#1210

I have been able to eliminate my itchy hives by alternating between 4 mg + GFJ + EVOO and 3 mg + GFJ + EVOO every other week. I guess this is as high as I can go without any side effects.

3 Likes
#1211

Me too. That is the exact dose that I have come to use. Otherwise I donā€™t get any symptoms, but my numbers go stinky bad and (even though itā€™s unproven that this is a bad thing) I get nervous about it and decide to reduce my dose rather than use MORE PHARMA.

3 Likes
#1212

I decided to try 6 mg + GFJ + EVOO today after taking a break last week. I am having a gut-wrenching stomachache. I think my body is telling me to stay at 5 mg + GFJ and below. I donā€™t think I want to go through this pain again. :stuck_out_tongue:

7 Likes
#1213

I am now wondering if it wouldnā€™t be more effective to aim for much smaller but more constant concentrations of rapamycin over time for purposes of controlling increasing mTOR activity associated with ageing while limiting off-target effects. I had to drop down to 2 mg/month to avoid dose limiting effects, for me aphthous ulcers and carbuncles, and had been tolerating that dose without problems. I attribute those side effects to mild immune disruption. I am now on 1 mg every two weeks and I am avoiding what are for me dose limiting effects. I wish I could experiment with 100 - 200 mcg/day.

Daily pterostilbene may be an alternative but the issue is lack of human studies on dose for adequate mTOR suppression.

1 Like
#1214

Have you tried 0.5mg to experiment with?

1 Like
#1215

I would consider it but being somewhat conservative, I prefer to use Pfizerā€™s rapamycin due to its well studied pharmacokinetics. Itā€™s only available in 1 mg doses from my supplier. I just saw they do make a 0.5 mg dose as well as an oral solution. The oral solution would work.

2 Likes
#1216

Pfizer produced 0.5 Rapamune pills (as well as 1 mg and 2 mg), however it discontinued production and sale in the U.S. on Dec 31, 2024 (patent expires and generic sirolimus is available). Are you sure you receive brand- name Rapamune by Pfizer from your supplier?

1 Like
#1217

Yes, it is sourced from Pfizer / Turkey. Thanks for your concern as there is a lot of contraband out there!

#1218

Below is a link to the LAM foundation letter regarding discontinued Rapamune in the U.S.

2 Likes
#1219

Just an observation that may not be of any importance. Since revising my rapamycin schedule from 4 to 5 mg every two weeks taken with grapefruit juice to 6 mg once weekly without grapefruit, Iā€™ve noticed a definite rise in side effects:

  • Post-dose fatigue: marked grogginess and a flare-up of my baseline chronic pain the day after dosing.
  • Oral ulcers: previously rare, now frequent (sometimes two at once). A stubborn sore beneath my tongue is currently making eating difficult.

Because this change reduced my expected systemic exposure, I hadnā€™t anticipated new or worsening symptoms. Any thoughts or experiences?

#1220

I was getting rapamune from Greenstone pharmacy when I started rapamycin in 2020. Then got switched to zydus.

I liked rapamune best!

2 Likes
#1221

Iā€™m not sure why we get mouth ulcers. Usually only inflammation cause that.

#1222

The higher the dose the more side effects. I can tell the difference between the doses. When my dose goes too high, I get hives. The more I take, the more hives I get.

2 Likes
#1223

AIUI the ulcers arise from a reduction in WBC.

2 Likes
#1224

I thought I would ask chatGPT and I copy the answer below. However, I know from my personal experimentation that the Neutrophil count drops really rapidly as a result of mTOR inhibition because they have a short half life. So that part of chatGPT that says WBC goes down slowly is not accurate.

Short answer

There is little direct evidence that rapamycin-associated mouth ulcers (mTOR-inhibitorā€“associated stomatitis, mIAS) are caused by the fall in white-blood-cell (WBC) count. Both events can appear in the same patient, but the bulk of clinical, pharmacokinetic and laboratory work points to a local, cytokine-driven epithelial toxicity that is largely independent of systemic myelosuppression.

