Medical Hypotheses 83 (2014) 673–676
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Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Potential use of Magnolia officinalis bark polyphenols in the treatment of cannabis dependence Maurizio Coppola a,⇑, Raffaella Mondola b a b
Department of Addiction, ASL CN2, Alba-Bra, Italy Department of Mental Health, ASL CN1, Saluzzo, Italy
a r t i c l e
i n f o
Article history: Received 30 August 2014 Accepted 13 September 2014
a b s t r a c t In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders, cognitive deficits, chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C. In this article we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting a potential application in the treatment of both cannabis dependence and cannabis-related disorders. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Cannabis derivatives are the most widely-spread illicit recreational substances around the world. It was estimated that in 2012, between 125 and 227 million people aged 15–64 have used cannabis with the highest prevalence rates observed in West and Central Africa, North America, Oceania, Western and Central Europe [1]. In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased [1]. At this regard, high potency cannabis products have contributed to the development of this trend worsening the impact of this drug on public health [1,2]. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders and cognitive deficits [3]. Moreover, cannabis consumption has been related to chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C [3]. Although the prevalence rate of cannabis induced dependence is lower than those induced by other psychoactive drugs, around 9% of chronic users developed dependence with withdrawal symptoms after suspension [4]. Numerous pharmacological and/or nonpharmacological (e.g. motivational intervention) treatments have ⇑ Corresponding author at: Corso Coppino 46, 12051 Alba (CN), Italy. Tel.: +39 0173316210; fax: +39 017335067. E-mail address: [email protected] (M. Coppola). http://dx.doi.org/10.1016/j.mehy.2014.09.015 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
been used to treat cannabis dependence. Literature data suggest that these therapies can produce benefits in many patients, however, relapses, residual symptoms, therapeutic dropout and functional impairment are frequently observed [5]. In order to develop new pharmacological alternatives for the treatment of cannabis dependence, we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting their potential use in the treatment of cannabis dependent patients. Plant derivatives are used in traditional medicine since immemorial time. In particular, magnolia bark has been and still is used in Chinese and Japanese herbal medicine for the treatment of various diseases including anxiety, sleep-disorders, inflammations, microbial infections and allergies [6]. The main active constituents of M. officinalis bark magnolol, honokiol and 4-O-methylhonokiol (this substances is a minor constituent of M. officinalis bark but the main constituent of Magnolia grandiflora L.) (Fig. 1) have long been investigated for their antioxidative, anti-inflammatory, anti-anxiety, antidepressant, antitumor and antimicrobial effects [6]. Furthermore, recent studies have demonstrated that, like cannabis psychoactive compounds, M. officinalis bark active principles have affinity for cannabinoid receptors as well as for G protein-coupled receptor 55 (GPR-55), G proteincoupled receptor 18 (GPR-18) and peroxisome proliferatoractivated receptors (PPARs) [7]. Pharmacodynamic comparison between M. officinalis bark active principles and natural cannabinoids such as delta-9-tetrahydrocannabinol (delta-9-THC) suggests a potential use of these substances in the treatment of cannabis dependence.
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M. Coppola, R. Mondola / Medical Hypotheses 83 (2014) 673–676
Magnolia is a large genus of flowering plant belonging to the Magnoliaceae family. M. officinalis bark is a deciduous tree native to the mountains and valleys of China and belonging to the magnolias subsection named ‘‘Rhytidospermum’’. This plant is largely used in Chinese and Japanese traditional medicine for treating anxiety, sleep-disorders, inflammations, microbial infections and allergies [6]. Pharmacological properties of M. officinalis bark are due to its polyphenols exerting antioxidant, anti-inflammatory, anti-anxiety, neuroprotective, antitumor, anti-depressant, anti-platelet, antiatherosclerosis, vascular-relaxant and antimicrobial effects [6,7]. The main active principles contained in the M. officinalis bark are three polyphenols: magnolol, honokiol and 4-O-methylhonokiol. Magnolol and honokiol are the most abundant constituents while 4-O-methylhonokiol is a minor constituent of M. officinalis bark, but it is a major active principle in other types of magnolia such as Magnolia grandiflora L. [7].
lol plasma half-life after an intravenous bolus of 5 mg/kg and an intravenous infusion of 76 micrograms/kg/min were 14.56 ± 1.77 and 15.71 ± 3.00 min, respectively, while total body clearances were 75.86 and 72.72 ml/min/kg, respectively. As the previous one, also this study confirmed a linear pharmacokinetics for magnolol [10]. Studies on Magnolol metabolism have highlighted that it is metabolized to isomagnolol, hydrogenated and hydroxyderivatives are glucuronidated and sulfated. High-performance liquid chromatography and liquid chromatography–mass spectrometry studies showed that the main urinary and fecal magnolol metabolites were: tetrahydromagnolol, 5-(1-propen-1(E)-yl)-50 -propyl2,20 -dihydroxybiphenyl, 5-allyl-50 -propyl-2,20 -dihydroxybiphenyl, isomagnolol (5,50 -di(1-propen-1(E)-yl)-2,20 -dihydroxybiphenyl), and 5-allyl-50 -(1-propen-1(E)-yl)-2,20 -dihydroxybiphenyl. Intestinal bacteria could contribute to the magnolol metabolism, however, in vitro incubation of magnolol with rat bacteria evidenced that they may produce isomerization of magnolol but not its reduction via hydrogenation [7].
