Metformin + berberberine = why not both?

[OuchThatHurts]

It's nice to take a load off your pancreatic beta cells with metformin (MET) but metformin and berberine (BBR) mechanisms of action are very different and do not compete with one another. The combined ancillary benefits (synergy) are well worth a look: reduced blood pressure, improved gut microbiome (probiotic action) and a statin-like effect on lipids without the statin toxicity, weight management, long-term type II prophylactic, improved energy, increased protein uptake, lipid management (particularly triglycerides and LDL), cardiovascular health, too many benefits to name. Combined you are really killing a lot of birds with a couple stones here.

I'm shocked you can get BBR without a prescription for all the benefits it has and MET has been used for centuries.

According to my BG readings, MET and BBR are better together than either alone. No doubt many are in a caloric deficit during this time of year and looking to maintain good energy levels while remaining at low levels of bodyfat and when it's back to full calories, your body will be ready for them. In the gut and at the cellular level. Definitely good additions to your diet in so many ways.

I've had excellent results on 500mg MET and 1600mg BBR daily. (MET x 500mg before bed or first thing morning, and 2 x 800mg nightly doses BBR after evening meals). When not taken around workouts, insulin can still be in play and you'll see you need much less as your insulin sensitivity will likely be higher. And combined with a product like Synthetine (L-carnitine) I feel like there is no limit I can't reach. Must haves for the calorie rich diets of the big eaters out there.

READ: Metformin and berberine, two versatile drugs in treatment of common metabolic diseases

READ: Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study)

Metformin and berberine are 100% proven therapeutically legitimate products and very well tolerated. This pair is backed by science and have been promoted by very knowledgeable board members for many years and are now mainstays in my permanent health and longevity mix. If you worry about lipids, heart health, pancreatic function, athletic performance, these should both be on your shopping list; no two ways about it.

 

[mslmn]

I actually do. Met. after first and last meal. Berb. between 1-3 times before meals.

 

[MR. BMJ]

Stewie explained a few times why it would not be ideal to take them together. I'd have to go back and find those posts though.

EDIT: Here is what he said:

The delivery of a drug is dependent on several different types of enzymes and or transport proteins. In the particulars you're asking, berberine inhibits two specific transport proteins---OCT1 and OCT2 (organic cation transporter 1 and 2). Given that, metformin is dependent on the proper function of these two organic cation transporters.

Berberine will basically cancel out most, if not all of metformins action.

So, no not a good idea.

https://www.professionalmuscle.com/forums/index.php?threads/berberine-with-metformin.143468/#post-2577889

 

[MR. BMJ]

https://www.professionalmuscle.com/forums/index.php?threads/my-fascination-with-injectable-l-carnitine.166391/page-18#post-2911347

Here's a post a made in a TRT Facebook group I frequent every now and again in regard to the aforementioned citation you shared. It repeats several commentaries I made here. I finally took a look at the full literature. It's nothing profound on the AR.

If I was to speculate the use of a fatty acid ester is to enhance the stability of carnitine and facilitate it as an excipient (vehicle) for enhanced cell permeability potentially reenforcing several metabolic processes of carnitine shuttle-> carnitine acyltransferases->further to fatty acyl-CoA-->ß(beta) oxidation->transformation to nitrogen retented shredded beast mode.

Although, we can't discredit the hydrolysis rate (cleavage) of the fatty acid ester, subsequently releasing the carnitine as free carnitine in circulation to target tissue(s) as a hydrophilic molecule then back to an esterified carnitine blazing away shuttling long chain fatty acids in thee inner-membrane of thee almighty mitochondria.

All that jibber sounded cogent, huh?

I'd call the pharmacist, Shaun Noorian at Empower and tease out his thoughts on the purported symphonics of a fatty acid ester vs an aquas solution.

Which ester is it?

On a serious note, it boils down to a steady release rate vs rapid. Nothing more.

But do we really want this type of release as insulin and glucose load (carbohydrates) helps with augmentation uptake of carnitine. See citations below.

Nevertheless, there's a few things I'd pay particular attention to. The fate of supplemental carnitine utilization to be transported requires a specific organic cation transport (OCT). There's a few different isoenzymes of OCT--1/2/3 that act on the influx and efflux (movement in and out of cells), detoxification, blah, blah blah to different anatomical sites throughout our bodies. Outside of this particular organic cation transport there's other carriers of carnitine to our mitochondrial such as ATB(0+) (laymens terms, amino acid transporter). There's more than likely a second messenger(s) systems that comes into play. Although, we should hyperfixate on the aforementioned transporter (OCT) as it's the most studied.

