Berberine

{{short description|Quaternary ammonium cation}} {{Use American English|date=August 2025}} {{Use dmy dates|date=August 2025}} {{cs1 config|name-list-style=vanc|display-authors=3}} {{chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 457785306 | ImageFile1_Ref = {{chemboximage|correct|??}} | ImageFile1 = Berberin.svg | ImageClass1 = skin-invert-image | ImageSize1 = | ImageFile2_Ref = {{chemboximage|correct|??}} | ImageFile2 = Berberine 3D.png | ImageClass2 = bg-transparent | ImageSize2 = | IUPACName = 9,10-Dimethoxy-7,8,13,13a-tetradehydro-2′''H''-[1,3]dioxolo[4′,5′:2,3]berbin-7-ium | SystematicName = 9,10-Dimethoxy-5,6-dihydro-2''H''-7λ5-[1,3]dioxolo[4,5-''g'']isoquinolino[3,2-''a'']isoquinolin-7-ylium<ref>{{BlueBook2013|rec=73.3.1}}</ref> | OtherNames =Umbellatine;<ref name="merck14"/> 5,6-Dihydro-9,10-dimethoxybenzo[''g'']-1,3-benzodioxolo[5,6-''a'']quinolizinium;<ref name="merck14"/> 7,8,13,13a-Tetradehydro-9,10-dimethoxy-2,3-(methylenedioxy)berbinium<ref name="merck14">The Merck Index, 14th ed., 1154. Berberine</ref> |Section1={{Chembox Identifiers | InChI = 1/C20H18NO4/c1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h3-4,7-10H,5-6,11H2,1-2H3/q+1 | InChIKey = YBHILYKTIRIUTE-UHFFFAOYAJ | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C20H18NO4/c1-22-17-4-3-12-7-16-14-9-19-18(24-11-25-19)8-13(14)5-6-21(16)10-15(12)20(17)23-2/h3-4,7-10H,5-6,11H2,1-2H3/q+1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = YBHILYKTIRIUTE-UHFFFAOYSA-N | CASNo_Ref = {{cascite|changed|??}} | CASNo =2086-83-1 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2263 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 12089 | PubChem =2353 | EC_number = 218-229-1 | KEGG = C00757 | 3DMet = | Beilstein = 3570374 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 0I8Y3P32UF | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 16118 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB04115 | SMILES = O1c2c(OC1)cc5c(c2)c4cc3ccc(OC)c(OC)c3c[n+]4CC5 }} |Section2={{Chembox Properties | C=20|H=18|N=1|O=4 | Formula_Charge =+ | Appearance =Yellow solid | Density = | MeltingPtC = 145 | MeltingPt_ref =<ref name = Merck>''The Merck Index'', 10th Ed. (1983), p.165, Rahway: Merck & Co.</ref> | BoilingPt = | Solubility =Slowly soluble<ref name = Merck/> }} |Section3={{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}

'''Berberine''' is an organic compound classified as benzylisoquinoline alkaloid.<ref name="hmd">{{cite web |title=Berberine |url=https://www.hmdb.ca/metabolites/HMDB0003409 |publisher=The Human Metabolome Database |access-date=21 August 2025 |date=7 March 2022}}</ref><ref name="pubchem">{{cite web |title=Berberine |url=https://pubchem.ncbi.nlm.nih.gov/compound/2353 |publisher=PubChem, US National Library of Medicine |access-date=21 August 2025 |date=16 August 2025}}</ref> Chemically, it is a quaternary ammonia compound.<ref name=hmd/><ref name=pubchem/>

Its name is derived from the genus of plants, ''Berberis''. Berberine occurs in the roots, bark, stems, and leaves of ''Berberis vulgaris'' (barberry), ''Berberis aristata'' (tree turmeric), ''Mahonia aquifolium'' (Oregon grape) and ''Hydrastis canadensis'' (goldenseal).<ref name=hmd/>