Magnolol
Honokiol
Magnolol, IUPAC name: 2-(2-hydroxy-5-prop-2-enylphenyl)-4prop-2-enylphenol, is a polyphenol with a molecular weight of 266.33432 g/mol [8]. A study performed in male Sprague–Dawley rats showed that magnolol plasma half-life after intravenous bolus injection of 2, 5 and 10 mg/kg was 54.1 ± 5.14, 49.05 ± 5.96 and 49.58 ± 6.81 min, respectively. Both areas under the plasma-time curve and under the moment–time curve of magnolol increased proportionally from 2 to 10 mg/kg. Results of the study were compatible with a linear pharmacokinetics. Moreover, the study evidenced no significant difference in magnolol concentration within the different brain regions [9]. In a rabbit study performed using a high-performance liquid chromatographic method, magno-
Honokiol, IUPAC name 2-(4-hydroxy-3-prop-2-enylphenyl)-4prop-2-enylphenol, is a polyphenol with a molecular weight of 266.33432 g/mol [11]. A study performed in male Sprague–Dawley rats showed that Honokiol plasma half-life after intravenous bolus injection of 5 and 10 mg/kg was 49.22 ± 6.68 and 56.2 ± 7.30 min, respectively. Plasma concentration–time curves evidenced a biphasic process consisting of a rapid distribution phase followed by a slower elimination phase [12]. A study performed in BALB/c mice showed that Honokiol plasma concentration observed after intraperitoneal injection of 250 mg/kg was 27.179 ± 6.252 min. Authors described the plasma disappearance curve as a first-order absorption one-compartment model with an absorption half-life of
Magnolia officinalis bark active principles information
Magnolol
4-O-Methylhonokiol
Honokiol
Delta-9-THC
Fig. 1. Chemical structure of magnolol, honokiol, 4-O-methylhonokiol, delta-9-THC.
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10.121 ± 2.761 min, and an elimination half-life of 5.218 ± 0.461 h [13]. Rat and human liver studies have displayed that glucuronidation and sulfation were the main metabolic pathways for honokiol [14]. 4-O-methylhonokiol 4-O-methylhonokiol, IUPAC name: 2-(4-methoxy-3-prop-2enylphenyl)-4-prop-2-enylphenol, is a polyphenol with a molecular weight of 280.3609 g/mol. A study performed in male Sprague Dawley rats showed that 4-O-methylhonokiol plasma half-life after intravenous bolus injection of 20 mg/kg was 3.6 ± 1.4 h. Volume of distribution was high (9.6 ± 2.3 L/kg) suggesting a significant distribution outside the vascular system. In the same study, authors investigated the metabolic stability of 4-O-methylhonokiol in rat liver microsomes and cytosol. This study evidenced that, in the presence of NADPH, 4-Omethylhonokiol was metabolized in honokiol via oxidative O-demethylation by cytochrome P450 [15]. The hypothesis Like cannabis, several evidences suggest that magnolol, honokiol and 4-O-methylhonokiol can produce anti-inflammatory, antidepressant and anxiolytic activities [6,7]. Moreover, preclinical studies have highlighted that M. officinalis bark polyphenols had affinity for CB1, CB2, and GPR-55 receptors. The hypothesis is that magnolol, honokiol and 4-O-methylhonokiol have anti-craving effects in cannabis dependent patients, are effective in the treatment of withdrawal symptoms, produce a reduction in cannabis consumption and are effective in preventing cannabis induced neurotoxicity and neuropsychiatric disorders. Evaluation of the hypothesis To date, no study has evaluated the effects of magnolol, honokiol and 4-O-methylhonokiol in cannabis dependent patients. However, pharmacological similarities with delta-9-THC suggest that M. officinalis bark polyphenols could produce both anticraving activity and reduction in cannabis consumption. Furthermore, considering their cannabinoid receptor affinity, these polyphenols could be used for treating cannabis withdrawal symptoms. Additionally, neuroprotective effect of M. officinalis bark polyphenols could protect patients from both neurotoxicity and neuropsychiatric disorders associated with chronic cannabis consumption. Like delta-9-THC, magnolol, honokiol and 4-O-methylhonokiol show affinity for CB1 and CB2 receptors [7]. Moreover, they act as agonists at GPR-55 receptors [7].
