Here is Christin’s case for this risk: Parkinson's disease - #23 by RapAdmin
3 Likes
The thing about the metformin health studies is that they have serious flaws in terms of selection bias.
As far as I am concerned I am not taking metformin because I see no good reason to do so. Initially I was looking at metformin, but I decided to take Berberine because metformin is a prescription drug in the UK. Having studied the issue in much more detail Berberine has so many stronger arguments for it and has a longer tradition of use notwithstanding that both are from natural sources originally. To me natural sources is not a particularly strong argument, however, the fact that people have taken something for hundreds of years is.
3 Likes
I read Christin’s article on metformin and Parkinsons. And also did a quick Google search of metformin and Parkinson’s disease. At a glance, I agree with you that there is nothing concrete in a variety of studies.
I am very cautious though about using such a strong toxic mitochondrial inhibitor like metformin. And particularly in combination with other inhibitors like glucosamine. In combination with certain supplements, negative outcomes would be likely.
I have used metformin only a few times orbiting my 10 days dose of rapamycin. I am dropping it out of caution. It might be safe at lower dosage but I think Berberine a good substitute to blunt a sugar response. I also use a number of other “blunters” like inositol, beta sitosterol
4 Likes
Berberine is also toxic to the mitochondria, it’s a poor man’s metformin. I would look at other drugs that also have a benefit in the ITP, like Canifaglozin, there is a large thread on this, but I don’t know much about it.
Pharma drugs have much more evidence of safety than supplements.
3 Likes
There’s toxic and then there’s toxic. A shallow opinion on my part, but Berberine to a lesser degree.
You’ve never heard about it before because it isn’t true 
. I disagree with most of Dr. Glorioso’s criticisms of the book, but her discussion of Outlive, metformin, and PD is where I don’t just disagree with her viewpoint, but see a clear departure from the facts and the evidence.
First, there are no “clinical trials pointing to a potential increase in risk of Parkinson’s disease in metformin users.” If there were, it would have been yanked off the market or at least black-boxed years ago: it certainly wouldn’t be the first-line T2D drug in every country on earth. I expect she is misremembering or misunderstanding observational studies such as these, some but not all of which find that metformin use by diabetics is associated with greater risk of PD.
In the Twitter thread reposted by @RapAdmin, she makes an argument from Complex I inhibition, but repeatedly ignores the facts (noted by user HairyBiologist and by geroscientist Jamie Justice) that these studies report Complex I inhibition in the liver, not the brain, and that it is a much weaker inhibitor than rotenone even there. And regardless, that’s a mechanism, not an outcome.
She brings this up in the context of claiming that Attia “has backpedalled on promoting Metformin for longevity in his blog but basically promotes it in this book”. Attia has been saying he doesn’t think metformin is a longevity therapeutic consistently on the blog and in the podcast since at least 2018, and I don’t remember him promoting it in the book. The only entry for metformin in the index is on page 87, which can’t reasonably be said to be ‘promoting’ metformin as a geroprotectant.
Then she says:
- Centenarians and smoking: this is not exactly a point of disagreement but there is a link between longevity and smoking in super centenarians and I don’t think this is an accident. People die increasingly from neurodegenerative diseases in the oldest ages and smoking is linked to less Parkinson’s disease. That’s not to say that we all should smoke- definitely not- smoking causes lung cancer and heart disease. But in people above a certain age- say 80 years old- we should consider creating nicotine pathway drugs or prescribing nicotine patches- my two cents. I think this has been wildly understudied.
Now, I’m glad she backed away from suggesting that peope should smoke to prevent PD, but this is still all based on false premises and failure to account for absolute risk. First, there is no “link between longevity and smoking in super centenarians”: I’m guessing that she’s jumped to conclusions from the singular case of Jeanne Calment. In Nir Barzilai’s centenarians, 59.6% of centenarians had smoked at least 100 cigarettes during their lives, compared to 74.5% of their contemporaries in NHANES I. In Thomas Perls’ New England Centenarian Study, 11% of centenarians reported having smoked more than 2 pack-years during their entire lives, which is substantially less than the general population today, let alone in the mid-20th century when they lived their lives.
She may be thinking of a report on the Okinawan supercentenarians: ""Approximately half (42%) of the supercentenarians had a history of smoking; however, of those participants who did smoke, most began later in life and tended to smoke < 20 cigarettes per day and/or quit by their 70s (data not shown). " Compare this to the general Japanese population:
In the late 1960s, 74% of men and 13% of women reported that they were current smokers, and 13% of men and 2% of women reported that they were former smokers (table 2). In later survey periods, the percentages of current smokers decreased in both sexes and the percentages of former smokers increased. Among current and formers smokers, 25% of men (5842 individuals) and 5% of women (357 individuals) reported that they had started smoking before the age of 20." Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study - PMC
Beyond that, her whole hypothesis here is inconsistent with the absolute risks involved. Smoking greatly reduces life expectancy by increasing the risk of lung, colorectal, kidney, bladder, and other cancers, as well as CVD and COPD. Yes, there is some epidemiological evidence that smoking reduces the risk of PD, and Parkinson’s disease is a terrible disease, but it is relatively rare and even less commonly kills its victims. Even amongst people aged 85+, only 3% of people have PD — and of course, not everyone with PD dies from PD. The idea that people have a better chance of living to 110 by reducing the risk of a rare disease like PD while greatly increasing the risk of the top two killers and several others of the top 10 is a clear case of an “extraordinary claim requiring extraordinary evidence.”
5 Likes
Please cite references to berberine
I heard it from Peter Attia, but I haven’t done more research than that since he typically is often right about things. I didn’t like berberine and it is a dirty drug so I don’t bother looking for pro/cons.