Due to their yellow pigmentation, raw ''Berberis'' materials were once commonly used to dye wool, leather, and wood.<ref name=hmd/><ref>{{cite journal|vauthors=Gulrajani ML|date=2001|title=Present status of natural dyes|url=http://nopr.niscair.res.in/handle/123456789/24928|journal=Indian Journal of Fibre & Textile Research|language=en-US|volume=26|pages=191–201|via=NISCAIR Online Periodicals Repository|access-date=2017-12-28|archive-date=2021-11-20|archive-url=https://web.archive.org/web/20211120183428/http://nopr.niscair.res.in/handle/123456789/24928|url-status=live}}</ref><ref name=unijena/> Under ultraviolet light, berberine shows a strong yellow fluorescence.<ref name=hmd/><ref name="unijena">{{cite web |title=Fluoreszenzfarbstoffe in der Natur |url=http://www.chemie.uni-jena.de/institute/oc/weiss/naturstoffe.htm |vauthors=Weiß D |year=2008 |access-date=17 July 2009 |language=de |archive-date=9 March 2007 |archive-url=https://web.archive.org/web/20070309172021/http://www.chemie.uni-jena.de/institute/oc/weiss/naturstoffe.htm |url-status=live }}</ref> As a natural dye, berberine has a color index of 75160.

Plants containing berberine have been used in traditional medicine, and berberine extracts are sold as dietary supplements. Other than in China as an over-the-counter drug, berberine is not approved as a prescription drug, regulated or proven safe in any country.<ref name="db">{{cite web |title=Berberine |url=https://go.drugbank.com/drugs/DB04115 |publisher=DrugBank |access-date=21 August 2025 |date=19 August 2025}}</ref>

==Biological sources== [[Image:Chelidonium majus flores.jpg|left|thumb|200px|Berberine is the yellow color of celandine poppies.]] The following plants are biological sources of berberine: * ''Berberis vulgaris'' (barberry) * ''Berberis aristata'' (tree turmeric) * ''Berberis thunbergii'' * ''Fibraurea tinctoria'' * ''Mahonia aquifolium'' (Oregon grape) * ''Hydrastis canadensis'' (goldenseal) * ''Xanthorhiza simplicissima'' (yellowroot) * ''Phellodendron amurense'' (Amur cork tree)<ref name="Cicero Baggioni 2016 pp. 27–45">{{cite book | last1=Cicero | first1=Arrigo F. G. | last2=Baggioni | first2=Alessandra | title=Anti-inflammatory Nutraceuticals and Chronic Diseases | series=Advances in Experimental Medicine and Biology | chapter=Berberine and Its Role in Chronic Disease | publisher=Springer International Publishing | publication-place=Cham | year=2016 | volume=928 | isbn=978-3-319-41332-7 | issn=0065-2598 | doi=10.1007/978-3-319-41334-1_2 | pages=27–45| pmid=27671811 }}</ref> * ''Coptis chinensis'' (Chinese goldthread) * ''Tinospora cordifolia'' * ''Argemone mexicana'' (prickly poppy) * ''Eschscholzia californica'' (California poppy)

Berberine is usually found in the roots, rhizomes, stems, and bark.<ref name=hmd/>

== Structure and biosynthesis == thumb|early stages in berberine biosynthesis|left|420px|class=skin-invert-image thumb|middle stages in berberine biosynthesis|left|420px|class=skin-invert-image {{clear}}

Berberine has a tetracyclic skeleton as is common for alkaloids classified as a benzylisoquinoline alkaloid. The overall skeleton is derived from two equivalents of L-tyrosine. L-Tyrosine is the precursor to L-DOPA and 4-hydroxyphenylacetaldehyde.<ref>{{cite book | vauthors = Dewick P |title=Medicinal Natural Products: A Biosynthetic Approach |url=https://archive.org/details/medicinalnatural00dewi_347 |url-access=limited |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page=[https://archive.org/details/medicinalnatural00dewi_347/page/n355 358] |isbn=978-0-471-49641-0}}</ref><ref>{{cite journal |last1=Tjallinks |first1=Gwen |last2=Mattevi |first2=Andrea |last3=Fraaije |first3=Marco W. |title=Biosynthetic Strategies of Berberine Bridge Enzyme-like Flavoprotein Oxidases toward Structural Diversification in Natural Product Biosynthesis |journal=Biochemistry |date=2024 |volume=63 |issue=17 |pages=2089–2110 |doi=10.1021/acs.biochem.4c00320 |pmid=39133819 |pmc=11375781 }}</ref>

