EDIT March 17, 2024: Today somebody shared a link to a two year old post of mine about a report on Berberine being neurotoxic and taking it off of my stack.
Within a few months I found other information on Berberine and, using my High School educated brain, decided that Berberine definitely needed to stay on my stack and I even increased to 1200 mg a day. I have been taking 1200 mg a day (800 in the morning, 400 at night) ever since.
So I have settled into a stack of supplements, but now I need to look at each of them and determine the best dosage, when to take, whether to take with food, why I think they would help, and if I need to cycle them.
I am starting with Berberine. I think I feel better when I take it.
We had a big thread on this 4 months ago, healthunlocked.com/cure-par..., and it looked like most people were taking 200 or 250 mg at breakfast.
I've been taking 400 mg once a day with my first meal.
I just noticed my bottle says I can take these twice a day with meals. That would get me to 800.
Then I look at this study: Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota 2021 nature.com/articles/s41392-... and they prescribed humans 500 mg twice a day.
Then there is this other study Pharmacological effects of berberine on mood disorders 2018 ncbi.nlm.nih.gov/labs/pmc/a... "Chronic administration of berberine (5 mg/kg, ip) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%)", and "1200‐2000 mg/d for at least 2 months significantly decreased total cholesterol levels and low‐density lipoprotein cholesterol without major adverse effects", and "500‐1500 mg daily for 3 months and they hypothesized that berberine induces a significant reduction in postprandial glucose levels", and "800 mg of berberine hydrochloride daily for 2 months, a trend of improvement was observed for IBS symptom scores compared with placebo", and "approximately 34.5% of patients treated with berberine (500 mg three times daily) experienced transient adverse gastrointestinal effects", and "Standard doses of berberine are usually well‐tolerated and adverse reactions are rare. In contrast, high doses have been associated with arterial hypotension, dyspnoea, flu‐like symptoms, gastrointestinal discomfort, constipation, and cardiac damage".
So this gets me to: My bottle says up to 400 mg twice a day. First study 500 mg twice a day. 2nd shows 5 mg/kg [this would be about 750 mg for me), 3rd 1200-2000, 4th 500-1500 mg, 5th 800 mg, 6th 34.5% get gastro problems at 500 mg 3 times a day, 7th high doses can cause serious problems.
It looks to me like 400 is too low, 1500 is too high, and 800 (400 twice a day) should hit the sweet spot. With food, just like the bottle says.
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The immunotoxic effects of the isoquinoline alkaloid berberine (BBR) were investigated in Balb/c mice. Here, BBR was administered daily by intraperitoneal injection at doses of 5 and 10 mg/kg for 14 days. Following the exposure, host spleen weight, cellularity and histopathology, as well as delayed-type hypersensitivity (DTH) responses, hemagglutination titers (HA), spleen cell subtype profiles, splenocyte cytokine production and lymphocyte proliferation were studied in all of the test groups of animals. The results showed that the high dose of BBR (10 mg/kg) could suppress both cellular and humoral immune functions in the treated hosts. BBR at 5 mg/kg only appeared to impact on DTH responses and lymphoproliferation. Based on the finding here, it would seem that BBR has effective immunosuppressive properties. Mechanistic studies are required to determine exactly how this material is acting to impart many of the immunotoxic effects demonstrated here. At the same time, further research should also be performed on BBR to further develop its potential use as an effective immunosuppressant or co-adjuvant for the treatment of diseases caused by an exaggerated or unwanted immune response."
I too am very interested in trying Berberine. I have heard of Amur Cork Tree Bark for PD, not knowing it is the same as Berberine. Have you found a good source you favor? Thank you!
Dave, Please post the spreadsheet results of, "...to look at each of them and determine the best dosage, when to take, whether to take with food, why I think they would help, and if I need to cycle them."
We should add what brand is best & best vale (as per Consumer Lab or some such.)
Effects of cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers 2011 pubmed.ncbi.nlm.nih.gov/216...
"Abstract
The effects of Cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers, and the compatibility mechanism of Jiao-Tai-Wan (JTW) composed of Rhizoma Coptidis granules and Cinnamon granules were investigated. The concentration of berberine in plasma of healthy male volunteers was determined directly by high performance liquid chromatography (HPLC) after an oral administration of Rhizoma Coptidis granules alone or combined with Cinnamon granules (JTW). The plasma concentration-time curves of berberine were plotted. The data were analyzed with Drug and Statistics (DAS) 2.0 pharmacokinetic program (Chinese Pharmacology Society) to obtain the main pharmacokinetic parameters. The results showed that the plasma concentration-time curve of berberine was described by a two-compartment model. The C(max), T(max), t(1/2) and CLz/F of berberine in Rhizoma Coptidis granules were 360.883 μg/L, 2.0 h, 3.882 h, 119.320 L·h(-1)·kg(-1) respectively, and those of berberine in JTW were 396.124 μg/L, 1.5 h, 4.727 h, 57.709 L·h(-1)·kg(-1) respectively. It was suggested that Rhizoma Coptidis granules combined with Cinnamon granules could increase the plasma concentration of berberine, promote berberine absorption and lengthen the detention time of berberine in healthy male volunteers."
