The American Journal of Medical Sciences and Pharmaceutical Research
65
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TYPE
Original Research
PAGE NO.
65-72
10.37547/tajmspr/Volume07Issue02-09
OPEN ACCESS
SUBMITED
21 December 2024
ACCEPTED
23 January 2025
PUBLISHED
25 February 2025
VOLUME
Vol.07 Issue02 2025
CITATION
Karim Chubin. (2025). The therapeutic benefits of berberine and its
effectiveness compared to metformin. The American Journal of Medical
Sciences and Pharmaceutical Research, 7(02), 65
–
72.
https://doi.org/10.37547/tajmspr/Volume07Issue02-09
COPYRIGHT
© 2025 Original content from this work may be used under the terms
of the creative commons attributes 4.0 License.
The therapeutic benefits
of berberine and its
effectiveness compared to
metformin
Karim Chubin
British-Trained Anthropologist. Swiss and German - trained Naturopath
and Nutritionist
Abstract:
Berberine is a plant extract that exhibits an
impressive array of therapeutic properties, including
accelerated weight loss, improved insulin sensitivity,
and protection from numerous chronic, degenerative
diseases. Berberine exerts its effects in several ways,
including by activating AMP- activated protein kinase
(AMPK), an enzyme that governs metabolism and
maintains whole-div energy homeostasis. Since AMPK
influences the ageing process, long-term berberine
consumption may extend lifespan by decelerating one’s
rate of ageing. Besides its impact on AMPK, berberine
also profoundly alters the gut microbiome, specifically
in ways that reduce metabolic endotoxemia, a condition
that promotes obesity and other metabolic disorders.
Berberine’s physiological effects are similar to those of
metformin, but in comparative studies, berberine either
matches or outperforms metformin. Considering
metfo
rmin’s minor side effects, berberine’s absence of
side effects, and berberine’s therapeutic potential
against neurological degenerative diseases and a host of
other chronic conditions, berberine is quickly gaining
recognition for being one of the most powerful and
most effective nutritional agents for weight loss, disease
prevention, anti-ageing, and overall wellness.
Keywords:
Activated protein kinase (AMPK), ageing
process, long-term berberine consumption.
Introduction:
Berberine is a bitter-tasting, vibrant
yellow alkaloid, which is extracted from the roots,
rhizomes, and stem bark of many plants, including
Hydrastis canadensis (goldenseal), Coptis chinensis
(coptis or golden thread), Berberis aquifolium (Oregon
grape), Berberis vulgaris (barberry), and Berberis
aristata (tree turmeric). Berberine has been used
therapeutically for at least 3,000 years, including
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The American Journal of Medical Sciences and Pharmaceutical Research
extensive use in Traditional Chinese Medicine and
Ayurvedic Medicine.1
Despite its long, illustrious history, interest in
berberine has surged during the past decade. The
PubMed database, for example, contains roughly
4,700 published articles referencing berberine, 2,800
of which have been published during the past ten
years. The recent buzz surrounding berberine i
sn’t
surprising, considering the wide array of therapeutic
benefits attributed to the molecule. For example,
research shows berberine to be protective against
cancer,
obesity,
inflammation,
atherosclerosis,
neurodegenerative diseases, rheumatoid arthritis,
cardiovascular disease, diabetes, and various
metabolic disorders, plus many other benefits.2, 3, 4,
5 For those seeking a “panacea” nutritional
supplement, which promotes overall wellbeing and
even has anti- ageing properties, berberine is a prime
candidate.
This review focuses on berberine’s usefulness in
weight loss while examining the two primary
mechanisms by which berberine exerts its powerful
therapeutic effects, namely by activating AMP-
activated protein kinase (AMPK) and by modulating
the gut microbiome. We also compare berberine with
metformin, one of the most widely prescribed
pharmaceutical drugs for treating diabetes. Finally, we
assess berberine’s usefulness in anti
-ageing therapy
while summarizing some of its other key benefits.
