Metformin or Berberine - For what conditions?

[Chu]

We can collect data and research about metformin (or its natural form, Berberine) in this thread. I'm starting off by quoting what we already have on another thread in the forum:

Verneuil's disease AKA Hydradenitis Suppurative

I have recently been reading a bit about the drug Metformin, and one thing leading to another, I found these articles which are quite interesting regarding HS, insulin and hormones. So, here are some excerpts, for whoever is interested. What seems cool about metformin is that there are hardly any side effects, for once!

https://www.ncbi.nlm.nih.gov/pubmed/22882365

Metformin for the treatment of hidradenitis suppurativa: a little help along the way.
Verdolini R1, Clayton N, Smith A, Alwash N, Mannello B.
Author information
Abstract
BACKGROUND:

Despite recent insights into its aetiology, hidradenitis suppurativa (HS) remains an intractable and debilitating condition for its sufferers, affecting an estimated 2% of the population. It is characterized by chronic, relapsing abscesses, with accompanying fistula formation within the apocrine glandbearing skin, such as the axillae, ano-genital areas and breasts. Standard treatments remain ineffectual and the disease often runs a chronic relapsing course associated with significant psychosocial trauma for its sufferers.
OBJECTIVE:

To evaluate the clinical efficacy of Metformin in treating cases of HS which have not responded to standard therapies.
METHODS:

Twenty-five patients were treated with Metformin over a period of 24 weeks. Clinical severity of the disease was assessed at time 0, then after 12 weeks and finally after 24 weeks. Results were evaluated using Sartorius and DLQI scores.
RESULTS:

Eighteen patients clinically improved with a significant average reduction in their Sartorius score of 12.7 and number of monthly work days lost reduced from 1.5 to 0.4. Dermatology life quality index (DLQI) also showed a significant improvement in 16 cases, with a drop in DLQI score of 7.6.
CONCLUSION:

Metformin helps control HS with minimal side effects and good patient compliance and can represent a further agent in the spectrum of treatments available in the treatment of this disease.

[...]
In our view Metformin provides a new option for the treatment of HS that may represent a new approach. The mechanism as to how Metformin operates in the treatment of HS is not entirely clear and studies are still needed, but it may be that it works through two pathways. The first is through its anti‐androgenic effect, thus influencing expression of the genes possibly involved in this condition and the second might be through lowering the insulin resistance that is usually present in some patients with HS.

Metformin induced a remission of the disease in the sense that if pustules were still present, they were less numerous, less severe and less debilitating. The disease was also not as painful with improvement to quality of life and the majority of patients continued on the treatment well past the time of the trial. The majority of the patients reported that, although the condition was still present, it was more tolerable, and not as debilitating as before.

Very importantly no significant adverse effects were recorded and blood tests regularly taken during the trial period have remained within the normal range for all patients. Only minor gastrointestinal disturbances at the beginning of treatment were recorded. Even patients who did not enroll in the study because of their difficulties in attending appointments (and who remained inconsistent with their follow‐up attendances) continued using Metformin which was prescribed by their GPs.

https://www.ncbi.nlm.nih.gov/pubmed/28868004

A Disease-Modifying Approach for Advanced Hidradenitis Suppurativa (Regimen with Metformin, Liraglutide, Dapsone, and Finasteride): A Case Report.
Khandalavala BN1.
Author information
Abstract

Hidradenitis suppurativa (HS) is a challenging skin disease with limited therapeutic options. Obesity and metabolic syndrome are being increasingly implicated and associated with younger ages and greater metabolic severity. A 19-year-old female with an 8-year history of progressively debilitating cicatricial HS disease presented with obesity, profound anemia, leukocytosis, increased platelet count, hypoalbuminemia, and elevated liver enzymes. A combination of metformin, liraglutide, levonorgestrel-ethinyl estradiol, dapsone, and finasteride was initiated. Acute antibiotic use for recurrences and flares could be slowly discontinued. Over the course of 3 years on this regimen, the liver enzymes normalized in 1 year, followed in2 years by complete resolution of the majority of the hematological and metabolic abnormalities. The sedimentation rate reduced from over 120 to 34 mm/h. She required 1 surgical intervention for perianal disease after 9 months on the regimen. Flares greatly diminished in intensity and duration, with none in the past 6 months. Right axillary lesions have completely healed with residual disease greatly reduced. Chiefly abdominal lesions are persistent. She was able to complete high school from home, start a job, and resume a normal life. Initial weight loss of 40 pounds was not maintained. The current regimen is being well tolerated and continued.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1468-3083.2012.04668.x

Metformin for the treatment of hidradenitis suppurativa: a little help along the way


R. Verdolini
N. Clayton
A. Smith
N. Alwash
B. Mannello
First published: 11 August 2012
https://doi.org/10.1111/j.1468-3083.2012.04668.x


Background  Despite recent insights into its aetiology, hidradenitis suppurativa (HS) remains an intractable and debilitating condition for its sufferers, affecting an estimated 2% of the population. It is characterized by chronic, relapsing abscesses, with accompanying fistula formation within the apocrine glandbearing skin, such as the axillae, ano‐genital areas and breasts. Standard treatments remain ineffectual and the disease often runs a chronic relapsing course associated with significant psychosocial trauma for its sufferers.

Objective  To evaluate the clinical efficacy of Metformin in treating cases of HS which have not responded to standard therapies.

Methods  Twenty‐five patients were treated with Metformin over a period of 24 weeks. Clinical severity of the disease was assessed at time 0, then after 12 weeks and finally after 24 weeks. Results were evaluated using Sartorius and DLQI scores.

Results  Eighteen patients clinically improved with a significant average reduction in their Sartorius score of 12.7 and number of monthly work days lost reduced from 1.5 to 0.4. Dermatology life quality index (DLQI) also showed a significant improvement in 16 cases, with a drop in DLQI score of 7.6.

Conclusion  Metformin helps control HS with minimal side effects and good patient compliance and can represent a further agent in the spectrum of treatments available in the treatment of this disease.

Very intersting articles - thanks Chu for posting. Metformin has some quite interesting properties, and it has recently genberated quite some interest in other fields than diabetology. See for instance:

Abstract
The generally accepted mechanism of metformin's effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an increase in AMP:ATP ratio in metabolic stress conditions including hypoxia and glucose deprivation. Lately, many novel pathways, besides AMPK induction, have been revealed, which can explain some of metformin's beneficial effects. It may help to identify new targets for treatment of diabetes and metabolic syndrome. Moreover, metformin is now attracting the attention of researchers in fields other than diabetes, as it has been shown to have anti-cancer, immunoregulatory and anti-aging effects. The aim of this review is to describe the potential anti-cancer and anti-aging properties of metformin and discuss the possible underlying mechanisms.