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at CB2 (Ki 1.44 ± 0.10 lM) as compared to CB1 (Ki 3.15 ± 1.65 lM) [20]. In cAMP assays, magnolol showed to be a partial agonist with a potency 6-fold higher at CB2 as compared to CB1 receptors [20]. Tetrahydromagnolol, the main fecal magnolol metabolite, showed to be 20-fold more potent than magnolol (CB1 Ki 2.26 ± 0.89 lM; CB2 Ki 0.416 ± 00.89 lM) acting as full agonist at CB1 receptors and partial agonist at CB2 receptors [20]. Trans-isomagnolol, the second fecal magnolol metabolite, displayed affinity at both CB1 and CB2 receptors, however, it was considerably less potent than magnolol and tetrahydro magnolol [20]. Conversely, dihydroxydihydromagnolol, the principal urinary magnolol metabolite, displayed no affinity at cannabinoid receptors [20]. Unlike magnolol, honokiol showed to be a full CB1 receptor agonist (Ki 4.46 ± 3.54 lM) and an inverse CB2 receptor agonist (Ki 5.61 ± 2.02 lM) [19]. In a radioligand binding assay performed on membranes from CB1 and CB2 receptor-transfected HEK293 cells, 4-O-methylhonokiol showed a weak binding affinity toward the human CB1 receptor (Ki 2400 ± 200 lM), but a strong binding affinity toward the human CB2 receptor (Ki 43.9 ± 5 lM) [21]. In the same work, a cAMP assay performed on CHO-K1 cells stably transfected with human CB2 receptor showed that 4-O-methylhonokiol exerted a significant inverse agonist effect comparable to those evoked by the potent CB2 receptor-selective inverse agonists AM630 and SR144528 [21]. 4-O-methylhonokiol shares structural similarities with some Cannabis sativa L. compounds such as cannabidiol and cannabidivarin [22], as well as with the synthetic CB receptor ligands CP55,940 and HU308 [21]. Activity at GPR-55 receptors GRP-55 is a G protein-coupled receptor identified and cloned in the end of 1990s in the human caudate nucleus, hippocampus and putamen [23]. Radioligand binding assay performed on embryonic kidney—HEK293s cells transfected with the human cDNA for GPR-55 showed that delta-9-THC, cannabinol and cannabidiol had affinity at GPR-55 receptor [24]. Delta-9-THC and cannabinol displayed to be GPR-55 agonists, while cannabidiol acted as antagonist [24]. Recent evidences suggest that L-a-lysophosphatidylinositol (LPI), which activates GPR-55 evoking intracellular Ca2+ oscillations through an inositol 1,4,5-trisphosphate (IP3)-sensitive mechanism mobilizing Ca2+ stores, but not CB1 or CB2 receptors, could be the GPR-55 endogenous ligand [25]. A beta-arrestin translocation assay has shown that M. officinalis extract may produce a complete inhibition of the LPI induced GPR-55 activation [20]. Like cannabidiol, tetrahydromagnolol showed to be a competitive GRP-55 antagonist (KB 13.3 ± 2.0 lM), while magnolol, transisomagnolol and 8,9-dihydromagnolol were inactive [20].
Activity at CB1 and CB2 receptors
Consequences of the hypothesis
CB1 receptors are the main targets of delta-9-THC and other psychoactive compounds present within the cannabis plant. They are G protein-coupled receptors largely expressed in the central and peripheral nervous system [16]. Psychotropic effects induced by cannabis appear to be due to the modulation of different brain reward area pathways via CB1 receptors [17]. Oral administration of SR141716A, the first selective and orally active antagonist of the brain cannabinoid receptors, antagonises all the psychotropic effects induced by cannabinoid receptor agonists [18]. CB2 receptors are G protein-coupled receptors principally expressed in glia and peripheral tissues [16], however, recent evidences confirm the presence of these receptors in neuronal cells [19]. A radioligand binding assay performed on human CB1 and CB2 receptor subtypes recombinantly expressed in Chinese hamster ovary cells showed that magnolol had affinity at both receptors with a higher potency
Cannabis is the most commonly used illicit drug around the world [1]. Cannabis-related emergencies, cannabis-use disorders and cannabis dependence are on the rise, however, there are no approved medicines for the treatment of these disorders [26]. In recent years, in order to fully understand their therapeutic potential, many pharmacological studies have investigated the neurobiological targets of M. officinalis bark polyphenols [6,7]. These studies highlighted that M. officinalis bark polyphenols ma produce antioxidative, anti-inflammatory, anti-anxiety, antidepressant and neuroprotective effects [7]. Preclinical studies showed that magnolol, honokiol, 4-O-methylhonokiol and their metabolites had affinity at cannabinoid and GPR-55 receptors (Table 1) [20]. Experimental confirmation of the hypothesis may demonstrate some predicted effects of M. officinalis bark polyphenols: (1) clinically significant reduction of withdrawal symptoms in
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M. Coppola, R. Mondola / Medical Hypotheses 83 (2014) 673–676
Table 1 Receptors affinity of M. officinalis bark active principles.
