Mahonia
1. Identity, Taxonomy, and Botanical Description
Mahonia is a genus of evergreen shrubs belonging to the family Berberidaceae. The genus, named to honor Bernard McMahon, an American horticulturalist of Irish origin, encompasses more than 70 species distributed across North America and Asia. Plants of the genus Mahonia Nuttall (Berberidaceae) have a long history of medical use, and the genus is described in the Flora of China as shrubs or small trees, evergreen, 0.3–8 m tall, lacking spines. The most pharmacologically studied species are:
- Mahonia aquifolium (Pursh) Nutt. — also known as Berberis aquifolium Pursh, Oregon grape, or holly-leaved barberry. It is a North American species of flowering plant in the family Berberidaceae: an evergreen shrub growing up to 3 metres (10 ft) tall and 1.5 m (5 ft) wide, with pinnate leaves consisting of spiny leaflets, exhibiting dense clusters of yellow flowers in early spring, followed by dark bluish-black berries.
- Mahonia bealei (Fort.) Carr. — Beale's barberry, a species of primary importance in Traditional Chinese Medicine (TCM).
- Mahonia fortunei (Lindl.) Fedde — Fortune's barberry, also widely used in TCM, interchangeably with M. bealei.
The current accepted botanical synonym for Oregon grape is Berberis aquifolium, placing the species within the consolidated genus Berberis. The vernacular name "barberry" is used both for members of the Berberis species and for members of the Mahonia species, reflecting their close botanical relationship. The native distribution of M. aquifolium extends from Western North America — British Columbia to northern California, east to Idaho and western Montana, where it grows in deep conifer forests and open, rocky woods.
The phytochemical research of the genus has resulted in the identification of more than 150 chemical constituents, among which alkaloids are predominant. More than 150 compounds, including alkaloids, terpenoids, steroids, phenols, lignans, and volatile oils, have been isolated from or identified in Mahonia plants used in TCM.
Common Forms and Preparations
- Topical cream/ointment: The most clinically studied form, typically as a 10% bark extract cream or ointment applied to the skin. A M. aquifolium ointment is used as a homeopathic preparation according to the German Homeopathic Pharmacopeia.
- Root and root bark extracts: Dried preparations of the root and stem bark, used internally or topically. Roots and stem bark of M. aquifolium are effectively used in the treatment of skin inflammatory conditions.
- Stem (Mahoniae Caulis): Mahonia species have a long history of medical uses in TCM; Mahoniae Caulis, which consists of stems of M. bealei or M. fortunei, is an important traditional medicine listed in the Chinese Pharmacopoeia.
- Berries: Used as food and for their antioxidant content. The small purplish-black fruits are edible raw after the season's first frosts; they were included in small quantities in the traditional diets of Pacific Northwest tribes, mixed with salal or another sweeter fruit, and today are sometimes used to make jelly.
- Dye: Native Americans made a yellow dye from the bark and wood of this shrubby species.
2. Traditional and Historical Use
Indigenous North American Traditions
Mahonia aquifolium was originally found in the Pacific Northwest and British Columbia, where it has been used for the treatment of psoriasis and eczema by Native North Americans for many centuries. Various root preparations of Berberis aquifolium were used by Native Americans for stomach trouble, hemorrhages, and tuberculosis; as a panacea, a tonic, a gargle, and an eye wash; and to purify blood. Oregon grape was often used by several native North American Indian tribes to treat loss of appetite and debility. The berries were a part of the traditional diet of some indigenous peoples of the Pacific Northwest.
American Herbal Medicine
In American medicine, M. aquifolium has been used to treat fever, diarrhea, dyspepsia, gout, rheumatic ailments, renal and biliary diseases, and particularly chronic relapsing dermatoses. Its current herbal use is mainly in the treatment of gastritis and general digestive weakness, to stimulate kidney and gallbladder function, and to reduce catarrhal problems. The root and root bark is alterative, blood tonic, cholagogue, diuretic, laxative, and tonic. It has been taken internally in the treatment of psoriasis, syphilis, haemorrhages, stomach complaints, and impure blood conditions.
Traditional Chinese Medicine (TCM)
Plants of the genus Mahonia have a long history of medical use in TCM for the treatment of a wide range of health disorders, such as tuberculosis, periodontitis, dysentery, pharyngolaryngitis, eczema, and wounds. In the theory of TCM, most Mahonia species exert the effects of relieving internal heat, eliminating dampness, removing toxins, suppressing pain, promoting blood circulation, inhibiting cough, and alleviating inflammation.
