk factors can determine individual susceptibility to RAS; in particular, several DNA polymorphisms of the NOD-like receptor 3(18), toll-like receptor 4(19), interleukin (IL)-6(20), E-selectin (21), IL-1β and TNF-α genes (22). However, despite the large number of factors examined, the underlying cause triggering the episodes of ulcers remains to be elucidated. Therefore, clinically, the emergence of new lesions cannot be avoided at present.](Essentials of recurrent aphthous stomatitis - PMC)
For treatment, while quite messy and somewhat distasteful but not too unbearable, I applied a topical steroid clobetasol propionate 0.05%, and after an hour or so, some good old clove oil which stings at first but last a few hours.
It may be that rapa at particular doses in particularly sensitive individuals (raising hand) may induce a hyperimmune response, much as seen in older folks having better responses to flu vaccination post rapa dosing. I reckon I’m conservative and don’t really want a hyperimmune response (if that is what causes the ulcers) if I don’t need it, plus it hurts, a lot!
I forgot to add that I also avoid toothpastes that contain sodium lauryl sulfate, which is also used to solubilize cells and “straighten out proteins for electrophoresis” i.e. disrupt secondary protein structure, and is known to be a risk factor for development of aphthous ulcers in some people.
Absolutely that seems likely for some people. I’ve only had one in the past 5 years, and at one of the lower doses that I’ve taken during that period, so I really can’t say I understand it. Others, like Peter Attia, have commented that if his young son head-butted him accidentally, the stress might cause Peter to get an apthous ulcer.
For practical purposes, I have decided to follow my NLR as a dosing guide, all things being equal. NLR can easily be calculated from a simple Hematology panel.
Neutrophils: White blood cells that fight infection and are elevated in acute inflammation or stress.
Lymphocytes: Immune cells involved in adaptive immunity, often decreased in chronic stress or inflammation.
NLR is a marker of systemic inflammation, stress, and immune balance, used in contexts like cardiovascular disease, cancer prognosis, and autoimmune disorders.
Target: An NLR of 1–2 is optimal, indicating minimal inflammation and good immune balance.
Actionable Thresholds:
If your NLR is >3, it might suggest underlying inflammation and pathology.
If your NLR is <1, it’s less likely but could indicate immunosuppression, which might be relevant if you have other signs (e.g., frequent infections).
After struggling with a very painful, non-healing tongue lesion (I had pushed my rapamycin upper limit), I got a helpful tip from a family member who suggested I try Colgate Peroxyl. It worked.
I’ve gotten ulcers again since then and needed to use it. Each time, one swish of this pleasant tasting peroxide product and the ulcer immediately stopped hurting and began to heal.
Took my first dose of 3mg and I noticed some worsening of psoriasis. Skin splitting in a painful way on my hands, it’s actually really annoying. I’ll lower the dose next time. I might skip the next dose as well if it doesn’t heal by then.
Yes. The old timers started with 1 mg a week for a month, then 2 mg in the 2nd month, then 3 mg in the 3rd month, etc… up to their terminal dose.
I, like you, started with 3 mg, but used GFJ. So 1 mg + GFJ every week for a month, then 2 mg + GFJ, etc. Now I’m at 4 mg + GFJ every week each month. More than that gave me too many side effects.
What side effects did you get?
Are you just consuming GFJ as you take the rapamycin or do you consume it elsewhere throughout the week?
I will say on the first few days after taking it I felt quite energetic. I can see this being beneficial if I get these side effects under control. I’m using a steroid cream I have for psoriasis to control this, I typically don’t use these as they’re not a long term solution.
I know of a case had a strong adverse reaction to taking a single large dose of rapamycin and ended up in the hospital. That same person apparently was fine after lower doses. While such reactions are unlikely, it is just generally safer to have slower absorption of drugs instead of a very high sharp peak.
Yes, longer lasting presence of rapamycin will turn out mTORC2, but longer lasting in that context is days or weeks of exposure. I don’t think that whether you absorb it fast over 3 hours or more slowly over 6 hours makes significant difference in this respect. The important thing is to space the doses far enough apart that you are on average spending a good portion of the days of the week with little to no levels in the blood.
Assuming mTORC2 is suppressed at any rapa level, and therefore you must reach zero in order to not suppress C2. And more globally it is assuming that we have proven that suppression of C2 is deleterious long term (um, what about animal data). And assuming that suppression of C2 is an “on-off” switch, rather than “suppressed by percentage x”, and furthermore we assume must be deleterious at any level of suppression.
When dosing rapa we necessarily make a lot of assumptions and guesses based on various levels of evidence. Who knows how right or wrong we are, at today’s knowledge level. Still, it’s good to keep track of where exactly we are making assumptions, instead of treating things as proven facts. YMMV.
That’s why it’s important to take blood tests. You can get a at least some idea of whether you’re inhibiting mTORC2 enough to cause harm by testing your glucose, insulin and blood lipids before and after taking rapamycin for a while.
I think I found the post about this unusual case. Apparently the person took 10 mg of rapamycin and experienced a strange reaction. Here is a copy of the post:
“A bad thing happened.
