Corktree

Other Names

Amur cork treeAmur cork tree barkAmur corktreeBarkhat AmurskiyChinese cork treeChinese corktreeChuan Huang BaiCork treeCork tree barkCortex PhellodendriCortex Phellodendri amurensisCortex Phellodendri chinenseGuan Huang BaiHuáng BǎiHuang BǎiHuang BaiHuang BòHuáng BòHuang BoHuang Bo PiHwangbyeokHwangbyeoknamuJapanese cork treeKihadaPhellodendri CortexPhellodendron amurensePhellodendron amurense f. insularePhellodendron amurense f. mollePhellodendron amurense f. suberosumPhellodendron amurense Rupr.Phellodendron amurense var. lavalleeiPhellodendron amurense var. lavalleei (Dode) SpraguePhellodendron amurense var. mollePhellodendron amurense var. molle (Nakai) S.H. Li & S.Z. LiouPhellodendron amurense var. sachalinensePhellodendron amurense var. sachalinense F. SchmidtPhellodendron amurense var. suberosumPhellodendron barkPhellodendron chinensePhellodendron chinense barkPhellodendron chinense Schneid.Phellodendron insularePhellodendron insulare NakaiPhellodendron japonicumPhellodendron japonicum Maxim.Phellodendron kodamanumPhellodendron kodamanum MakinoPhellodendron lavalleiPhellodendron lavallei DodePhellodendron sachalinensePhellodendron sachalinense (F. Schmidt) Sarg.Phellodendron wilsoniiPhellodendron wilsonii Hayata & Kaneh.Sakhalin cork treeSakhalin corktreeShikerebe-niSiberian cork treeSikerpeБархат амурскийБархатное деревоПробковое деревоキハダ黃柏皮黄柏黄檗

Synopsis

Corktree (Phellodendron amurense): A Comprehensive Reference

Identity and Botanical Classification

Phellodendron amurense is a species of tree in the family Rutaceae, commonly called the Amur cork tree. The genus name derives from the Greek phellos, meaning "cork," and dendron, meaning "tree," while the epithet amurense refers to the Amur region of mainland China. The species is known by a variety of names across East Asia: it is a major source of huáng bò (Chinese: 黄柏 or 黄檗), one of the 50 fundamental herbs used in traditional Chinese medicine, and is known as hwangbyeok in Korean and kihada in Japanese.

Native to eastern Asia — including northern China, northeast China, Korea, Ussuri, Amur, and Japan — the Amur cork tree is considered invasive in many parts of North America. It is a deciduous tree with a rounded, broad-spreading crown, and has distinctive bark with a porous appearance and a spongy or corky texture; below the surface of the bark the tree bears a neon-green layer with important chemical properties.

In the botanical and regulatory literature, the dried bark is referred to as Phellodendri Cortex or Cortex Phellodendri. Phellodendri Cortex is prepared from the dried cortex of plants in the Rutaceae family, including Phellodendron amurense, Phellodendron chinense, Phellodendron amurense var. sachalinense, and Phellodendron wilsonii. The medicinal part is overwhelmingly the inner bark (cortex), though a pressed fruit oil also exists; it contains a variety of biologically active substances including flavonoids (diosmin), alkaloids (berberine, jatrorrhizine, palmatine), saponins, and coumarins, and medicinal applications of the oil have included treatment of pancreatitis, reduction of cholesterol and blood sugar, and treatment of various skin diseases.

Common Forms and Preparations

Portions of the root, berry, twig, or bark are cut and made into a fine mesh powder, which can then be easily encapsulated. In formal clinical and traditional contexts, the bark has been prepared as a dried powder, a decocted extract, an alcohol (ethanol or methanol) extract, or a standardized proprietary extract. The proprietary extract Nexrutine® is a standardized bark extract used in several published clinical and preclinical studies. Nexrutine (NX) is a marketable herbal extract from the traditional Chinese herbal plant Phellodendron amurense, majorly used for the resolution of inflammation, gastroenteritis, and some tissue-specific cancer. Another proprietary combination, Relora®, pairs Phellodendron amurense extract with Magnolia officinalis extract and has been investigated in human clinical trials for stress and mood management.