Mahoniae Caulis, with the properties "clearing heat and dry dampness, purge fire and remove toxins," has been used for the treatment of dampness-heat diarrhea, dysentery, jaundice, red urine, red painful swelling eyes, toothache caused by stomach fire, sore and deep-rooted boils, swelling and abscesses, as listed in the Chinese Pharmacopoeia 2010.
Species belonging to the genus Mahonia have been used in TCM for disorders like inflammation, pharyngolaryngitis, stomach disorders, infections like hepatitis, and diseases of the skin, besides various other purposes. Some Mahonia species, which are traditionally used for pelvic inflammation, pharyngolaryngitis, periodontitis, and acute conjunctivitis, have had their anti-inflammatory properties documented scientifically.
3. Key Constituents and Active Compounds
Alkaloids (Primary Class)
Alkaloids are considered the major constituents of Mahonia species, and may be responsible for most activities shown by these plants, such as antimicrobial, anti-inflammatory, and antimutagenic activities. The alkaloids representing the main compounds in M. aquifolium belong to two major classes: the protoberberines and the bisbenzylisoquinolines (BBIQ).
The principal identified alkaloids include:
- Berberine: The most prominent protoberberine alkaloid, present in high concentrations in roots and stem bark. Through bioassay-guided fractionation, berberine was isolated as one of the main active alkaloids responsible for relevant effects in numerous studies; berberine was reported to exhibit a range of pharmacological and biological activities, with particular interest focused on its antioxidative potential.
- Jatrorrhizine: A protoberberine alkaloid found alongside berberine; berberine and jatrorrhizine showed the strongest antimicrobial activity against 20 clinical isolates of Propionibacterium acnes from skin lesions, with MIC values between 5 and 50 μg/ml.
- Palmatine, columbamine, and magnoflorine: Additional protoberberine alkaloids. Magnoflorine, berberine, palmatine, jatrorrhizine, and columbamine are alkaloids that can be isolated from the roots of the shrub.
- Berbamine and oxyacanthine: Bisbenzylisoquinoline (BBIQ) alkaloids. The main alkaloid constituents — berberine, berbamine, and oxyacanthine — have been studied for their effects on 5-lipoxygenase, lipid peroxidation, and free radical reactivity.
Phenolic Compounds
Phytochemical analysis of M. aquifolium has also evidenced the presence of secondary metabolites such as chlorogenic acid, p-coumaric acid, ferulic acid, rutin, isoquercitrin, and quercetin. Chlorogenic acid has emerged as a predominant phenolic compound across several plant organs. The leaf extract exhibits the highest phenolic and flavonoid contents.
Other Constituent Classes
Several useful compounds have been extracted from Mahonia species, including alkaloids, triterpenes, flavonoids, phytosterols, and lignans, sourced from leaves, stem, and roots. M. aquifolium is a good source of phenols, flavonoids, anthocyanins, and antioxidants.
4. Mechanisms of Action
Inhibition of Lipoxygenase and Anti-Inflammatory Pathways
Alcoholic extracts of M. aquifolium, analyzed for their qualitative and quantitative alkaloid content, showed an in vitro inhibiting effect on cyclooxygenase (CO) of sheep seminal vesicles and 5-lipoxygenase (5-LO) of porcine leukocytes. The extract of M. aquifolium inhibits 5-LO with an IC50 value of 50 μM. Notably, the major alkaloids of M. aquifolium extracts — berberine, palmatine, magnoflorine, and jatrorrhizine — were found to be inactive in both anti-inflammatory assays, suggesting a different mechanism of action for the alkaloids, or further undetected compounds in the extract.
The bisbenzylisoquinoline alkaloids are the most potent lipoxygenase inhibitors, whereas berberine and magnoflorine exhibit only low potencies. Berbamine and oxyacanthine are effective inhibitors of lipid peroxidation. The mechanism of lipoxygenase inhibition may be related to the inhibition of lipid hydroperoxide substrate accumulation, either through a direct reaction with peroxide or by scavenging lipid-derived radicals.
The most prominent feature of M. aquifolium is its efficacy in inhibition of lipid peroxidation (IC50 = 5 μM), which was not mediated by the alkaloids berberine, berbamine, and oxyacanthine alone.