Source: Postepy Hig Med Dosw (Online). 2017 Mar 2;71(0):170-175

I had a look at the last article you quoted as to metformin dosages used:

Metformin was up-titrated from a starting dose of 500 mg once ⁄ day (OD) in the first week, to 500 mg twice ⁄ day (BD) in the second week, with a maximum dose of 500 mg three times ⁄ day (TDS) introduced from the third week onwards.
The maximum Metformin dose that nine patients in the series could tolerate (due to gastrointestinal discomfort or lifestyle compromise) was 500 mg BD. The Metformin dose for another patient with a particularly high BMI was suitably adjusted to 850 mg BD.

Of course anyone trying this drug should do that under the care of a sympathetic medical practitioner, as it can induce low blood sugar - having said that apparently if you are not a diabetic person, this seems to happen infrequently.

Thanks again, Chu!

That is pretty interesting research on metformin and hydradenitis suppurativa.

Some people in longevity circles are using it to sensitize insulin levels, e.g. Dominic D'Agostino and his keto protocol. Others prefer nature's metformin: berberine.

It seems that anything that sensitizes your insulin is pretty good. I received a notification a few months ago on a liraglutide study showing that it reduced cardiovascular disease and had some benefits like metformin. Liraglutide is another insulin sensitizer.

I think it mostly highlights how insulin resistance is so evil. However, there might be other mechanisms of action to metformin that researchers don't know about and/or are studying.

Several studies are underway on metformin and cancer research.

There is some controversy on metformin's effect on cognitive function, but it appears there is not enough data to blame it:

https://joshmitteldorf.scienceblog.com/2015/08/24/report-from-rejuvention-biotech-2015/

I have been an advocate of metformin for everyone, and enthusiastic about Nir Barzilai’s trial of metformin as an anti-aging drug. Last week, I learned from Brian Hanley that metformin has a dark side, to wit, a statistical association with higher frequency of Alzheimer’s disease [ref, ref]. There is a biochemical mechanism that makes the epidemiology more compelling. B12 supplementation may mitigate the risk.

Other studies [ref, ref] have found that diabetes patients have elevated risk of dementia, and that that risk is reduced when they take metformin. So it’s fair to say that there is contradictory evidence, and the direction of the effect may depend on individual variation. Here is a balanced view of both sides.

A reader of this blog, George Goldsmith has written to me that berberine is a good herbal substitute for metformin. Everything we know about berberine looks really good–it is an anti-inflammatory as well as helping preserve insulin sensitivity, acting through the AMPK pathway. But we have much more experience with metformin, both clinically and in the lab. Metformin increases life span in mice, and to my knowledge, this test has yet to be performed with berberine. Magnesium supplements also can help prevent insulin resistance, and there are other good reasons to take magnesium.

Gynostemma pentaphyllum, sold by LEF under the brand name AMPK Activator, is another herbal alternative to metformin.

More info:

What is Metformin? And Why Do Scientists Think It Can Extend Your Lifespan?
https://www.naturalstacks.com/blogs/news/metformin-and-why-scientists-think-it-can-extend-your-lifespan

Very interesting! I've never heard of metformin before...

I did a very brief search on the natural alternative that Gaby mentioned and found an interesting article in Dermatology News that could give a clue as to why it could work for HS.

Mahonia aquifolium, also known as Oregon grape root, belongs to the Berberidaceae or barberry family. This evergreen shrub, native to the American northwest and adjacent areas of Canada, has been used in folk medicine to treat chronic eruptions and various rashes, especially those containing pustules or resulting from consumption of fatty foods (Dermatol. Ther. 2003;16:106–13).

In numerous investigations, Oregon grape root has displayed a wide range of biologic activities, including antioxidant, antimicrobial, and antimutagenic properties. Although this column will focus on the Mahonia aquifolium species, it is worth noting that Mahonia bealei (also of the Berberidaceae family), native to China, exhibits anti-influenza effects in vitro (Zhong Yao Cai. 2003;26:29–30).

Research on the extract of the bark of Mahonia aquifolium has indicated that its primary bioactive characteristic is the inhibition of lipid peroxidation, and that its main constituents are the alkaloids berberine, berbamine, and oxyacanthine (Planta Med. 1994;60:421–4).

Mahonia aquifolium bark extract has been shown to inhibit keratinocyte growth. In one study, berberine was as effective as the mahonia extract at inhibiting cell growth, while berbamine and oxyacanthine, the benzylisoquinoline alkaloid constituents of mahonia, were three times as effective at cell growth suppression (Planta Med. 1995;61:74–5).

Berberine-containing herbs have been used in folk medicine to relieve neonatal jaundice (Comp. Med. East West 1977;5:161–8), as anti-inflammatory agents (for lumbago and rheumatism), and as antinociceptive and antipyretic medications (Life Sci. 2002;72:645–57; J. Ethnopharmacol. 1998;59:211–5). Further, researchers studying the use of berberine as an antiacne medication in Japanese Kampoh (Japanese herbal medicine based on Chinese methods) found that the alkaloid inhibited lipogenesis in hamster sebaceous glands by 63% (Skin Pharmacol. 1993;6:56–60).

Source: https://www.mdedge.com/edermatologynews/article/8816/infectious-diseases/mahonia

From what I can understand so far about HS, "keratinocyte growth" and "lipogenesis in sebaceous glands" are very linked to it, so it makes sense that it would help.

It seems like a promising finding Chu! Thanks for sharing!

Interesting knowledge! We never end learning.
I knew metformin only as anti-diabetic. I ignored there were plants with same properties. Finally, all remedies are in nature! (plants, soils, minerals, sunlight, earthing, some energetic waves, etc)

Yas, you are one of the people I was mostly thinking of while reading all this, given how you are quite sensitive to carbs, and how HS in your case (and many others) also has some relationship with hormones. So, in your case, I would definitely ask my doctor about it, and see if metformin has the same effect as berberine, and in what dosages.

I'll start a new thread where we can collect more data we find. This may be something potentially useful for people with cardiovascular diseases, insulin resistance, skin problems, etc.

Nature, yes indeed! It is said to be for only diabetics, but it would make sense that it is being tested on cancer, if we take the hypothesis that cancer can be of metabolic origin, and that cancer cells feed from sugar.