Traditional and Historical Use

Traditional Chinese Medicine (TCM)

For thousands of years the bark from the Phellodendron amurense tree has been used as an ingredient in herbal formulas in Chinese medicine. Traditionally, these formulas have been used for upset stomach and diarrhea. It has also been used as an antibacterial and anti-inflammatory.

Phellodendron's use dates back to around 200 BCE and it can be found in the Shennong Bencaojing — a Chinese book on agriculture and medicinal plants containing 365 entries — and its use is theorized to have been documented even further back. In Chinese traditional medicine, different herbs and foods are grouped by organs and tastes; phellodendron is categorized as Wu Xing (bitter and cold), meaning it must clear heat, dry dampness, reduce fire, and release toxins.

In TCM theory, Phellodendron amurense is bitter and cold, enters the kidney and bladder meridians, and has the effects of heat-clearing and damp-drying, purging fire and clearing hectic fever, and detoxicating and treating sores. It was used to treat diarrhea under humid heat, jaundice and reddish urine, leukorrhea and pruritus vulvae, heat gonorrhea and astringent pain, beriberi, hectic fever and consumptive fever, night sweating, spermatorrhea, toxic swelling of sores and ulcers, and eczema.

It has been used as a Chinese traditional medicine for the treatment of meningitis, bacillary dysentery, pneumonia, tuberculosis, tumours, jaundice, and liver cirrhosis, and was also used orally to treat abdominal pain, diarrhea, gastroenteritis, and urinary tract infections.

In TCM, phellodendron bark is one of the "three huangs," or bright yellow plants used for treating inflammation and infection (the other two are scute root and coptis rhizome).

In classical materia medica texts, phellodendron is indicated for conditions including diarrhoea, dysentery, jaundice, painful urination, thick yellow vaginal discharge, sores, exanthemas, infections in the lower burner, cystitis, vaginitis, salpingitis, and scrotal inflammations, as well as for antibiotic, antihypertensive, antitussive, and anti-asthmatic effects. Topical applications have included vaginitis, trichomonal cervicitis, and eczema of the ear.

Korean and Japanese Traditional Use

Koreans used the plant to break fever. In China the plant was considered, like ginseng, as a panacea used to treat, among other things, diabetes, tuberculosis, dysentery, pneumonia, and meningitis. The various parts of the Amur corktree — especially the bark — have been instrumental in traditional medicine throughout China, Japan, Korea, and India for thousands of years, and continue to be used and studied.

Ainu Use

The Ainu people used the fruit, which they called shikerebe-ni (Ainu: sikerpe), as a painkiller.

Cultural and Non-Medicinal Uses

Dye extracted from the bark was used historically across East Asia to color paper for sutras and other documents, including the Diamond Sutra. The yellow dye also protected documents against insect damage. The Amur corktree gained particular importance in the realm of ancient Chinese government and religion; its inner bark was used to make a specific yellow dye that distinguished religious and bureaucratic documents from less important ones.

Key Constituents and Active Compounds

Isoquinoline Alkaloids

The major chemical constituents of its bark are the isoquinoline alkaloids palmatine, jatrorrhizine, and phellodendorine, with berberine found within the leaves. Quantitative analysis of stem bark extracts has confirmed these proportions: stem bark extract analysis identified polyphenols (gallic acid, 4-hydroxybenzoic acid, caffeic acid, and ferulic acid) and alkaloids (berbamine, jatrorrhizine, palmatine, and berberine); quantitative determination of alkaloids revealed that berberine had the highest concentration at 2.44 ± 0.22 mg/g.

Berberine is the most pharmacologically studied constituent. Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids, found in several plants including Phellodendron amurense (Amur corktree), Hydrastis canadensis (goldenseal), Coptis chinensis (Chinese goldthread), and others.

