21 replies to this topic

[NeuroGeneration]

I posted this as a comment on another thread, but figure it probably deserves to be a topic of its own. Does anyone have any insight into, 1- the potential for genotoxicity (based on the below cited studies), and 2- if it fulfills the purported life-extension properties of metformin (i.e., the same mechanisms). For some reason, the Examine.com post on Berberine doesn't cover the studies below.

 

Regarding 1, here are studies that I came across from someone's Reddit post:

 

Mechanism study of goldenseal-associated DNA damage http://www.ncbi.nlm....pubmed/23747414[1]

"As measured by the Comet assay and the expression of γ-H2A.X, berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells."

Berberine induces double-strand DNA breaks in Rev3 deficient cellshttp://www.ncbi.nlm....pubmed/24584584[2]

"Following berberine treatment, cell cycle analysis identified that G2/M arrest was increased in Rev3-/- cells. Furthermore, compared with wild-type cells (WT), berberine also induced a significant increase in double-strand breaks (DSBs) in Rev3-/- cells, as revealed by chromosomal aberration (CA) analysis."

Genotoxicity of the isoquinoline alkaloid berberine in prokaryotic and eukaryotic organismshttp://www.ncbi.nlm..../pubmed/7681536[3]

"Among the different repair-deficient mutants examined, a mutant blocked in the DNA strand-break repair pathway (rad52-1) was found to be the most sensitive to the cytotoxic effect of berberine."

Berberine induces apoptosis and DNA damage in MG‑63 human osteosarcoma cellshttp://www.ncbi.nlm....pubmed/25050485[4]

"Furthermore, berberine induced significant concentration- and time-dependent increases in DNA damage compared with that in the negative control [in the MG-63 cells]"

*Toxicology and carcinogenesis studies of goldenseal root powder (Hydrastis Canadensis) in F344/N rats and B6C3F1 mice (feed studies). * http://www.ncbi.nlm....pubmed/21372858[5]

 

Regarding 2, this article ( http://www.inquisitr...n-to-120-years/) mentions that "Researchers believe that metformin works by boosting availability of oxygen to body cells. This boosts the vigor of cells and prolongs their lifespan." Does Berberine do the same? Or is Metformin actually much better for life extension than Berberine?

[maxwatt]

Look at the concentration in the studies.  Dollars to donuts, they were in vitro and  far higher than anything you can get in your serum from oral administration.

[NeuroGeneration]

Thanks, maxwatt – good point. Do you know about my second question – that is, whether berberine could potentially offer similar life extension qualities as Metformin. Keeping insulin & blood sugar low is obviously helpful, but the article mentions how metformin boosts the availability of oxygen to cells. I know very little about this; does berberine do the same?

[maxwatt]

I've read that berberine works by a different mechanism than metformin.  Also, it is more effective when combined with baicalin as long as ther ratio is less than 1:1 baocalin to berberine.

Pubmed search should turn up the relevant papers. 

 

[Darryl]

Insofar as they are both AMPK activators, they both function by interfering with respiratory complex I.

 

Hawley SA et al. 2010. Use of cells expressing γ subunit variants to identify diverse mechanisms of AMPK activation. Cell metabolism, 11(6), 554-565.

We found that most compounds tested inhibit mitochondrial ATP production and thus activate AMPK indirectly by altering cellular AMP:ATP ratios. This included the classical mitochondrial inhibitors oligomycin and DNP; the guanidine derivatives metformin, phenformin, and galegine; the thiazolidinedione troglitazone; the barbiturate phenobarbital; and the phytochemicals resveratrol, quercetin, and berberine. These agents caused phosphorylation and activation of AMPK only in WT and not in RG cells, inhibited cellular oxygen uptake, and (apart from metformin) significantly increased ADP:ATP ratios. Except for phenobarbital and galegine, most of these agents have already been reported to inhibit the function of isolated mitochondria. Thus, metformin, phenformin, thiazolidinediones, and berberine inhibit respiratory chain complex I.

 

Yes, berberine intercalates DNA and interferes with the topoisomerases. However, this doesn't cause significant toxicity or mutagenicity at therapeutic doses.

 

I like berberine because metabolites with similar efficacy appear to circulate systemically, unlike metformin, where the effects are mostly in the liver and gut microbiome.

 

More on berberine through 2013, here. I should probably scan for more recent well-cited results, but I have had an alert for anything with berberine in the title.

 

 

[NeuroGeneration]

Wow, thank you for sharing, @Darryl! I'm going to dig into some of these studies you have saved to your google drive when I have the chance.

 

Would you be able to summarize the overall risks (if any, at therapeutic doses), benefits and potential benefits? Also, are you taking it? What's your dosing regimen?