Yesterday I was in emergency with my husband while they ran test after test to find out why he had crippled up overnight with sever muscle and joint pain and stiffness. Yesterday was Tuesday. Sunday we had both taken ten mg. Rapa before a planned two week washout period. This was far more than we had taken previously when we were doing weekly intervals. My husband is 69 and healthy and has had never experienced this before and of course I was worried sick that it had something to do with the higher dose Rapamycin we took on Sunday. I also wondered about the remote possibility that it was a rare condition that can happen with Metformin called Lactic Acidosis, rare, but not impossible and his symptoms matched.
After hours of testing their diagnosis was “Polymyalgia”. It is thought to be hereditary and his mother did experience fibromyalgia when she was alive. This condition happens out of the blue and according to things I’ve since read, lasts about two years. They really don’t know what causes it. It is controlled with “Prednisone” which is a strong steroid. I’m sick about it. This is a rheumatoid inflammatory condition where your immune system is over-reacting. My question is “Why on earth did this happen, when Rapamycin is an immune suppressant”? It doesn’t make any sense to me. I thought it worth posting this for discussion, as sharing our experiences benefits everyon”
I’m not saying this is something to be concerned about. I’m just pointing out that in the very rare case that someone has some weird reaction to rapamycin, where it triggers something bad, a higher peak could result in a stronger reaction or a higher chances of it ending badly. Note that I don’t know if that person ramped up the dose slowly over weeks and was ok at lower doses.
Thanks. I am not so sure that this would be triggered directly by Rapamycin. I am myself interested in tracking edema. This clearly is at times triggered by Rapamycin. Because I take high infrequent doses so far without negative consequences apart from sleep disruption, but as I normally get drunk when I take rapamycin I don’t notice the same sleep disruption.
I asked chatGPT about Rapamycin and Polymyalgia. I think it said, maybe but probably not
Q: does rapamycin trigger polymyalgia give reasons for and against
The bottom line
There is no convincing evidence that rapamycin (sirolimus) regularly precipitates true polymyalgia rheumatica (PMR). A handful of signals suggest it could provoke PMR-like pain in rare cases, but several mechanistic and clinical observations actually argue against it being a typical trigger. Here is the current state of the evidence, pro and con.
“For” – why rapamycin might provoke a PMR-like syndrome
Thread of evidence
What we know
How it could imitate/trigger PMR
Paradoxical inflammatory syndrome
Transplant recipients given sirolimus sometimes develop a cytokine-driven “sirolimus-induced inflammatory syndrome” with fevers, arthralgia and myalgia. (PubMed Central)
In a patient >50 y the sudden shoulder/hip girdle ache, raised CRP/ESR and morning stiffness could be mis-labelled as PMR.
Musculoskeletal adverse-event profile
Package inserts and pharmacovigilance lists include arthralgia, myalgia and joint stiffness among common side-effects. (Mayo Clinic, RxList, Drugs.com)
If diffuse, symmetrical and steroid-responsive, these symptoms again resemble PMR.
Although not PMR per se, it shows the drug can, at least rarely, ignite inflammatory joint disease.
Pharmacology that can push IL-6 up (context-dependent)
In some experimental systems rapamycin increases IL-6 output from immune or glial cells. (Nature)
IL-6 is the cytokine that drives PMR; a surge might tip a predisposed host into disease.
“Against” – why rapamycin is unlikely to be a routine PMR trigger
Counter-argument
Supporting data/logic
Robust anti-inflammatory profile overall
Low-dose sirolimus reduces disease activity in rheumatoid arthritis and systemic lupus trials. (PubMed, Frontiers)
Direct mTOR inhibition should damp IL-6 in macrophages
Rapamycin suppressed IL-6 release in LPS-activated macrophages via autophagy induction. (Oncotarget)
No pharmacovigilance signal for PMR
Despite > 20 years of use in transplantation, PMR is absent from FDA label safety sections and large FAERS summaries; only generic “muscle/joint pain” is listed. (Drugs.com)
Age & indication confounding
Most rapamycin users in longevity self-experiment or transplantation are > 50 y—the same demographic that naturally develops PMR. Temporal coincidence does not prove causation.
Some see rapamycin as a treatment candidate for PMR
Patient forums and small academic groups are exploring it as a steroid-sparing option, not reporting disease induction. (Mayo Clinic Connect)
Putting the pieces together
True PMR versus PMR-mimic
Rapamycin certainly causes musculoskeletal pain and stiffness in a minority of users; laboratory inflammatory markers are usually normal in those cases, unlike genuine PMR.
The rare inflammatory-syndrome cases can show high CRP/ESR, but they are typically multisystem and short-lived.
Biological plausibility
PMR pathogenesis hinges on IL-6, GM-CSF and JAK/STAT signalling. Rapamycin can push those pathways up or down depending on dose, cell type and metabolic state, so a susceptible host effect is biologically plausible—but not predictable.
Weight of evidence
For now, the balance of published data favours rapamycin being neutral-to-protective against classic PMR rather than a consistent trigger.
Whenever PMR-like symptoms appear soon after starting rapamycin, clinicians should first look for the broader “sirolimus inflammatory syndrome”, drug-induced myopathy, statin interaction, or simply coincident idiopathic PMR.
Practical take-aways
Scenario
Suggested clinical approach
New shoulder/hip girdle pain, normal CRP/ESR
Think drug myalgia → consider dose reduction/temporary stop, CK check.
Pain plus high CRP/ESR, fever, mucositis, cytopenias
Suspect sirolimus inflammatory syndrome → discontinue drug, short prednisone taper.