Magnolol Tetrahydromagnolol Honokiol 4-O-methylhonokiol
CB1
CB2
GPR-55
Partial agonist Full agonist Full agonist Full agonist
Partial agonist Partial agonist Inverse agonist Inverse agonist
Inactive Antagonist Antagonist No data
cannabis dependent patients; (2) clinically significant reduction of craving in cannabis dependent patients; (3) clinically significant reduction of cannabis consumption in cannabis dependent patients; (4) prevention of cannabis induced neurotoxicity and neuropsychiatric disorders; effects associated with a direct activity at CB1, CB2 and GPR-receptors. These predictions will be crucial to testing the hypothesis. Other predictions, such as the activity at GPR-18 and PPARs receptors are desirable but not crucial to testing the hypothesis. The development of medicines for treating cannabis induced withdrawal and craving are a new frontier in the pharmacological treatment of cannabis dependence and M. officinalis bark polyphenols such as magnolol, honokiol, 4-O-methylhonokiol and their metabolites are potential candidates to become a new generation of anti-craving, anti-abstinence and neuroprotective drugs. In particular, considering their pharmacological characteristics, a combination of polyphenols could be more effective of a single polyphenol. Magnolol, honokiol and tetrahydromagnolol, which possess CB1 receptor agonism o partial agonism, could substitute the activity of delta-9-THC, while 4-O-methylhonokiol and tetrahydromagnolol, which possess anti-inflammatory and GPR-55 antagonistic effect, could substitute the activity of cannabidiol. Recently, some magnolol derivatives and analogues have been synthesized in order to improve the pharmacological characteristics of M. officinalis bark polyphenols [27]. Conflicts of interest This work was not supported by any government, corporate or institutional funding. The authors have not perceived funding and they have not other conflicts of interest that could influence this work. References [1] United Nations Office on Drugs and Crime. World Drug Report 2014. United Nations publication 2014. Available at: (visited August 20, 2014). [2] European Monitoring Centre for Drugs and Drug Addiction. Cannabis problems in context: understanding the increase in European treatment demands. European Monitoring Centre for Drugs and Drug Addiction 2004. Available at: (visited August 20, 2014). [3] Coppola M, Mondola R. Cannabis consumption systemic adverse effects. Int J High Risk Behav Addict 2014;3:e18627.
[4] Danovitch I, Gorelick DA. State of the art treatments for cannabis dependence. Psychiatr Clin North Am 2012;35:309–26. [5] Coppola M, Mondola R. Palmitoylethanolamide: from endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence. Med Hypotheses 2013;81:619–22. [6] Shen JL, Man KM, Huang PH, Chen WC, Chen DC, Cheng YW, et al. Honokiol and magnolol as multifunctional antioxidative molecules for dermatologic disorders. Molecules 2010;15:6452–65. [7] Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther 2011;130:157–76. [8] PubChem Project. Magnolol. 2014. Available at: (visited August 22, 2014). [9] Tsai TH, Chou CJ, Chen CF. Pharmacokinetics and brain distribution of magnolol in the rat after intravenous bolus injection. J Pharm Pharmacol 1996;48:57–9. [10] Tsai TH, Chou CJ, Chen CF. Disposition of magnolol after intravenous bolus and infusion in rabbits. Drug Metab Dispos 1994;22:518–21. [11] PubChem Project. Honokiol. 2014. Available at: (visited August 25, 2014). [12] Tsai TH, Chou CJ, Cheng FC, Chen CF. Pharmacokinetics of honokiol after intravenous administration in rats assessed using high-performance liquid chromatography. J Chromatogr B Biomed Appl 1994;655:41–5. [13] Chen F, Wang T, Wu YF, Gu Y, Xu XL, Zheng S, et al. Honokiol: a potent chemotherapy candidate for human colorectal carcinoma. World J Gastroenterol 2004;10:3459–63. [14] Böhmdorfer M, Maier-Salamon A, Taferner B, Reznicek G, Thalhammer T, Hering S, et al. In vitro metabolism and disposition of honokiol in rat and human livers. J Pharm Sci 2011;100:3506. [15] In the same study, authors investigated the metabolic stability of 4-Omethylhonokiol in rat liver microsomes and cytosol. This study evidenced that, in the presence of NADPH, 4-Omethylhonokiol was metabolized in honokiol via oxidative O-demethylation by cytochrome P450. [16] Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997;74:129–80. [17] Lupica CR, Riegel AC, Hoffman AF. Marijuana and cannabinoid regulation of brain reward circuits. Br J Pharmacol 2004;143:227–34. [18] Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 1994;350:240–4. [19] Morgan NH, Stanford IM, Woodhall GL. Functional CB2 type cannabinoid receptors at CNS synapses. Neuropharmacology 2009;57:356–68. [20] Rempel V, Fuchs A, Hinz S, Karcz T, Lehr M, Koetter U, et al. Magnolia extract, magnolol, and metabolites: activation of cannabinoid CB2 receptors and blockade of the related GPR55. ACS Med Chem Lett 2012;4:41–5. [21] Schuehly W, Paredes JM, Kleyer J, Huefner A, Anavi-Goffer S, Raduner S, et al. Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB(2) receptor inverse agonists. Chem Biol 2011;18:1053–64. [22] Vollner L, Bieniek D, Korte F, Hashish XX. Cannabidivarin, a new hashish constituent. Tetrahedron Lett 1969;3:145–7. [23] Sawzdargo M, Nguyen T, Lee DK, Lynch KR, Cheng R, Heng HH, et al. Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res 1999;64:193–8. [24] Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007;152:1092–101. [25] Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci USA 2013;110:5193–8. [26] Hart CL. Increasing treatment options for cannabis dependence: a review of potential pharmacotherapies. Drug Alcohol Depend 2005;80:147–59. [27] Fuchs A, Rempel V, Müller CE. The natural product magnolol as a lead structure for the development of potent cannabinoid receptor agonists. PLoS ONE 2013;8:e77739.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Potential use of Magnolia officinalis bark polyphenols in the treatment of cannabis dependence Maurizio Coppola a,⇑, Raffaella Mondola b a b
Department of Addiction, ASL CN2, Alba-Bra, Italy Department of Mental Health, ASL CN1, Saluzzo, Italy
a r t i c l e
i n f o
Article history: Received 30 August 2014 Accepted 13 September 2014
a b s t r a c t In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders, cognitive deficits, chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C. In this article we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting a potential application in the treatment of both cannabis dependence and cannabis-related disorders. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Cannabis derivatives are the most widely-spread illicit recreational substances around the world. It was estimated that in 2012, between 125 and 227 million people aged 15–64 have used cannabis with the highest prevalence rates observed in West and Central Africa, North America, Oceania, Western and Central Europe [1]. In recent years, epidemiological data confirm that cannabis-related emergencies, cannabis-use disorders and dependence are significantly increased [1]. At this regard, high potency cannabis products have contributed to the development of this trend worsening the impact of this drug on public health [1,2]. Cannabis is generally considered a little dangerous substances of abuse, however, chronic consumption has been associated to the development of mental disorders and cognitive deficits [3]. Moreover, cannabis consumption has been related to chronic bronchitis, emphysema, increased risk of myocardial infarction in the hour after use, increased mortality after myocardial infarction, liver inflammation and steatosis in patients affected by hepatitis C [3]. Although the prevalence rate of cannabis induced dependence is lower than those induced by other psychoactive drugs, around 9% of chronic users developed dependence with withdrawal symptoms after suspension [4]. Numerous pharmacological and/or nonpharmacological (e.g. motivational intervention) treatments have ⇑ Corresponding author at: Corso Coppino 46, 12051 Alba (CN), Italy. Tel.: +39 0173316210; fax: +39 017335067. E-mail address: [email protected] (M. Coppola). http://dx.doi.org/10.1016/j.mehy.2014.09.015 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
been used to treat cannabis dependence. Literature data suggest that these therapies can produce benefits in many patients, however, relapses, residual symptoms, therapeutic dropout and functional impairment are frequently observed [5]. In order to develop new pharmacological alternatives for the treatment of cannabis dependence, we described the pharmacological characteristics of Magnolia officinalis bark active principles suggesting their potential use in the treatment of cannabis dependent patients. Plant derivatives are used in traditional medicine since immemorial time. In particular, magnolia bark has been and still is used in Chinese and Japanese herbal medicine for the treatment of various diseases including anxiety, sleep-disorders, inflammations, microbial infections and allergies [6]. The main active constituents of M. officinalis bark magnolol, honokiol and 4-O-methylhonokiol (this substances is a minor constituent of M. officinalis bark but the main constituent of Magnolia grandiflora L.) (Fig. 1) have long been investigated for their antioxidative, anti-inflammatory, anti-anxiety, antidepressant, antitumor and antimicrobial effects [6]. Furthermore, recent studies have demonstrated that, like cannabis psychoactive compounds, M. officinalis bark active principles have affinity for cannabinoid receptors as well as for G protein-coupled receptor 55 (GPR-55), G proteincoupled receptor 18 (GPR-18) and peroxisome proliferatoractivated receptors (PPARs) [7]. Pharmacodynamic comparison between M. officinalis bark active principles and natural cannabinoids such as delta-9-tetrahydrocannabinol (delta-9-THC) suggests a potential use of these substances in the treatment of cannabis dependence.