The incorporation of an extra carbon atom as a bridge is distinctive. Formation of the berberine bridge is rationalized as an oxidative process in which the ''N''-methyl group, supplied by ''S''-adenosyl methionine (SAM), is oxidized to an iminium ion, and a cyclization to the aromatic ring occurs by virtue of the phenolic group.<ref>{{cite book | vauthors = Dewick P |title=Medicinal Natural Products: A Biosynthetic Approach |url=https://archive.org/details/medicinalnatural00dewi_015 |url-access=limited |edition=3rd |publisher=Wiley |location=West Sussex, England |year=2009 |page=[https://archive.org/details/medicinalnatural00dewi_015/page/n354 357] |isbn=978-0-471-49641-0}}</ref>

[[File:BerberrubineSyn.svg|thumb|320px|class=skin-invert-image|Pyrolysis of berberine gives "berberrubine", which protonates to "protoberberine"]]

Reticuline is a precursor to some protoberberine alkaloids in plants.<ref>{{cite journal | vauthors = Park SU, Facchini PJ | title = Agrobacterium rhizogenes-mediated transformation of opium poppy, ''Papaver somniferum l.'', and California poppy, ''Eschscholzia californica cham.'', root cultures | journal = Journal of Experimental Botany | volume = 51 | issue = 347 | pages = 1005–16 | date = June 2000 | pmid = 10948228 | doi = 10.1093/jexbot/51.347.1005 | doi-access = }}</ref>

Heating at 190 °C, berberine demethylates giving ''berberrubine''. Alkylation of the resulting zwitterion gives access to many berberine-like derivatives.<ref name=Tillhon>{{cite journal |title=Berberine: New perspectives for old remedies |journal=Biochemical Pharmacology |date=2012 |volume=84 |issue=10 |pages=1260–1267 |doi=10.1016/j.bcp.2012.07.018 |pmid=22842630 |url=http://dspace.utpl.edu.ec/handle/123456789/19237 | vauthors = Tillhon M, Guamán Ortiz LM, Lombardi P, Scovassi AI }}</ref>

==Research== Although plants containing berberine are used in traditional medicine, it has higher bioavailability in its berberine HCL form, indicating limited biological activity in vivo, with no patents issued for its use as a drug.<ref name=hmd/><ref name=db/> Clinical research investigating the use of berberine in humans is limited.<ref name=db/><ref name="song">{{cite journal |vauthors=Song D, Hao J, Fan D |title=Biological properties and clinical applications of berberine |journal=Frontiers of Medicine |volume=14 |issue=5 |pages=564–582 |date=October 2020 |pmid=32335802 |doi=10.1007/s11684-019-0724-6 |s2cid=216111561 |url=}}</ref> Although numerous clinical trials have been conducted or are underway, as of 2025, berberine has frequently been withdrawn as a drug candidate, and is not approved as a prescription drug in any country.<ref name=db/><ref name=hern/>

A 2023 review concluded that berberine may improve lipid concentrations.<ref name="hern">{{cite journal |vauthors=Hernandez AV, Hwang J, Nasreen I, Sicignano D, Pasupuleti V, Snow-Caroti K |title=Impact of Berberine or Berberine Combination Products on Lipoprotein, Triglyceride and Biological Safety Marker Concentrations in Patients with Hyperlipidemia: A Systematic Review and Meta-Analysis. |journal=Journal of Dietary Supplements |year=2023 |volume=21 |issue=2 |pages=242–259 |pmid=37183391 |doi=10.1080/19390211.2023.2212762 |pmc= |s2cid=258687419 }}</ref> High-quality, large clinical studies would be required to properly evaluate the effectiveness and safety of berberine in various health conditions.<ref name=song/>

==Supplements, regulation, and safety== thumb|Berberine powder Although widely available, dietary supplements have not been approved in the United States for any specific medical use.<ref name=db/> The quality of berberine supplements can vary across brands: a 2017 study found that out of 15 different products sold, only six contained at least 90% of the specified berberine quantity.<ref name="funk">{{cite journal |vauthors=Funk RS, Singh RK, Winefield RD, Kandel SE, Ruisinger JF, Moriarty PM, Backes JM |title=Variability in Potency Among Commercial Preparations of Berberine |journal=Journal of Dietary Supplements |volume=15 |issue=3 |pages=343–351 |date=May 2018 |pmid=28792254 |pmc=5807210 |doi=10.1080/19390211.2017.1347227}}</ref>

