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Therapeutic prospects of cannabidiol for alcohol use
disorder and alcohol-related damages on the liver and
the brain
Julia DE TERNAY1*, Mickael NAASSILA2, Mikail NOURREDINE1, Alexandre LOUVET3, François
BAILLY4, Guillaume SESCOUSSE5, Pierre MAURAGE6, Olivier COTTENCIN3, Patrizia
CARRIERI7, Benjamin ROLLAND1
1Service Universitaire d’Addictologie de Lyon, Centre Hospitalier Le Vinatier, France,
2University of Picardie Jules Verne, France, 3Centre Hospitalier Regional et
Universitaire de Lille, France, 4Hospices Civils de Lyon, France, 5INSERM U1028 Centre
de Recherche en Neurosciences de Lyon, France, 6Catholic University of Louvain,
Belgium, 7INSERM U912 Sciences Economiques et Sociales de la Santé et Traitement de
l’Information Médicale (SESSTIM), France
Submitted to Journal:
Frontiers in Pharmacology
Specialty Section:
Experimental Pharmacology and Drug Discovery
ISSN:
1663-9812
Article type:
Review Article
Received on:
20 Feb 2019
Accepted on:
15 May 2019
Provisional PDF published on:
15 May 2019
Frontiers website link:
www.frontiersin.org
Citation:
De_ternay J, Naassila M, Nourredine M, Louvet A, Bailly F, Sescousse G, Maurage P, Cottencin O,
Carrieri P and Rolland B(2019) Therapeutic prospects of cannabidiol for alcohol use disorder and
alcohol-related damages on the liver and the brain. Front. Pharmacol. 10:627.
doi:10.3389/fphar.2019.00627
Copyright statement:
© 2019 De_ternay, Naassila, Nourredine, Louvet, Bailly, Sescousse, Maurage, Cottencin, Carrieri and
Rolland. This is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted,
provided the original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction
is permitted which does not comply with these terms.
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Frontiers in Pharmacology | www.frontiersin.org
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Therapeutic prospects of cannabidiol for alcohol use disorder and
alcohol-related damages on the liver and the brain
_
Julia D’AVIAU DE TERNAY1*, Mickaël NAASSILA2, Mikail NOURREDINE1,
Alexandre LOUVET3, François BAILLY4, Guillaume SESCOUSSE5, Pierre MAURAGE6,
Olivier COTTENCIN7, Patrizia Maria CARRIERI8, Benjamin ROLLAND 1,5,*
_
1. Service Universitaire d’Addictologie de Lyon (SUAL), CH Le Vinatier, F-69500 Bron,
France
2. Université de Picardie Jules Verne, Centre Universitaire de Recherche en Santé,
INSERM UMR 1247, Groupe de Recherche sur l’Alcool & les Pharmacodépendances,
Amiens, France
3. Service des maladies de l'appareil digestif, CHU Lille, Universit de Lille and INSERM
U995, Lille, France
4. Service d’Addictologie et d’Hpatologie, GHN, HCL, Lyon, France
5. Universit de Lyon, UCBL, Centre de Recherche en Neurosciences de Lyon (CRNL),
Inserm U1028, CNRS UMR5292, PSYR2 , France
6. Laboratory for Experimental Psychopathology (LEP), Psychological Science Research
Institute, Universit catholique de Louvain, Louvain-la-Neuve, Belgium.
7. CHU de Lille, universit Lille, service d'addictologie, CNRS, UMR 9193, SCALab,
quipe psyCHIC, CS 70001, 59037 Lille cedex, France
8. INSERM, UMR_S 912, Sciences Economiques & Sociales de la Sant et Traitement de
l'Information Mdicale (SESSTIM), 27 bd Jean Moulin, 13385, Marseille, France.
* Correspondence: postal address: Dr. Julia De Ternay, Service Universitaire d’Addictologie de
Lyon (SUAL), Ple MOPHA, CH Le Vinatier, 95 Bd Pinel, 69500 Bron, France; phone
number: +33 437 915 555; fax: +33 437 915 556; e-mail: jdeternay@gmail.com
Keywords: Alcohol Use Disorder, Alcohol related damage, Cannabidiol, Liver fibrosis and
cirrhosis, Neuroprotection, Addiction
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ABSTRACT
Background
Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex
immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that
CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the
brain and the liver.
Aim
To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental
studies.
Methods
Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the
improvement of any aspect of alcohol-related toxicity in AUD.
Results
Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by
reducing ethanol intake, motivation for ethanol, relapse, anxiety and impulsivity. Moreover, CBD reduces
alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy,
modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells.
Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and
immunomodulatory properties.
Conclusions
CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials
in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain
damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of
the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in
AUD, in order to protect the organs of subjects with an ongoing AUD.
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1. Introduction
Alcohol use disorder (AUD) is an addictive disorder characterized by a progressive loss of
control upon alcohol use. AUD consists of several clinical criteria that include alcohol tolerance,
withdrawal symptoms, craving, as well as medical and psychosocial consequences. AUD is
responsible for a severe burden of disease. Worldwide, AUD causes more than 3 million deaths
every year, which represents 5% of all deaths (1). More specifically, subjects with AUD may be
affected by the consequences of recurrent alcohol abuse on the body, including alcohol-related
liver disease (ARLD), and alcohol-related brain injury (ARBI).
ARLD is a progressive alcohol-induced liver injury, which starts with an increase in the amount
of fat in the liver – a process called steatosis – and continues into a progressive cell loss, fibrosis,
and hepatic insufficiency – a process called cirrhosis (2). ARLD may result in severe liver failure,
and represents a major risk factor for liver cancer. Overall, alcohol-attributable liver damage is
responsible for 493,300 deaths every year, and 14,544,000 disability adjusted life years
(DALYs), representing 0.9% of all global deaths and 0.6% of all global DALYs all over the
world (3). In subjects with ARLD, preventing the transition from steatosis to cirrhosis is a major
treatment goal, and this usually requires to stop or to dramatically reduce the average amount of
consumed alcohol in the long term (4). AUD also affects the brain, through ARBI. Subjects with
AUD display reduced grey matter volumes and reduced cortical thickness, as well as increased
ventricular volumes, when compared to matching healthy controls (5). The most significant
reductions in grey matter volumes are observed in the corticostriatal-limbic circuits, including
the insula, superior temporal gyrus, dorso-lateral prefrontal cortex, anterior cingulate cortex,
striatum and thalamus (5). Cognitive functions associated with these brain areas (e.g., executive
functions, working memory, emotion recognition, or long-term memory) are impaired in subjects
with AUD (6). Generally, cognitive dysfunctions start to improve quickly after alcohol
withdrawal, but patients substantially recover only within the first weeks to months of alcohol
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abstinence, and sometimes remain impaired (6,7). Similarly, the recovery of structural brain
alterations can be highly variable depending on brain areas and individual features (8,9). Overall,
both ARLD and ARBI involve alcohol-related inflammatory processes (10,11). Current
medications for reducing alcohol drinking or supporting alcohol abstinence in AUD subjects are
still insufficiently effective at a population level, and new therapeutic prospects are needed
(12,13). Moreover, no drug for reducing alcohol-related harms, either on the brain or the liver,
has ever been studied.
Cannabidiol (CBD) is a natural constituent of Cannabis sativa. Unlike tetra-hydrocannabinol
(THC), CBD has no psychotomimetic properties. However, CBD exerts several important effects
on the central nervous system, including anxiolytic, antipsychotic (14), analgesic, or antiepileptic
effects (15,16). In this respect, an oromucosal spray with CBD and THC in a 1:1 ratio
(SATIVEX®, GW Pharmaceuticals) has been approved in Canada as a treatment for multiple
sclerosis spasticity (17) since 2005, and is now approved in 22 countries worldwide.
More recently, CBD has been approved in the US for seizures prevention in Dravet and Lennox-
Gastaut syndromes, and will therefore be available for clinical practice very soon (18). Due to its
action on cognitive processes and anxiety regulation, CBD is also increasingly considered as a
potential treatment for other neuropsychiatric disorders, including anxiety, depression, and
substance use disorders (15,16). In addition to its actions on the brain, CBD has systemic effects,
through its complex immunomodulatory and antioxidant properties (19). This has raised
increasing interest in CBD for various inflammatory or immunological diseases, such as cancer
(20), neurodegenerative diseases (21,22), colitis (23), cardiovascular diseases (24), and diabetes
(25).
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CBD is a weak, non-competitive, negative allosteric modulator of cannabinoid-1 (CB1) receptors
(26–28), however, a large part of the pharmacological action of CBD seems to be based on
mechanisms that do not involve cannabinoid receptors. For example, the molecular mechanisms
through which CBD prevents seizures are currently debated on, but several potential molecular
targets other than cannabinoid receptors have been identified. In particular, CBD is a partial
antagonist of G protein-coupled receptor 55 (GRP55), identified as an endocannabinoids’ target
(29), which could be involved in the decrease of neuronal excitability, through an action on
gamma-aminobutyric acid-ergic (GABAergic) neurotransmission (30–32). CBD also regulates
Calcium (Ca2+) homeostasis by acting on mitochondria stores (33), and blocks low-voltage-
activated (T-type) Ca2+ channels, modulating intracellular calcium levels (34). Other hypotheses
include inhibition of anandamide hydrolysis via fatty acid amide hydrolase (FAAH) (35–37),
activation of peroxisome proliferator-activated receptor γ (PPAR-γ) (30), positive allosteric
modulation of serotonin 1A receptors (5-HT1A receptors) (38), activation of transient receptor
potential vanilloid type 1 (TRPV1), and reduction of adenosine reuptake increasing adenosine
levels (39,40).