Inhibition of Keratinocyte Proliferation
Berberine, as one of the main constituents, is an inhibitor of human keratinocyte (HaCaT cell) growth with an IC50 value of 30 μM. The benzylisoquinoline alkaloids berbamine and oxyacanthine are more potent inhibitors with IC50 values of 11 and 13 μM, respectively. This observation may be linked to the phenolic property of these constituents. Although these constituents appear to be only moderate compared with the antipsoriatic agent anthralin (IC50=0.7 μM), HaCaT cells significantly responded to all of these materials at a concentration of 10 μM.
NF-κB Modulation and Cytokine Inhibition
The extract of M. aquifolium has been shown to inhibit keratinocyte proliferation and reduce the production of pro-inflammatory cytokines such as IL-8. The anti-proliferative action of M. aquifolium is attributed to its ability to modulate the NF-κB signaling pathway, thereby reducing inflammation and keratinocyte hyperproliferation.
In a cell-based study using the LPS-stimulated human monocytic cell line THP-1, the crude extract of M. aquifolium at 20 μg/ml inhibited IL-8 production by about 30%, while the bisbenzylisoquinoline (BBIQ) alkaloid fraction at 0.1 μg/ml exhibited 40% inhibition of IL-8 production. The protoberberine alkaloid fraction had no significant inhibitory activity. Weak or no inhibition of IL-8 production was found after treatment with berberine, jatrorrhizine, and berbamine individually; however, the BBI alkaloids baluchistine (approximately 20%) and aromoline (up to 30%) did inhibit IL-8 production.
Berberine-treated cells also showed a decline in cyclooxygenase activity with a subsequent reduction in prostaglandin E2.
Anticomplement Activity
Crude extracts obtained from the stem bark of M. aquifolium have been investigated for anticomplementary activity. The results show that their anticomplementary activity is mainly due to the alkaloid components. Especially the BBI alkaloid fraction and berberine showed a strong inhibitory effect on the CH50 total hemolytic complement assay. The crude extract of M. aquifolium was less active than berberine or the BBI alkaloid fractions, indicating that these alkaloids largely account for the immunomodulatory activity of the crude extract.
Antioxidant Mechanisms
Berberine, the key alkaloid derived from Berberidaceae family plants, enhances cellular defenses against oxidative stress through several mechanisms. It activates the AMP-activated protein kinase (AMPK) pathway, which reduces mitochondrial reactive oxygen species (ROS) production and improves energy metabolism. Furthermore, it boosts the activity of key antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), thus protecting cells from oxidative damage.
Antimicrobial Mechanisms
Bacterial cytological profiling indicates that berberine destroys the structure of cell walls, disrupts membrane integrity, and further changes cell morphology with increasing concentration. Berberine has also shown synergistic antibacterial properties when combined with other antibiotics.
5. Scientific Evidence by Area of Use
5.1 Dermatology: Psoriasis (Most Studied Application)
The topical use of M. aquifolium extract in plaque psoriasis is the area with the strongest and most consistent clinical evidence base.
Human Clinical Evidence:
A systematic review identified 502 articles, of which eight met inclusion criteria; seven trials studied the effects of M. aquifolium in psoriasis and one in atopic dermatitis. Clinical trials have not been identified in any other cutaneous disorder using this plant extract. Risk of bias of included trials were either unclear or low risk. Five of seven studies showed a statistically significant improvement with M. aquifolium in psoriasis, while one study showed efficacy in the treatment of atopic dermatitis.
Several studies have shown that M. aquifolium leads to a statistically significant improvement of symptoms in psoriasis and atopic dermatitis with minimal side effects. Based on the clinical trials performed to date, M. aquifolium has been deemed a safe and effective therapeutic option in such studies. Side effects were minimal and well-tolerated, limited to pruritus, rash, or burning sensation.
A published review summarizes three recent clinical trials of M. aquifolium 10% topical cream in patients with psoriasis. Study 1 was an open-label study evaluating safety in 39 patients treated for 12 weeks, with assessments made using modified PASI and global assessments.
Gulliver et al. determined that M. aquifolium was equal to or better than calcipotriol and tazarotene gel in all 33 patients studied. A second study showed that 63 percent of patients considered Mahonia cream to be equal to or better than the standard treatments calcipotriol and fluticasone propionate.
The clinical trial evidence provides limited support for preparations containing extracts of M. aquifolium, indigo naturalis, and aloe vera for the topical management of plaque psoriasis, based on multiple studies.
There was a significant improvement in quality of life, used as a subjective parameter, and the tolerability of M. aquifolium ointment was evaluated as good or very good by 82.4% of patients in one observational study.
