Berberine is a quaternary ammonium salt belonging to the protoberberine subclass of benzylisoquinoline alkaloids, distributed in the roots, rhizomes, and stems of over 500 plant species indigenous to Asia and North America, including the medicinal species Hydrastis canadensis (goldenseal), Coptis chinensis (Coptis or goldenthread), Berberis aquifolium (Oregon grape), and Berberis vulgaris (barberry) (Kumar et al, 2015; Singh and Sharma, 2018). Through antiproliferative and anti-adhesive actions, berberine inhibits a wide range of microbial pathogens including Staphylococci, Streptococci, Salmonella, Clostridium, H. pylori, Shigella, Vibrio, and Cryptococci. Accordingly, berberine-containing plants have an extensive history in Ayurvedic and Chinese medicine, as antibacterial, antifungal and antidiarrheal agents, with medicinal use dating back over 2,500 years (Birdsall et al, 1997; Domandia et al, 2008). Multifarious actions in the host intestine include remediation of mucosal damage and anti-inflammatory effects, which are thought to contribute to its utility in chronic, non-infectious conditions such as irritable bowel syndrome and inflammatory bowel disease (Chen et al, 2015; Habtermariam, 2016).
In 1998, berberine was reported to ameliorate hyperglycemia in diabetic patients undergoing treatment for diarrhea (Ni et al, 1988). Lipid-lowering effects were later demonstrated and confirmed in multiple human intervention trials (Kong et al, 2004). Diabetes, metabolic syndrome and dyslipidemia have since comprised the predominant focus of clinical research, with the totality of evidence supporting insulin sensitizing and cholesterol-reducing efficacy at doses of 500-1500 mg/day as berberine hydrochloride (Zeng et al, 2003; Kong, et al, 2004; Zhang et al, 2008; Zhang et al, 2010; Dong et al, 2012; Wei, et al, 2012; Perez-Rubio et al, 2013; Lan et al, 2015; Yan et al, 2015).
An eclectic repertoire of protein interactions, genomic signatures and gut microbial shifts has emanated from the preclinical literature, collectively suggesting a mechanistic departure from all other dietary ingredients. While metabolic effectors bear partial redundancy with polyphenols and metformin (e.g. AMPK activation), new findings underscore unique and esoteric targets such as the LDL receptor regulator PCSK9 (proprotein convertase subtilisin/kexin type 9), which contributes to lipid-lowering effects in humans (Lee et al, 2006; Pirillo and Catapano, 2015; Dong et al, 2015).
In integrative and functional medicine, berberine is gaining recognition as an evidence-based modality for highly prevalent metabolic conditions in the U.S., for which there is a growing demand for alternative and complementary options. Thus, berberine has the potential for significant consumption as both a single agent and adjunct. A critical examination of the safety of this compound is warranted for several reasons. First, it is worth noting that isolated plant alkaloids have seldom appeared on the dietary supplement market. Moreover, the divergent pharmacological behaviors of berberine may potentially extend to a distinctive and unfamiliar risk profile. In addition, doses required for metabolic application exceed those for historical antimicrobial uses; further, berberine is now preferred as a pure salt, not as constituent of whole herbs or extracts that have more extensive safety records. Exposure may be further amplified by the continuous use encouraged by the chronicity of metabolic disorders. Finally, the potential for berberine to disrupt intestinal microbial ecology with long-term treatment is a tenable point of speculation appearing in Natural Standard, which advises caution “when taking longer than eight weeks due to theoretical changes in bacterial gut flora.”
Bioavailability & pharmacokinetics in humans
The massive oral doses needed to cause systemic toxicity are underpinned by the reported absolute oral bioavailability of <1%, which is due to limited aqueous solubility, low passive permeation, post-absorptive efflux and pre-systemic biotransformation (Chae et al, 2008; Chen et al., 2011; Liu et al, 2016; Feng et al, 2018). The absorbed fraction is subject to extensive pre-systemic demethylation, demethylenation, reduction, hydroxylation and subsequent conjugation. Of these reactions, hepatic CYP2D6 is pivotal, metabolizing the majority of the small fraction reaching the liver (Guo et al, 2011). In humans given berberine orally at lipid-lowering doses (900-1500 mg/day), peak plasma levels only reach 0.004 to 0.40 mg/ml after one dose, at best (Hua et al, 2007; Li et al, 2008) and 6.1 ± 4.9 ng/ml after 3 months at daily dosing of 1000 mg (Zhang et al, 2008). Plasma levels and tissue distribution of metabolites, generated by xenobiotic metabolizing enzymes and by intestinal microbiota, may exceed those of the parent compound (Tan et al, 2013; Feng et al, 2018). However, their contribution to the clinical pharmacology of berberine in humans remains unclear.
Such modest exposure of target tissues to the parent compound offers a viable explanation for why inhibition of certain proteins of toxicological significance in vitro (e.g. cardiac hERG channels, IC50= 1-100 μM; Yu et al, 2017) is not overtly evident in humans taking supplements. Such interactions would require profound bioavailability enhancement or parenteral administration to become clinically manifest. The low micromolar IC50 range for a variety of protein target inhibitions in vitro is thousands of times greater than plasma berberine levels in orally supplemented humans (Wang et al, 2018), questioning the translational viability of many in vitro investigations performed thus far.
Drug interactions
Numerous studies have explored potential influences of isolated berberine on phase I drug metabolism (cytochromes p450), but only a small number of these interactions have been validated in vivo. In human liver microsomes, berberine inhibits CYP2D6 (IC50 =45 μM) and to a lesser extent, CYP2C9 and CYP3A4 (IC50 ~400 μM) (Etheridge et al, 2007). Partial P-glycoprotein (P-gp) and CYP3A4 blockade are implicated in a well-documented interaction with cyclosporin A (Pan et al, 2002; Wu et al, 2005; Xin et al, 2006; Qiu et al, 2009; Columbo et al, 2014). The interaction has been demonstrated at doses as low as 300 mg berberine/day in healthy volunteers (Xin et al, 2006).
