Chen C, Tao C, Liu Z, et al. A randomized clinical trial of berberine hydrochloride in patients with diarrhea-predominant irritable bowel syndrome. Phytother Res. 2015;29(11):1822-1817.
In this 14-week single-center, double-blind, placebo-controlled clinical trial, patients were randomized into 2 groups, after a 2-week run-in, to receive either study medication or placebo taken twice a day for 8 weeks. Treatments were discontinued after 8 weeks and the patients followed for an additional 4 weeks.
All participants fulfilled the inclusion criteria based on the Rome III classification system for irritable bowel syndrome-diarrhea predominant (IBS-D). Between May 2011 and January 2015, 196 patients with IBS-D, aged 18 to 65 years, were recruited for this study from the Tenth People’s Hospital of Shanghai, Tongji University School of Medicine, Shanghai, China. A number of these patients were either excluded or unable to complete the study. In the end, 70 patients in the berberine group and 62 in the placebo group completed the study. Patients ranged in age from 19 to 61 years in berberine group and from 18 to 65 years in placebo group.
Study Medication and Dosage
Berberine hydrochloride 200 mg twice a day was the active medication. Vitamin C, 200 mg twice a day, was used as the placebo. Both products were made by Shanghai Sine Tianping Pharmaceutical Co., Ltd.
Diarrhea, abdominal pain, urgent need for defecation, frequency, and any adverse events were assessed via daily questionnaires. Prior to administration of the medication and after completing the treatment, IBS symptom scores, depression and anxiety scale scores, and the IBS scale for quality of life (QOL) were assessed.
Both the berberine and the placebo groups reported a reduction in symptoms during the 8 weeks they took medication, though the placebo group reported less benefit. At week 8, diarrhea frequency was significantly lower in the berberine group than the placebo group (P=0.032).
The berberine group, but not the placebo group, reported less urgency and frequency in defecation starting in week 4 and persisting through week 8 (P<0.01).
Both groups reported less abdominal pain during the 8 weeks of treatment. In the berberine group significant reductions in pain frequency were seen starting in week 3 of the study and continuing through week 8. The pain frequency scores for week 8 represented a 64.6% (1.54 ± 0.26 vs 4.35 ± 0.58) reduction compared with initial scores. In the placebo group the final score represented a 29.4% (2.88 ± 0.37 vs 4.08 ± 0.23) reduction. The pain reduction was significantly greater in the berberine group than in the placebo group on week 6 (P<0.01) and week 8 (P<0.01).
Berberine significantly decreased overall IBS symptom score, anxiety score, and depression score (P<0.01). Berberine treatment was also associated with an increased QOL score (P<0.05). No significant changes were seen on these scores in the placebo group (P>0.05).
The overall IBS symptoms score, anxiety score, and depression score were significantly lower in the berberine group compared to the placebo (P<0.05).
Berberine may be an effective way to manage symptoms of IBS-D.
IBS is a common disorder that reduces patients' quality of life. It is a chronic condition characterized by abdominal pain or discomfort associated with disordered defecation but the absence of identifiable structural or biochemical abnormalities. Alteration in neurohumoral mechanisms and psychological factors, bacterial overgrowth, genetic factors, gut motility, visceral hypersensitivity, and immune system factors are theorized to underlie IBS, but a clear understanding of etiology still eludes us. At this point IBS treatment is dictated by the patient's most bothersome symptoms.1
The overall IBS symptoms score, anxiety score, and depression score were significantly lower in the berberine group compared to the placebo.
This clinical trial reveals 2 things. First, and most importantly, that berberine is effective in the treatment of IBS when the predominant symptom is diarrhea. The second is that many patients may also experience some benefit from simply taking a placebo.
Berberine’s beneficial actions are more complex and far-reaching than previously thought. In the past we considered only its antibiotic properties, narrowly employing it to treat infectious gastritis. In this trial by Chen et al, patients who took berberine not only experienced reduced frequency, urgency, diarrhea, and abdominal discomfort, they also experienced significant reductions in anxiety and depression.
The berberine used in this study was isolated from Chinese goldthread rhizome (Coptis chinensis). In North America, commercial sources are generally extracted from Oregon grape (Mahonia aquifolium).
