Berberine

My Dose:

• 400 mg 3 times a day (2 x 400 mg at 9 AM and 1 x 400 mg at 9 PM).

Effects of Berberine:

1. Lowers blood glucose levels (1).

2. Reduces insulin resistance (2).

3. Regulate blood glucose and blood lipid (2).

4. Reduce the level of inflammatory response in the body (2).

5. Berberine is a potent oral hypoglycemic agent with beneficial effects on lipid metabolism (3).

6. Boosts brain function (4).

7. Can suppress the expression of inflammatory factors in PD patients and improve the disorder of intestinal flora (5).

8. Oral administration of berberine hydrochloride can trigger the biosynthesis of BH4 in the intestinal flora, increase the blood and brain dopa/dopamine concentration to enhance TH activity to produce L-dopa (5).

9. After treatment, the levels of IL-8, IL-6, and TNF-α were lower in the observation group than those in the control group (5).

10. Recent evidence suggests that berberine inhibits the production of neuroinflammation, oxidative, and endoplasmic reticulum stress (6).

11. Berberine normalizes the production of inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β (6).

12. Berberine inhibits cell death induced by 6-OHDA, and increases the expression of HO-1, ultimately protecting dopaminergic neurons (6).

13. Preclinical studies have found that berberine increases the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, at the same time, berberine also increases striatum dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid levels (Shin et al., 2013) (6).

14. Meanwhile, there are several studies offer some important insights into the neurotoxic effects of berberine. It is reported that in the Parkinson’s disease model rats induced by 6-OHDA, berberine aggravate the degeneration of dopaminergic neuron in the substantia nigra of rats (Shin et al., 2013). In addition, berberine can aggravate the cytotoxicity induced by 6-OHDA in PC12 cells and aggravate of dopaminergic neuron death (Kwon et al., 2010) (6).

15. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content (7).

16. Subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury (7).

17. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine (7).

18. Pharmacological data suggest that berberine has poor bioavailability and that only nanomolar plasma concentrations are reached in both humans and animals [20]. According to several reports, however, BBR accumulates in organs such as lungs, liver and the brain, resulting in effective concentrations in the low micromolar range (7).

19. Our study raises concerns of acute BBR neurotoxicity due to its prominent effects on mitochondria and NMDA receptors, especially when applied at micromolar concentrations close to the levels suggested to be attainable by oral dosing (7).

20. Recently, Pereira et al. characterized the effects of BBR on melanoma cell mitochondria as well as isolated mitochondrial fractions [22], [35]. They demonstrated that BBR can accumulate in mitochondria causing mitochondrial depolarization and fragmentation, mitochondrial PTP induction, increased oxidative stress, decreased cellular ATP content, and cell cycle arrest [35]. Our results from primary neurons support these findings. While these effects may be desirable for antitumor agents, they may also cause toxicity in neurons, which are sensitive to metabolic disturbances and thus particularly sensitive to mitochondrial dysfunction [40], [41], [63], [66]. Our current results suggest that mitochondria are centrally involved in the toxic effects of BBR in neurons (7).

21. One key point seems to be that, while BBR is not very bio-available, over time it accumulates in the brain (7).

22. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic L-DOPA administration. Long-term L-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms (8).

23. These results suggested that berberine aggravated 6-OHDA-induced cytotoxicity in PC12 cells, and led to the degeneration of dopaminergic neuronal cells in the substantia nigra of 6-OHDA-lesioned rats. It is, therefore, suggested that the use of long-term l-DOPA therapy with isoquinoline derivatives including berberine may need to be examined for the presence of adverse symptoms (9).

24. BBR protected neurons from apoptosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) through the down regulation of the Bcl2/Bcl-2-associated X protein (BAX) ratio, through AMP-activated protein kinase (AMPK)-dependent enhancement of autophagy, or by preventing NLRP3 inflammasome activation. In the 6-hydroxydopamine-induced PD model, BBR reduced ROS production, caspase-3 activation, and subsequent neuronal death (10).

25. BBR also increased the expression of tyrosine hydroxylase (TH), a rate-limiting Cells enzyme for dopamine synthesis, to promote neurogenesis (10).

26. Additionally, a recent study demonstrated that BBR could ameliorate PD by regulating gut microbiota (10).

27. BBR enhanced TH to produce L-dopa by triggering the biosynthesis of tetrahydrobiopterin in the gut microbiota and subsequently led to an increased brain dopa level, therefore improving brain function in MPTP-induced PD mice (10).

28. In addition, rotenone is also widely used to establish PD models, whereas the effect of BBR on the rotenone model is less well understood and controversial. There is no in vivo study of BBR on the rotenone-induced PD model. For the in vitro efficacy, Kysenius and colleagues claimed that the subtoxic nanomolar concentration (30 nM) of BBR could sensitize neurons to rotenone injury, while Han and colleagues found that BBR protected SH-SY5Y cells from rotenone injury by activating the antioxidant and PI3K/AKT signaling pathway (10).