Flavonoids

Compounds in the leaves — quercetin, quercetin-3-O-beta-D-glucoside, quercetin-3-O-beta-D-galactoside, and kaempferol-3-O-beta-D-glucoside — demonstrated significant free radical scavenging activity comparable to vitamin E. The fruit oil also contains the flavonoid diosmin.

Limonoids, Sterols, and Other Constituents

Other active constituents include magnoflorine, candicin, obacunone, 7-dihydrostigmasterol, beta-sitosterol, and campesterol. Palmatine, jatrorrhizine, and obacunone are additional alkaloids and limonoids contributing to antioxidant, liver-supportive, and anti-tumor properties.

Established Mechanisms of Action

Anti-Inflammatory Mechanisms

The anti-inflammatory activity of P. amurense extract and its alkaloids has been examined in both in vitro and in vivo systems. Phellodendron amurense has anti-inflammatory and antioxidant effects, but the mechanisms are not completely elucidated. In the context of joint disease, a study investigated the effects of Phellodendron amurense in protecting cartilage, including regulating the levels of aggrecanases, matrix metalloproteinases (MMPs)/tissue inhibitor of metalloproteinase (TIMP), proinflammatory cytokines, and signaling of the mitogen-activated protein kinase (MAPK) pathway in human osteoarticular cartilage and chondrocytes. Phellodendron amurense showed no evident cytotoxicity on human articular cartilage; it significantly inhibited the IL-1α-induced degradation of glycosaminoglycan (GAG) and type II collagen from human osteoarticular cartilage in a concentration-dependent manner; and it dose-dependently decreased the levels of aggrecanase-1 and -2, MMP-1, -3, and -13, while it increased TIMP-1 expression in human osteoarticular cartilage.

Metabolic and AMPK Activation (Berberine)

The core mechanism of berberine — the primary alkaloid — involves activation of AMPK (adenosine monophosphate-activated protein kinase), the body's metabolic master switch, the same pathway that is activated by exercise or caloric restriction. Through AMPK activation, berberine modulates glucose uptake and lipid metabolism. In vitro it exerts significant anti-inflammatory and antioxidant activities; in animal models berberine has neuroprotective and cardiovascular protective effects; and in humans its lipid-lowering and insulin-resistance improving actions have been clearly demonstrated in numerous randomized clinical trials.

Antimicrobial and Antifungal Mechanisms

The tree has both antibiotic and antimicrobial properties due to the alkaloids contained within the plant material. The major alkaloids are the isoquinoline alkaloids palmatine, jatrorrhizine, and phellodendorine. In acne-related research, berberine was shown to effectively inhibit the proliferation of Cutibacterium acnes, with disruption of cell wall and cell membrane structure confirmed by leakage of cellular contents such as potassium, magnesium, and alkaline phosphatase; berberine also reduced the transcript levels of genes associated with peptidoglycan synthesis (murC, murD, mraY, and murG). Phellodendron amurense exhibits antifungal activity mainly through bioactive components including berberine hydrochloride and palmatine hydrochloride.

Antitumor Mechanisms (Preclinical)

Berberine, when administered orally through the diet, inhibits in vivo tumorigenesis of both p53-expressing and p53-null lung tumor xenografts equally whether administered in its pure form or as a part of P. amurense extract; berberine was also shown to induce G1 cell cycle arrest, inhibit proliferative kinase signaling, and arrest the growth of lung tumor cells in culture. This work was conducted entirely in animal and cell-culture models and has not been replicated in human clinical trials.

Neuroprotective Mechanisms (Preclinical)

Berberine is planar, cationic, neuroprotective, and neurotrophic; berberine, palmatine, and coptisine at a dose of 5 μg/mL enhanced neurite formation of rat pheochromocytoma (PC12) cells exposed to nerve growth factor (NGF) by 30%, 5%, and 20%, respectively, suggesting transient activation of extracellular signal-regulated kinase (ERK1/2).

Animal research has examined whether Phellodendron amurense (PA) and its major alkaloid compound berberine (BER) improved memory defects caused by administering scopolamine in rats, and investigated effects on the acetylcholinergic system and pro-inflammatory cytokines in the hippocampus. Daily administration of PA and BER improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test; PA and BER also significantly alleviated memory-associated decreases in cholinergic immunoreactivity and restored brain-derived neurotrophic factor and cAMP-response element-binding protein mRNA expression in the hippocampus. This evidence is preclinical (rodent models) only.