Another thing that caught my attention was that, if metformin/berberine helps evacuate the sugar from the smallest vessels irrigating the organs, then it could be good for any systemic problem related to glucose/insulin. Not just cancer cells floating around, but also, say, viral infections, systemic candida, psoriasis, arthritis, etc.?

As far as drugs go, and if berberine doesn't happen to be quite as effective (?), I have to say that I wouldn't mind taking metformin. From what I head it's an old-school drug (not being pushed by pharmaceuticals), and has hardly any side effects.

 

[Gaby]

Another thing that caught my attention was that, if metformin/berberine helps evacuate the sugar from the smallest vessels irrigating the organs, then it could be good for any systemic problem related to glucose/insulin. Not just cancer cells floating around, but also, say, viral infections, systemic candida, psoriasis, arthritis, etc.?

I was reviewing recently Dr. Rosedale's research. He is a very respected longevity researcher who highlights the evilness of insulin. He is one of the main advocates for a low carb diet and for eating 0.8g of protein per kilo of ideal weight (to not overstimulate ageing-inducing mTOR pathway) in order to keep insulin levels working.

He says that the massive amounts of insulin within the context of a high carb diet flowing through a patient's bloodstream are akin to shouting instructions so loudly and abrasively that the cells quit listening, resulting in insulin resistance. The diet and insulin sensitizers reestablishes the signal, so that the receptors respond appropriately.

With communication restored between insulin and the rest of the body, many other problems begin to resolve. Electrolyte balance gets restored and blood vessels dilate, resulting in normal blood pressure. Vessel occlusions begin to clear up and nerves begin to heal.

Many diseases are just symptoms with insulin resistance at the root.

Insulin receptor resistance is a prime cause of mitochondrial dysfunction.

If you drip insulin into the femoral artery of a dog, as Dr Cruz of U. of Texas did in the early 70s, the artery will become almost totally occluded with plaque in just over three months.

Insulin resistance is at the root of many corrosive aging processes, including elevated triglycerides, magnesium deficiencies, increased cell division, glycation of proteins, inhibition of autophagy, etc.

As far as drugs go, and if berberine doesn't happen to be quite as effective (?), I have to say that I wouldn't mind taking metformin. From what I head it's an old-school drug (not being pushed by pharmaceuticals), and has hardly any side effects.

I take metformin sporadically since nearly a year ago. Mainly during night shifts and specifically because of that. It is all well and dandy when there are lifestyle changes that help you avoid pharmaceuticals. But in most cases, those lifestyle changes amount to the "life of the rich and famous" who can afford to forego certain responsibilities in order to have the ideal lifestyle.

After reviewing the metformin research, I thought that there was no good reason to forego metformin as an aide. I also use liraglutide sporadically as well.

 

[Gaby]

More on Dr. Rosedale's research:

Insulin, Leptin and the Control of Aging
https://www.sott.net/article/242888-Insulin-Leptin-and-the-Control-of-Aging

Neurodegenerative Disease, Hormones and Diet
https://www.sott.net/article/243316-Neurodegenerative-Disease-Hormones-and-Diet

Restricting your protein intake will help you live longer and improve your overall health
https://www.sott.net/article/317857-Restricting-your-protein-intake-will-help-you-live-longer-and-improve-your-overall-health

Diabetes Is Not A Disease Of Blood Sugar
https://www.sott.net/article/211904-Diabetes-Is-Not-A-Disease-Of-Blood-Sugar

Insulin Resistance: The Real Culprit
https://www.sott.net/article/236090-Insulin-Resistance-The-Real-Culprit

 

[Gaby]

Some interesting articles on insulin:

Insulin resistance, tinnitus and ketones
https://www.sott.net/article/368194-Insulin-resistance-tinnitus-and-ketones

The cholesterol and calorie hypotheses are both dead — it is time to focus on the real culprit: insulin resistance
https://www.sott.net/article/357434-The-cholesterol-and-calorie-hypotheses-are-both-dead-it-is-time-to-focus-on-the-real-culprit-insulin-resistance

Insulin, not cholesterol, is the true culprit in heart disease
https://www.sott.net/article/368407-Insulin-not-cholesterol-is-the-true-culprit-in-heart-disease

The Insulin-Illness Connection
https://www.sott.net/article/367100-The-Insulin-Illness-Connection

Insulin resistance, poor health, and poor vision
https://www.sott.net/article/368199-Insulin-resistance-poor-health-and-poor-vision

The Alzheimer's antidote: using a low-carb, high-fat diet to fight Alzheimer's disease, memory loss, and cognitive decline
https://www.sott.net/article/366816-The-Alzheimers-antidote-using-a-low-carb-high-fat-diet-to-fight-Alzheimers-disease-memory-loss-and-cognitive-decline

There is more in SOTT under "insulin".

 

[hiker]

Re-posted from the Ketogenic diet -thread:

Regarding the podcast with Chad Macias, below are some of the points highligted by him, with links to the pertinent studies.

http://sigmanutrition.com/wp-content/uploads/2017/03/Points-Highlighted-by-Chad-Macias-2.pdf


D'Agostino does not recommend ketogenic diets in e.g. breast and prostate cancers, but caution appears to be needed with brains cancers as well:

But Schwarz et al. using a ketogenic diet as a mono therapy in patients with Glioblastoma observed
the expression of two critical mitochondrial ketolytic enzymes, advancement in tumor growth and
creation of new lesions during a 12 week intervention. "It has been proposed that energy-restricted
ketogenic diets (ERKD) might serve as a metabolic treatment to improve survival of primary brain
cancer patients. Subjects were trained by an experienced registered dietitian (RD) to assure
competency for adherence to the ERKD protocol. The energy-restricted ketogenic diets protocol was
to be administered for 12 weeks as medically appropriate. The patients who enrolled in our ERKD
pilot study were monitored with twice daily measurements of blood glucose and ketones and daily
weights. However, both patients showed tumor progression while on the energy-restricted
ketogenic diet therapy. Immunohistochemistry reactions showed that their tumors had tissue
expression of at least one of the two critical mitochondrial ketolytic enzymes succinyl CoA: 3-oxoacid
CoA transferase, beta-3-hydroxybutyrate dehydrogenase 1. These data suggest that some of the
malignant cells in these patients’ cancers could metabolize ketones and derive energy for
subsequent growth.

https://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-015-0129-1

Gliomas have been thought to rely upon glycolysis for energy production, yet recent results from
human NMR spectroscopy studies suggest that glucose contributes to <50% of acetyl-CoA
production in gliomas. We observed the presence of enzymes required for fatty acid oxidation within
human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major
contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown
under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity
in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant
glioma. Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this
metabolic pathway reduces energy production and cellular proliferation in glioma cells"

http://neuro-oncology.oxfordjournals.org/content/early/2016/06/29/neuonc.now128.full