Weight Loss through AMPK Activation
Physical exercise increases energy expenditure,
thereby contributing to weight loss, primarily by
activating AMP-activated protein kinase (AMPK), an
enzyme that plays a critical role in controlling whole-
div energy homeostasis.6 Besides exercise, AMPK
can be activated pharmacologically (by drugs, such as
metformin), through plants (berberine), and through
other activities, such as fasting. In fact, AMPK arose
during early eukaryotic evolution as a regulatory
pathway that enables organisms to survive periods of
food scarcity.7
Commonly regarded as the “master regulator of
metabolism,” AMPK restores energy imbalances
caused by metabolic stress at both the cellular and
physiological levels.8, 9 AMPK functions as a “cellular
fuel gauge,”
meaning it senses low-fuel situations, at
which time it switches off energy- consuming activities
while switching on energy producing activities.10 If
AMPK were a computer’s battery sensor, for example,
it would sense when battery reserves were low,
subsequently sending recharge notifications while
attempting to conserve energy by hibernating certain
apps.
With respect to AMPK’s energy regulation, we are
referring specifically to adenosine triphosphate (ATP),
the so-
called “molecular currency” of intracellu
lar
energy transfer, a molecule that stores and transports
chemical energy within the cells. AMPK is activated
when the ratio between 5’
-adenosine monophosphate
(AMP) and ATP becomes too high. To restore cellular
energy homeostasis, AMPK activates catabolic
pathways that generate ATP, including the burning of
excess fat (fatty acid oxidation).11 Simultaneously,
AMPK switches off ATP-
consuming activities that aren’t
essential to short-term cell survival, including almost all
anabolic pathways (e.g. fatty acid synthesis, sterol
synthesis, cell growth and proliferation).12
Besides burning fat cells, AMPK also improves blood
glucose homeostasis and lipid profiles, while preventing
insulin resistance, partly by inhibiting pathways that
antagonize insulin signaling.13 In simpler terms, as the
master regulator of metabolism, AMPK prevents energy
balance disorders, including type-2 diabetes and
obesity, as well as metabolic derangements, including
cancer and various inflammatory diseases. Since being
discovered and formally defined in the late 1980s, over
9,000 papers have been published concerning the AMPK
system.14, 15
Berberine is a potent AMPK activator, which has been
demonstrated to activate AMPK in both fat cells and
muscle cells, thereby resulting in reduced fat
accumulation and improved insulin sensitivity. For
example, the authors of a 2006 study published by the
American Diabetes Association’s Diabetes Journal,
observed, “Strikingly, berberine acutely stimulated
AMPK activity in both myotubes [fibers involved with
muscle generation] and adipocytes [fat cells] in vitro,
contributing to enhanced GLUT4 translocation in
myotubes and reduced lipid mass in adipocytes.”16
They went on to suggest that berberine could become a
major therapeutic tool for treating obesity and insulin
resistance.
Weight Loss through Gut Microbiome Modulation
Energy imbalances are just one of many factors that
contribute to weight gain and obesity. For example, an
imbalanced gut microbiome can also promote these
conditions. Poor diet and lifestyle choices, for example,
can undermine the gut microbiome, causing changes
that decrease mucosal barrier function, meaning the
intestinal barrier becomes compromised.17, 18 This
leads to intestinal permeability and access to the
bloodstream
by
microbiome-derived
lipopolysaccharides (LPS).
Metabolic
endotoxemia
(ME)
is
a
condition
characterized by elevated serum LPS.19 ME triggers a
signaling cascade of pro-inflammatory pathways, which
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leads to chronic low-grade inflammation and oxidative
stress, both of which are associated with obesity.
Recent research suggests, “metabolic endotoxemia
may serve [as] a key mediator of metabolic
derangements observed in obesity” and cardio
-
metabolic disease.20 In 2007, for example, Cani et al.
induced obesity in mice through a high-calorie diet rich
in corn oil. The stages leading to obesity were a)
alterations of the gut microbiota, including reductions
in Bifidobacterium and Eubacterium spp, b) two- to
threefold increases in circulating LPS levels (which
classifies as ME), and c) 30 and 40% increases in
subcutaneous and visceral fat deposits, respectively.21
Berberine has been shown to protect against obesity
by regulating ME. In 2017, for example, Xu et al.
induced obesity in rats and then tested berberine’s
effects.
