Can any meaningful conclusions of efficacy/harm ever be drawn form individual experience/"self experimentation"?

Hi. This post might irritate, but I mean well. It's prompted by a useful article I read this morning...about the nocebo effect with statin's. https://www.nejm.org/doi/full/10.1056/NEJMc2031173

I reflected on other examples of therapy that "everyone" knew were effective... say arthroscopic debridement in patients with degenerative knee disease. In fact hundreds of millions of dollars spent yearly... until this...https://pubmed.ncbi.nlm.nih.gov/12110735/

Note the use of sham surgery...a requirement for surgical RCT's.

In my case I elected to have  a thymectomy for my MG, based on a solid, randomized, but not sham-surgery-controlled trial... believe me, a thymectomy is one hell of a placebo...but I remain hopeful that the observed effects (a massive decrease in steroid dose and a huge decrease in time spent on a ventilator in the ICU...were not just because of the impact of belief on immune response.

I am one who takes Rapamycin (in my case to treat autoimmune disease, not to "live longer"). I made the decision to start because of both experimental MG data (in mice) and the magnitude of other mechanistic data as well as limited case-series and small trials in other autoimmune disease. I hope it's a good call... but I do not know its a good call!

I'm doing well... but have no idea whatsoever whether my current status is as a result of the Rapamycin...or in spite of it. This is because I as an individual, I have only taken one path... the one that includes Rapamycin.

I know many on this site believe they can tell whether a given medicine has helped (this includes physicians who prescribe medications to others), and whether their side-effects are due to the medication, whether perceived benefits result from the intervention.

I believe this is a false assumption. The history of medicine should demonstrate to anyone who pays attention, that both open label trials as well as case-control studies cannot effectively determine efficacy. If you disagree, please present your evidence.

I once conducted an n of 1 trial in family practice. A kid was labelled as having ADHD and put on Ritalin by a pediatric neurologist. Nearly everyone was happy... the doc, the school (in particular), and one of the parents. The dad, recalling his happy but active youth... was not. I was open...

With some effort, we elected to do a trial. I got a local pharmacist to make up active and placebo medications. The parents and all teachers agreed to complete daily ADHD scores using a validated tool (so long ago I cannot remember specifics). We cycled (in random order determined by the pharmacist) between active drug and placebo. After repeated cycles (either 7 or 9), the trial was stopped (partly because the school was agitating because of perceptions of problematic behaviour during what they were sure was the placebo weeks). The results were analyzed..and eventually the code was broken.

There was zero impact of the Ritalin and the boys behaviour. Now Ritalin is a perfect drug for this sort of trial, because its effects occur rapidly and diminish equally rapidly. This is not the case with Rapamycin). Of note, even when evidence of lack of efficacy was presented to the school, they refused to accept it...because they knew the Ritalin worked. They went so far to say that the child would not be allowed back... unless he was drugged. So much for the scientific medicine.

So, my rhetorical question is: are the interventions you are engaged in, helping you, hurting you, or neutral? How do you know? Is it based on belief...or knowledge? Could you be making the same attribution errors that have occurred thousands of times in the history of medicine?

As I said earlier, I hope the Rapamycin is helping me... but I do not know this...

Looking forward to a useful discussion...

Steve

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  • BTW... another sham controlled RCT but this time for meniscus tear... https://www.nejm.org/doi/full/10.1056/NEJMoa1305189

    I can provide hundreds of examples...where the observed benefits held by both doc's and patients..were due to the placebo effect.

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    • Steve Roedde Extrapolation's from laboratory animal studies are what is guiding rapamycin use and many of those studies are pure scientific method. I'm interestingly awaiting results from the dog aging project regarding rapamycin real world effects rather than laboratory animals. 

      It is an interesting conundrum regarding the n of 1 issue. Epigenetics is one possible avenue to measure result through the n of 1 study. Much like blood glucose can be a measure of the effect of diabetic treatment. The Horvath measure seems the most relvant and for $299 you can have biologic age measured via epigentics. This can be measured perhaps every 5 or every 10 years to see if interventions are slowing biological aging. I would be dumfounded if placebo effect is relevant for measures of DNA methylation sites.

      I have had this done and it seems like my two year exposure with rapamycin has had a fairly significant impact on biological age measured with this method. I plan to test again in 5 more years. 

      There is also some value to clinical observations regarding effects of treatment. There seems to be some consistant effects in humans on rapamycin (dosing makes a difference) in regards to mood, anxiety, motivation. When enough people express the same effects it can be assumed a drug affect. It is not possible to simply observe longer life but I think the epigenetics can also be used as a treatment measure.

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    • Mark Thimineur Thanks for your prompt and thoughtful reply. I concur about the reasons many of us have embarked on a path that includes rapamycin and the role of well conducted animal studies in this process.  In my case, I looked at the totality of evidence...but as with it's indications in aging, the human data is sparse, largely case-series and case studies. Still, we must make decisions in the face of uncertainty and make the best call we can. In the case of MG, the alternative proposed therapies had even less in the way of quality evidence.