In fact, neuroblastoma and glioblastoma cells are only able to utilize ketone bodies as substrates for lipid synthesis"

http://journal.frontiersin.org/article/10.3389/fendo.2016.00005/full

Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis. We show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by∼2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047616/

Neuron, astrocyte, and oligodendrocyte cultures were examined for their utilization of glucose,
ketone bodies, and free fatty acids by oxidative processes. All three cell populations readily utilized
the ketone bodies for oxidative metabolism at rates 7-9 times greater than they utilized glucose"

https://www.ncbi.nlm.nih.gov/m/pubmed/3481403/

Apparently, biomarkers could be used to check if a cancer responds to ketogenic diet:

"Results suggest that many of these tumors have alterations in mitochondrial metabolism. On the
other hand, the positive expression of ACAT1, also a mitochondrial enzyme, in most tumors suggests
that the observed decreases of OXCT1 and BDH1 do not necessarily reflect a complete loss or
absence of mitochondria enzymes in these tumors. Nevertheless, our results showing that GBMs
from different patients have different expression of these enzymes are consistent with previous
molecular genetic studies showing that these are genetically heterogeneous tumors. Our results are
also consistent with a recent study showing variable but positive expression of the ketone body
metabolizing enzymes in several human glioma cell lines. Our results suggest that the differential
expression of these enzymes could serve as potentially useful biomarkers to select human glioma patients who may or may not respond optimally to KD"

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707813/

Ketone bodies serve as sources for energy and as precursors for lipid synthesis in developing brain.
Using purified populations of neurons and astrocytes and purified oligodendroglia from bovine brain,
the activities for the three enzymes involved in ketone body metabolism were evaluated.
Surprisingly, astrocytes had the highest levels of activity for both 3-ketoacid-CoA transferase and acetoacetyl-CoA thiolase; these activites showed dramatic changes during development.
Nonetheless, neurons, astrocytes and oligodendroglia are all quite capable of using ketone bodies as metabolic fuels"

https://www.ncbi.nlm.nih.gov/m/pubmed/20501089/

Metformin seems to work as a cancer drug as well:

We showed here that both ketones and lactate promote the growth of embryonic stem (ES) cells.
Consistent with these findings, a recent study showed that ES cells preferentially use mitochondrial
oxidative metabolism, and that their dependence on mitochondria decreases as they undergo
differentiation. This fits well with the idea that ES cells use lactate and ketones as fuel for the TCA
cycle and oxidative mitochondrial metabolism, thereby stimulating stem cell growth. In
accordance with our assertion that cancer cells use mitochondrial oxidative phosphorylation for energy
production, metformin treatment prevents and/or inhibits tumor formation both in diabetic patients
and in mouse animal models. Moreover, metformin also kills “cancer stem cells”. We see that these
high-energy metabolites induce a “stem-like” transcriptional profile that is specifically associated
with tumor recurrence, metastasis and poor clinical outcome. Finally, it is quite ironic that such a
promising anti-cancer drug (metformin) exerts its therapeutic effects by inducing a type of
metabolism (aerobic glycolysis) that has been proposed to be the “root-cause” of cancer for the last 85 years. Thus, induction of aerobic glycolysis in cancer cells may not be the “cause of cancer,” but rather it may be the “cure for cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117136/

Well, looks like treating brain cancer with diets isn't so simple and clear cut after all!

 

[Yupo]

This is all very interesting. Thanks you so much for sharing the information with us. Glioblastoma is a really bad actor. 2 members of my extended family died of this.

 

[Chu]

Thank you for those links and the explanations, Gaby! Super interesting. In one of the articles, vitamin D is also mentioned, and we know that most of the population is low on that nowadays. I had no idea before, but apparently vitamin D is not a vitamin, but a hormone! http://www.hollandandbarrett.ie/the-health-hub/vitamin-d-important-2/ So, another one to add to the mix of chemicals that may have something to do with insulin.

About dosages they seem to be the same for Berberine as for Metformin (referring to the doses quoted by nicklebleu)

https://examine.com/supplements/berberine/

Berberine is an alkaloid extracted from various plants used in traditional Chinese medicine.

Berberine is supplemented for its anti-inflammatory and anti-diabetic effects. It can also improve intestinal health and lower cholesterol. Berberine is able to reduce glucose production in the liver. Human and animal research demonstrates that 1500mg of berberine, taken in three doses of 500mg each, is equally effective as taking 1500mg of metformin or 4mg glibenclamide, two pharmaceuticals for treating type II diabetes. Effectiveness was measured by how well the drugs reduced biomarkers of type II diabetes.

[...]
Berberine’s main mechanism is partly responsible for its anti-diabetic and anti-inflammatory effects. Berberine is able to activate an enzyme called Adenosine Monophosphate-Activated Protein Kinase (AMPK) while inhibiting Protein-Tyrosine Phosphatase 1B (PTP1B).

Berberine has a high potential to interact with a medications, and some interactions may be serious.

Berberine is one of the few supplements in the Examine.com database with human evidence that establishes it to be as effective as pharmaceuticals.

Here is a comparative study about Berberine and Metformin:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/

Efficacy of Berberine in Patients with Type 2 Diabetes
Jun Yin,a,b,* Huili Xing,a and Jianping Yeb

Abstract

Berberine has been shown to regulate glucose and lipid metabolism in vitro and in vivo. This pilot study was to determine the efficacy and safety of berberine in the treatment of type 2 diabetic patients. In study A, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (0.5 g t.i.d.) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (HbA1c; from 9.5% ± 0.5% to 7.5% ± 0.4%, P<0.01), fasting blood glucose (FBG; from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L, P<0.01), postprandial blood glucose (PBG; from 19.8 ± 1.7 to 11.1 ± 0.9 mmol/L, P<0.01) and plasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03 mmol/L, P<0.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering FBG and PBG from one week to the end of the trial. HbA1c decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced by 28.1% and 44.7% (P<0.001), respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly as well. During the trial, 20 (34.5%) patients suffered from transient gastrointestinal adverse effects. Functional liver or kidney damages were not observed for all patients. In conclusion, this pilot study indicates that berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism.

[...]