Where's all this going.

There could be some competitive inhibition that some drugs and supplements may blunt the uptake of carnitine in target tissue, not just specifically skeletal muscle tissue.

Metformin is a cation, as well an AMPK activator. As aforementioned, carnitine, like metformin utilizes a specific drug delivery transportation system called -Organic Cation Transporter or OCT. There's different OCT isoenzymes. If you get bored, you can rummage through the interweb to get a feel for which of these isoenzymes are specific to different anatomical sites, the bi-directional pathways, detoxification, so-on and so forth If this interests you. For the berberine crowd, this could muddy the waters for competitive inhibition of carnitine as well due to berberine being a master slayer of inhibiting OCT's.

Nevertheless, there's some very good suggestive literature (in-vitro, unfortunately) that both cation dependent drugs and AMPK activators can either competitively inhibit or inhibit carnitine utilization in muscle and other anatomical sites.

Onward to the overhyped purported enrichment on upregulation of the AR. If you look at the full literature (materials and methods, graphs and charts) the terminology the researchers use denoting "statistical significance" (vs placebo) --"preexercise AR content compared with PL (12.9+/-5.9 vs 11.2+/-4.0 au, respectively)." -Oh boy, that's a whopping 1.7+/-% difference. I feel my manly-hood coming to life. Here's some statistical significance. If I pushed a car uphill 12.67 meters 5 times, on my 6th time if I pushed this same car under the same conditions 12.68 meters, I significantly pushed it further than the previous 5 times. I can now label this as a significant increase ___<- insert "p" value here.

But hey! Any dynamic increase is an increase, right!? Ya fool!

Finally, as for the purposed carcinogenicity and atherosclerotic burden from thee dreaded TMAO. This, amongst a couple of well designed studies say differently.

If TMAO troubles your thoughts. Supposedly allicin (crushed garlic) mitigates this bastardizing of our microbiome. If you're a murine model that is.

Yet, we have the following:

"Plasma Trimethylamine-N-oxide following Cessation of L-carnitine Supplementation in Healthy Aged Women"

(There's been a few replication studies with very similar outcomes)

Nutrients. 2019 Jun; 11(6): 1322.
Published online 2019 Jun 13. doi: 10.3390/nu11061322
PMCID: PMC6627560

Wall BT, Stephens FB, Constantin-Teodosiu D, Marimuthu K, Macdonald IA, and Greenhaff PL. Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans. J Physiol 589: 963-973, 2011.

Stephens FB, Evans CE, Constantin-Teodosiu D, and Greenhaff PL. Carbohydrate ingestion augments L-carnitine retention in humans. Journal of applied physiology (Bethesda, Md : 1985) 102: 1065-1070, 2007

Stephens FB, Constantin-Teodosiu D, Laithwaite D, Simpson EJ, and Greenhaff PL. Insulin stimulates L-carnitine accumulation in human skeletal muscle. Faseb J 20: 377-379, 2006

I prefer ALCAR.

Possibly, Anthony Llabres, Jeffrey Ruterbusch or Gil could shed some light on the use of a fatty acid ester?

 

[OuchThatHurts]

@MR. BMJ , can you describe how this interplay is somehow not extremely beneficial in the areas I cited above? Are you suggesting that these compounds somehow negate acetyl L-carnitine uptake and mitochondrial transport of glucose and/or intracellular oxidation of fatty acids?

Please explain.

Does any of this discuss the half lives of metformin and berberine or the benefits of both when NOT taken concomitantly? How about in vivo studies of these not taken concomitantly? In fact, is there anything at all to show that you cannot experience the health benefits of both of these compounds on healthy male athletes?

And I only touched on L-carnitine and insulin co-administration.

Sure, there may be some overlap where very, very specific particular actions are lessened temporarily, but one or the other is always acting to help maximize and there is no net resultant suppressive or toxic interaction at all. I see zero reason why someone would take an alarmist approach to concomitantly ingesting these. In other cases, quite the contrary.

For example: The enhancement of combination of berberine and metformin in inhibition of DNMT1 gene expression through interplay of SP1 and PDPK1

 

[Mufasa123]

Interested in this as I just started metformin 500mg SR with last meal (zero sides or noticeable impact). This was based off all I read here and my use of hgh - last fasting glucose was fine. Was planning on going to 1000mg. Sitting on a bottle of berberine as well.