I have read comments and a few knowledgeable blogs saying you should take a day off a week from Berberine, or go 8 weeks on and 2 weeks off, based on something like this: "Continual use of berberine can impact cytochrome P450 (CYP) enzymes in the liver which may affect drug-to-drug interactions. Therefore, it’s recommended to use it in a pulsed 8-week cycle with two to four weeks off, then starting again if symptoms have not resolved."
I am still reviewing scientific papers to support this cycling advice.
Dose-response of Berberine on Hepatic Cytochromes P450 mRNA Expression and Activities in Mice 2011 ncbi.nlm.nih.gov/labs/pmc/a...
"Ethnopharmacological relevance
Berberine is an isoquinoline alkaloid isolated from the root and bark of plants such as goldenseal, Berberis, and Chinese goldthread. Berberine-containing crude drugs have been used as an antimicrobial remedy against gastrointestinal infections for thousands of years. It is also widely used in Asian countries for diabetes, hypertension, and hypercholesterolemia therapy.
Aim of the Study
Potential drug-drug interactions are of concern because of the wide usage of berberine. A few studies have reported interactions between berberine and cytochromes P450 (CYPs) in vitro, but little is known about whether berberine influences CYPs in vivo, especially after repeated administration. In this study, eight-week-old male C57BL/6 mice were given berberine orally (0,10, 30, 100, 300 mg/kg, i.g., daily for 14 days), and the effect of berberine on over 20 major Cyps and related nuclear receptors in mice livers were examined at both the mRNA and enzyme activity levels.
Results
In general, liver function of mice treated with various doses of berberine had no significant change, and repeated oral administration of the 3 lower doses of berberine for 14 days did not affect the expression of genes examined. However, after the highest dose of berberine (300 mg/kg), Cyp3a11 and Cyp3a25 mRNA decreased 67.6 and 87.4%, respectively, whereas Cyp1a2 mRNA increased 43.2%, and enzyme activities of Cyp3a11 and Cyp2d22 decreased 67.9 and 32.4%, respectively. Cyp2a4, 2b10 and Cyp2c29 were not altered at both mRNA and enzyme activity levels.
Conclusions
If studies in mice extrapolate to humans, lower doses of berberine appear to present a low risk of producing drug-drug interactions as a result of changed Cyp enzyme activity. However, high doses of berberine may suppress Cyp activities and result in drug-drug interactions."
Yes, I was looking into this and since I'm taking a couple of pharmaceuticals that are primarily metabolized by CYP3A4, I'm reticent to try Berberine. I know these reactions are complex, but I wouldn't want to risk increasing blood concentration of those drugs.
Cytochrome P450 drugs: In human studies, repeated oral intake of berberine at a dose used in some studies significantly decreased CYP2D6, 2C9, and 3A4 activities (29).
Tacrolimus: In a pediatric patient with idiopathic nephrotic syndrome, clinically relevant increases in tacrolimus concentrations and renal toxicity occurred when berberine was added to control diarrhea (30).
Sulfonylureas: In vitro studies indicate that berberine coadministration may compromise the metabolism of sulfonylureas or mutually affect the metabolism of both compounds (32). Clinical relevance has yet to be determined.
Interesting info on the effect of Berberine on the microbiome: Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment 2021 hindawi.com/journals/ecam/2...
"3.4. Regulating Gut Microbiota
The ecological balance of the intestinal flora will have a significant impact on the therapeutic effect of drugs. Drug prototypes and their metabolites will have a certain impact on the number and abundance of the intestinal flora, resulting in changes in intestinal homeostasis, thus affecting disease occurrence and development [95]. Current studies have shown that metabolic syndrome is closely related to the role of intestinal flora, and abnormal metabolism of substances mediated by intestinal flora is a significant pathological mechanism of metabolic syndrome. Due to the low BBR bioavailability, the classical pharmacokinetic theory is not enough to fully explain its hypoglycemic effect. Therefore, many scholars believe that the BBR hypoglycemic effect is not produced after absorption, but plays a role in the intestine [33]. Chen et al. [96] showed that BBR did have the ability to regulate the intestinal flora, protect the intestinal mucosal barrier, resist inflammation, and inhibit glucose absorption. Moreover, Xu et al. demonstrated that BBR treatment significantly altered the overall intestinal microbiota structure and enriched many butyrate-producing bacteria, thereby reducing blood sugar levels and alleviating inflammation [97]. Through the regulation of these florae, the levels of blood lipids and blood sugar in patients with metabolic diseases can improve, and it has a positive effect on the treatment of obesity, hypertension, T2DM, and other diseases.