Scientific Evidence by Area of Use

1. Metabolic Health: Blood Sugar and Lipids

The best-studied clinical area for the key constituent berberine is metabolic disease. In humans, berberine's lipid-lowering and insulin-resistance improving actions have clearly been demonstrated in numerous randomized clinical trials. Moreover, preliminary clinical evidence suggests the ability of berberine to reduce endothelial inflammation and improve vascular health, even in patients already affected by cardiovascular conditions. These trials have overwhelmingly studied berberine as an isolated compound or as derived from other berberine-containing plants (especially Berberis species and Coptis chinensis), not as Phellodendron amurense bark extract specifically. Evidence for isolated berberine in metabolic disease is considered moderately strong based on multiple RCTs, but extrapolation to P. amurense whole-bark preparations should be made cautiously.

A combination extract study of Phellodendron amurense bark and Citrus sinensis peel (NP 06-1) in osteoarthritis patients also reported cardiovascular endpoints. An 8-week, placebo-controlled, randomized, double-blind study was conducted with four groups in overweight and normal-weight subjects diagnosed with primary osteoarthritis of the knee. NP 06-1 (370 mg capsules twice daily) or matching placebo were given; outcome measures included lipid levels, weight, BMI, blood pressure, and fasting glucose. Eighty subjects were enrolled and 45 completed the study. No serious adverse events were reported. NP 06-1 administration was associated with a general improvement in lipid levels; both overweight and normal-weight treatment groups had significant reductions in triglycerides and LDL-cholesterol, as well as a significant increase in HDL-cholesterol. This is a small pilot study with a high dropout rate (44%), and as NP 06-1 is a combination product, the individual contribution of P. amurense cannot be isolated.

2. Osteoarthritis and Joint Health

Phellodendron amurense has been widely used to treat inflammatory diseases including arthritis, and there is much evidence that it has anti-inflammatory, immunostimulatory, and anti-tumor activities.

The strongest human evidence for joint-related outcomes comes from a study by Oben et al. (2009). An 8-week placebo-controlled, randomized, double-blind study was conducted with four groups comparing the effects of NP 06-1 to placebo in overweight and normal-weight subjects diagnosed with primary osteoarthritis of the knee. NP 06-1 (a combination of Phellodendron amurense bark and Citrus sinensis peel) or matching placebo was given in a dose of two capsules (370 mg each) twice daily. The outcome measures were the Lequesne Algofunctional Index (LAI) for joint pain and movement, as well as biomarkers of inflammation (CRP and ESR). Eighty subjects were enrolled and 45 subjects completed the study; no serious adverse events were reported. Treatment for 8 weeks resulted in a statistical improvement in the LAI score in the overweight treatment group compared to placebo (6.3 ± 2.3 vs 11.8 ± 1.5; p < 0.0001). These results are promising but must be interpreted with caution: the completion rate was only 56%, the extract is a combination product, and the study was small. This is preliminary-level evidence.

In vitro cartilage research using actual human osteoarthritic tissue lends biological plausibility: P. amurense significantly inhibited the IL-1α-induced degradation of GAG and type II collagen from human osteoarticular cartilage in a concentration-dependent manner; celecoxib did not significantly inhibit IL-1α-induced release of GAG and only slightly reduced type II collagen; P. amurense also dose-dependently decreased the levels of aggrecanase-1 and -2, MMP-1, -3, and -13, and increased TIMP-1 expression in human osteoarticular cartilage.

