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Magnolia Bark Extract

Scientific Name(s): Magnolia officinalis Rehd. et Wils.
Common Name(s): "Hu-bak", Magnolia bark

Clinical Overview

Use

Most literature sources are from Japanese and Chinese foreign-language publications, clinical studies are on the efficacy of magnolia bark extract (MBE) are limited. Documentation on the materials and extracts for several studies is also limited. In vitro and animal studies document potential efficacy as an antibacterial, anti-inflammatory, and anticancer agent, as well as for use with Alzheimer disease, depression, diabetes, and menopause.

Dosing

MBE is commercially available in the United States and throughout Europe. Dosage varies depending on the condition treated, with weight loss products containing MBE available mostly in powder form. Several strengths are available for Relora, a patented blend marketed as "a natural stress management supplement" that includes MBE. Dosing recommendations include taking a 300 mg capsule of Relora 2 to 3 times per day. One small, randomized, controlled study treated patients with one 60 mg tablet of MBE daily to help relieve menopausal symptoms.

Contraindications

Avoid use if hypersensitivity exists for any of the components in MBE. No absolute contraindication could be found in the medical literature.

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of limited clinical data. An animal study found that honokiol and magnolol blocked uterine contractions in rat uterus.

Interactions

Drug-herb interactions are documented, and caution is advisable in patients self-medicating with MBE. Magnolol may interact with acetaminophen. Additive adverse reactions with antiplatelet medications may occur in patients also self-medicating with magnolol. MBE and honokiol may interact with benzodiazepines. Magnolol may stimulate corticosterone secretion or increase steroid medication concentrations. MBE may cause excess sleepiness, vertigo, and dizziness in patients taking muscle relaxants.

Adverse Reactions

No dermatologic adverse effects were documented with topical application of magnolol and honokiol; however, several cases of allergic dermatitis have been documented in case reports. In one small clinical trial, a patient dropped out because of a number of adverse reactions, including heartburn, shaking hands, perilabial numbness, sexual dysfunction, and thyroid dysfunction.

Toxicology

Some sources document case reports of progressive interstitial renal fibrosis in patients consuming an herbal blend containing M. officinalis.

Source

Numerous documented medicinal properties are associated with 2 major phenolic constituents, magnolol and honokiol, from the stem bark of M. officinalis Rehd. Et Wils.1, 2 Concentration variations of magnolol and honokiol exist in bark sourced from different provinces in China, as recorded in The Pharmacopoeia of the People's Republic of China. The plant is primarily indigenous to China and found at elevations of 200 to 3,000 meters.3

History

MBE has been used for over 1,000 years as a folk medicine in Asia.4, 5 In traditional Asian medicine, MBE has been prescribed for treating acute pain, headaches, diarrhea, allergies, asthma, and gynecological disorders. It has also been used to treat fever, anxiety, nervous disorders, depression, muscular pain, abdominal fullness, constipation, and thrombotic stroke.6, 7, 8, 9 In Chinese and Japanese folk medicine, MBE has been used to treat bronchitis and emphysema.10

Chemistry

Magnolol and honokiol are the 2 primary active phenolic constituents of MBE.1, 2, 3

Uses and Pharmacology

Most literature sources are from Japanese and Chinese foreign-language publications, and clinical studies on the efficacy of magnolia bark extract are limited. Documentation on the materials and extracts for several studies is also limited. In vitro and animal studies document potential efficacy as an antibacterial, anti-inflammatory, and anticancer agent, as well as for use with Alzheimer disease, depression, diabetes, and menopause.