 

Thanks again!

[Logic]

You may be interested in looking into Pterostilbene:

 

A Review of Pterostilbene Antioxidant Activity and Disease Modification
...Zhang and colleagues have demonstrated that pterostilbene treatment induces autophagy in oxLDL-stimulated VECs through activation of AMP-activated protein kinase (AMPK), intracellular calcium (Ca2+), and mammalian target of rapamycin (mTOR) signaling...

...The authors concluded that the effects of pterostilbene were comparable to the experimental effects of 500 mg/kg oral metformin...

...Pterostilbene was also shown to exhibit comparable and synergistic effects when compared to medications used in the treatment of human disease, specifically clofibrate, metformin, Tamoxifen, and the chemotherapy regimen FOLFOX...

http://www.hindawi.c...cl/2013/575482/

A summary by yours truly:  
http://www.pterostilbene.com/

[NeuroGeneration]

Interesting. Thanks @Logic. I'm actually taking 1/2 dose of BASIS by Elysium daily, which provides 25mg of pterostilbene + 125mg of Nicotinamide Riboside.

 

With that said, would a small dose of metformin or berberine still offer additional benefits?

[NeuroGeneration]

As a followup, I'm also very much into fitness and weight lifting. I've read about the study done in Copenhagen where they found that resveratrol blunted the beneficial effects of exercise for healthy 60 year old men. I assume that pterostilbene would do the same? Berberine?

 

Are these worthwhile to take in the AM, if I work out in the PM? I'm looking for optimal health and maximal gym performance. I know I can't necessarily have both at 100%, but perhaps 90/90 is feasible if I supplement intelligently. Any thoughts on this (resveratrol, ptersotilbene, berberine, metformin, in relation to exercise, longevity, timing & dosage).

 

Thanks!

[Logic]

As a followup, I'm also very much into fitness and weight lifting. I've read about the study done in Copenhagen where they found that resveratrol blunted the beneficial effects of exercise for healthy 60 year old men. I assume that pterostilbene would do the same? Berberine?

 

Are these worthwhile to take in the AM, if I work out in the PM? I'm looking for optimal health and maximal gym performance. I know I can't necessarily have both at 100%, but perhaps 90/90 is feasible if I supplement intelligently. Any thoughts on this (resveratrol, ptersotilbene, berberine, metformin, in relation to exercise, longevity, timing & dosage).

 

Thanks!

 

I remembered a NASA study that said more or less the opposite and had a quick look.
It seems that 'The Devil's in the dosage',  as usual, but you will have to research this further yourself.

Do let me know what dosage does what when you find the info Neuro.

 

http://www.fasebj.or...4c-ae5bf3150298

http://news.discover...vity-110711.htm

http://newstonight.c...r-muscles-study

[Hebbeh]

As a followup, I'm also very much into fitness and weight lifting. I've read about the study done in Copenhagen where they found that resveratrol blunted the beneficial effects of exercise for healthy 60 year old men. I assume that pterostilbene would do the same? Berberine?

 

Are these worthwhile to take in the AM, if I work out in the PM? I'm looking for optimal health and maximal gym performance. I know I can't necessarily have both at 100%, but perhaps 90/90 is feasible if I supplement intelligently. Any thoughts on this (resveratrol, ptersotilbene, berberine, metformin, in relation to exercise, longevity, timing & dosage).

 

Thanks!

 

http://www.longecity...trol-excercise/

[Sith]

What concentration of Metformin would be optimal for longevity for a non-diabetic? I feel this is a grey area. 

[mait]

Interesting new article just got published: prolonged metformin treatment seems to lower neurotrophic factor levels and Nrf2 in brains of old mice. Either its harmful effect of metformin itself OR organism’s adaptive response in situation where age relating damage accumulation is being slowed down, thus metabolically costly antioxidant defences (Nrf2) and neurotrophic factors (BDNF, NGF, NTF3) can be down-regulated. The last speculative line of reasoning seems to have support in paper’s finding that memory performance wasn’t impaired concurrently to lowering of neurotrophic factors and Nrf2.

 

Here is the article: http://www.sciencedi...166432815303260

 

Here is the abstract:

Highlights

A mouse model was used to determine the effect of high fat diet and metformin treatment on cognition, brain neurotrophic factor expression and Nrf2 expression.

Transcripts of three major neurotrophic factors were decreased in brains of metformin treated mice.

Brain protein and mRNA levels of the antioxidant regulatory factor Nrf2 were decreased by metformin treatment.

Long-term high dose metformin use may create disadvantageous biochemical conditions in the brain.

 

Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin’s effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control ©, high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.

 

 

Edited by mait, 29 December 2015 - 03:39 PM.