3. Stress, Anxiety, and Cortisol Modulation

The combination extract Relora® (Magnolia officinalis + Phellodendron amurense) has been evaluated in at least two randomized clinical trials. One study measured the effects of Relora® on anxiety, stress, and sleep in healthy premenopausal women. The randomized, parallel, placebo-controlled clinical study was conducted with healthy, overweight (BMI 25–34.9) premenopausal female adults aged 20 to 50 years who ate more in response to stressful situations. The intervention was Relora (250 mg capsules) or identical placebo 3 times daily for 6 weeks. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not effective in reducing long-standing feelings of anxiety or depression as measured using the Spielberger TRAIT questionnaire. Other assessments, including salivary cortisol and amylase levels, appetite, body morphology, and sleep quality/latency, were not significantly changed by Relora in comparison to placebo. The study concluded that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety. There were no safety concerns or significant adverse events observed.

A second Relora® trial (Talbott et al., 2013) examined effects on cortisol and mood state in moderately stressed subjects. In a human clinical trial involving 56 subjects experiencing moderate stress, four weeks of daily Relora supplementation resulted in significantly decreased salivary cortisol and significantly improved mood, including higher indices of Global Mood State, as compared to placebo. Both studies are pilot-level, testing a combination product. Attributing the effects specifically to P. amurense versus Magnolia officinalis is not possible from these data, and the evidence is characterized as preliminary.

4. Prostate Cancer (Nexrutine®)

Phellodendron amurense is able to inhibit prostatic contractility, suggesting it may be useful in the treatment of urological disorders caused by prostatic urethral obstruction such as benign prostatic hyperplasia (BPH). Nexrutine (bark extract from Phellodendron amurense) may have potential to prevent prostate tumor development.

The only available human study on Nexrutine® in prostate cancer was a tolerance/safety-focused Phase II trial. Phellodendron amurense bark extract (Nexrutine®) had shown a favorable effect on prostate cancer in vivo and in vitro. The trial evaluated its tolerance in patients undergoing surgery or radiation for prostate cancer. Patients received Nexrutine® orally (500 mg three times daily) either one to two months pre-operatively or one to two months prior to and with radiation therapy. Common Terminology Criteria for Adverse Events (CTCAE) were used to measure tolerance. In total, 21 patients (9 surgery and 12 radiation) underwent treatment. During the Nexrutine® alone component, there were 2 transient grade 3 toxicities (hypokalemia and urinary incontinence); there was no grade 4 toxicity. For the combined Nexrutine® and radiation component, no additional patients suffered a grade 3 toxicity. All toxicities were transient. By the end of neoadjuvant treatment, 81% of patients had a decline in PSA. This was the first report of prostate cancer patients being treated with Phellodendron amurense bark extract and it was described as very well tolerated; toxicities were minimal and self-limited, and the authors concluded the compound can be safely used in further evaluation of a treatment effect on cancer. This is a single, small, non-randomized safety/tolerability study; efficacy conclusions cannot be drawn.

5. Antimicrobial Activity

A study evaluating up to 12 medicinal plants for their ability to inhibit the growth of Candida fungus found that an alcohol (methanol) extract of Phellodendron amurense significantly inhibited the growth of numerous Candida species; berberine and palmatine were identified as the predominant active ingredients in the extract.

Regarding acne-causing bacteria, in vitro experiments showed that berberine exhibited significant inhibition zones against four Cutibacterium acnes strains, with the minimum inhibitory concentration (MIC) in the range of 6.25–12.5 μg/mL and minimum bactericidal concentration (MBC) in the range of 12.5–25 μg/mL; BBR-treated C. acnes exhibited obvious growth inhibition on bacterial growth curves. This evidence is in vitro only; human clinical trials of P. amurense preparations for acne are lacking.

For dermatophytosis (fungal skin infections), Phellodendron amurense exhibits antifungal activity mainly through berberine hydrochloride and palmatine hydrochloride; a study evaluated the antifungal effects of these compounds and their mixture against Microsporum canis in vivo and in vitro. This research was conducted in rabbit models, not human clinical trials.

6. Antioxidant Activity

Compounds in the leaves (quercetin, quercetin-3-O-beta-D-glucoside, quercetin-3-O-beta-D-galactoside, and kaempferol-3-O-beta-D-glucoside) demonstrated significant free radical scavenging activity comparable to vitamin E. This is in vitro data only, and its relevance to oral supplementation in humans is not established.

