MAGNOLIA BARK (MAGNOLIA OFFICINALIS)

A flowering plant native to China, but commonly used throughout history in not only Tradition Chinese, but also in Japanese and Korean medicine. These historical indications were thought to primarily stem from its ability to ease anxiety, promote sleep, in addition to even treating certain types of allergies and asthma, amongst other things.

This article will overview preliminary and non-human trials on the mechanism of action involved with the long history of the traditional use of this ancient medicine, including its implementation in Traditional Chinese Medicine (TCM).

Flash forward to modern times, we're now aware of various bioactive compounds within the tree which not only act as anti-bacterial, anti-allergy, and even anti-inflammatory effects, its two primarily focused and clinically studied compounds, Honokiol and Magnolol, appear to exert a majority of at least its generally sedative effects and anxiolytic effects.

This post will overview of the multi-layered mechanisms through which magnolia bark extracts can be therapeutically used with a dose-dependent response and standardisation methods for a range of different ailments anywhere from anxiety and insomnia, to some anti-inflammatory, pain relieving and anti-depressant actions via multiple mechanisms which will be further explained in detail.

First and foremost, it should be noted that the majority of its clinical benefits have only been scientifically proven in regards with anxiolytic and gabaergic effects, in addition to an effect in noradrenaline inhibition and a modulatory effect on the endocannabinoid system, which likely contribute to the vast majority of its anti-anxiety effects, anti-stress effects and its partially pain relieving and anti-inflammatory characteristics, respectively(Breus, 2018).

We will also briefly cover some of its nootropic and neuroprotective values which could serve for prevention of Alzheimer's disease and other memory and cognitive disorders which respond to similar mechanisms which will be analysed. Its also worth mentioning that similarly to kava and ashwagandha, different parts of the plant appear to have differing effects and mechanisms, especially in regards with their application use.

For example the flowering buds of the plant are what contribute to most of its anti-allergy effects when applied orally or topically, and is therefore primarily only used for sinus infections, anti-allergy and headaches (Dharmananda, 2002., Amblard, 2007., Li N. et al. 2007).

Major constituents of the plant is an assorted mix of essential oils (terpenes), poly-phenols most importantly of which are the two lignans found in the whole plant and the bark, being honokiol and Magnolol, respectively. In addition to terpenes and these lignans (as well as many other terpenes with currently no known application of use on their own, outside of a synergistic entourage effect) are some alkaloids, more notable of which is phenethylamine and aporphine.

Naturally, a relative level of minerals mainly Potassium (with levels as high as 2560 ppm) and Calcium (with levels as high as 6350 ppm), have also been found in plant extracts possibly at least partially due and dependent on the soil, nutrition or medium in which its been cultivated. Keep in mind that each ppm (parts per million) is roughly equivalent to 1mg/ml (Dharmananda, 2002., Lee et al., 2011).

As well as the well-studied effects of ligands, honokiol and magnolol, secondary metabolites of this herb produces primarily isoquinoline-type alkaloids which are typically of the aforementioned aporphine, and benzylisoquinoline derivatives (based on the precursor amino acids tyrosine and dopa) (Yan et al., 2011). Its volatile oils consisting of approximately up to 95% essential oils are in the form of sesquiterpenoid alcohols and vary greatly based on factors like harvesting period or even sites (EPCNF, 2009).

When it comes to its mood elevating effects on depression however, most of its constituents, especially the two main ones studied don't seem to perform similarly to traditional antidepressants which to varying degrees of selectivity and potency either potentiate or block the re-uptake of certain monoamines and neurotransmitters (including serotonin, norepinephrine and dopamine) most sub-receptors within this region seemed to be subtly affected, the response of delta sub-units were seemingly 2 to 3 times more sensitive than the rest when affected by standardized levels of magnolol and honokiol (Alexeev et al., 2012; Chen et al., 2012; Woodbury et al., 2013).

When it comes to its mood elevating effects on depression however, most of its constituents, especially the two main ones studied don't seem to perform similarly to traditional antidepressants which to varying degrees of selectivity and potency either potentiate or block the re-uptake of certain monoamines and neurotransmitters (including serotonin, norepinephrine and dopamine).

Instead they appear to be more involved with adenosine 1 receptor, dopamine transport, direct dopamine D5 antagonist activity, which may play a role in ADHD, Parkinson’s and Alzheimer’s disease, serotonin sub-receptors 5HT1B and 5HT6 antagonist acitivty, and some potentially up-regulating activity at the GABA benzodiazepine receptor at minimal concentrations (Koetter et al., 2009).