Alzheimer disease

In vitro and animal data

Magnolol and honokiol exhibited central depressant effects by producing sedation, ataxia, muscle relaxation, and a loss of the righting reflex in young chicks.19 The compound 4-O-methylhonokiol (4-O-MH) promoted neurite outgrowth in a concentration-dependent manner in cultured embryonic neuronal cells. The compound also increased expression of neurotrophins, which are believed to promote neurite outgrowth.20 An ethanol extract of M. officinalis and 4-O-MH suppressed beta amyloid peptide (eg, Aβ1–42)–induced memory impairment in mice, perhaps by inhibiting neuronal cell death, and increased reactive oxygen species expression.21 The compound 4-O-MH may also inhibit activation of the mitogen-activated protein kinase (MAP kinase) pathway, which is important in neuronal cell death.22 An ethanol extract of M. officinalis and 4-O-MH improved memory impairment induced by scopolamine in a dose-dependent manner.23

Antibacterial

In vitro data

In an agar dilution study, honokiol and magnolol inhibited (minimum inhibitory concentration [MIC] = 25 mcg/mL) the growth of periodontal pathogens Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Micrococcus luteus, and Bacillus subtilis11 and were less potent than tetracycline. MBE, honokiol, and magnolol were all effective against killing bacteria responsible for halitosis and formation of dental caries (ie, Streptococcus mutans).11, 12, 13 The MIC ranged from 8 to 31 mcg/mL for magnolol, honokiol, and MBE against Porphyromonas gingivalis, Fusobacterium nucleatum, and S. mutans. Mint candies containing MBE 0.2% reduced oral bacteria by 99.9% within 5 minutes of treatment. Similar antibacterial activity was demonstrated with MBE chewing gum.12 The antibacterial activity of MBE may include nonionic surface agent activity leading to disruption of the cell membrane and lipid protein interface.13

Honokiol and magnolol inhibited the growth of acne-causing bacteria Cutibacterium acnes and Cutibacterium granulosum.14 Both phenolic compounds also reduced inflammation by inhibiting the secretion of interleukin-8 and tumor necrosis factor alpha (TNF-alpha) induced by P. acnes. A human skin irritation test in 30 healthy patients demonstrated no adverse effects from topical application of the phenolic compounds.

MBE may also have antimicrobial activity against Helicobacter pylori.12

Clinical data

Chewing sugarless gum containing either MBE (0.17%) + xylitol or xylitol without MBE was shown to improve mutans streptococci levels and bleeding on probing significantly better than control. However, MBE + xylitol reduced mutans streptococci concentrations (P=0.04) and bleeding upon probing (P=0.04) significantly better than xylitol without MBE.71 (Campus, 2011)

Anti-inflammatory

In vitro and animal data

Magnolol reduced swelling and inflammation in edema induced by carrageenan, compound 48/80, polymyxin B, and reversed passive Arthus reaction in mice.15 When compared with dexamethasone, magnolol did not increase glycogen levels in the liver. The mechanism of action appears to involve reducing the levels of eicosanoid mediators rather than affecting glucocorticoid activity or steroid hormone activity from the adrenal gland.15, 16

In mice, honokiol and magnolol reduced inflammatory pain by blocking the inflammatory mediators substance P and prostaglandin E2, and the neurotransmitter glutamate.17 Honokiol inhibited several signal transduction cascades (eg, protein kinase C, mitogen-activated protein kinase, nuclear transcription factor kappa-B) involved with regulating inflammatory mediator and gene expression.18

Antioxidant

In vitro and animal studies document potent antioxidant activity for magnolol and honokiol in protecting against myocardial and cerebral ischemia by inhibiting neutrophil infiltration and reactive oxygen species production.48, 49, 50

Antiviral

Magnolol and honokiol have weak activity against HIV-1 in human peripheral blood mononuclear cells.51

Anxiety

Extracts of M. officinalis may have benzodiazepine-like activity as documented by a strong affinity on the benzodiazepine-binding site of the gamma aminobutyric acid (GABA) receptor. Honokiol also interacts with the GABA receptor and exhibited activity similar to that of diazepam.8, 52

Asthma

Magnolol may stimulate corticosterone secretion by the adrenal gland, a mechanism similar to the action of exogenous glucocorticoids in the treatment of asthma.58

Atherosclerosis

Magnolol inhibited expression of monocyte chemoattractant protein-1 in vascular smooth muscle cells, which contributes to the development of atherosclerosis and re-stenosis.53 Magnolol also induced apoptosis53 and inhibited cell viability in TNF-alpha cytokine54-stimulated vascular smooth muscle cells. Magnolol's antioxidant activity appears to also play a role in preventing atherosclerotic vascular disease.55, 56 Antiplatelet activity relaxes vascular smooth muscle by releasing endothelium-derived relaxing factor and inhibiting calcium influx through voltage-gated calcium channels.57