22 Berberine significantly altered the rats’ gut
microbiomes, including increases in the abundance of
14 genera, and decreases in 20 genera. This led to
decreased intestinal permeability (via improved
expression and distribution of tight junctions), reduced
ME, and reduced inflammation. Moreover, berberine
caused significant improvements regarding weight
loss, fasting blood insulin, and insulin resistance.
For a similar study, published in 2018 in
Atherosclerosis, researchers used berberine to alter
the gut microbiomes of mice, including increases in the
abundance of Akkermansia, which caused increased
intestinal expression of tight junction proteins and
increased thickness of the colonic mucus layer. 23
These changes restored gut integrity and reduced ME,
while also reducing arterial and intestinal expression of
pro-inflammatory cytokines.
Berberine versus Metformin
In 2008, berberine captured the attention of the
healthcare community when it outperformed
metformin, the popular diabetes drug, in a
comparative study published in Metabolism. After
treating 36 recently diagnosed type-2 diabetes
patients with diet alone, researchers randomly
assigned the patients to receive either berberine or
metformin, three times daily (500mg doses) for a
period of 13 weeks.24
The berberine group matched or outperformed the
metformin group in all categories. With respect to
glucose metabolism, including improvements in
HbA1c, fasting blood glucose (FBG), postprandial blood
glucose (PBG), fasting insulin, and postprandial insulin,
both groups exhibited similar improvements. With
respected to lipid metabolism, however, including
triglycerides and total cholesterol, the berberine group
exhibited significantly better results compared to the
metformin group.
For a 2012 study published in the European Journal of
Endocrinology, researchers compared the effects of
berberine and metformin on women diagnosed with
polycystic ovary syndrome, a
common reproductive and metabolic disorder
associated with insulin resistance.25 Eighty-nine
subjects were randomized into one of three groups,
corresponding to a three-month treatment regimen
inclusive of berberine (1500mg daily), metformin
(1500mg daily), or placebo.
The berberine group, compared to the metformin
group, exhibited significant reductions in waist
circumference, waist-to-hip ratio, total cholesterol (TC),
triglycerides (TG), and low-density lipoprotein
cholesterol (LDLC), as well as significant increases in
high-density lipoprotein cholesterol (HDLC) and sex
hormone-binding globulin.
So berberine and metformin both activate AMPK, and
both modulate the gut microbiome. Both have similar
effects on glucose metabolism, lipid metabolism, and
weight loss, but when compared in head-to-head clinical
trials, berberine has thus far performed better.
Regarding side effects, berberine has no significant side
effects, whereas for metformin there are some
concerns.
Metformin and Gastrointestinal Distress
Around 20-30% of patients taking metformin suffer
gastrointestinal side effects, including 5% for whom
these side effects are so severe that they warrant
discontinuation of the drug.26 In 2016, researchers
publishing in Diabetic Medicine identified a genetic
component to this metformin side effect. Specifically,
they found that patients with specific variants of the
OCT1 gene have more than double the odds of
experiencing
common
metformin-induced
gastrointestinal side effects.
Berberine, on the other hand, has been used since
ancient times to treat gastrointestinal disorders. Recent
studies confirm berberi
ne’s significant therapeutic
impact on the gastrointestinal tract, including
effectiveness against diarrhea and gastroenteritis.27
Additionally, as discussed above, berberine modulates
the gut microbiome, thereby protecting the mucosal
lining of the gut an
d preventing “leaky gut” by
attenuating disruptions of tight junctions in the
intestinal epithelium.28 Berberine is not associated with
any significant adverse gastrointestinal side effects.
Metformin and Liver Risks
The risks of metformin for those who suffer from
advanced liver inflammation have been hotly contested.