Discussion

The hypoglycemic effect of berberine was reported in 1988 when it was used to treat diarrhea in diabetic patients in China [8]. Since then, berberine has often been used as an anti-hyperglycemic agent by many physicians in China. There are substantial numbers of clinical reports about the hypoglycemic action of berberine in Chinese literature. However, most of the previous studies were not well-controlled and experiments were not well-designed. Additionally, none of them used HbA1c as a parameter due to poor research conditions. Thus, the anti-diabetic effect of berberine needs to be carefully evaluated.

In this pilot study, berberine significantly decreased HbA1c levels in diabetic patients. The effect of decreasing HbA1c was comparable to that of metformin, a widely-used oral hypoglycemic agent [9, 10]. In monotherapy, berberine and metformin all improved glycemic parameters (HbA1c, FBG and PBG). But their effects on lipid metabolism were different. Berberine decreased serum triglyceride and total cholesterol significantly. HDL-C and LDL-C levels of patients treated with barbering were also reduced but the decreases did not reach statistic significance. Whether berberine has a lowering effect on HDL-C needs further investigation. Compared with berberine, metformin had little effects on these lipid parameters.

In combination with other agents, berberine exhibited consistent activities in improvement of glycemic and lipid parameters in diabetic patients. Insulin sensitivity was enhanced by berberine as the HOMA-IR value was reduced by nearly 50%. This effect may be related to fat distribution by berberine because waist and waist/hip of the patients were decreased significantly in the absence of weight change. Interestingly, both fasting and postprandial C-peptides increased significantly in patients when berberine was used together with insulin, which suggests that long-term berberine treatment may improve insulin secretion of the patients with consequent failure of oral hypoglycemic agents. The effects of berberine on islet function need further studies.

The mechanism of berberine on glucose metabolism is still under investigation. We and others have demonstrated that berberine has an insulin sensitizing effect in vivo and in vitro [3, 4, 5, 11, 12]. In diet-induced obese rats, berberine reduced insulin resistance, similar to metformin [13, 6]. In hepatocytes, adipocytes and myotubes, berberine increased glucose consumption and/or glucose uptake in the absence of insulin [3, 6, 14]. Berberine enhancing glucose metabolism may be due to stimulation of glycolysis, which is related to inhibition of oxidation in mitochondria [6]. Berberine may also act as an alpha-glucosidase inhibitor. It inhibited disaccharidases activities and decreased glucose transportation cross the intestinal epithelium [15, 16]. This may contribute to the adverse gastrointestinal effects of berberine in some patients. This side effect was often observed when berberine was used in combination with metformin or acarbose, which also have similar gastrointestinal side effects by themselves. Thus, when combined with these two agents, the dosage of berberine should be reduced to 0.3 g t.i.d. to avoid the severe flatulence or diarrhea.

Berberine is proposed to have potential as a therapeutic agent for lipid lowering. In this pilot study, berberine reduced serum cholesterol, triglycerides and LDL-C. This activity is similar to that reported elsewhere in vivo [17, 18]. However, further studies including outcome studies in humans are needed to confirm this activity and its benefit. The mechanism of berberine regulating lipid metabolism has been investigated by several groups. In hamsters with hyperlipidemia, berberine reduced serum cholesterol and LDL-C, and increased LDL receptor mRNA as well as protein in the liver [19]. These effects were partly due to stabilization of LDL receptor mRNA mediated by the ERK signaling pathway [20]. In addition to up-regulation of the LDL receptor, berberine was reported to inhibit lipid synthesis in human hepatocytes through activation of AMPK [21].

In summary, that berberine is a potent oral hypoglycemic agent with modest effect on lipid metabolism. It is safe and the cost of treatment by berberine is very low. It may serve as a new drug candidate in the treatment of type 2 diabetes. However, this is a pilot study. The efficacy of berberine needs to be tested in a much larger population and characterized as a function of the known duration of the diabetes. Further studies are needed to evaluate the action of berberine on type 2 diabetes in other ethnic groups.

For those who can read the entire article and understand the jargon, does it mean that in the end, berberine showed better results than metformin regarding triglycerides and cholesterol, or was it about the same? And either way, could Beberine or Metformin be a good addition to a treatment for cardiovascular problems (or would it interact badly with statins and blood thinners)?

 

[Gaby]

For those who can read the entire article and understand the jargon, does it mean that in the end, berberine showed better results than metformin regarding triglycerides and cholesterol, or was it about the same? And either way, could Beberine or Metformin be a good addition to a treatment for cardiovascular problems (or would it interact badly with statins and blood thinners)?

Berberine would be a good choice for some people, but the sample of this study is rather small. The advantage of metformin is that there are studies with thousands of patients available and a very long track record in clinical practice. The clinical experience comes from people with dyslipidemia, diabetes, who are using potent blood thinners, statins, and even have mild kidney failure. In this last case, when and if kidney failure progresses, metformin should be stopped. Those with heart failure seem to fair better in terms of their prognosis when they use metformin. Close clinical symptoms must be monitored closely though. During the stable stage, despite the different diagnosis (kidney failure, heart failure, use of potent blood thinners, etc), it should be safe enough as long as a close check-up is followed up.

 

[Ollie]

For those who can read the entire article and understand the jargon, does it mean that in the end, berberine showed better results than metformin regarding triglycerides and cholesterol, or was it about the same? And either way, could Beberine or Metformin be a good addition to a treatment for cardiovascular problems (or would it interact badly with statins and blood thinners)?

Berberine would be a good choice for some people, but the sample of this study is rather small. The advantage of metformin is that there are studies with thousands of patients available and a very long track record in clinical practice. The clinical experience comes from people with dyslipidemia, diabetes, who are using potent blood thinners, statins, and even have mild kidney failure. In this last case, when and if kidney failure progresses, metformin should be stopped. 9b]Those with heart failure[/b] seem to fair better in terms of their prognosis when they use metformin. Close clinical symptoms must be monitored closely though. During the stable stage, despite the different diagnosis (kidney failure, heart failure, use of potent blood thinners, etc), it should be safe enough as long as a close check-up is followed up.

Being someone who uses both blood thinners and statins, and who has mild kidney failure and heart failure, what do you suggest for close check-ups - i.e., what close clinical symptoms need to be monitored?

 

[Gaby]

Being someone who uses both blood thinners and statins, and who has mild kidney failure and heart failure, what do you suggest for close check-ups - i.e., what close clinical symptoms need to be monitored?

If there was a temporary exacerbation of heart failure due to an infection, the kidney receives less blood flow and the test results would reflect kidney failure (pre-renal insufficiency).