[DbCooper]

 

Interesting new article just got published: prolonged metformin treatment seems to lower neurotrophic factor levels and Nrf2 in brains of old mice. Either its harmful effect of metformin itself OR organism’s adaptive response in situation where age relating damage accumulation is being slowed down, thus metabolically costly antioxidant defences (Nrf2) and neurotrophic factors (BDNF, NGF, NTF3) can be down-regulated. The last speculative line of reasoning seems to have support in paper’s finding that memory performance wasn’t impaired concurrently to lowering of neurotrophic factors and Nrf2.

 

Here is the article: http://www.sciencedi...166432815303260

 

Here is the abstract:

Highlights

A mouse model was used to determine the effect of high fat diet and metformin treatment on cognition, brain neurotrophic factor expression and Nrf2 expression.

Transcripts of three major neurotrophic factors were decreased in brains of metformin treated mice.

Brain protein and mRNA levels of the antioxidant regulatory factor Nrf2 were decreased by metformin treatment.

Long-term high dose metformin use may create disadvantageous biochemical conditions in the brain.

 

Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin’s effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control ©, high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.

 

 

 

Regardless of NRF2 the Metformin was protective. They performed better and lost body fat even on a high fat diet while being given massive doses, am I missing something here?

 

Does anybody have a study showing Metformin using HUMANS are developing neurological disorders faster and more often than a control population in spite of being in poorer general health due to diabetes?

 

 

Edited by DbCooper, 31 December 2015 - 03:35 PM.

[stefan_001]

What I find peculiar is that Metformin is decreasing telomerase activity similar as Berberine. While that may be good for cancer I could imagine that with long term use this may lead to shorter Telomeres. Any opinions on that?

[docmaas]

First, why are there no Multiquote or quote buttons on the initial post but there are on every subsequent reply?

 

Second, I followed down the first reference on berberine:  

 

"Regarding 1, here are studies that I came across from someone's Reddit post:

Mechanism study of goldenseal-associated DNA damage http://www.ncbi.nlm....pubmed/23747414[1]

"As measured by the Comet assay and the expression of γ-H2A.X, berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells.""

 

They were doing in vitro on hep cells with micromolar concentrations; not very useful for assessing the dose.  However they referred to an earlier paper where goldenseal extract was given to mice and rats and the percentage of goldenseal that was active berberine was given.  The results are not encouraging.

 

The original paper cited above located here:  https://www.research...ated_DNA_damage says on page 69:

For such reasons, a number of herbal dietary supplements have been assessed by the NTP for toxicity and tumorigenicity (Fu et al., 2008; Guo et al., 2008, 2009, 2010). Goldenseal root powder was one of the herbal dietary supplements selected for assessment, and the primary finding of the NTP’s study was that chronic exposure to goldenseal causes an increase in liver tumors in rodents (Dunnick et al., 2011; NTP, 2009). 

 

Fortunately the Dunnick et al paper is available in its entirety here:  http://tpx.sagepub.c...t/39/2/398.full

 

There are two charts of interest:  The first shows the dosages in both mice and rats and the second the necropsy results for the differing groups:

Dosages: http://tpx.sagepub.c...98/T2.large.jpg

Necropsies:  http://tpx.sagepub.c...98/T3.large.jpg

 

My bottle of berberine says 500mg of berberbine hcl before each carb containing meal.  I usually take two a day.  I weigh 60kg so that works out to 16.6 mg/kg.  That's pretty close to some of the mouse doses and greater than that of some of the rats.  Add to that the fact that they have higher metabolic/consumption rates and the 500mg-1500mg recommended dose for humans begins to look a little high.  I find it troubling that we are not even seeing a single order of magnitude difference.  Admittedly, the stats for the controls in the mice look a little strange with only 50% survival and also the difference between control, 3000ppm, and 9000ppm for the rats is pretty minimal and pretty small just increasing the berberine to the sketchily recommended up to 1500 mg could bring one into the questionable area.  

 

There is one more chart of interest:   http://tpx.sagepub.c...98/F3.large.jpg

This is a graphical representation of what the researchers perceive to be the difference between mouse and human dosage.  I don't see what their assumptions were but I'm pretty sure they don't agree with the directions on the bottles of berberine currently being sold.  

 

I think I will cut back to 500mg/day.

 

Please correct me if you see flaws in my understanding.

 

 

[Nate-2004]

Because I have ET, I am about to begin low dose berberine (200mg twice a day) based on the results in this study, which show positive results at 20mg/kg in rats which HED is around 180mg for my weight. I shall report back on results in 60 days.

 

It could be that the negative effects linked earlier in this thread are the result of too high of a dose. I would suggest that unless there's a bioavailability issue, most substances tend to do better at lower doses.