What the data actually show

Evidence stream Key findings What it says about WBC ā†“ as cause of ulcers
Large oncology trials (e.g. BOLERO-2, solid-tumour meta-analysis) Stomatitis in 59-70 % of everolimus-treated patients; 80 % of first episodes occur within 8 weeks, often before any grade ā‰„ 2 cytopenia appears. allianceforclinicaltrialsinoncology.orgAnnals of Oncology Timing argues against leukopenia as trigger.
Population PK study (n = 67 cancer pts) Severity of stomatitis tracks drug exposure (AUC, Ctrough); haematologic values not predictive. PubMed Exposureā€“response, not WBCā€“response.
Prospective LAM cohort on sirolimus (n = 50) 89 % developed stomatitis. Low baseline haemoglobin and evolving micro-cytosis predicted ulcers; WBC counts had no association. PubMed Again, no link.
Regulatory safety datasets & expanded-access programmes Stomatitis and leukopenia listed as separate adverse events; they often co-occur but are not graded together. FDA Access DataPMC Co-incidence ā‰  causation.
Mechanistic/ in-vitro work Organotypic oral-mucosa models and biopsy studies show mTOR inhibition ā†’ keratinocyte cell-cycle arrest, ā†‘TNF-Ī± / IL-2, and aphthous-like ulceration; no role for neutrophil depletion. JAMA NetworkJomos

How to read these findings

  1. Temporal dissociation
    2.Ulcers usually appear in the first 1ā€“3 weeks*, long before significant leukopenia is measurable.
  2. Dose- or exposure-response, not cell-count-response
    The best-demonstrated predictor of ulcers is higher rapamycin (or everolimus/sirolimus) exposure; adjusting the dose or using mouth-rinse prophylaxis lowers ulcer rates even though blood counts are unchanged.
  3. Pathobiology is local and inflammatory
  • mIAS lesions are small, shallow, and histologically resemble recurrent aphthous ulcers rather than classic mucositis.
  • mTOR blockade slows keratinocyte turnover; local trauma + increased TNF-Ī± & IL-2 create an exaggerated aphthoid response.
  • Corticosteroid or dexamethasone mouthwashes prevent/short-circuit the lesions without affecting systemic immunity.
  1. Leukopenia still mattersā€”but mostly for healing & infection
    Severe neutropenia can prolong ulcer healing or allow secondary infection, so monitoring counts is still prudent; itā€™s just not the initiating event.

Bottom line for clinicians & patients

  • Expect ulcers even when the CBC is normal.
  • Manage exposure (lower peak/trough rapamycin levels if ulcers are dose-limiting).
  • Start prophylactic topical steroids in high-risk settings (strong evidence in SWISH and other trials).
  • Reserve WBC support (e.g., G-CSF) for true cytopenia; it will not, by itself, stop the ulcers.

In sum, current research does not support a causal WBC-driven mechanism; mouth ulcers arise from direct mucosal effects of mTOR inhibition and local inflammatory mediators, with leukopenia playing at most a secondary, complicating role.

#1225

Iā€™ve never experienced hives, at least as far as Iā€™m aware, sounds nasty! This painful mouth ulcer under my tongue just wonā€™t go away. Normally, when I get ulcers, theyā€™re not painful, but this one has been quite difficult, possibly because itā€™s in an aggravating location. Iā€™ve started rinsing with salt water and Iā€™m using a lidocaine gel sparingly to manage. Hopefully it heals soon.

Iā€™ve noticed an increase in mouth ulcers since switching to a weekly dose regimen. For me, it might be more about the frequency. Iā€™m planning to try three weeks of 1mg per day next to see how that affects things. Will report back.

1 Like
#1226

What can we do to mitigate it?

#1227

I donā€™t think you can mitigate the reduction in WBC. That is part of inhibiting mTOR. I think the reason I donā€™t get those side effects although I take higher doses (intermittently) is primarily other things I am doing to strengthen my immune system and secondarily that I drop my rapamycin levels really low before the next dose not just for a day, but for some weeks (at the moment).

1 Like
#1228

Aphthous ulcers are a likely a sign of immune dysregulation, according to the literature on the subject, which is why I titrated my rapa dose to a level where they do not manifest.

2 Likes
#1229

It doesnā€™t happen to me all the time but at times it is annoying. My only remedy is to use mouth wash during those time. But then again I donā€™t like using Listerine too often. Because we have different beneficial bacteria in the mouth too.

1 Like