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M. Coppola, R. Mondola / Medical Hypotheses 83 (2014) 673–676
Magnolia is a large genus of flowering plant belonging to the Magnoliaceae family. M. officinalis bark is a deciduous tree native to the mountains and valleys of China and belonging to the magnolias subsection named ‘‘Rhytidospermum’’. This plant is largely used in Chinese and Japanese traditional medicine for treating anxiety, sleep-disorders, inflammations, microbial infections and allergies [6]. Pharmacological properties of M. officinalis bark are due to its polyphenols exerting antioxidant, anti-inflammatory, anti-anxiety, neuroprotective, antitumor, anti-depressant, anti-platelet, antiatherosclerosis, vascular-relaxant and antimicrobial effects [6,7]. The main active principles contained in the M. officinalis bark are three polyphenols: magnolol, honokiol and 4-O-methylhonokiol. Magnolol and honokiol are the most abundant constituents while 4-O-methylhonokiol is a minor constituent of M. officinalis bark, but it is a major active principle in other types of magnolia such as Magnolia grandiflora L. [7].
lol plasma half-life after an intravenous bolus of 5 mg/kg and an intravenous infusion of 76 micrograms/kg/min were 14.56 ± 1.77 and 15.71 ± 3.00 min, respectively, while total body clearances were 75.86 and 72.72 ml/min/kg, respectively. As the previous one, also this study confirmed a linear pharmacokinetics for magnolol [10]. Studies on Magnolol metabolism have highlighted that it is metabolized to isomagnolol, hydrogenated and hydroxyderivatives are glucuronidated and sulfated. High-performance liquid chromatography and liquid chromatography–mass spectrometry studies showed that the main urinary and fecal magnolol metabolites were: tetrahydromagnolol, 5-(1-propen-1(E)-yl)-50 -propyl2,20 -dihydroxybiphenyl, 5-allyl-50 -propyl-2,20 -dihydroxybiphenyl, isomagnolol (5,50 -di(1-propen-1(E)-yl)-2,20 -dihydroxybiphenyl), and 5-allyl-50 -(1-propen-1(E)-yl)-2,20 -dihydroxybiphenyl. Intestinal bacteria could contribute to the magnolol metabolism, however, in vitro incubation of magnolol with rat bacteria evidenced that they may produce isomerization of magnolol but not its reduction via hydrogenation [7].
Magnolol
Honokiol
Magnolol, IUPAC name: 2-(2-hydroxy-5-prop-2-enylphenyl)-4prop-2-enylphenol, is a polyphenol with a molecular weight of 266.33432 g/mol [8]. A study performed in male Sprague–Dawley rats showed that magnolol plasma half-life after intravenous bolus injection of 2, 5 and 10 mg/kg was 54.1 ± 5.14, 49.05 ± 5.96 and 49.58 ± 6.81 min, respectively. Both areas under the plasma-time curve and under the moment–time curve of magnolol increased proportionally from 2 to 10 mg/kg. Results of the study were compatible with a linear pharmacokinetics. Moreover, the study evidenced no significant difference in magnolol concentration within the different brain regions [9]. In a rabbit study performed using a high-performance liquid chromatographic method, magno-
Honokiol, IUPAC name 2-(4-hydroxy-3-prop-2-enylphenyl)-4prop-2-enylphenol, is a polyphenol with a molecular weight of 266.33432 g/mol [11]. A study performed in male Sprague–Dawley rats showed that Honokiol plasma half-life after intravenous bolus injection of 5 and 10 mg/kg was 49.22 ± 6.68 and 56.2 ± 7.30 min, respectively. Plasma concentration–time curves evidenced a biphasic process consisting of a rapid distribution phase followed by a slower elimination phase [12]. A study performed in BALB/c mice showed that Honokiol plasma concentration observed after intraperitoneal injection of 250 mg/kg was 27.179 ± 6.252 min. Authors described the plasma disappearance curve as a first-order absorption one-compartment model with an absorption half-life of
Magnolia officinalis bark active principles information
Magnolol
4-O-Methylhonokiol
Honokiol
Delta-9-THC
Fig. 1. Chemical structure of magnolol, honokiol, 4-O-methylhonokiol, delta-9-THC.