In a two-phase randomized-crossover clinical study in healthy male subjects, berberine (300 mg t.i.d., p.o. for two weeks) resulted in plasma elevations of co-administered CYP2D6, CYP2C9 and CYP3A4 substrates. Berberine increased plasma accumulation of dextromethorphan, losartan and midazolam, probe drugs for CYP2D6, CYP2C9 and CYP3A4, respectively (Guo et al, 2012; Li et al, 2016). These interactions justify caution when using berberine in conjunction with these agents.
Of all the p450 enzymes interrogated with regard to berberine thus far, CYP2D6 is most sensitive to inhibition (Etheridge et al, 2007; Guo et al 2012). Since CYP2D6 is paramount to phase I biotransformation of berberine itself, substrate competition is a probable mechanism of catalytic blockade (Guo et al, 2012). Given the relatively high potency of this interaction, together with supporting clinical evidence, special mention of CYPD26 in cautionary statements should be considered. It is should be noted that highly prevalent CYP2D6 “slow metabolizer” genotypes are generally more vulnerable to interactions of this nature. Since berberine is a CYP2D6 substrate, risk allele carriers may also acquire higher plasma levels than normal- and fast-metabolizers.
Berberine’s potential for pharmacodynamic interactions with antihypertensive drugs is mentioned ubiquitously in the clinical reference literature. Natural Medicines Comprehensive Database and Natural Standard also advise caution with glucose-lowering drugs. Despite the theoretical basis for these interactions, such warnings in product literature are prudent.
Effects on intestinal microbiota
According to Natural Medicines Comprehensive Database, “in vitro research shows that berberine can inhibit the growth of certain probiotic species, including Bifidobacterium longum and Bifidobacterium bifidum” citing a study using a preliminary antibiotic paper disk assay (Chae et al, 1999). These findings were never corroborated, and similar studies of berberine’s effects on these species in vitro is lacking.
In contrast, multiple studies support a selective and beneficial influence on gut bacteria in animals with diet-induced metabolic deregulation, in which berberine enriches beneficial taxa in conjunction with amelioration of systemic metabolic pathology (Xie et al, 2011; Zhang et al, 2012; Zhang et al, 2015; Wang et al, 2017; Sun et al, 2017; Li et al, 2016). Improvements in metabolic parameters correlated with growth of short-chain fatty acid (SCFA)-producing symbionts, including Allobaculum, Bacteriodes, Blautia, Butyricoccus, and Phascolarctobacterium, with simultaneous increases in Lactobacilli (Xie et al, 2011; Zhang et al, 2012; Zhang et al, 2015; Li et al, 2016). Restoration of Bifidobacteria, Akkermansia and the ratio of Bacteroidetes/Firmicutes with berberine treatment accompanied reversal of diet-induced metabolic and vascular dysregulation (Cao et al, 2016; Zhu et al, 2018). In dogs, levels of butyrate, a therapeutically active SCFA, increased by 1.3 fold in plasma after 7 days of oral berberine treatment (Feng et al, 2018).
Taxonomic shifts in the microbiota are now believed to play a role in berberine-induced reversal of hypercholesterolemia and insulin resistance. Attenuation of intestinal permeability and metabolic endotoxemia may also occur via the microbiota (Han et al, 2011; Xu et al, 2017). The possibility that the clinical effects of berberine ramify from primary influences at the gut level offers a potential explanation for its remarkable efficacy despite modest systemic exposures.
The discourse on diabetes drugs and their interface with the microbiome is not new. Emerging research on metformin, a widely prescribed hypoglycemic drug with antimicrobial properties, underscores modification of the microbiota as a potential mechanism of action (Lee et al, 2014; Wu et al, 2016; Malik et al, 2018). Metformin’s taxonomic imprints bear several similarities with those of berberine (Zhang et al, 2015). Like berberine, metformin significantly augments SCFA-producing bacterial genera, along with Akkermansia and Bifidobacteria (Shin et al, 2014; Montandon et al, 2017). From a safety standpoint, redundant effects of these drugs offers some qualified reassurance that many effects of berberine on gut bacteria have been seen before, and are likely to occur in a large proportion of the population receiving ongoing metformin thearpy. Naturally, the similarities also evoke skepticism as to whether changes in the microbiota occur as a corollary of systemic metabolic improvements, and would therefore be achievable with any antidiabetic modality. Lessons learned from metformin may inform future research directions for berberine.
Although preliminary, the totality of preclinical evidence does not support untoward effects of berberine on the gut bacterial profile. To date, no controlled investigations have examined berberine’s influences on the taxonomic signatures in humans. Given the critical contributions of intestinal microecology to general health, clarifying these obscurities in humans will be vital to confirming the long-term safety of berberine.
Conclusions
Berberine is not well absorbed into the systemic circulation. The intestinal microbiota may comprise a target organ where berberine imparts modifications that improve insulin sensitivity.
Berberine is generally well tolerated. Adverse effects reported in the clinical literature include mild to moderate nausea, vomiting, abdominal bloating, and constipation.
Caution is advised for patients taking drugs metabolized by CYP2C9 and CYP3A4, particularly losartan and midazolam. Berberine may increase blood levels of these drugs.
Berberine may inhibit CYP2D6, so use caution when using berberine in combination with dextromethorphan and other drugs metabolized by this enzyme.
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Integrative Pharmacology 