1 Like
Are you taking Acarbose for sugar control? I just started a 25 mg dose.
1 Like
Ok so no reliable evidence. Traditional medicines have been taken for many years. Some such as ashwagandha have a record of bad side effects. Others dont. French lilac (metformin) has its functions. The evidence does not substantiate its use by non diabetics. My HbA1c is below 5, lowest 4.18% (probably after a real bender).
2 Likes
On reading @RapamycinCurious well written post, something about his mention of rotenone triggered a thought/memory so I thought I’d add it.
There is a belief that Parkinson’s may be caused by exposure to environmental toxins, if that is true….
Epidemiological studies link exposure to environmental toxicants – like rotenone, paraquat and trichloroethylene – to increased risk of PD , even though the exposures may have occurred decades before the emergence of symptoms
….then metformin should have a protective effect on dopaminergic neurons.
Metformin has a protective effect on DA neurons against rotenone-induced neurotoxicity through inhibiting neuroinflammation and ER stress in PD mouse model.
Protective effect of metformin against rotenone-induced parkinsonism in mice - PubMed.
5 Likes
A lot of it is metabolic. I say this in a pub in the UK having drunk 4 pints of Old Peculiar (that’s me) and on my third 100ml of port. If my CRP is unmeasurably low i must have got the biochemistry right. Hic!
I am neutral on Berberine supplementation.
After reading several articles, it appears berberine at clinically useful doses has a wide safety margin. I can find no articles concerning what the maximum safe dose is.
Most studies that I have read have used dosages between 900-1500 mg per day, split into 3 doses. “The optimal dose of BBR was 1 g/day for TG, TC, and weight, 1.8 g/day for insulin and HOMA-IR, and 5 g/day for HDL”
The cytotoxicity is dose-dependent.
I have been taking Berberine on and off for decades with no apparent ill effects.
Now that I am older, I don’t want to take any supplement that might be damaging.
I was taking berberine as a supplement because I quit taking metformin. I did a self-experiment with metformin. After cutting metformin for a few days my whole gut and digestive system felt better. I tried metformin on and off a few times and found indeed metformin was affecting my digestive system.
Oddly enough my doctor prescribed metformin based only on one blood test that showed a higher than normal reading.
After quitting both metformin and berberine my fasting and HEMOGLOBIN A1c levels are normal. Probably because I am on a low-carbohydrate diet.
That said, I believe in metformin both as glucose-lowering and life extension benefits.
If you can tolerate metformin I would take it over Berberine.
Berberine attenuates mitochondrial dysfunction by inducing
autophagic flux in myocardial hypoxia/reoxygenation injury
https://sci-hub.se/10.1007/s12192-020-01081-5
Biological properties and clinical applications of berberine
https://sci-hub.se/10.1007/s11684-019-0724-6
3 Likes
FYI, it is widely studied. It’s just that it failed:
- “One-year transdermal nicotine treatment did not slow progression in early Parkinson’s disease.” Transdermal Nicotine Treatment and Progression of Early Parkinson’s Disease 2023
- “PD smokers tended to have fewer deaths from neurologic causes but were significantly more likely to die from smoking-related cancers such as lung cancer. We presented a nonsignificant association between smoking and mortality of PD, and cigarette smoking is not recommended in individuals with PD.” Association between smoking and all-cause mortality in Parkinson’s disease 2023
(but yes, for sure, smoking is protective against Parkinson’s, like diabetes by the way)
2 Likes
I’m curious about using Metformin or berberine for short bursts to improve akkermansia. There seems to be reasonable evidence for both, and it would seem to be easier than sourcing probiotics.
Have you ever had a gut microbiome test?
1 Like
But sometimes that doesn’t make them any less “dirty”. In case of metformin vs. berberine that are both “dirty” drugs and just cause one is pharmaceutical does not make it less “dirty”. And poor man’s is just for entertainment purposes I suppose, as metformin is one of the cheapest drugs probably. I picked up a pack of 100 x 500mg pills for a little over 2 EUR, but do not take it for the same reason as I don’t take berberine, they are both “dirty” and mitochondrial toxins plus metformin seems to blunt exercise benefits which berberine does not.
2 Likes
Of course. I was comparing Cana with Berberine, but I don’t know how clean it is.
That trial is the latest amongst many small trials of similar design, almost all of which have failed. To be fair to Dr. Glorioso, an important caveat is that all of these trials were for treatment of people with existing PD, whereas the epidemiology suggests that smoking may reduce the risk of developing PD. This would require an extremely long trial in many subjects (since PD is not common and there aren’t really any high-risk groups if you leave aside people with genetic cases and maybe some agricultural workers), and based on the trials, you’d likely get a high dropout rate due to side-effects.
Yes, I’d ask her to provide scientific studies instead of speculative hearsay. We need to go hard on the science here and from what I’ve seen, Ms. Glorioso’s evidence is observational at best and hearsay at worst. If someone can provide some scientific studies, I’d be interested.
It could be that diabetics overcome their diabetes with Metformin, live longer but then develop PD because of the diabetes. That’d make more sense to me.
I would posit there’s a simple reason why smokers don’t develop PD. It’s not the nicotine preventing PD. It’s the cancer from smoking killing you before PD can develop.
No, diabetes is protective against PD. If you give a high sugar diet to PD models, their PD symptoms decrease. (But they die earlier of CVD 
) And metformin is only associated with PD at high doses. At low doses metformin is protective (some people are even studying low-dose metformin as a disease-modifying treatment for PD). No one knows why. One assumption is that PD may be caused by toxins (such as pesticides) crossing a leaky gut over time and then reaching the CNS and the brain. And (low dose?) metformin and smoking both reinforce the gut barrier. But that’s just one assumption.
2 Likes