      I also concur that methylation clocks of some type may be a useful surrogate end-point. I don't know enough about the evidence-base for these markers but wonder whether they been validated prospectively to see if they work as well moving forward in time as in a derivation set?

      The N of 1 study design requires multiple cycles of active intervention and placebo to generate the statistical power that one gets in a large n RCT. Failing this, one is left with uncertainty about whether any observed changes are merely chance phenomena. Because of both the long half life of rapamycin and the potential for fairly long lasting effects...  with long washout periods, a very long trial would be required

      It's well known that the placebo effect is modulated by both behavioral conditioning and autonomic tone. In my case, it is quite conceivable that any improvement in my condition is in fact a result of a placebo effect on my immune function. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049477

      "There is also some value to clinical observations regarding effects of treatment. There seems to be some consistent effects in humans on rapamycin (dosing makes a difference) in regards to mood, anxiety, motivation. When enough people express the same effects it can be assumed a drug affect."

      I agree that it is of "some use" (particularly in terms of hypothesis generation) but strongly disagree about the assumption of a drug effect. Note that both the orthopedic surgeons and their surgical patients  prior to the in the studies I posted being conducted.... all observed positive effects... but the observed positive effects were due to the placebo effect of surgery.

      For a really useful discussion as to why and how we can be suckered, this is a really useful plain language analysis of an asthma study. https://medium.com/beingwell/placebos-can-fool-your-mind-but-not-your-body-75c8a66790f7

      I look forward to more positive and helpful discussion on this topic.

      Again, Thank you.

      Steve

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    • Mark Thimineur  we previously corresponded about my 145lb, 30 yr old daughter with Lyme disease and you also diagnosed her problem as Autoimmune polyglandular syndrome which fits her condition and symptoms exactly. 

      she started on rapamycin 1 mg and was not able to go to tolerate it which I discussed with you.
       

      However through experimentation we discovered that if she did not take it with her supplements especially vitamin C she could handle it with only a little gas.

      so she has been taking 4 mg once a week (per your suggestion) for 3 months and we haven’t noticed any effects on her and I’m thinking of increasing her dosage. I have read that even Dr. Green is now suggesting 10 mg once a week. Any recommendations  as to increasing her dosage as I value your opinion and comments?

      i’m also curious how your new protocol it’s turning out?

      thank you.

      John

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  • Mark, I agree this is the crux of the challenge...quantifying (hard scientific data) anti-aging benefit of our interventions? Forget all the mice studies and theories...what's the actual biological impact on HUMANS? We know from a plethora of studies that superior cardio respiratory fitness is a proven life extender in humans. As pharmacological interventions have become more mainstream, how do we prove efficacy whilst the large scale human RCT studies are missing (and very likely may never get done)?

    Can you share your rapamycin regiment and did you do a Horvath epigenetic before and after intervention re your "fairly significant impact on biological age comment"? And did you undertake other epigenetic interventions in the interim that may have also contributed to the reduction, and possibly confounding the sole rapamycin effect?

    I have implemented a range of interventions over the last 4 years, and a first (recent) Horvath test came back 52 yrs vs 55 actual. I plan to another in another in say 5 yrs. I am also tracking blood biomarkers, CCAC, volumetric brain MRI, neuropsychological testing to try and "scientifically" track my progression. I am trying to put aside any placebo effect, and rely solely on the data.

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    • MAC  Thank you as well for your thoughts and useful comments. Are you certain that a placebo cannot impact the supposedly "objective" measures you are following? How do you know? The review in medium states that a placebo can't fool your body... but in the case of immune response... it certainly can.

      I concur about the difficulty in distinguishing the confounding impacts of many interventions... metformin, D+Q, Omega 3's, NMN, resveratrol and many others.

      Again, in my case, it turns out that many anti-aging interventions also have positive effects on modulating a hyper-responsive immune system. I too take many of these things. There is so much noise... I couldn't detect a signal even if it existed...

      Again, Thank you.

      Steve

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  • I am not certain of anything...sigh. But as an engineer, I have to instinctively go on the data. Am I stronger, fitter, low inflammation, no chronic disease or ailments, stellar biomarkers, clean arteries, large and unshrinking hippocampus, good memory, etc. But...I do not discount the overall  "health and well being" effect being actually holistically and biologically mechanistic by some  unmeasurable pathways. I can tell you 100% I feel a lot better about myself re health and my aging outlook than I did 4 years ago simply due to actually having mental fortitude to start and MAINTAIN the lifestyle changes. This mental sentiment may be very powerful indeed.

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    • MAC , The older I get... the less I know... and the more stuff I knew was true... turns out to be false. It sounds like the entire process has been both helpful and useful for you! As with my initial query... its about whether observed changes are due to what we believe are causal factors. It's really, really, hard to find out on an individual basis. RCT's are the best we have... but there too, problems with inclusion criteria and other factors still leave uncertainty...

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  • We may NEVER know what is singularly or in combination causal. But one can either be purist process or transactionally end result driven. On the latter, why not embark on implementing everything one thinks is beneficial, knowing full well the interventions not singularly trackable for cause, yet monitor and MEASURE an actual positive biological outcome? I really couldn't care less which of the myriad of interventions, individually or synergistically, makes me live healthier and longer...as long as I do. Yes, I am science and process driven to select the levers, but ultimately, all I care about is outcome. 