Honokiol also enhances hippocampal acetylcholine release, whilst although not through re-uptake of any kind, magnolol modulates serotonergic activity, believed initially as early as 2003 to be mainly central and certainly prominent yet is its now well regarded to be much more specific in nature of sub-types involved (Nakazawa et al., 2003).

While, unrelated to psychopharmacology, it should also be noted that there is also an influence on serum corticosterone levels, and the up-regulating of the cyclic adenosine monophosphate pathways through its platelet adenylate cyclase activity (Poivre & Duez, 2017).

More importantly, the role of standardized extracts of magnolia bark can be beneficial in the treatment of Alzheimer's disease which is a common form of dementia, and whilst currently pharmaceuticals which target this condition vary greatly but are often in the form of antagonizing effects of acetylcholinestrase whilst also being accompanied by cholinergic effects which reportedly increase the levels of this enzyme and can have a role in treating and delaying the disease in certain individuals (Poivre & Duez, 2017).

Honokiol appears to be the primary anxiolytic compound and although there are only a limited number of human studies on its isolated or standardized form and effect at a dose of 100 ug/ml displaying a benzodiazepine inhibition effect of up to 61% in some studies, similarly to the figures seen in its adenosine receptor inhibition of 48% +/- 15, (and compared to a relatively lower effect on the serotonin sub receptors at the same doses only inhibited less than 25% of sub-types such as 5HT1B and 5HT6 antagonist activity effect) when compared with classical anxiolytic agents, in mice, seven daily treatments with 0.2 mg/kg and higher of the lignand, produced an effect equal in anxyolysis to 1mg/kg of diazepam but without any change in motor activity or muscle tone, and lacked any significant muscle relaxation (Kuribara et al., 2012).

This effect was also reversible by the GABA-A antagonist flumazenil and even caffeine (due to its adenosine. The exact inhibition effect on 5HT6 receptors were as high as 48% at the 100 ug/ml dose, and as low as 15% for as low as 10 ug/ml (Koetter et al., 2009).

There's no denying that a standardized can be used as milder alternatives or even tools for benzodiazepine withdrawal as a natural alternative, with generally fewer side effects and a less selective yet more multi-layered and balanced mechanism.

And although no peer-reviewed article to date has shown any magnolia bark extract dependence or addiction liability has been noted to date, caution is advised for those with a psychiatric history of benzodiazepine use/especially misuse and mistaking the fact that its natural as somehow side effect free.

The standardized and appropriate use of the herb can be safely used in full spectrum form, there may be potential for the misuse of synthetic analogues of magnolol and especially honokiol as far as GABAergic and cannabimimetic compounds are concerned. This is similar to the emergence of high potency THC extracts becoming more popularised due to increased potency, selectivity and faster acting effects (Schifano et al., 2017).

In regards with metabolism, a number of CYP450 enzymes are affected at different values, with magnolol itself mainly having an inhibitory effect on CYP1A with an IC50 value of as low as 1.62 uM, and to a slightly lesser extend, CYP2C (5.56 uM) and to a far lesser extent, CYP3A (35 uM). This means that there can be some potential herb/drug interactions with certain pharmaceuticals which are substrates or inducers of these CYP enzymes.

Mean plasma concentrations of magnolol achieved after oral consumption is 426.4 ± 273.8 ng/mL (when tested in rats), with its bioavailability appearing to be as high as 17.5 +/- 9.7%. The absolute bioavailibility of isolated magnolol typically being much lower (as low as 4-5%).

Lastly, two main metabolites, namely isomagnolol and tetrahydromagnolol have been predicted to exhibit a synergistic effect with magnolol and the other constituents within the herb and directly acting on both CB receptors (with a slight preference for CB1) as a moderately potent agonist and regulatory effects (albeit potentially far weaker than is the case with kava and cannabis). (Zhang et al., 2019).

Magnolol has a half life of roughly 15 minutes, whilst honokiolol has shown a half life of up to 40-60 minutes, with maximum plastma concentrations reaching between 20-30 minutes.

Its therefore can be hypothesized that multiple dosing throughout the day may sometimes be necessary, similarly to other short acting anxiolytics which are used for similar indications, especially once our understanding of high quality clinical trials have been established.

It should be especially noted that there is a lack of quality human trials at this point in time. Comparative, in addition to randomized, double blind, placebo controlled human trials will be needed to determine the full spectrum of effects produced by the ancient tree, as well as to assist in determining doses based on its standardized, active consistuents.