The systemic immunomodulatory and antioxidant properties of CBD appear to be based on
complex mechanisms. CBD acts on many cellular pathways of inflammation, such as the Nuclear
Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (41–43), as well as the
Interferonβ/Signal Transducer and Activator of Transcription proteins (IFNβ/STAT) pathway
(42). Through activation of adenosine receptor A2a, and inhibition of adenosine reuptake (39,44),
CBD can modulate the activity of multiple inflammatory cells, including neutrophils,
macrophages, or T-cells. CBD also decreases the production of inflammatory mediators such as
Interferon-c (IFN-c), interferon-γ (IFN-γ) (45), Tumor Necrosis Factor α (TNF-α) (41,43,46,47),
interleukin (IL)-1β (IL-1β) (47,48), IL-6 (45), and the expression of Intercellular Adhesion
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Molecule 1 (ICAM1) and Vascular Cell Adhesion Molecule 1 (VCAM1) (41). Furthermore,
CBD decreases caspase 9 (44) and caspase 3 activation (41,49–51), which are factors involved
in apoptosis. CBD up-stimulates anti-inflammatory cytokines IL-10 (52). Finally, CBD activates
the PPAR-γ, a nuclear receptor that plays a central role in the regulation of metabolic and
inflammatory cell processes, including those leading to apoptosis (53).
Because of its various effects on the brain and on systemic inflammation, CBD involves a large
potential array of complementary therapeutic applications in AUD. First, CBD could help
patients with AUD reduce their level of alcohol drinking. Second, by modulating the
inflammatory processes in the liver, CBD could reduce alcohol-induced liver steatosis and
fibrosis, thus constituting a novel harm reduction agent among subjects with AUD, particularly
among those who still exhibit heavy drinking. Third, CBD could reduce ARBI. The aim of this
narrative review is to offer a comprehensive overview of the current body of evidence about these
three specific applications of CBD in subjects with AUD or animal models of AUD, and to
discuss what should be the next steps of research on these topics.
2. Methods
A narrative review was performed after a systematic search on PubMed, using the following
algorithm: “cannabidiol AND (alcohol OR ethanol)”.
On the basis of the 143 studies published between 1974 and June 2018, 26 original studies were
included in the present review. Additional articles useful for the rationale of the review were
selected from the reference list of initially selected studies, or using independent search results
on Pubmed.
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Results are sorted in three independent sections: cannabidiol for reducing alcohol drinking,
cannabidiol for reducing alcohol-related liver inflammation, and cannabidiol for reducing
alcohol-related brain injuries.
3. Cannabidiol for reducing alcohol drinking levels
CBD effects on alcohol drinking were tested in preclinical studies using several procedures to
investigate AUD, including propensity to drink ethanol with the two-bottle choice or the operant
self-administration procedure, and behavioral sensitization. Four main studies have been
published so far, and they provide thorough and congruent evidence that, in rodents, CBD can
reduce ethanol intake, motivation for ethanol, relapse, reinstatement after extinction, as well as
the levels of anxiety and impulsivity correlated with ethanol intake.
A first study in male C57BL/6J mice, an ethanol-preferring strain, demonstrated that the
administration of CBD reduced reinforcing properties, motivation and ethanol relapse (54).
Increasing doses of CDB (30, 60 and 120mg/kg) administered intraperitoneally (i.p.)
progressively decreased both ethanol preference (from 75% to 55%) and intake (from about 6g
of pure ethanol/kg body weight/day to 3.5g/kg/day) in a two-bottle choice paradigm (water
versus 8% ethanol solution). The results were confirmed in an operant paradigm in which mice
had to press a lever to get access to 36mL of 8% ethanol solution. In the operant paradigm,
animals had to work (press a lever) to get access to ethanol; this is useful to assess motivation to
drink ethanol, because the price to pay (effort) can be increased by the experimenter. In the
context of this operant paradigm that includes a saccharin fading phase, administration of the
CBD-controlled release microparticle subcutaneous (s.c.) formulation (30 mg/kg/day, s.c.)