Cancer

In vitro and animal data

Honokiol induced apoptosis and inhibited angiogenesis via the Bcl-2 and caspase-3 pathway in ovarian tumor cells.24 Honokiol increased apoptotic DNA fragmentation in cultured human prostate cancer cells irrespective of their androgen responsiveness or p53 status and inhibited growth of an androgen-independent p53 mutant cell line xenograft in mice without causing weight loss or any other adverse reactions.25 Magnolol inhibited growth and induced apoptosis, and G1- and G2/M phase cell cycle arrest in human urinary bladder cancer 5637 cells by activating extracellular signaling.26 Magnolol inhibited growth of human malignant melanoma A375-S2 cells by both the death receptor pathway and the mitochondrial pathway.27 Honokiol reduced cell survival and inhibited growth in human chondrosarcoma cells, a malignant primary bone tumor.28 The anticancer activity involves mitochondria dysfunction and induced cell death mediated by increased endoplasmic reticulum stress, eventually resulting in apoptosis. Honokiol induced apoptosis and inhibited HeLa cell proliferation through many proteins and multiple pathways.29

Magnolol induced apoptosis in human lung cancer CH27 cells through activation of signaling pathways responsible for cell death, including regulation of the Bcl-2 family proteins and release of cytochrome c from mitochondria into the cytosol, leading to activation of the caspase cascade.30

Magnolol and honokiol exhibited cytostatic rather than cytotoxic effects on HL-60 leukemia cells. Both compounds also enhanced vitamin D3 and all-trans-retinoic acid induced HL-60 leukemic cell differentiation.31

Magnolol suppressed growth of cultured human U373 malignant glioblastoma cells by inhibiting DNA synthesis and activating apoptosis. Magnolol is able to cross the blood brain barrier, as documented by pharmacokinetic studies in rats.32

Honokiol alone inhibited the growth of human lung cancer A549 in lung carcinoma models, and when combined with cisplatin, enhanced antitumor efficacy by increasing apoptosis and inhibition of angiogenesis.33 Honokiol inhibited several human breast cancer cell lines, as well as drug-resistant breast cancer cell lines. The mechanism involved inhibition of cell proliferation, induced cell cycle arrest, and apoptosis. Honokiol also enhanced the proapoptotic activity of lapatinib or rapamycin in her-2 over-expressed or low-expressed breast cancer models.34

Honokiol-hydrogel reduced the number of pleural tumor foci and prolonged survival time in malignant pleural effusion–bearing mice when compared with controls. The mechanism involved inhibition of angiogenesis, and histological analysis of the pleural tumors revealed application of the gel increased the rate of apoptosis.35

Cardiac arrhythmia

Honokiol reduced the infarct zone, duration of ventricular tachycardia, and ventricular fibrillation in coronary ligated rats.59 The cardioprotective effect may be associated with increased nitric oxide synthesis.60

Cataracts

Honokiol inhibited hydrogen peroxide–induced apoptosis in human lens epithelial cells by modulating various signaling pathways in cataract formation.61

Depression

In vitro and animal data

A mixture of honokiol and magnolol at 20 and 40 mg/kg inhibited stress-induced decreases of serotonin in the frontal cortex, hippocampus, striatum, hypothalamus, and nucleus accumbens in mice. The mixture also increased serotonin metabolite levels in the frontal cortex, striatum, and nucleus accumbens at 40 mg/kg. Honokiol and magnolol also reduced elevated corticosterone concentrations and normalized hypothalamic–pituitary–adrenal hyperactivity and reduced platelet adenylyl cyclase activity by upregulating the cyclic adenosine monophosphate pathway.36