 

[TheOtherOne55]

Interested in this. Definitely a @Stewie thread

 

[joos23]

Interested as well

 

[MR. BMJ]

@MR. BMJ , can you describe how this interplay is somehow not extremely beneficial in the areas I cited above? Are you suggesting that these compounds somehow negate acetyl L-carnitine uptake and mitochondrial transport of glucose and/or intracellular oxidation of fatty acids?

Please explain.

Does any of this discuss the half lives of metformin and berberine or the benefits of both when NOT taken concomitantly? How about in vivo studies of these not taken concomitantly? In fact, is there anything at all to show that you cannot experience the health benefits of both of these compounds on healthy male athletes?

And I only touched on L-carnitine and insulin co-administration.

Sure, there may be some overlap where very, very specific particular actions are lessened temporarily, but one or the other is always acting to help maximize and there is no net resultant suppressive or toxic interaction at all. I see zero reason why someone would take an alarmist approach to concomitantly ingesting these. In other cases, quite the contrary.

For example: The enhancement of combination of berberine and metformin in inhibition of DNMT1 gene expression through interplay of SP1 and PDPK1

I would have to look into this myself, I have not done so personally. I was just throwing out possible negative interactions (it looks like via the Organic Cation Transporters) by combining the two together per what Stewie has noted here at the forum....it was not an alarmist approach, just something to think about. I feel Stewie's thoughts on the matter are worth noting. I am not an expert on OCT's, but if berberine inhibits OCT1 (not allowing metformin to enter the liver to exert it's effects) and OCT2 (elimination from the kidneys), then this seems like it would not be an ideal situation in terms of blood sugar control and possible effects tom the kidneys. If one cancels out the other, are you just getting the effects of 1 compound at that point? I don't know the answer to that. However, it seems, by the quick glance on OCT's I have done, that by berberine inhibiting metformin's uptake into the live via OCT1, that it will lead to higher plasma levels of Metformin, which could lead to unwanted side-effects (ie lactic acidosis, etc). I can't imagine inhibiting it's clearance via OCT2 and the kidneys is a good thing either. I am open to hearing otherwise though, because as i noted above, I am not an expert in this area (or any), my area is nutrition and food science.

As for it's (berberine) effects on l-carnitine, all i have is what was noted in Stewie's post above. I am not sure if he wrote more on that, I believe he did, but i'd have to look further (or you can as well). Per his post, there appears to only be suggestive research via in-vitro studies...."Nevertheless, there's some very good suggestive literature (in-vitro, unfortunately) that both cation dependent drugs and AMPK activators can either competitively inhibit or inhibit carnitine utilization in muscle and other anatomical sites." That's all I have to go on, and i'm not a big fan of in-vitro studies. I'm not sure if @homonunculus has mentioned anything in this area pertaining to l-carnitine and berberine?

There are studies showing the drug cimetidine inhibiting metformin's actions via OCT1 and OCT 2, but I have not looked into them. If berberine causes the same drug-drug interaction, then it may be worth noting possible equal effects.

Drug Interactions of Metformin Involving Drug Transporter Proteins

Metformin is a most widely used medication all around the world to treat Type 2 diabetes mellitus. It is also found to be effective against various conditions including, Prediabetes, Gestational diabetes mellitus (GDM), Polycystic Ovarian Syndrome (PCOS), ...

www.ncbi.nlm.nih.gov

Cimetidine-induced lactic acidosis and acute pancreatitis - PubMed

Cimetidine-induced lactic acidosis and acute pancreatitis

pubmed.ncbi.nlm.nih.gov

Reduction of metformin renal tubular secretion by cimetidine in man.

To determine whether cimetidine altered the renal handling of metformin, seven subjects took 0.25 g metformin daily with and without cimetidine 0.4 g twice daily. Blood and urine samples were collected and assayed for metformin, cimetidine and creatinine ...

www.ncbi.nlm.nih.gov

I like both supplements (berberine and metformin), and I use both. I agree, they are both proven to be beneficial, but if taking them together cancels the effect of one over another, as noted again by Stewie's posts, and similar to cimetidine's effects, then i'm going to take them separately at this time...unless there is something proving otherwise.

That said, if you find them both beneficial together, then keep on doing what you are doing, or anybody else that has found this to be the case.