Once the heart stabilizes after the original trigger is treated (e.g. infection), blood reaches the kidney better. You can confirm the real kidney function with blood tests and an urine test to calculate glomerular filtration rate (GFR). The kidney usually recovers and the function would be normal. If there is mild failure, metformin can still be taken with positive results. When GFR is less than 30 (severe kidney failure), metformin is no longer advisable.

If there is kidney failure even after the initial heart failure decompensation that triggered it is resolved, it is a good idea to get it checked by a kidney specialist (nephrologist). At least, it is good to have a complete kidney function test which includes an analysis in the urine of filtrated proteins to see if there is microalbuminuria and how the kidney filtrates.

Depending on of when was your last check-up, you'll need a complete blood test and urinalysis at least once per year to make sure there is appropriate liver and kidney function, the electrolytes are balanced, the urine is cleared, that the cholesterol is not low with statins, and that the markers of inflammation stay leveled. When there is increased shortness of breath, fluid retention in the legs, less urine and increased brain fog, this might be an indication of heart failure decompensation. In this case, get checked for a potential readjustment of the treatment and to find the trigger. Usually there is a trigger, e.g. an underlying infection. If you're feeling fine, getting your regular control tests will help determine the lowest possible dose of statins and if you need to readjust supplements depending on the electrolyte results, kidney and liver function. If there is an imbalance, and you do or get a readjustment in treatment or supplements or lifestyle changes, get everything checked again within 6 months.

Usually you'll get easily bruised with potent blood thinners, but anything more than that might be an indication that a supplement might be potentiating the effect of the blood thinner.

I think you'll do alright. Just don't ignore red flag symptoms that might be an indication that a readjustment of treatment is needed. When something doesn't feel quite alright, report symptoms and signs as objectively as you can without any censoring filter in order to get the most appropriate feedback and treatment by the local doc. Other than that, regular blood and urine controls will help you get the feedback that you'll need.

 

[Ollie]

Thank you for the detailed reply, Gaby.

 

[Atreides]

This side effect was often observed when berberine was used in combination with metformin or acarbose, which also have similar gastrointestinal side effects by themselves. Thus, when combined with these two agents, the dosage of berberine should be reduced to 0.3 g t.i.d. to avoid the severe flatulence or diarrhea.

I have a particularly sensitive intestine and IBS, how can I take Berberine/Metformin and be sure to minimize the possibility of gastro-intestinal side-effects? Is it a matter of slowly reducing the dosage until such side-effects decline? Is there something that can be taken with metformin to combat the gastrointestinal side-effects?

 

[RedFox]

I have a particularly sensitive intestine and IBS, how can I take Berberine/Metformin and be sure to minimize the possibility of gastro-intestinal side-effects? Is it a matter of slowly reducing the dosage until such side-effects decline? Is there something that can be taken with metformin to combat the gastrointestinal side-effects?

The following might be useful (although I do not know how well they translate to your particular personal condition):

_https://www.ncbi.nlm.nih.gov/pubmed/26400188

A Randomized Clinical Trial of Berberine Hydrochloride in Patients with Diarrhea-Predominant Irritable Bowel Syndrome.

Abstract

We aimed to evaluate clinical symptoms in diarrhea predominant irritable bowel syndrome (IBS-D) receiving berberine hydrochloride in a randomized double-blind placebo-controlled clinical trial. Overall, 196 patients with IBS-D were recruited for this study; consequently, 132 patients randomized to receive daily 400 mg of berberine hydrochloride, delivered twice daily or placebo for 8 weeks followed by a 4-week washout period. After a 2-week run-in period, diarrhea, abdominal pain, urgent need for defecation frequency and any adverse events were recorded daily. Prior to administration of the medication and after completing the treatment, assessment of IBS symptom scores, depression and anxiety scale scores and the IBS scale for quality of life (QOL) was carried out. The effects of berberine hydrochloride on IBS-D, defined by a reduction of diarrhea frequency (P = 0.032), abdominal pain frequency (P < 0.01) and urgent need for defecation frequency (P < 0.01), were significantly more pronounced in the berberine group than the placebo group in the 8 weeks of treatment. A trend of improvement (P < 0.05) was observed with berberine hydrochloride for IBS symptom score, depression score and anxiety score and the IBSQOL, compared with placebo. At last, berberine hydrochloride was well tolerated. So we concluded that berberine hydrochloride is well tolerated and reduces IBS-D symptoms, which effectively improved patients QOL.

_http://www.jnmjournal.org/journal/view.html?uid=1186&vmd=Full&
(lots of useful info here)

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments
[..]
Berberine

Berberine is an alkaloid found in several plants amongst which the most famous ones are Berberis spp. from the family Berberi-daceae.132,133 Anti-inflammatory,134 antioxidant,135 and anti-ulcer136 activity of berberine chloride have been demonstrated in several studies. Deng et al137 evaluated 12 berberine derivatives, which showed their remarkable activity for the treatment of IBS. In a post inflammation-IBS model induced by 4% acetic acid in rats, abdominal withdrawal reflex scores to colorectal distention were significantly lower in berberine treated animals compared with a placebo group, which represents the activity of berberine in reduction of VH. Berberine could also decrease defecation times and improved stool consistency. Inhibition of berberine effect by the concomitant administration of aminoguanidine (a nitric oxide synthetase inhibitor) suggests a role for nitric oxide in the visceral antinociceptive effect of berberine.138 Berberine could be proposed as an adjuvant treatment for IBS; however, recent studies showed an alteration in plasma level of berberine in animal models of IBS which suggests the necessity of dose adjustment for patient with IBS.139
[..]

_https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725385/

Antinociceptive effect of berberine on visceral hypersensitivity in rats

AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity.

METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 °C) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement.

RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000).

CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.

_https://healinghistamine.com/barberry-helps-leaky-gut/

A 2009 study published in Fitoterapia, the Journal for the Study of Medicinal Plants, found that extracts of berberine could reduce epithelial gut permeability in vitro using human cells [2].

A number of other studies have come to similar conclusions based on test tube (in vitro) studies, including one published in the European Journal of Pharmaceutical Sciences in 2010 [3].

Authors of an interesting but scary sounding 2014 study in the Journal of Marine Drugs used a nano carrier based on chitosan and fucoidan to deliver berberine locally to restore barrier function compromised by bacteria-derived lipopolysaccharides (LPS) which play a role in IBS and other inflammatory bowel conditions [4].

The studies I’ve read explain that berberine works by strengthening/protecting the intestinal epithelial tight junctions which prevents bacteria and others from coming into contact with the immune system.