Evidence strength: Moderate. Multiple small-to-medium controlled clinical trials support topical efficacy in mild-to-moderate plaque psoriasis. Head-to-head comparisons with standard treatments are promising but limited by sample size. Most studies used a 10% topical cream or ointment formulation. The systematic review methodology identified limitations including variable methodological quality and risk of bias. Large randomized controlled trials (RCTs) confirming benefit are still lacking.
5.2 Dermatology: Atopic Dermatitis
Of 502 articles identified in a systematic review, eight met inclusion criteria; only one studied the effects of M. aquifolium specifically in atopic dermatitis. A clinical trial by Donsky and Clarke (2007) used Reliéva, a M. aquifolium extract, for the treatment of adult patients with atopic dermatitis (published in American Journal of Therapeutics). A herbal ointment containing M. aquifolium, Viola tricolor, and Centella asiatica was also evaluated in a randomized, double-blind, vehicle-controlled, half-side comparison for mild-to-moderate atopic dermatitis.
Evidence strength: Weak to preliminary for atopic dermatitis specifically. Only one qualifying clinical trial was identified in the 2018 systematic review, and clinical trial evidence is much more limited than for psoriasis.
5.3 Antimicrobial Activity
The major chemical constituents of M. aquifolium, berberine and jatrorrhizine, showed the strongest activity against 20 clinical isolates of Propionibacterium acnes isolated from skin lesions of patients, with MIC values between 5 and 50 μg/ml, as well as bacteriostatic and bactericidal activities against nine different oral bacteria.
Berberine and jatrorrhizine also significantly inhibited drug-resistant Candida tropicalis with MIC values of 31.3 and 125 μg/ml, respectively, and showed moderate antifungal properties against six strains of lipophilic Malassezia spp. isolated from patients with pityriasis versicolor or seborrheic dermatitis.
The compounds tested against Malassezia were generally found to possess only weak to moderate antifungal properties, with MICs for individual strains ranging from ≤50 to ≥1000 mg/L.
Extracts of M. fortunei and M. bealei inhibited Bacillus thuringiensis, Staphylococcus aureus, and Bacillus subtilis, and M. fortunei stems showed the best antimicrobial activity against S. aureus. The stem extracts were more active than leaf extracts.
The stem bark of M. aquifolium, whose main constituent is the berberinisoquinolone alkaloid berberine, has been used to treat patients with gastroenteritis and diarrhea.
Evidence strength: The antimicrobial evidence is predominantly in vitro. The clinical relevance of the MIC values observed in cell culture studies requires confirmation through well-designed human clinical trials. It may be difficult to achieve clinically relevant blood concentrations after routine administration, due to berberine's poor bioavailability.
5.4 Anticancer and Antimutagenic Activity
M. aquifolium and its secondary metabolites have been shown to have anticancer potential. Studies have used MTT, scratch, and colony formation assays, and have analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry following treatment of lung adenocarcinoma cells. In vitro and in vivo pharmacological effects including anticancer, antimutagenic, and antitumoral activities have been demonstrated in crude extracts.
Evidence strength: Entirely preclinical (cell-line and animal models). No human clinical trial evidence has been published in this area.
5.5 Digestive and Gastrointestinal Applications
Pharmacological studies have demonstrated that the alkaloid content of M. aquifolium contributes to antidiarrheal, antimicrobial, anti-psoriasis, and anti-inflammatory properties. The stem bark of M. aquifolium has been used to treat gastroenteritis and diarrhea, and berberine has been shown to have bactericidal, anti-cholera toxin, cholesterol-lowering, anti-inflammatory, and anticolitic effects.
Preparations containing Mahonia species have been demonstrated to exert good efficacy for the clinical treatment of dysentery, internal and external hemorrhage, acne vulgaris, and chronic pharyngitis, among other diseases.
Evidence strength: The gastrointestinal evidence largely derives from traditional use reports and from studies on berberine specifically (not always as M. aquifolium extract per se). Well-designed RCTs using M. aquifolium extracts for GI indications in humans are not currently established in the literature.
5.6 Alzheimer's Disease and Neurological Activity (Preliminary)
Alkaloids from the genus Mahonia are regarded as promising drug candidates for Alzheimer's disease (AD) therapy. The findings of one review support the use of Mahonia species as an alternative therapy source for treating AD. All parts except the leaf of M. bealei exhibited potent acetylcholinesterase (AChE)-inhibitory activity in laboratory studies.
Evidence strength: Entirely preclinical. No human clinical trials in this area have been reported.