7. Antiviral Activity (Preclinical)

The bark of Phellodendron amurense has been described as antiherpesviral, antipolioviral, anti-measles virus, anti-varicella-zoster virus, and anti-CMV, as well as an anti-DNA virus and anti-RNA virus agent. This evidence is based on laboratory and in vitro models; no human clinical trials have been published on antiviral outcomes.

Body Systems and Health Areas of Association

Gastrointestinal system: Historically and in traditional use — dysentery, diarrhea, gastroenteritis, abdominal pain, peptic ulcers, digestive stimulation.
Metabolic system: Blood glucose regulation, lipid modulation (LDL, triglycerides, HDL), insulin resistance — primarily via berberine's AMPK-activating mechanism, with human RCT evidence for isolated berberine.
Musculoskeletal system: Osteoarthritis — pilot clinical evidence for reduced joint pain and inflammation markers; in vitro cartilage-protective evidence.
Immune and infectious disease: Antibacterial, antifungal, and antiviral activity — largely in vitro and animal data.
Dermatological: Eczema, skin infections, acne (C. acnes inhibition), and fungal dermatitis — in vitro and traditional evidence; limited human clinical data.
Urological: Urinary tract infections, BPH (inhibition of prostatic contractility); one human tolerability trial in prostate cancer patients.
Neuroendocrine / stress axis: Cortisol modulation and transient anxiety reduction — two small pilot RCTs using the Relora® combination extract.
Neurological: Neuroprotective and memory-supporting effects — exclusively preclinical (rodent) models.
Hepatobiliary: Liver and gallbladder support — traditional use for jaundice and liver cirrhosis; berberine has demonstrated hepatoprotective effects in cell and animal models.

Dosage Forms and Reported Dosages

The following dosages are those stated in the identified published sources and do not represent recommendations:

Dried powder: 3 to 10 grams per day. 4:1 dried decoction: 1 to 3 grams per day.
Phellodendri Cortex is described in the literature as bitter and nontoxic; treatment doses are typically cited as 1 to 11 g per day.
In the Nexrutine® prostate cancer tolerability trial, patients received 500 mg three times daily (1,500 mg/day), administered either 1 to 2 months pre-operatively or 1 to 2 months prior to and with radiation therapy.
In the Kalman et al. (2008) Relora® anxiety trial, the intervention was Relora (250 mg capsules) 3 times daily for 6 weeks.
In the Oben et al. (2009) osteoarthritis trial, NP 06-1 (Phellodendron amurense bark and Citrus sinensis peel) was given in a dose of two capsules (370 mg each) twice daily.
One commercial berberine standardization product uses Phellodendron 20:1 extract at 440 mg per tablet (from 8.8 g stem bark), containing berberine 200 mg per serving.

Safety Considerations and Interactions

General Tolerability

When taken by mouth, phellodendron is possibly safe when used in combination with other ingredients short-term; however, there is not enough reliable information to know if phellodendron is safe or what the side effects might be when used as a single ingredient.

Preclinical acute toxicity testing of Nexrutine® found that a single oral dose of 2,000 mg/kg body weight was administered to assess acute toxic properties; simultaneously, repeated-dose toxicity was evaluated through daily administration of three doses (250, 500, 750 mg/kg body weight) for 28 days; single administration showed no signs of toxicity and morbidity, suggesting an LD50 of Nexrutine greater than 2,000 mg/kg body weight.

Pregnancy and Lactation

It is considered unsafe to use phellodendron during pregnancy. Phellodendron contains berberine, which can cross the placenta and might harm the fetus. It is also considered unsafe during breastfeeding: berberine can be transferred to the infant through breast milk and can cause brain damage in newborns, especially premature newborns with jaundice.

Berberine is contraindicated for pregnant women throughout the entire pregnancy, breastfeeding mothers, and newborns. Berberine may interfere with bilirubin excretion in the liver, increasing bilirubin levels in the blood and causing jaundice in the fetus, which can lead to seizures. It may also increase uterine contractions, potentially causing premature labor.