29. Collectively, BBR maintains neural viability in PD models. BBR not only lessens neuron loss, but also promotes neurogenesis (10).

30. Restore autophagic function (10).

31. The results of this study show that the natural compound berberine demonstrates a superior ability to reduce excess iron and chelate it in tissues, including liver, kidney and lung. By reducing oxidative stress, it can also improve the activity of the antioxidant enzymes catalase and superoxide dismutase. This remarkable ability of berberine is comparable to and often superior to that of deferoxamine as a common chelator (11).

32. We showed that treatment with berberine significantly ameliorates the degeneration of dopaminergic neurons in substantia nigra compacta (SNc) and improves motor impairment in MPTP-treated mice (12).

33. Berberine also significantly decreased the level of α-synuclein and enhanced the microtubule-associated protein light chain 3 (LC3-II)-associated autophagy in the SN of MPTP-treated mice (12).

34. Furthermore, adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) was activated by berberine (12).

35. This study discovered first that the gut microbiota is a new source of dopa/dopamine in the body, and second, BBR enhanced TH to produce L -dopa by triggering the biosynthesis of BH 4 in the gut microbiota. As BBR has been an OTC drug for many years, it might have immediately applicable potential in regulating gut–brain dialog and improving brain function in humans (13).

36. BBR can influence the gut microbiota composition and metabolism by directly interacting with gut microbiota, thus assisting in the amelioration of diseases (13).

37. BBR is a natural compound with direct antibacterial effects (14).

38. BBR (32 μg/mL) can inhibit the growth of Candida albicans by inhibiting biofilm formation, and 128 μg/mL (14).

39. BBR can inhibit methicillin-resistant Staphylococcus aureus (S. aureus) (14).

40. When Escherichia coli (E. coli) is exposed to BBR (750 μg/mL), the cellular lifespan of E. coli decreases with prolonged exposure time (14).

41. In addition, BBR has direct inhibitory effects on bacteria such as Clostridium difficile, Actinobacillus, and Bacillus subtilis (14).

References

1. Berberine Drug Interactions: https://www.rxlist.com/berberine/supplements.htm

2. Effects of berberine on glucose-lipid metabolism, inflammatory factors and insulin resistance in patients with metabolic syndrome https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434235/

3. Efficacy of Berberine in Patients with Type 2 Diabetes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/

4. Plant Compound Berberine May Boost Brain Function https://parkinsonsnewstoday.com/news/plant-compound-berberine-brain-function-parkinsons-study/

5. Effect of Berberine Hydrochloride on the Diversity of Intestinal Flora in Parkinson’s Disease Patients https://www.hindawi.com/journals/cmmi/2022/8381870/

6. Berberine: A Promising Treatment for Neurodegenerative Diseases 2022 https://www.frontiersin.org/articles/10.3389/fphar.2022.845591/full

7. Mitochondria and NMDA Receptor-Dependent Toxicity of Berberine Sensitizes Neurons to Glutamate and Rotenone Injury 2014 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107129

8. Neurotoxic effects of berberine on long-term L-DOPA administration in 6-hydroxydopamine-lesioned rat model of Parkinson's disease 2013 https://pubmed.ncbi.nlm.nih.gov/23539311/

9. Effects of berberine on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and a rat model of Parkinson's disease 2010 https://pubmed.ncbi.nlm.nih.gov/20851167/

10. Therapeutic Efficacies of Berberine against Neurological Disorders: An Update of Pharmacological Effects and Mechanisms https://mdpi-res.com/d_attachment/cells/cells-11-00796/article_deploy/cells-11-00796.pdf

11. Berberine Is a Promising Alkaloid to Attenuate Iron Toxicity Efficiently in Iron-Overloaded Mice https://journals.sagepub.com/doi/full/10.1177/1934578X211029522

12. Protective effects of berberine against MPTP-induced dopaminergic neuron injury through promoting autophagy in mice https://pubs.rsc.org/en/content/articlelanding/2021/fo/d1fo01360b

13. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota https://www.nature.com/articles/s41392-020-00456-5.pdf?proof=t%25C2%25A0

14. Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine https://www.sciencedirect.com/science/article/pii/S2095177921001179

15. Enhanced Clearance of Neurotoxic Misfolded Proteins by the Natural Compound Berberine and Its Derivatives 2020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279252/

16. Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential 2019 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712296/

Berberine Precautions and Drug Interactions:

https://www.rxlist.com/berberine/supplements.htm

Precautions:

• 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.

There are quite a few Berberine drug interactions (This list may not be complete):

• Cyclosporine (Neoral, Sandimmune) Interaction Rating: Major Do not take this combination.