A comparative study of berberine on colitis in rats rounds up quite a bit of information pointing to its benefits in treating inflammatory bowel changes [5]. In this vein moringa oleifera [6], caraway [7] and rosemary oil [8] have also been found to be beneficial.

So, theoretically berberine is well tollerated in IBS. That doesn't mean it is in all cases.
Contraindications for anyone considering it:

_https://www.webmd.com/vitamins-supplements/ingredientmono-1126-BERBERINE.aspx

BERBERINE Side Effects & Safety

Berberine is POSSIBLY SAFE for most adults for short-term use when taken by mouth or applied to the skin.

Special Precautions & Warnings:
Children: It’s UNSAFE to give berberine to newborns. It can cause kernicterus, a rare type of brain damage that can occur in newborns who have severe jaundice. Jaundice is yellowing of the skin caused by too much bilirubin in the blood. Bilirubin is a chemical that is produced when the old red cells break down. It is normally removed by the liver. Berberine may keep the liver from removing bilirubin fast enough.

Pregnancy and breast-feeding: It’s UNSAFE to take berberine by mouth if you are pregnant. Researchers believe berberine can cross the placenta and might cause harm to the fetus. Kernicterus, a type of brain damage, has developed in newborn infants exposed to berberine.

It’s also UNSAFE to take berberine if you are breast-feeding. Berberine can be transferred to the infant through breast milk, and it might cause harm.

Diabetes: Berberine can lower blood sugar. Theoretically, berberine may cause blood sugar to become too low if taken by diabetics who are controlling their blood sugar with insulin or medications. Use with caution in people with diabetes.

High bilirubin levels in the blood in infants: Bilirubin is a chemical that is produced when the old red blood cells break down. It is normally removed by the liver. Berberine may keep the liver from removing bilirubin fast enough. This can cause brain problems, especially in infants with high levels of bilirubin in the blood. Avoid using.

Low blood pressure: Berberine might lower blood pressure. Use with caution in people with low blood pressure.

_https://liftmode.com/blog/berberine-side-effects/

Recommended Dosage

The recommended daily Berberine dosage to lower blood sugar is around 1500mg. [2]

You can take Berberine 500 mg, three times daily to reach the correct recommended dosage. Using separate doses avoids potential gastrointestinal side effects like stomach cramps and nausea.

Top 5 Berberine Side Effects:
1. Interacts with medication

Although Berberine is considered a very safe dietary supplement with a low toxicity and few side effects, it has the potential to interact with a large number of medications. For this reason, we do not recommend using Berberine HCl if you are taking any other type of medication.

Please speak to your doctor if you’re taking any medication and would like to use a Berberine vulgaris extract. The most important Berberine interactions include:

May potentiate (increase) the effects of drugs that lower blood sugar. This is primarily due to Berberine’s blood sugar lowering effects.[3]

Berberine inhibits certain cytochromes: CYP2D6, CYP2C9, and CYP3A4. These cytochromes are the targets of a large number of medications, and by using Berberine HCl with other medication, you run a risk of potential dangerous side effects.[4]

Berberine has a powerful effect on anion transporter proteins in the cell membrane. A few medications use these transporters to access your cells and deliver their effects. One important medication is Metformin – a prescribed compound for type 2 diabetes.[5]


2. High doses may cause diarrhea, stomach cramps

Berberine toxicity is considered to be extremely low. It is a very safe dietary supplement and natural plant extract. The few Berberine side effects include mild gastrointestinal discomfort at high doses. It’s useful to know that Berberine was once used as a treatment for diarrhea.

Berberine’s absorption in your stomach is less-than-optimal due to the action of a number of enzymes. These enzymes affect the efficiency of Berberine’s uptake. This is why, at high doses, the few side effects of Berberine can include:

Stomach cramps
Gastrointestinal discomfort
Nausea
Diarrhea

In order to avoid these side effects, doctors and scientists recommend taking a daily Berberine HCl dosage in three separate servings. This equates to a Berberine 500 mg dosage three times per day. Using a lower dosage prevents upsetting your stomach and allows you to avoid the gastrointestinal side effects of Berberine.

Despite the potential side effects at high doses, researchers have praised Berberine for it’s mild side effects when compared to other substances that lower blood sugar. For example, the metformin and diarrhea side effect is a powerful one that causes problems for many people.

3. Dangerous interaction with macrolide antibiotics

One important and potentially dangerous interaction to mention is Berberine with macrolide antibiotics. There is evidence that Berberine can interact with a certain class of antibiotics called macrolide antibiotics. These include the antibiotics azithromycin and clarithromycin.

The Berberine toxicity occurs at hERG channels in the heart. There is a potential for serious negative health effects in these interactions. Please make sure that you avoid taking Berberine if you are using antibiotics, especially macrolide antibiotics.[6]

On another note, some preliminary research shows Berberine's potential antibiotic effects in the laboratory. Recent studies have indicated that Berberine may have a synergistic relationship with some antibiotic medications. [7] Multidrug resistance (MDR) pump inhibitors may also increase Berberine’s antibiotic activity in the lab. [8]

So with a super sensitive gut, if you want to try berberine, perhaps divide the dose from 400mg-500mg into 3 or 4 throughout the day, so you only take 100mg at a time. fwiw

 

[Gaby]

The first time I used metformin, it caused me diarrhea. The next doses were better and now I can take it most of the time without noticing increased intestinal transit. I stay in the lowest tolerated dose and take it with some green algae capsules (Aphanizomenon flos-squae), that seems to help. Berberine might be better tolerated?

 

[Yas]

I've found an interesting article by Mercola this week and thought it would be good to post it here. Mercola advocates for the use of berberine instead of metformin because it's safer. But, I guess that if metformin is very safe drug, then it might be better for a stronger effect if needed.

I'll quote some excerpts from the article:

Berberine May Ease Symptoms of Anxiety and Depression — And Much More

As noted by Dr. Michael Murray:

… I think [berberine] is poised to be the biggest thing in the natural product industry … Here is why: Berberine has been shown to:

• Produce results in clinical trials in improving Type 2 diabetes on par or better than conventional drugs including metformin.
• Improve blood lipid levels better than statins.
• Lower blood pressure in many subjects as well as any class of antihypertensive medication.
• Improve liver function and promote anti-obesity effects.
• Exert significant beneficial effects on digestive health and the microbiome.
• Produce very encouraging experimental data in a wide range of modern health issues including cancer, Alzheimer’s disease, Parkinson’s disease and others.

You've already mentioned the AMPK enzyme, but I've found what Mercola says about it very interesting:

What Makes Berberine Such a Powerful Remedy?