The intestinal microecological imbalance in patients with T2DM is mainly manifested by changes in the composition, abundance, and function of the intestinal flora. More than 90% of the human intestinal flora are phylum Firmicutes and Bacteroidetes, which can be divided into three categories: beneficial bacteria (Bifidobacterium, Bacteroides, Lactobacillus, Blautia, and so on), conditional pathogenic bacteria (Enterococcus, Escherichia coli, and so on), and harmful bacteria (Staphylococcus, Proteus, and so on) [98, 99]. Among them, Bifidobacterium and Lactobacillus can improve the level of inflammatory factors. In addition, blood lipids can also be reduced and antihypertensive substances (e.g., angiotensin-converting enzyme inhibitory peptides), which can directly or indirectly reduce blood pressure and improve the level of blood lipids in patients, can be produced. Firmicutes can increase the absorption of carbohydrates and fat in the human intestine (called fat bacteria), while the role of Bacteroides is just the opposite (called lean bacteria). The decrease of the ratio of Firmicutes/Bacteroides can inhibit the growth of Enterococcus faecalis in the intestinal tract and simultaneously promote the growth of beneficial bacteria and suppress the incidence of obesity. After BBR treatment, the abundance of Blautia and Bacteroides increased and the abundance of Faecalibacterium prausnitzii and Escherichia flora decreased. Meanwhile, the ratio of Bacteroides/Firmicutes restoration resulted in decreasing levels of blood sugar and blood lipids, as well as IR improvement [87, 100–102].
BBR mainly affects the short-chain fatty acid metabolism, bile acid metabolism of the intestinal flora, and chronic low-grade inflammation caused by increased LPS for diabetes treatment. Through certain metabolic pathways, the intestinal microflora can produce short-chain fatty acids, which can protect the intestinal mucosal barrier, regulate host energy intake and metabolism, reduce the level of blood glucose and blood lipids, alleviate chronic low-grade inflammation, and inhibit endotoxins [103, 104]. Animal experiments have proved that the intestinal flora produces butyrate and the content of butyrate in plasma or feces was significantly increased after BBR treatment, confirming that butyrate was an active endogenous metabolite that cooperated with BBR to lower blood lipids [75, 105]. BBR promoted the production of butyric acid bacteria through the acetyl-CoA-butyryl-CoA-butyrate pathway and enables it to synthesize butyrate, and butyrate then entered the blood, thus decreasing blood sugar and blood lipids [97, 104, 106].
Experiment results demonstrated that BBR could improve the intestinal microenvironment, thereby protecting the intestinal barrier function, which may be achieved by regulating intestinal microorganisms [87]. In the diabetic rat model, BBR treatment is efficient in improving endotoxemia, restoring intestinal permeability, and repairing the damaged intestinal mucosa and systemic inflammation by regulating intestinal microflora. Meanwhile, these effects of increasing endocrine regulatory peptide (peptide, PYY), regulating the GLP-1 and GLP-2 secretions, promoting the differentiation of L cells in the colon, and improving the intestinal peptide level in rats fed with a high-fat diet all resulted from BBR [107–109]. Farnesol X receptor (FXR) activation had a pretty favorable effect on the treatment of hyperlipidemia, hyperglycemia, and diabetes [110–112]. Moreover, Sun et al. proved that BBR could activate the FXR signal and directly affect intestinal flora to change bile acid metabolism, thereby improving diabetes and its complications [113]."