Until recently, doctors typically discontinued metformin
for patients diagnosed with cirrhosis due to fears of
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adverse reactions. A 2014 study conducted by the
Mayo Clinic, however, found that continuation of
metformin after a cirrhosis diagnosis reduces the risk
of death by 57 percent.29
Despite persistent concerns, metformin appears to be
safe and effective, even for those with weakened
livers. In fact, for a 2012 mouse study, metformin
reversed steatosis and inflammation in non-diabetic
subjects afflicted by nonalcoholic steatohepatitis
(NASH).30
Despite a limited number of quality trials, for a 2016
meta-analysis regarding the effects of berberine on
non-alcoholic fatty liver disease (NAFLD), researchers
concluded that berberine positively affects blood
lipids, blood glucose, liver function, insulin resistance,
and fatty liver condition, with respect to NAFLD
patients.31 Berberine’s liver
-protective properties are
attributable primarily to its ability to suppress
inflammation.32 Additionally, researchers have
demonstrated berberine’s ability to modulate gene
expression with respect to hundreds of genes
associated with liver metabolism and NAFLD-related
functions, thereby conferring additional protective
effects against NAFLD.33
Metformin and Vitamin B12 Deficiency
Long-term use of metformin has been shown in cross-
sectional,
retrospective,
and
longitudinal
observational studies to be associated with vitamin
B12 deficiency. This side effect is attributed to
metformin’s interference with vitamin B12
-intrinsic
factor absorption.34
Metformin and Renal Impairment
Metformin belongs to a class of glucose-lowering drugs
called biguanides. Other biguanides, such as
phenformin and buformin, were previously pulled
from the market based on compelling evidence linking
them to lactic acidosis.35 Metformin poses similar
risks, but only for a small subset of the population,
including those with impaired renal function, impaired
hepatic function, and/or circulatory dysfunction.
Metformin-associated lactic acidosis (MALA) is a
condition characterized by increased serum lactate
along with impaired clearance ability. This occurs in
people with impaired renal function and/or impaired
hepatic metabolism, including those who acutely
develop impaired renal function via dehydration,
vomiting, diarrhea, or simply through old age (based
on age-related renal decline).36, 37, 38
With mortality rates ranging from 25 to 50%, the
consequences of MALA are severe.39 The prevalence
of MALA, however, is very low
–
7.4 cases per 100,000
patient-years for metformin users, compared to 2.2
cases of lactic acidosis per 100,000 person-years for
nonusers of metformin.40 Nevertheless, in the interest
of preventing MALA, metformin is currently
contraindicated for those diagnosed with moderate to
severe renal impairment.
As discussed throughout this article, berberine delivers
all the benefits of metformin (and more), but without
metformin’s side effects.
With respect to lactic acidosis,
this is also the case.
Berberine not only doesn’t cause lactic acidosis, but it
may also protect against lactic acidosis caused by
metformin.
For a 2017 study, scientists induced diabetes in rats
before randomizing them into groups receiving
metformin alone or metformin plus berberine (at 50 or
100 mg/kg div weight). Serum lactate (an indicator of
lactic acidosis) was observed at 1.87 mmol/L for the
metformin group, compared to 1.62 for the metformin
plus 50mg/kg berberine group and 1.47 for the
metformin
plus
100mg/kg
berberine
group.
Additionally, the berberine groups fared better with
respect to fasting glucose, fasting insulin, insulin
resistance, and HOMA-IR.41
Besides its apparent benefits vis-à-vis MALA, berberine
also provides general kidney support and protection.
For a 2017 study published in Molecular Medicine, for
example, scientists concluded that berberine can inhibit
renal fibrosis while improving symptoms associated
with diabetic nephropathy (kidney damage caused by
diabetes).42 Moreover, for a 2015 study published in
Natural
Product
Communications,
scientists
demonstrated that long-term berberine treatment
attenuates renal injury in spontaneously hypertensive
rats (rats with kidney damage resembling that observed
in some cases of human essential hypertension).43
Additional Berberine Benefits
Anti-Ageing Properties
AMPK is one of the key governors of the ageing process
due to its impact on metabolic homeostasis, stress
resistance, and cellular maintenance/upkeep, all of
which are hallmarks of improved quality of life and
extended lifespan. It has been demonstrated that the
ageing process diminishes the responsiveness of AMPK
activation.44 The mechanisms responsible for this
diminished responsiveness are currently unknown, but
researchers suspect that inflammation, cellular stress,
and age-related changes to protein phosphatase
function are involved.45 Berberine, based on its
remarkable ability to activate AMPK, is regarded as one
of the plant kingdom’s most powerf
ul anti-ageing
molecules.