Many of berberine’s health benefits have been linked to its ability to activate adenosine monophosphate-activated protein kinase (AMPK). AMPK is an enzyme inside your body's cells. It’s sometimes referred to as a "metabolic master switch" because it plays an important role in regulating metabolism.

Low AMPK has been linked to insulin resistance, mitochondrial dysfunction, obesity, neurodegeneration and chronic inflammation — all of which lay the groundwork for a wide variety of serious chronic diseases. In an article discussing the clinical uses of berberine for metabolic syndrome and Type 2 diabetes, the Natural Medicine Journal highlights its effect on AMPK:

"AMPK induces a cascade of events within cells that are all involved in maintaining energy homeostasis… AMPK regulates an array of biological activities that normalize lipid, glucose and energy imbalances. Metabolic syndrome occurs when these AMPK-regulated pathways are turned off, triggering a syndrome that includes hyperglycemia, diabetes, lipid abnormalities and energy imbalances …

AMPK helps coordinate the response to these stressors, shifting energy toward cellular repair, maintenance or a return to homeostasis and improved likelihood of survival. The hormones leptin and adiponectin activate AMPK. In other words, activating AMPK can produce the same benefits as exercise, dieting and weight loss — the lifestyle modifications considered beneficial for a range of maladies …

One way to appreciate berberine's potential is to think of it as having the same effect on a patient as increasing exercise while at the same time restricting calorie intake. Think of the effects of AMPK suppression as similar to those of eating a high-calorie diet while leading a very sedentary lifestyle."

So, these are kind of like the benefits of doing a Keto diet and/or intermittent fasting and doing excercise.

Berberine Helps Ease Anxiety and Depression

AMPK is also an important neuroprotector. As explained in the Journal of Neurochemistry, “AMPK senses metabolic stress and integrates diverse physiological signals to restore energy balance. Multiple functions are indicated for AMPK in the [central nervous system] …” Berberine also benefits brain health and psychological well-being by increasing key neurotransmitters.

A number of studies have demonstrated berberine’s usefulness against anxiety and depression, in part by inhibiting monoamine oxidase, an enzyme that breaks down serotonin, noradrenaline and dopamine in your brain. These neurotransmitters play important roles in mood and have been implicated in depression.

He goes on to mention some studies, which we could probably check as well.

Berberine Supports Gut Health and Much More

Berberine has also been shown to support a healthy gastrointestinal tract and microbiome in a number of different ways, and this too can have a beneficial impact on your mood and mental health. There’s ample research showing your gut health plays a very important role in your brain health, and can influence your mood for better or worse. As for improving your gut health, studies have shown berberine helps:

• Prevent diarrhea by delaying the amount of time it takes for food to pass through your small intestine
• Lower your risk of leaky gut
• Protect against gut damage caused by high alcohol consumption
• Lower intestinal inflammation caused by inflammatory cytokines
• Preferentially nourish microbes that produce beneficial short-chain fatty acids, known to have many health benefits
• Improve symptoms of fatty liver disease by normalizing the gut microbiome
• The normalization of gut bacteria also resulted in lower body weight, lower serum levels of lipids, lower glucose and insulin levels, and the normalization of insulin resistance20

He also links to other articles on each of the points he mentions above... so maybe they are worth checking too.

The first time I used metformin, it caused me diarrhea. The next doses were better and now I can take it most of the time without noticing increased intestinal transit. I stay in the lowest tolerated dose and take it with some green algae capsules (Aphanizomenon flos-squae), that seems to help. Berberine might be better tolerated?

If berberine works as Mercola says in his article, it should be better tolerated by people who have very sensitive digestive systems. But I guess it's better to have a look at the articles he puts as references to be sure.

And this interesting for the ones taking other medications too:
(He doesn't mention blood thiners, but I guess that it's good to know that it can augment the effects of some drugs and hinder some others)

Drug Interactions

While berberine is quite safe and well-tolerated, it may be contraindicated if you’re taking medications. For example, berberine may hinder absorption of tetracycline and other similar antibiotics, rendering them ineffective. Also, because berberine significantly inhibits CYP3A enzymes — enzymes needed to metabolize most drugs — it can lower the clearance of medications, which in turn can augment their effect. This can lead to overdose, the risks of which will vary depending on the drug in question.

Berberine inhibits CYP3A just like curcumin, which impairs phase 2 detoxification, where your body makes toxins water soluble so they can be excreted. So, this would not be supplements to use during fasting where you have large lipolysis and liberation of stored toxins that need to be metabolized.

Because of all its benefits, I have been taking berberine for over two years. However, because it is a potent alkaloid, I believe it needs to be cycled. So, I take it for a week then take a week off. Alternatively, you can skip it on the weekends. The general principle is cycling, just like one does with the ketogenic diet. It is not wise to be continuously ketogenic.

Also, as noted by Murray: “Berberine … enhances the effects of oral hypoglycemic drugs used in the treatment of Type 2 diabetes through its multitude of antidiabetic effects. People on oral hypoglycemic drugs should monitor blood glucose levels if taking berberine and adjust their dosage of their medications as needed and under the care of a medical professional.” I tell virtually everyone taking metformin to switch to berberine as it is far safer.

RedFox already mentioned this, but Mercola has an older article too where he says:

Finding the Ideal Berberine Dosage for Your Needs

Just because berberine comes from natural sources it doesn’t mean that it’s OK to take in any amount. The ideal dosage for this supplement is around 900 to 1,500 milligrams. Since it has a short half-life, it’s necessary to divide its daily dosage into three separate doses, taken before meals, to maintain stable blood levels.

Make sure that you still consult your physician, though, since the dosage may also depend on your age and health condition. Be careful not to overdose on this supplement, as it may cause undesirable side effects.

Possible Side Effects That You May Experience When Taking Berberine

Berberine has a remarkable safety profile, and according to a study published in the American Journal of Physiology, it does not exhibit toxicity in the cells. Keep in mind, though, that it may still cause a few side effects if taken incorrectly. Some of the side effects that are commonly associated with this supplement include:

• Cramping
• Diarrhea
• Flatulence
• Constipation
• Nausea
• Stomach pain

Berberine is possibly unsafe for pregnant and breastfeeding women, since it can be transferred to the infant through breastmilk or by crossing the placenta. Newborn infants who were exposed to berberine are reported to develop kernicterus, a rare type of brain damage.

Berberine may also inhibit the body’s ability to break down other medications, so make sure that you consult your doctor before taking other drugs with this supplement.