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10.121 ± 2.761 min, and an elimination half-life of 5.218 ± 0.461 h [13]. Rat and human liver studies have displayed that glucuronidation and sulfation were the main metabolic pathways for honokiol [14]. 4-O-methylhonokiol 4-O-methylhonokiol, IUPAC name: 2-(4-methoxy-3-prop-2enylphenyl)-4-prop-2-enylphenol, is a polyphenol with a molecular weight of 280.3609 g/mol. A study performed in male Sprague Dawley rats showed that 4-O-methylhonokiol plasma half-life after intravenous bolus injection of 20 mg/kg was 3.6 ± 1.4 h. Volume of distribution was high (9.6 ± 2.3 L/kg) suggesting a significant distribution outside the vascular system. In the same study, authors investigated the metabolic stability of 4-O-methylhonokiol in rat liver microsomes and cytosol. This study evidenced that, in the presence of NADPH, 4-Omethylhonokiol was metabolized in honokiol via oxidative O-demethylation by cytochrome P450 [15]. The hypothesis Like cannabis, several evidences suggest that magnolol, honokiol and 4-O-methylhonokiol can produce anti-inflammatory, antidepressant and anxiolytic activities [6,7]. Moreover, preclinical studies have highlighted that M. officinalis bark polyphenols had affinity for CB1, CB2, and GPR-55 receptors. The hypothesis is that magnolol, honokiol and 4-O-methylhonokiol have anti-craving effects in cannabis dependent patients, are effective in the treatment of withdrawal symptoms, produce a reduction in cannabis consumption and are effective in preventing cannabis induced neurotoxicity and neuropsychiatric disorders. Evaluation of the hypothesis To date, no study has evaluated the effects of magnolol, honokiol and 4-O-methylhonokiol in cannabis dependent patients. However, pharmacological similarities with delta-9-THC suggest that M. officinalis bark polyphenols could produce both anticraving activity and reduction in cannabis consumption. Furthermore, considering their cannabinoid receptor affinity, these polyphenols could be used for treating cannabis withdrawal symptoms. Additionally, neuroprotective effect of M. officinalis bark polyphenols could protect patients from both neurotoxicity and neuropsychiatric disorders associated with chronic cannabis consumption. Like delta-9-THC, magnolol, honokiol and 4-O-methylhonokiol show affinity for CB1 and CB2 receptors [7]. Moreover, they act as agonists at GPR-55 receptors [7].
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at CB2 (Ki 1.44 ± 0.10 lM) as compared to CB1 (Ki 3.15 ± 1.65 lM) [20]. In cAMP assays, magnolol showed to be a partial agonist with a potency 6-fold higher at CB2 as compared to CB1 receptors [20]. Tetrahydromagnolol, the main fecal magnolol metabolite, showed to be 20-fold more potent than magnolol (CB1 Ki 2.26 ± 0.89 lM; CB2 Ki 0.416 ± 00.89 lM) acting as full agonist at CB1 receptors and partial agonist at CB2 receptors [20]. Trans-isomagnolol, the second fecal magnolol metabolite, displayed affinity at both CB1 and CB2 receptors, however, it was considerably less potent than magnolol and tetrahydro magnolol [20]. Conversely, dihydroxydihydromagnolol, the principal urinary magnolol metabolite, displayed no affinity at cannabinoid receptors [20]. Unlike magnolol, honokiol showed to be a full CB1 receptor agonist (Ki 4.46 ± 3.54 lM) and an inverse CB2 receptor agonist (Ki 5.61 ± 2.02 lM) [19]. In a radioligand binding assay performed on membranes from CB1 and CB2 receptor-transfected HEK293 cells, 4-O-methylhonokiol showed a weak binding affinity toward the human CB1 receptor (Ki 2400 ± 200 lM), but a strong binding affinity toward the human CB2 receptor (Ki 43.9 ± 5 lM) [21]. In the same work, a cAMP assay performed on CHO-K1 cells stably transfected with human CB2 receptor showed that 4-O-methylhonokiol exerted a significant inverse agonist effect comparable to those evoked by the potent CB2 receptor-selective inverse agonists AM630 and SR144528 [21]. 4-O-methylhonokiol shares structural similarities with some Cannabis sativa L. compounds such as cannabidiol and cannabidivarin [22], as well as with the synthetic CB receptor ligands CP55,940 and HU308 [21]. Activity at GPR-55 receptors GRP-55 is a G protein-coupled receptor identified and cloned in the end of 1990s in the human caudate nucleus, hippocampus and putamen [23]. Radioligand binding assay performed on embryonic kidney—HEK293s cells transfected with the human cDNA for GPR-55 showed that delta-9-THC, cannabinol and cannabidiol had affinity at GPR-55 receptor [24]. Delta-9-THC and cannabinol displayed to be GPR-55 agonists, while cannabidiol acted as antagonist [24]. Recent evidences suggest that L-a-lysophosphatidylinositol (LPI), which activates GPR-55 evoking intracellular Ca2+ oscillations through an inositol 1,4,5-trisphosphate (IP3)-sensitive mechanism mobilizing Ca2+ stores, but not CB1 or CB2 receptors, could be the GPR-55 endogenous ligand [25]. A beta-arrestin translocation assay has shown that M. officinalis extract may produce a complete inhibition of the LPI induced GPR-55 activation [20]. Like cannabidiol, tetrahydromagnolol showed to be a competitive GRP-55 antagonist (KB 13.3 ± 2.0 lM), while magnolol, transisomagnolol and 8,9-dihydromagnolol were inactive [20].