 

[MR. BMJ]

btw...here is two of like 3+ studies I quickly found discussing the inter-actions of taking both supplements together. They are in rats, which I am not a fan of, but it's worth noting and keeping in mind if one is going to go this route (co-administration).

Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine - PubMed

Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only...

pubmed.ncbi.nlm.nih.gov

Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin - PubMed

Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin...

pubmed.ncbi.nlm.nih.gov

 

[luki7788]

personally, I also use 1500mg of berberine during the day and 500-750mg of long-acting berberine at night and it works very well for me - even at 15iu gh my morning sugar remains between 68-82

 

[OuchThatHurts]

personally, I also use 1500mg of berberine during the day and 500-750mg of long-acting berberine at night and it works very well for me - even at 15iu gh my morning sugar remains between 68-82

Have you ever used berberine and metformin at different times of the day? You seem very pro-berberine (I am too).

 

[OuchThatHurts]

btw...here is two of like 3+ studies I quickly found discussing the inter-actions of taking both supplements together. They are in rats, which I am not a fan of, but it's worth noting and keeping in mind if one is going to go this route (co-administration).

Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine - PubMed

Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only...

pubmed.ncbi.nlm.nih.gov

Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin - PubMed

Berberine, the main active component of the herbal medicine Rhizoma Coptidis, has been reported to have hypoglycemic and insulin-sensitizing effects and, therefore, could be combined with metformin therapy. Thus, we assessed the potential drug-drug interactions between berberine and metformin...

pubmed.ncbi.nlm.nih.gov

Just keep in mind that even if there is some inhibition of clearance, the half-life of MET is only 6hrs. So my metformin is well on it's way out when I do my nightime berberine. I've never been a big proponent of doing something on a constant basis. This keeps my MET dose low and by BBR dose low also. I do like the idea of the BBR extended release. That I might have to look into. I like to look at the extended release method. There are many novel approaches to creating an extended release product. Some good. Some not so good.

 

[luki7788]

Have you ever used berberine and metformin at different times of the day? You seem very pro-berberine (I am too).

Yes I am a fan of berberine.

I use 500mg berberine for breakfast (I train after the 2nd meal) then 500mg for meals no. 4 and 5
by the 6th last meal I give metformin

 

[OuchThatHurts]

Yes I am a fan of berberine.

I use 500mg berberine for breakfast (I train after the 2nd meal) then 500mg for meals no. 4 and 5
by the 6th last meal I give metformin

Dobre. Robie bardzo to samo.

 

[Knight9]

I would love to get a firm idea if this is optimal or not. I remember several times in the past where I presumed it would be and after reading thoughts/citations from well-educated members, it seemed that it was definitely not optimal. It would be interesting to re-visit and see if that has changed with new data or if it is still not a good idea.

 

[MR. BMJ]

Just keep in mind that even if there is some inhibition of clearance, the half-life of MET is only 6hrs. So my metformin is well on it's way out when I do my nightime berberine. I've never been a big proponent of doing something on a constant basis. This keeps my MET dose low and by BBR dose low also. I do like the idea of the BBR extended release. That I might have to look into. I like to look at the extended release method. There are many novel approaches to creating an extended release product. Some good. Some not so good.

Yes, I would keep them as far away as possible throughout the day, or one in the am and the other in the pm, etc., if co-administering. In this case, it may be less favorable to use an extended release, if I had to guess, but it depends on the half-life of the ER versions. Dosage would come into play like it always does, if I had to further guess. In the rat study above, they used a IC50 dosage, and i'm not sure how much that would equate in a human dosage amount, of both compounds used together.

 

[luki7788]

Dobre. Robie bardzo to samo.

You can come to Poland, brother

 

[Type-IIx]

I think their use in combination is beneficial (great, even) for glucose management, and these interactions simply affect pharmacokinetics/pharmacodynamics ("Co-administration of berberine increased the initial plasma concentration and AUC of metformin and decreased systemic clearance and volume of distribution of metformin in rats"). Just something to be aware of, not a deterrent to their combined use. You can probably just use this information as a rationale to reduce daily Met dose & expect a more rapid lowering of blood glucose.

 

[jaxino]

I never noticed any better glucose readings by adding berberine to metformin.

My glucose readings improved when i added 25iu Lantus before bed, and now at 850g carbs ed and 10iu hgh my glucose is always around 80-85.

I guess that my pancreas isn't making a lot of insulin on it's own....