The GM is also known to affect drug metabolism, both directly and indirectly, and particularly with regards to drugs that are administered orally. Berberine reduces the levels of lipids and glucose in the blood via multi-target mechanisms, including modulation of the GM composition (Zhang et al., 2012). Berberine is also known to reduce the diversity of the GM and interfere with the relative abundance of Desulfovibrio, Eubacterium, and Bacteroides (Cui et al., 2018b). In addition, Bacteroides were shown to be enriched in the colon and terminal ileum of mice (C57BL/6) treated with berberine, but berberine treatment reduced the populations of Ruminococcus gnavu (Genus of Mediterraneibacter), Ruminococcus schinkii (Genus of Blautia), Lactobacillus acidophilus (Genus of Lactobacillus), Lactobacillus murinus (Genus of Ligilactobacillus), and Lactococcus lactis (Genus of Lactococcus) (Guo et al., 2016). Recent studies have shown that berberine has beneficial effects on the immune cells of the intestinal immune system and affects the expression of several intestinal immune factors. Berberine has also been shown to inhibit the mRNA expression of interleukin (IL)-1β, IL-4, IL-10, macrophage migration inhibitory factor (MIF), and tumor necrosis factor (TNF)-α, while also reducing low-grade inflammation (Gong et al., 2017). Short-term exposure to berberine alters the populations of intestinal bacteria by reducing the activity of Clostridium cluster XIVa and IV, and their bile salt hydrolase (BSH), thus leading to the accumulation of taurocholic acid (TCA). TCA can activate intestinal farnesoid X receptor (FXR) which can then mediate the metabolism of bile acids, lipids, and glucose (Tian et al., 2019). Butyrate is a short-chain fatty acid (SCFA) produced during fermentation of fibers and other substrates by an anaerobic bacteria resident in the gastrointestinal tract (Roediger et al., 1982). Berberine has also been shown to enrich the population of butyrate-producing bacteria in the GM, thus promoting the synthesis of butyrate via the acetyl CoA-butyryl CoA-butyrate pathway. Subsequently, the butyrate enters the blood and reduces the levels of lipids and glucose (Wang et al., 2017b).
The GM is known to play a key role in the development of metabolic disorders. One factor underlying the application of berberine treatment is that berberine can increase the rates of cellular glucose uptake and metabolism (Cok et al., 2011). Other research studies are investigating the effects of berberine against cancer. In this article, we review the role of the GM on non-transmissible diseases following berberine treatment."
This may be disturbing (or not): "Berberine treatment has also been shown to increase the abundance of Akkermansia in the intestine" frontiersin.org/articles/10...
"Akkermansia was consistently found to be more abundant in PD stool samples [39, 40, 43, 44, 50,51,52]. Akkermansia muciniphila is a recently identified mucin-dwelling species of the genus Akkermansia. A. muciniphila has been shown to mediate glucose tolerance via an IFNγ dependent mechanism and protect against obesity in mice [62]. Additionally, reduced levels of A. muciniphila in gut microbiota were reported for children with asthma [63]. A recent study showed that A. mucniphila can induce different T-cell responses based on the other species present in a given microbiota [64]. This can then explain why A. muciniphila, generally thought to mediate anti-inflammatory effects, has surprisingly been shown to be over-abundant in PD feces compared to controls." translationalneurodegenerat...
So this is how my HS Graduate brain is understanding this information:
1: PwP have a lot more Akkermansia in their intestines.
2: Berberine may generate more Akkermansia.
3: Akkermansia is anti-inflammatory in the mucus.
My guess is Akkermansia is not causing the problem with PD but is trying to address the inflammation. So I don't think more Akkermansia is a bad thing.
"Research has shown that berberine fumarate (BF) may play a hypoglycemic role in rats with DM by regulating GM and metabolism. The administration of BF has been shown to significantly ameliorate metabolic disorders, and increase the populations of Bacteroidetes, Clostridia, Lactobacillales, Prevotellaceae, and Alloprevotella." ncbi.nlm.nih.gov/labs/pmc/a...
So it looks like Berberine could boost Prevotellaceae (and that might be a good thing).
I am taking 1600 mg/day total. I take it a half hour before eating. Not everyone can tolerate that dose as it can cause upset stomach in some people. Slowly increasing the dose can help some people to overcome the gastro discomfort. I have gone as high as 2000mg/day, but did not feel the need to maintain that high of a dose because 1500 mg in studies seems to be adequate for obtaining significant health benefits.
I'm trying for reduced glucose and A1c along with reduced inflammation. My primary told me that my last test showed my HbA1c is at the top of the normal range, so I am trying to be proactive. Based on studies, Berberine should be useful as a first line treatment to prevent reaching into the prediabetes range.
In PD, insulin resistance is common and Berberine is useful in decreasing insulin resistance while also helping to increase dopamine. It has anti oxidative stress effects as well as anti inflammatory effects and neuroprotective effects. The anticancer effects are also good.
Berberine is a major component in TCM and has shown benefit in multiple areas of health besides diabetes. Berberine has very poor bioavailability, but is quite effective at manipulating the gut microbiome toward a healthier bias, if the dose is high enough. I think this is its main method of action, gut microbiome manipulation.
Another reason I am taking it is for its synergy with melatonin which is important in the effects they have together.
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