Experimentally induced depression in mice was inhibited by magnolol and its metabolite hydroxydihydromagnolol.37 An ethanol extract of a traditional Chinese medicine containing M. officinalis exhibited antidepressant effects in mice similar to the effects of fluoxetine.38 In a stress-induced model in rats, the combination of honokiol, magnolol, and ginger oil exhibited antidepressant effects. Honokiol and magnolol increased serotonin levels in numerous brain regions, while ginger reduced gastric mucosa cholecystokinin and serum gastrin levels.39

Diabetes

In vitro and animal data

Magnolol reduced metabolic parameters common in diabetic nephropathy, such as blood glucose, plasma insulin, sorbitol, and advanced glycation end products in an experimental type 2 diabetes rat model. Magnolol also attenuated upregulation of renal transforming growth factor beta 1, which plays a key role in the pathogenesis of diabetic nephropathy, and reduced expression of extracellular matrix protein as type IV collagen.40 In mature adipocytes, magnolol improved insulin sensitivity by increasing basal and insulin stimulated glucose uptake through peroxisome proliferator-activated receptors.41 KIOM-4, a plant extract obtained from M. officinalis, protected pancreatic beta cells against streptozotocin-induced oxidative damage.42 KIOM-4 induced a rate-limiting enzyme through the extracellular regulated kinase pathway, which resulted in cytoprotection against diabetic conditions and increased insulin release from the pancreas. Another plant extract combination containing M. officinalis, KIOM-79, inhibited xylose-induced lens opacity.43 KIOM-79 also protected human lens epithelial-B3 cells from the toxic effects of high glucose levels by inhibiting transforming growth factor beta, which is involved in the pathophysiology of ocular damage. An antioxidant mechanism may be involved with KIOM-79, protecting against oxidative stress-induced apoptosis in diabetic retinopathy.44

Gynecological disorders

Honokiol and magnolol blocked calcium-dependent uterine oscillatory contractions in rat uterus.5 The mechanism may be associated with blocking receptor-operated cation and voltage-operated calcium channels.5

Liver disease

Magnolol reduced acetaminophen-induced liver damage in rats by inhibiting lipid peroxidation and formation of reactive oxygen species.6 Honokiol reversed the effects of induced alcoholic fatty liver in rats by inhibiting lipid accumulation or fatty acid synthesis.62

Menopause

Clinical data

A small, controlled, randomized, multicenter study examined the effects of 2 formulations, one containing magnolia bark extract (60 mg) and magnesium (50 mg), in symptomatic menopausal women with sleep or mood alterations. The magnolia extract and magnesium combination appeared to be effective in reducing psychoaffective and sleep disturbances from menopause.45 A small pilot study examined the effects on body weight from a dietary supplement containing extracts of M. officinalis and Phellodendron amurense in 28 premenopausal women. The supplement reduced evening cortisol levels and may have improved systolic blood pressure as well as perceived stress.46 Another randomized, placebo-controlled trial indicated that the same dietary supplement may reduce mild transitory anxiety in premenopausal women.46, 47 Postmenopausal women with mild affective symptoms, borderline anxious-depressive behaviors, and/or sleep disorders were enrolled in a randomized, controlled trial (n=634) that compared the activity of isoflavones + lactobacilli with and without MBE. After 12 weeks, the addition of MBE provided a significant improvement in insomnia, irritability, and libido at 4, 8 and 12 weeks.70

Oral health

A double-blind, randomized, controlled interventional trial (n=120) in Italy investigated the effect of MBE on factors related to dental caries, such as cariogenic bacteria (especially mutans streptococci), fermentable carbohydrates intake, plaque acidity, and saliva flow. MBE was delivered by means of a sugar-free chewing gum containing xylitol, which itself has also been shown to exhibit caries preventative activity. Enrolled participants were adults at high risk of dental caries and were randomized to MBE (0.17%) + xylitol, xylitol, or a control group. Participants were instructed to chew 1 or 2 pieces of gum for 5 minutes 3 times daily for 30 days (5 pieces/day); this regimen delivered 11.9 mg/day of magnolol and 2.2 g/day of honokiol. After 30 days, MBE + xylitol and xylitol gums provided significant protection against plaque acidity (P=0.01 and P=0.04, respectively) compared to baseline, with protection by MBE also being significantly better than control (P=0.04) Additionally, both MBE + xylitol and xylitol gums improved mutans streptococci levels and bleeding upon probing significantly better than control. However, compared to xylitol, MBE + xylitol significantly reduced mutans streptococci concentrations (P=0.04) and bleeding upon probing (P=0.04).71