Edited by Nate-2004, 28 August 2017 - 07:22 PM.

[Nate-2004]

Reporting back, no effect on tremor thus far. I am now using the Tremor Test iPhone app to measure effects of various substances. My average reading throughout the day is around 120 milli-Gs peaking at 240 after a workout. The moment I drink any alcohol it drops down to 30 milli-Gs in amplitude. Anything 10 and under is considered normal and undetectable for everyone. Propanolol also seems to bring it down to 30 milli-Gs briefly before settling around 70 until the drug is sufficiently metabolized.

 

200 to 300 mg Berberine literally has no effect that I can tell thus far. Not sure if it takes time or if I am dosing high enough. I may consider dosing 500mg to 1000mg towards the end of my experiment but from the study it appears that could make it worse, not better.

 

Another review states that glutamine inhibition would only have a modest effect on tremor.

 

My belief is that ET is largely norepinephrine related, not GABA related. All my experience through experimentation, reading, dozens of neurologists including consultation with top experts in movement disorders at both Johns Hopkins and University of Maryland, leads me to conclude that it's definitely something to do with norepinephrine. 

[Gayle63]

What other supplements are you trying for your ET? Have you tried NR? I have no idea if it would be helpful, but it may be worth a try?

[Darryl]

Nate, have you tried a low harman(e) diet? Its endogenous to muscle products (and elevated by high temperature cooking), highest in broiled beef, chicken and pork.

 

Totsuka et al, 1999. Quantification of the co-mutagenic β-carbolines, norharman and harman, in cigarette smoke condensates and cooked foods. Cancer letters, 143(2), pp.139-143.

Louis et al, 2007. Blood harmane is correlated with cerebellar metabolism in essential tremor A pilot study. Neurology, 69(6), pp.515-520.

Louis et al, 2007. Quantification of the neurotoxic β-carboline harmane in barbecued/grilled meat samples and correlation with level of doneness. Journal of Toxicology and Environmental Health, Part A, 70(12), pp.1014-1019.

Louis et al, 2008. Cancer and blood concentrations of the comutagen harmane in essential tremor. Movement Disorders, 23(12), pp.1747-1751.

Louis et al, 2008. Dietary epidemiology of essential tremor: meat consumption and meat cooking practices. Neuroepidemiology, 30(3), pp.161-166.

Louis et al, 2010. β-Carboline alkaloids and essential tremor: exploring the environmental determinants of one of the most prevalent neurological diseases. The Scientific World Journal, 10, pp.1783-1794.

Louis et al, 2011. Blood harmane, blood lead, and severity of hand tremor: Evidence of additive effects. Neurotoxicology, 32(2), pp.227-232.

Louis et al, 2012. Blood harmane concentrations in essential tremor: repeat observation in cases and controls in New York. Journal of Toxicology and Environmental Health, Part A, 75(12), pp.673-683.

Laviță et al, 2016. The role of β-carboline alkaloids in the pathogenesis of essential tremor. The Cerebellum, 15(3), pp.276-284.

[Nate-2004]

ET is not harmane induced as there are too many drugs that work for harmane induced tremor that do not work for ET.  I tried this a long time ago. There was one study linking a possible connection between harmane and ET and there has since been zero follow up research except to comment on that first sentence.

 

I assume whatever possible follow up there was, was never published due to negative results. Who knows?

 

Gayle I've been taking NR for 18 months, no such luck. I am now following the fission/fusion protocol and seeing the first ever positive results especially compared to anything else I've ever done including alcohol and propranolol. See the manipulating mitochondrial dynamics thread for details.

[maxwatt]

How similar is ET to muscle cramping?  Rhetorical question; cramping is a continuing and painful contraction of muscle, tremor is pulsed contractions.  Both are involuntary.  Would the remedy for one help with the other?

 

For muscle cramping quinine is the gold star remedy, as for restless leg syndrome.  I have found it prevents leg cramps that used to trouble me terribly after long, hard bicycle rides.  The FDA has taken quinine pills off the market due to rare side effects in a minority of people, much to the distress of sufferers of restless leg cramps.  But the herbal remedy on which it is based can be purchased online: Chichona bark.  The cut-up pieces and powder are brought to a boil  in water, then turned down to simmer for five minutes.  The resulting tea is as effective.  

 

Would it work for ET?  I've no idea.  If you want to try it, it's even on Amazon.

 

 

Why quinine pills were banned:

 

 

Stop using quinine and call your doctor at once if you have any of these serious side effects:

• fever, chills, confusion, weakness, sweating;
• severe vomiting, stomach pain, diarrhea;
• problems with vision or hearing;
• chest pain, trouble breathing, severe dizziness, fainting, fast or pounding heartbeats;