This safety concern is recognized at the regulatory level: French regulatory authorities (DGCCRF) have indicated that isoquinoline alkaloids (berberine and palmatine) are substances to be monitored in Phellodendron amurense and that "labels shall include a warning advising pregnant women not to use them."

Neonatal Use

Phellodendron is considered unsafe in newborn infants, as it can cause brain damage, especially in premature infants with jaundice.

Long-Term Use

In classical TCM references, long-term use is contraindicated as it may damage yin and fluids; the berberine content may inhibit biliary conjugation in the fetus or newborn and thus lead to hyperbilirubinemia. Use is not recommended after the first trimester of pregnancy, in newborns, or during the first month of breastfeeding.

Drug Interactions: CYP Enzyme Inhibition

The most clinically significant interaction concern relates to berberine's inhibitory effects on cytochrome P450 enzymes. Berberine inhibits CYP3A4, CYP2D6, and CYP2C9; these are liver enzymes that break down most prescription drugs, and when berberine slows them, medications that depend on those pathways can accumulate to dangerous levels.

A randomized crossover clinical study in healthy male subjects provided direct human evidence of this interaction: a two-phase randomized crossover clinical study was performed in healthy male subjects; after 2 weeks of berberine (300 mg three times daily) administration, probe substrates were used to evaluate enzyme activities of CYP3A4, 2C19, 2D6, 2C9, and CYP1A2; a decrease in CYP2D6 activity was observed as urinary dextromethorphan/dextrorphan ratio increased ninefold (P < 0.01); the losartan/E-3174 ratio doubled (P < 0.01) after berberine administration, indicating a decrease in CYP2C9 activity.

The interaction with cyclosporine (ciclosporin) is particularly well-documented. Berberine is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) transporter substrate; interaction studies have shown that coadministration markedly elevates the blood concentration of cyclosporine A. The increase in cyclosporine bioavailability may be partly due to decreased metabolism because of CYP3A4 inhibition and partly due to increased uptake from the gut due to competition for the P-gp transporter. In view of these findings, concomitant use of medicines containing berberine must be avoided during cyclosporine treatment.

A clinical pharmacokinetic study in renal-transplant recipients confirmed that berberine can markedly elevate the blood concentration of cyclosporine A; the authors noted that the combination may allow a reduction of the CsA dosage; the mechanism is most likely explained by inhibition of CYP3A4 by berberine in the liver and/or small intestine.

Affected drug classes include cyclosporine, several statins, SSRIs, macrolide antibiotics, warfarin, and heart-rhythm medications.

Dose-Dependence of Drug Interactions

The magnitude of CYP interaction appears dose-dependent. If studies in mice extrapolate to humans, lower doses of berberine appear to present a low risk of producing drug-drug interactions as a result of changed CYP enzyme activity; however, high doses of berberine may suppress CYP activities and result in drug-drug interactions.

Nomenclature Confusion

A recurring safety note in the literature concerns misidentification: phellodendron should not be confused with the houseplant called philodendron; the names are similar but the plants are entirely unrelated. Similarly, phellodendron should not be confused with corkwood tree, as these are not the same plant.

Limitations of the Evidence Base

Due to the extensive traditional use of phellodendron cortex in Chinese medicinal herbal formulas, most of the information regarding phellodendron stems from these herbal formulas. The use of multiple herbs in a formula makes it difficult to determine which herb may be responsible for which pharmacological activity. The majority of human clinical studies available for P. amurense have tested it in proprietary combination products (Relora®, NP 06-1, Nexrutine®) rather than as an isolated single-ingredient extract, limiting conclusions about the contribution of phellodendron alone. Most mechanistic work has been conducted in cell cultures or animal models. People use phellodendron for acne, diabetes, obesity, osteoarthritis, stress, and many other conditions, but there is no good scientific evidence to support these uses. Clinical trials that do exist are predominantly small, short-term, and pilot in nature.

References

Health Conditions

Health conditions that Corktree may help support.

No conditions available.

Body Systems

Body systems that Corktree may help support.

No body systems available.