In 2 double-blind, randomized, placebo-controlled trials in Italy, the acute effect of MBE plus zinc acetate on halitosis was evaluated via 2 doseforms: a sugarless gum and a sugarless tablet. A total of 123 and 100 adults completed the respective trials. Although the gum and tablet test products provided significant reductions in oral volatile sulfur compounds within 10 minutes and 1 hour compared to controls, the investigators did not provide data on MBE without zinc; the latter of which itself has been shown to have protective effects against the development of volatile sulfur compounds and halitosis. Both delivery forms were well tolerated with no reported problems.74, 75 A 2017 systematic review of chewing gum and its impact of halitosis parameters (ie, volatile sulfur compounds, organoleptic scores) in adults evaluated 10 trials that exhibited high heterogeneity; no study was at low risk of bias in all analysis items. The study summarized above was the only study included that evaluated magnolia bark extract.73

Seizure

Honokiol and magnolol inhibited excitatory amino acid-evoked cation signals and N-methyl-D-aspartate acid (NMDA)–induced seizures.63 Honokiol was more selective in blocking the NMDA receptor and demonstrated greater inhibition against NMDA-induced seizures.

Sepsis

Magnolol prevented hypotension, bradycardia, and multiple organ failure induced by lipopolysaccharide in rats.64 Potential mechanisms of action include: reducing the plasma TNF-alpha and nitrate/nitrite concentrations, suppressing organ superoxide anion level, and suppressing the blood coagulation cascade and expression of inflammatory genes.

Dosing

MBE is commercially available in the United States and throughout Europe, as documented by Internet search engines. Dosage varies depending on the condition treated, with weight loss products containing MBE available mostly in powder form. Several strengths are available for Relora, a patented blend marketed as "a natural stress management supplement" that includes MBE. Dosing recommendations include taking a 300 mg capsule of Relora 2 to 3 times per day. A small, randomized, controlled study treated patients with one 60 mg tablet of MBE daily to help relieve menopausal symptoms.45

Pregnancy / Lactation

Avoid use during pregnancy and lactation because of limited clinical data. An animal study documented that honokiol and magnolol blocked calcium-dependent uterine oscillatory contractions in rat uterus.5

Interactions

Drug-herb interactions are documented, and caution is advisable in patients self-medicating with MBE. Magnolol may interact with acetaminophen; one study documented reduced acetaminophen-induced liver damage in rats.6 Additive adverse reactions with antiplatelet medications may occur in patients also self-medicating with magnolol.57 MBE and honokiol may interact with benzodiazepines.8, 52 Magnolol may stimulate corticosterone secretion58 or increase steroid medication concentrations.65 MBE may cause excess sleepiness, vertigo, and dizziness in patients taking muscle relaxants.

Adverse Reactions

No adverse dermatologic effects were documented with topical application of magnolol and honokiol.14 In one small clinical trial, a patient dropped out because of a number of adverse reactions, including heartburn, shaking hands, perilabial numbness, sexual dysfunction, and thyroid dysfunction.46 A few cases of allergic contact dermatitis have been reported in 4 patients who presented with a variety of symptoms, including vesicular, edematous, pruritic, scaly, and/or erythematous lesions after applying cosmetic creams containing M. officinalis bark extract. All patients’ hypersensitivity were validated with positive reactions to patch testing.72, 76

Toxicology

Dietary administration of MBE in rats at doses of up to 480 mg/kg in a 21-day study and 240 mg/kg in a 90-day study resulted in no clinically important toxicity.7 Some sources document the development of progressive interstitial renal fibrosis in patients consuming an herbal blend containing M. officinalis.66, 67 In vitro studies demonstrate no genotoxic effects from MBE in chromosomal aberration assays.68 One study documented that magnolol in liver graft preservation enhanced apoptotic events under cold preservation instead of preserving hepatocyte integrity.69

References

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