The body breaks down cyclosporine (Neoral, Sandimmune) to get rid of it. Berberine might decrease how fast the body breaks down cyclosporine (Neoral, Sandimmune). Cyclosporine (Neoral, Sandimmune) might build up in the body and could possible cause side effects. Cyclosporine is used for people with organ transplants.

• Medications for diabetes (Antidiabetes drugs) Interaction Rating: Major Do not take this combination.

Berberine might lower blood sugar. Diabetes medications are also used to lower blood sugar. Taking berberine along with diabetes medications might cause your blood sugar to go too low. Monitor your blood sugar closely. The dose of your diabetes medication might need to be changed.

Some medications used for diabetes include glimepiride (Amaryl), glyburide (Diabeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others.

• Dextromethorphan (Robitussin DM, and others) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

The body breaks down dextromethorphan (Robitussin DM, others) to get rid of it. Berberine might decrease how quickly the body breaks down dextromethorphan (Robitussin DM, others). Taking berberine while taking dextromethorphan (Robitussin DM, others) might increase the effects and side effects of dextromethorphan (Robitussin DM, others).

• Losartan (Cozaar) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

The liver activates losartan (Cozaar) to make it work. Berberine might decrease how quickly the body breaks down losartan (Cozaar). Taking berberine while taking losartan (Cozaar) might decrease the effects of losartan.

• Medications changed by the liver (Cytochrome P450 2C9 [CYP2C9] substrates) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Some medications are changed and broken down by the liver. Berberine might decrease how quickly the liver breaks down some medications. Taking berberine along with some medications that are broken down by the liver can increase the effects and side effects of some medications. Before taking berberine, talk to your healthcare provider if you are taking any medications that are changed by the liver.

Some medications changed by the liver include celecoxib (Celebrex), diclofenac (Voltaren), fluvastatin (Lescol), glipizide (Glucotrol), ibuprofen (Advil, Motrin), irbesartan (Avapro), losartan (Cozaar), phenytoin (Dilantin), piroxicam (Feldene), tamoxifen (Nolvadex), tolbutamide (Tolinase), torsemide (Demadex), and S-warfarin (Coumadin).

• Medications changed by the liver (Cytochrome P450 2D6 [CYP2D6] substrates) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Some medications are changed and broken down by the liver. Berberine might decrease how quickly the liver breaks down some medications. Taking berberine along with some medications that are broken down by the liver can increase the effects and side effects of some medications. Before taking berberine, talk to your healthcare provider if you are taking any medications that are changed by the liver.

Some medications changed by the liver include amitriptyline (Elavil), codeine, desipramine (Norpramin), flecainide (Tambocor), haloperidol (Haldol), imipramine (Tofranil), metoprolol (Lopressor, Toprol XL), ondansetron (Zofran), paroxetine (Paxil), risperidone (Risperdal), tramadol (Ultram), venlafaxine (Effexor), and others.

• Medications changed by the liver (Cytochrome P450 3A4 [CYP3A4] substrates) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Some medications are changed and broken down by the liver. Berberine might decrease how quickly the liver breaks down some medications. Taking berberine along with some medications that are broken down by the liver can increase the effects and side effects of some medications. Before taking berberine, talk to your healthcare provider if you are taking any medications that are changed by the liver.

Some medications changed by the liver include cyclosporin (Neoral, Sandimmune), lovastatin (Mevacor), clarithromycin (Biaxin), indinavir (Crixivan), sildenafil (Viagra), triazolam (Halcion), and many others.

• Medications for high blood pressure (Antihypertensive drugs) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Berberine might decrease blood pressure in some people. Taking berberine along with medications used for lowering high blood pressure might cause your blood pressure to go too low. However, it's not known if this is a big concern. Do not take too much berberine if you are taking medications for high blood pressure.

Some medications for high blood pressure include include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), amlodipine (Norvasc), hydrochlorothiazide (HydroDIURIL), furosemide (Lasix), and many others.

• Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Berberine might slow blood clotting. Taking berberine along with medications that also slow clotting might increase the chances of bruising and bleeding.

Some medications that slow blood clotting include aspirin, cilostazol (Pletal), clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and others.

• Midazolam (Versed) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

The body breaks down midazolam (Versed) to get rid of it. Berberine can decrease how quickly the body breaks down midazolam (Versed). Taking berberine along with midazolam (Versed) might increase the effects and side effects of midazolam (Versed).

• Sedative medications (CNS depressants) Interaction Rating: Moderate Be cautious with this combination. Talk with your health provider.

Berberine might cause sleepiness and drowsiness. Medications that cause sleepiness are called sedatives. Taking berberine along with sedative medications might cause too much sleepiness.

Some sedative medications include benzodiazepines, pentobarbital (Nembutal), phenobarbital (Luminal), secobarbital (Seconal), thiopental (Pentothal), fentanyl (Duragesic, Sublimaze), morphine, propofol (Diprivan), and others.