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Berberine and the Brain
Cognitive dysfunction is a consequence of chronic
hyperglycemia, oxidative stress, and cholinergic
dysfunction, all of which are associated with type-2
diabetes and metabolic syndrome. When diabetes is
induced in rats, they suffer severe deficits in learning
and memory, which is associated with increased lipid
peroxidation, decreased glutathione levels, and
elevated choline esterase (ChE) activity. In multiple
studies, berberine has been shown to improve learning
and memory impairment by reducing synaptic
dysfunction and by lowering hyperglycemia, oxidative
stress, and ChE activity.46, 47
Berberine also exhibits mood enhancing and
antidepressant-like properties, thanks to its ability to
boost neurotransmitter activity, specifically in the
hippocampus and frontal cortex, but also in the entire
brain.48 In mice, acute administration of berberine (5
mg/kg) increased norepinephrine (31%), serotonin
(47%), and dopamine (31%) levels. Chronic
administration for 15 days was shown to maintain
these elevated levels, while mitigating behavioral
patterns of despair vis-à-vis forced swim tests and tail-
suspension tests.49
A follow-up study published in The Pharmacogenomics
Journal was designed to test berberine’s effect on
serotonin transporter (5-HTT), which indirectly
regulates mood, emotion, and appetite by modulating
extracellular
fluid
serotonin
concentrations.50
Depending on genetic variations concerning 5-HTT
expression, berberine increased 5-HTT promoter
activities
from 28 to 129%, thereby providing “a
convincing example of how herbal compounds
influence the expression of one of the most intensively
studied psychiatric candidate genes, the serotonin
transporter.”51
Finally, berberine is emerging as a promising candidate
for therapeutic approaches to preventing or delaying
the process of Alzheimer’s disease (AD).52 The two
hallmark pathologies of AD are the accumulation of β
-
amyloid (Aβ) plaque deposits and the accumulation of
neurofibrillary tangles (NFTs) of tau proteins.
Berberine has been shown in numerous studies to
decrease the accumulation of both antagonists,
although the mechanisms behind these improvements
remain unclear.53 What is clear, however, is that
berberine crosses the blood-brain barrier, thereby
conferring numerous neuro-protective benefits,
including the reduction of oxidative stress and the
reduction of neuro-inflammation.54
During the past several years, the pharmaceutical
industry has suffered many setbacks regarding
Alzheimer’s research. “The lar
ge number of major
failed trials in Alzheimer’s is quite frightening. It has
really scared off big pharma,” explained Lennart Mucke,
director of the Gladstone Institute of Neurological
Disease at UC San Francisco.55 In fact, in January 2018,
Pfizer announced it would be abandoning research
aimed at developing drugs to treat AD and Parkinson’s
disease.56 Perhaps this astonishing announcement
signals a new era during which herbal and botanical
treasures like berberine will rise to prominence.
CONCLUSION
Berberine is an ancient herbal medicine, which, during
the past decade, has emerged as a superstar of
naturopathy. Berberine has been shown in clinical trials
to have a wide range of therapeutic benefits, including
weight loss, improved insulin sensitivity, and protection
against many chronic diseases, including cancer,
atherosclerosis,
cardiovascular
disease,
various
neurodegenerative diseases, diabetes, and various
metabolic disorders.
With respect to weight loss, two of the most important
mechanisms be
hind berberine’s effects are its impact
on AMPK and on the gut microbiome. Berberine
activates the AMPK, thereby regulating metabolism and
prompting the div to burn stored fat deposits. With
respect to the gut microbiome, berberine alters the gut
microbiome in ways that restore gut integrity and
prevent metabolic endotoxemia, thereby reducing
inflammation and promoting weight loss.
Metformin, one of the most prescribed diabetes
medications, has similar effects compared to berberine,
but in head-to-head studies, berberine equals or
outperforms metformin, and without any significant
side effects. Finally, the vast array of therapeutic
benefits attributed to berberine cannot be overstated.
During the next several years, berberine has the
potential to gain widespread recognition among the
general public as one of the world’s most important
nutritional treasures.
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