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  • Mac. Would that extend to a positive outcome if all due to a placebo effect? It is also possible that some interventions are helpful...and others detrimental but there is a net benefit... it really is a problem for which I do not have a solution. I won't either, until RCT's are conducted for each intervention...and they will be done.

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      • MAC
      • MAC
      • 3 mths ago
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      Steve Roedde Absolutely. Like I said, all I care about is positive trending for biologically "positive" markers that I can/choose to measure, and net outcome. I won't try to wrap my head about what "exactly" is causative. When I have a chance to talk to some long lived, they have no idea why they are still kicking around. I'd like to have that same sentiment. 

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    • MAC Just adding some more fodder. Rapamycin has well established effects on mood such as having both anti-depressive and anxiolytic effects. 10.1097/FBP.0000000000000334 . I took notice of these effects early on in my own experience without even being aware of its effects on the concentration of biogenic amines in the midbrain. When patients have noted changes in mood, motivation, and addictions, I have assumed this to be drug effects because it actually is. However nice this is, subjective perceptions become unreliable in the presence of the effects on mood.

      As far as epigenetics - before starting any intervention I measured 9 years younger than chronological which reflects tremendous longevity and health in my family - my genetics. After two years of rapamycin, metformin, lithium, and aspirin, I measure 14 years less than chronological. I can only surmise it is probably the interventions. If your wondering about the lithium - dose is 9mg elemental which is derived from 60mg lithium carbonate.

      As mentioned previously, we have the dog aging project to watch carefully. The dogs do not have placebo effect and the various health measures and longevity benefits (if any) will be a from drug effect. Personal experience with my own pet and others indicates changes in canine behavior that suggests they are feeling better. Maybe it's just their mood.

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      • MAC
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      Mark Thimineur So your lower epigenetic age is most all "genetics" your surmise? You already measured 9 years younger prior to interventions. "Tremendous longevity" is quite a strong familial signal. The long lived in Sardinia supposedly are all connected to FIVE origin families! I've read a great many papers on all things longevity, and genetics is likely the strongest determinant. The reported long lived "blue zones", it's most all genetics (these zones are mainly isolated islands, very little genetic mixing, enriched for longevity: Okinawa, Sardinia, Crete).

      Do you know your APOE status? APOE2 is highly enriched in long lived vs APOE4.

      Which dna clock did you use?

      Do you track any other biological measurements that you deem meaningful to longevity?

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    • MAC Six out of 15 family members from great grandparents through aunts/uncles lived past 100 yrs. Ancestry from Naples and central France. Strangely, Mom's side has very tall thin people ranging as tall as 7 ft while Dads side is short and thin. Mom and Dad going strong late 80's without a single age related disease except spinal stenosis at a single segment. It does not surprise that epigenetic age was 16% less than chronological before intervention. It now measures 24% after intervention. 

      I have used the Horvath epigenetic clock through "Epimorphy" (www.myDNAge.com) which is kind of a gold standard in this field.

      I have no information on my APOE status. 

      I have yearly standard bloodwork performed but I don't track any biological measurements relevant to longevity.

      Personal rapa dosing is somewhat different than others have described.

      Plan to strictly enroll about 20-25 people into a similar protocol as my personal one and track with Horvath clock. 

      Awaiting data on the "dogs"

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      • MAC
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      Mark Thimineur 6/15 over 100! Looks like you won the genetic lottery, and thus your epigenetic data is not surprising. And it doesn’t seem at all you are waiting for anything...you are full on intervention. Have you published already in this forum your rapa protocol? 

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      • MAC
      • MAC
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      Mark Thimineur Mark, on longevity and APOE:

      APOE2 is associated with longevity independent of Alzheimer’s disease  

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588231/pdf/elife-62199.pdf

      Oct 19, 2020 published. The cohort are NACC subjects (National Alzheimer Coordinating Center), so I assume his is a cross section of Americans.

      In some cohorts, such as southern mediterranean men, however, APOE4 is highly represented in long lived. So there are nuances in the cohort genetics, but as a general rule, APOE2 is highly enriched for longevity.

      Would be extremely curious to know your APOE status.

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  • This is precisely why I would like someone that has been applying topical rapa for some time, to post before and after photos.

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  • Yes, I always discount stories about someone feeling better, claiming better mental acuity or improved mood.

     

    my personal testing regime

    life extension comprehension male panel every 6 months

    epigenetic testing annually 

    a daily measure of:

    BP

    HRV

    pulse Ox

    RHR

    sleep (total, deep, REM)

    reaction time

    grip strength

    glucose

    temp

    FEV

    PEF

     

    About 90% of these markers have improved in the last 12 months, the others neutral ( hard to improve BP of 104/64 or RHR of 48)

    so I don’t think this is all placebo 

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  • Paul, how long have you kept this up, wasn’t so long ago I gave u that spreadsheet, what about the blood tests?

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    • Ross Barker year and a half

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