Berberine itself has antimicrobial action, but it also enhances the action of some antibiotics against common oral streptococcus species.2 It also has an antifungal action and a synergistic action when given in combination with antifungal drugs.3 Berberine’s effect on diarrhea is more complex. It limits secretory diarrhea in part by enhancing absorption of sodium and water from the intestinal lumen.4 Berberine significantly increases pain tolerance in rats by affecting nitric oxide pathways.5 It slows gastrointestinal motility, apparently by activating opioid pathways,6 an action that is perhaps also responsible for the increased pain tolerance.
While the benefits of berberine exceeded those reported in the vitamin C group, the placebo did have significant benefit at least during some weeks of this trial. Placebo benefit is common in IBS studies. A 2010 meta-analysis by Ford and Moayyedi identified 73 randomized controlled trials (RCTs) that included 8,364 patients with IBS allocated to placebo. The pooled placebo response rate was 37.5% [95% confidence interval (CI): 34.4%-40.6%]. Response rates were higher in European RCTs, RCTs that used physician-reported outcomes, and RCTs using shorter duration of therapy.7 While this study was conducted in China, the 29.4% placebo response is remarkably close to Ford’s result. This placebo effect must be kept in mind when treating patients with IBS; about a third will respond even to a placebo for some period of time.
Berberine also has many parallel uses to the drug metformin. Both increase insulin sensitivity and are used to treat type 2 diabetes mellitus and polycystic ovary syndrome (PCOS).8-9 Both have similar actions on the gut microbiome, decreasing bacterial diversity and increasing production of short-chain fatty acids.10 Yet they seem to have different effects on gastric motility. For many patients, metformin causes diarrhea and even vomiting through still-unknown mechanisms.11
These current results on IBS raise the question—could berberine help reduce some of the gut-related side effects of metformin? At this point there are no reports in the medical literature to inform us; however, it certainly is tempting to prescribe berberine to patients taking metformin, in particular those with digestive upset that they attribute to the drug. Of course, potentiation of effects may be expected and close monitoring of serum glucose would be warranted.
There is a cautionary bit of information related to berberine that is newly reported in the literature. In August 2015, Zhi et al reported that berberine acts in combination with 2 macrolide antibiotics, azithromycin (Zithromax) and clarithromycin (Biaxin), to block the hERG channels that regulate cardiac repolarization, increasing the risk of long QT syndrome (LQTS). Berberine combined with clarithromycin also significantly inhibits cytochrome P450 3A (CYP3A).12 While this was a preliminary study, it should caution us against the use of berberine in combination with either of these antibiotics or with drugs that are dependent on CYP3A action.
- Lazaraki G, Chatzimavroudis G, Katsinelos P. Recent advances in pharmacological treatment of irritable bowel syndrome. World J Gastroenterol. 2014;20(27):8867-8885.
- Dziedzic A, Wojtyczka RD, Kubina R. Inhibition of oral streptococci growth induced by the complementary action of berberine chloride and antibacterial compounds. Molecules. 2015;20(8):13705-13724.
- Liu H, Wang L, Li Y, et al. Structural optimization of berberine as a synergist to restore antifungal activity of fluconazole against drug-resistant Candida albicans. ChemMedChem. 2014;9(1):207-216.
- Zhang Y, Wang X, Sha S, et al. Berberine increases the expression of NHE3 and AQP4 in sennosideA-induced diarrhoea model. Fitoterapia. 2012;83(6):1014–1022.
- Tang QL, Lai NL, Zhong YF, Wang AM, Su JK, Zhang MQ. Antinociceptive effect of berberine on visceral hypersensitivity in rats. World J Gastroenterol. 2013;19(28):4582–4589.
- Feng Y, Li Y, Chen C, et al. Inhibiting roles of berberine in gut movement of rodents are related to activation of the endogenous opioid system. Phytother Res. 2013;27(10):1564–1571.
- Ford AC, Moayyedi P. Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome. Aliment Pharmacol Ther. 2010;32(2):144-158.
- Zhang H, Wei J, Xue R, et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59(2):285-292.
- Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012;166(1):99-105.
- Zhang X, Zhao Y, Xu J, et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5:14405.
- Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabetes Metab. 2011;37(2):90-96.
- Zhi D, Feng PF, Sun JL, et al. The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides. Eur J Pharm Sci. 2015;76:149-155.