From 2020 to 2022, the US Food and Drug Administration issued warning letters to eight manufacturers of berberine dietary supplements for false advertising and misbranded drug products.<ref name="fda-warn">{{cite web |title=Warning letters regarding berberine supplements (search "berberine") |url=https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters |publisher=Inspections, Compliance, Enforcement, and Criminal Investigations, US Food and Drug Administration |access-date=21 August 2025 |date=19 August 2025}}</ref> In the United States, berberine is not generally recognized as safe (GRAS).<ref name=fda-warn/>

== Adverse effects == Longer-term human clinical trials have reported flatulence and diarrhea as common issues.<ref>{{cite journal |last1=Yue |first1=Shi-Jun |last2=Liu |first2=Juan |last3=Wang |first3=Wen-Xiao |last4=Wang |first4=Ai-Ting |last5=Yang |first5=Xin-Yu |last6=Guan |first6=Hua-Shi |last7=Wang |first7=Chang-Yun |last8=Yan |first8=Dan |title=Berberine treatment-emergent mild diarrhea associated with gut microbiota dysbiosis |journal=Biomedicine & Pharmacotherapy |date=August 2019 |volume=116 |article-number=109002 |doi=10.1016/j.biopha.2019.109002|pmid=31154270 |doi-access=free }}</ref>

== Drug interactions == Berberine is known to inhibit the activity of CYP3A4, an enzyme important to drug metabolism and clearance of endogenous substances, including steroid hormones such as cortisol, progesterone, and testosterone.<ref name=hmd/><ref name=db/> Several studies have demonstrated that berberine can increase the concentrations of cyclosporine in renal transplant patients and midazolam in healthy adult volunteers, confirming its inhibitory effect on CYP3A4.<ref name="pmid34620272">{{cite journal |vauthors=Abushammala I |title=Tacrolimus and herbs interactions: a review |journal=Pharmazie |volume=76 |issue=10 |pages=468–472 |date=October 2021 |pmid=34620272 |doi=10.1691/ph.2021.1684 |url=}}</ref><ref name="pmid22855269">{{cite journal |vauthors=Hermann R, von Richter O |title=Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions |journal=Planta Med |volume=78 |issue=13 |pages=1458–77 |date=September 2012 |pmid=22855269 |doi=10.1055/s-0032-1315117 |bibcode=2012PlMed..78.1458H |url=}}</ref><ref name="pmid25678418">{{cite journal |vauthors=Niwa T, Murayama N, Imagawa Y, Yamazaki H |title=Regioselective hydroxylation of steroid hormones by human cytochromes P450 |journal=Drug Metab Rev |volume=47 |issue=2 |pages=89–110 |date=May 2015 |pmid=25678418 |doi=10.3109/03602532.2015.1011658 |url=}}</ref>

==Use in China== It is approved in China as an over-the-counter drug for diarrhea treatment, with the package insert claiming efficacy against ''E. coli'' and ''Shigella'' spp.<ref name=pki>{{cite web |last1=精华制药集团股份有限公司 |title=盐酸小檗碱片说明书 |url=https://ypk.39.net/843793/manual |website=ypk.39.net |language=zh|trans-title=Package Insert: Berberine Hydrochloride Tablets}}</ref>

The Chinese package insert contraindicates berberine for people with hemolytic anemia and with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency). The insert also specifically precautions its use in children with G6PD deficiency because it can produce hemolytic anemia and jaundice.<ref name=pki/>

== References == {{Reflist}}

{{Other antibacterials}} {{Muscarinic acetylcholine receptor modulators}} {{PPAR modulators}} {{Sigma receptor modulators}} {{Authority control}}

Category:Aromatase inhibitors Category:Benzylisoquinoline alkaloids Category:CYP2D6 inhibitors Category:CYP3A4 inhibitors Category:DNA-binding substances Category:Lipid-lowering agents Category:M2 receptor agonists Category:Methylenedioxyphenethylamines Category:Nitrogen heterocycles Category:Quaternary ammonium compounds Category:Traditional Chinese medicine