6. Body Systems and Health Areas
Based on the available pharmacological and ethnopharmacological literature, Mahonia is most consistently associated with the following body systems and health areas:
- Integumentary system (skin): M. aquifolium, native to the United States, has been recently shown to have anti-inflammatory properties useful in cutaneous disorders. Clinical evidence exists for psoriasis; preclinical/limited evidence for atopic dermatitis, seborrheic dermatitis, and acne.
- Gastrointestinal system: Long-standing traditional and ethnopharmacological use for diarrhea, dysentery, gastritis, and digestive weakness, supported by berberine's well-documented antidiarrheal properties.
- Immune system: The same extracts exhibited immunostimulating activities in two phagocytosis assays. Anticomplement and cytokine-modulating properties are documented in vitro.
- Hepatobiliary system: Crude extracts have been shown to exhibit hepatoprotective activity in pharmacological studies. Traditional use as a cholagogue is well documented.
- Antimicrobial/antifungal: Broad-spectrum antibacterial and antifungal activities demonstrated in vitro against clinically relevant organisms.
- Neurological system (preclinical): AChE inhibitory activity identified in laboratory studies of M. bealei.
7. Dosage Forms and Reported Dosages
Dosages and forms appearing in the clinical and pharmacological literature include:
- Topical cream/ointment, 10% extract: The most consistently studied formulation across clinical trials for psoriasis. A clinical trial program evaluated M. aquifolium 10% topical cream; one open-label study enrolled 39 patients treated for 12 weeks.
- Topical preparation with 0.1% berberine: Donsky conducted a study in which 32 patients with mild-to-moderate psoriasis applied M. aquifolium containing 0.1% berberine.
- Berberine (isolated), oral, 300 mg three times daily: In a two-phase randomized-crossover clinical study in healthy male subjects, berberine (300 mg three times daily, orally, for two weeks) was used to assess metabolic drug-drug interaction effects. This dosage regimen is specific to berberine pharmacokinetic/interaction studies and is not the same as an M. aquifolium whole-extract dose.
No universally accepted standardized oral dosage for M. aquifolium extract is established in the clinical literature reviewed. The plant part, method of preparation, and indication vary substantially across traditional and investigational use contexts.
8. Safety Considerations and Drug Interactions
General Tolerability in Clinical Trials
Several studies have shown that M. aquifolium leads to a statistically significant improvement of symptoms in psoriasis and atopic dermatitis with minimal side effects. Side effects in clinical dermatology trials were minimal and well-tolerated, limited to pruritus, rash, or burning sensation.
Cytochrome P450 and Drug Metabolism Interactions
Regarding the crucial role of CYP2D6 and CYP3A4 in metabolizing clinically used drugs, and the inhibitory effects of berberine on these two CYP450 isoforms, the most important drug interaction to be considered relates to berberine's inhibitory effect on CYP2D6 and CYP3A4. 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).
Berberine exerts an influence on the function of various CYP450 isoforms, including CYP3A4/5, CYP2D6, CYP2C9, CYP2E1, CYP1A1/2, and most isoforms within the CYP2B subfamily.
Cyclosporin A and P-Glycoprotein Interactions
Partial P-glycoprotein (P-gp) and CYP3A4 blockade are implicated in a well-documented interaction between berberine and cyclosporin A. This interaction has been demonstrated at doses as low as 300 mg berberine/day in healthy volunteers.
Bioavailability Limitation
In primary studies, some extracts of Mahonia species exert biological activity at high concentrations. It may be difficult to achieve such levels in the blood after routine administration, due to poor bioavailability. This caveat is particularly relevant when extrapolating in vitro antimicrobial or anti-inflammatory data to clinical settings.
Pregnancy and Special Populations
Berberine, the primary alkaloid, has been documented in preclinical research to have uterine-stimulating properties. While this specific consideration for M. aquifolium as a whole-plant preparation requires further dedicated study, it is a pharmacologically grounded concern given the alkaloid's prominence in the plant's chemistry.
Evidence Quality and Research Gaps
Further studies employing rigorous scientific technologies and methods are warranted to reveal the phytochemistry of this genus, particularly to detail the active compounds and the underlying mechanisms. As widely used species in TCM, M. bealei and M. fortunei are applied interchangeably, but it is unclear whether these species can be fully substituted for each other; comparative studies should be conducted. Antimicrobial activities of plant extracts should be corroborated by standard methods, and pharmacokinetic studies are particularly important for further investigation of these potential resources.
References
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