Activity at CB1 and CB2 receptors
Consequences of the hypothesis
CB1 receptors are the main targets of delta-9-THC and other psychoactive compounds present within the cannabis plant. They are G protein-coupled receptors largely expressed in the central and peripheral nervous system [16]. Psychotropic effects induced by cannabis appear to be due to the modulation of different brain reward area pathways via CB1 receptors [17]. Oral administration of SR141716A, the first selective and orally active antagonist of the brain cannabinoid receptors, antagonises all the psychotropic effects induced by cannabinoid receptor agonists [18]. CB2 receptors are G protein-coupled receptors principally expressed in glia and peripheral tissues [16], however, recent evidences confirm the presence of these receptors in neuronal cells [19]. A radioligand binding assay performed on human CB1 and CB2 receptor subtypes recombinantly expressed in Chinese hamster ovary cells showed that magnolol had affinity at both receptors with a higher potency
Cannabis is the most commonly used illicit drug around the world [1]. Cannabis-related emergencies, cannabis-use disorders and cannabis dependence are on the rise, however, there are no approved medicines for the treatment of these disorders [26]. In recent years, in order to fully understand their therapeutic potential, many pharmacological studies have investigated the neurobiological targets of M. officinalis bark polyphenols [6,7]. These studies highlighted that M. officinalis bark polyphenols ma produce antioxidative, anti-inflammatory, anti-anxiety, antidepressant and neuroprotective effects [7]. Preclinical studies showed that magnolol, honokiol, 4-O-methylhonokiol and their metabolites had affinity at cannabinoid and GPR-55 receptors (Table 1) [20]. Experimental confirmation of the hypothesis may demonstrate some predicted effects of M. officinalis bark polyphenols: (1) clinically significant reduction of withdrawal symptoms in
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Table 1 Receptors affinity of M. officinalis bark active principles.
Magnolol Tetrahydromagnolol Honokiol 4-O-methylhonokiol
CB1
CB2
GPR-55
Partial agonist Full agonist Full agonist Full agonist
Partial agonist Partial agonist Inverse agonist Inverse agonist
Inactive Antagonist Antagonist No data
cannabis dependent patients; (2) clinically significant reduction of craving in cannabis dependent patients; (3) clinically significant reduction of cannabis consumption in cannabis dependent patients; (4) prevention of cannabis induced neurotoxicity and neuropsychiatric disorders; effects associated with a direct activity at CB1, CB2 and GPR-receptors. These predictions will be crucial to testing the hypothesis. Other predictions, such as the activity at GPR-18 and PPARs receptors are desirable but not crucial to testing the hypothesis. The development of medicines for treating cannabis induced withdrawal and craving are a new frontier in the pharmacological treatment of cannabis dependence and M. officinalis bark polyphenols such as magnolol, honokiol, 4-O-methylhonokiol and their metabolites are potential candidates to become a new generation of anti-craving, anti-abstinence and neuroprotective drugs. In particular, considering their pharmacological characteristics, a combination of polyphenols could be more effective of a single polyphenol. Magnolol, honokiol and tetrahydromagnolol, which possess CB1 receptor agonism o partial agonism, could substitute the activity of delta-9-THC, while 4-O-methylhonokiol and tetrahydromagnolol, which possess anti-inflammatory and GPR-55 antagonistic effect, could substitute the activity of cannabidiol. Recently, some magnolol derivatives and analogues have been synthesized in order to improve the pharmacological characteristics of M. officinalis bark polyphenols [27]. Conflicts of interest This work was not supported by any government, corporate or institutional funding. The authors have not perceived funding and they have not other conflicts of interest that could influence this work. References [1] United Nations Office on Drugs and Crime. World Drug Report 2014. United Nations publication 2014. Available at: (visited August 20, 2014). [2] European Monitoring Centre for Drugs and Drug Addiction. Cannabis problems in context: understanding the increase in European treatment demands. European Monitoring Centre for Drugs and Drug Addiction 2004. Available at: (visited August 20, 2014). [3] Coppola M, Mondola R. Cannabis consumption systemic adverse effects. Int J High Risk Behav Addict 2014;3:e18627.
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