significantly reduced the number of active lever presses by about 40% in a fixed-ratio one
schedule (one press required to get ethanol) as well as in a more demanding fixed-ratio three
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schedule (three presses required to get ethanol). It also reduced motivation to drink ethanol by
about 50% in a progressive ratio schedule, and relapse by about 30% after an extinction session
with a 120mg/kg i.p. dose. It had no effect on water reinforcement or motivation. In addition,
CBD reduced 3.0g/kg ethanol-induced hypothermia and 4.0g/kg ethanol-handling-induced
convulsions but did not have any effect on blood ethanol concentration. CBD treatment was
associated with changes in gene expression of key targets closely related to AUD. A single
administration of CBD (30 mg/kg/day, s.c.) during oral ethanol self-administration decreased
gene expression of Oprm1, GPR55 and CB1 receptor in the nucleus accumbens (NAc), while
CB2 receptor expression was increased; it also decreased gene expression of gene encoding
tyrosine hydroxylase (TH) in the ventral tegmental area (VTA). In a second study, the same
authors tested the effect of CBD (20mg/kg s.c.), of naltrexone (0.7mg/kg per os), and of their
combination in male C57BL/6J mice using the same operant paradigm (55). They found that
combining CBD and naltrexone reduces ethanol consumption and motivation to drink ethanol
more efficiently than either drug administered alone. 5-HT1A receptor gene expression was
reduced in the dorsal raphe nucleus after CBD treatment.
A third study was carried out in male Wistar rats using an operant paradigm in which animals
pressed a lever to get a 10% ethanol solution during 30-minute sessions (56). CBD was
administered transdermally (gel concentration: 2.5 g CBD/100 g gel) to avoid low oral
bioavailability (~6%) and conversion into psychoactive cannabinoids in gastric fluid.
Transdermal CBD produces stable and sustained plasma CBD levels. Rats were trained for two
weeks during the sweet solution fading phase, then trained for only ten days under a fixed ratio
1 schedule and finally, extinction sessions were carried out (i.e. sessions without ethanol and
ethanol-associated cues). After extinction and baseline (vehicle treatment) reinstatement, the
effect of 15 mg/kg CBD (delivered every 24 hours over a seven-day treatment phase) was tested
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on reinstatement induced either by context, by pharmacological stress (yohimbine 1.25mg/kg
i.p.) or by physical stress (footshock). CBD reduced the number of responses during context-
induced reinstatement (~50% decrease) on sessions (days) 1, 4 and 7 of the treatment phase. CBD
effect was long-lasting, since the 50% reduction was still visible 3, 18, 48 and even 138 days
(sessions) after the CBD treatment phase. CBD treatment was also efficient on stress-induced
reinstatement and particularly on the one induced by yohimbine pharmacological stress. As for
the effect of the context-induced reinstatement, the stress-induced reinstatement was strongly
reduced 138 days after CBD treatment. Since the benefit of CBD treatment may come from its
anxiety prevention properties, the authors also tested its effect in the elevated plus maze on rats
that had consumed ethanol and ethanol-naïve rats. CBD (15 mg/kg) decreased anxiety in both
groups. CBD effects do seem AUD-specific since it had no effect on reward seeking motivated
by palatable sweet solution. Moreover, AUD is associated with impulsivity in humans and
impaired impulse control is a risk factor for relapse. Interestingly, the authors tested the effect of
CBD (15 mg/kg) on impulsivity in rats with a history of ethanol intake using a delay discounting
task (preference for delayed large over small immediate reward as a function of delay time).
Preference for delayed large reward was significantly lower in rats with ethanol history compared
to ethanol-naïve rats and this effect was fully reversed by CBD.
A fourth study in male DBA/2 mice tested the effect of CBD on behavioral sensitization to the
motor stimulant effects of ethanol (57). Behavioral sensitization is a relevant animal model used
to study the incentive salience sensitization theory of drug addiction. The sensitization to the
motor stimulant effects of ethanol may reflect the sensitization to the motivation to consume
ethanol during the development of addiction, and may be of particular importance during
escalation of drug use and during relapse, since it is a very long-lasting phenomenon (even after
a long period of abstinence). Sensitization is considered to be a first step in neuroplasticity
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associated with drug dependence and may mimic the transition from use to abuse and
dependence. In the sensitization model, CBD (2.5mg/kg) had no effect on the acquisition and
expression phases.
In summary, preclinical evidence show that CBD may be of strong therapeutic interest in AUD
and could have a significant action on drinking levels in human subjects with AUD, since it is
effective on different aspects of the disease (intake, motivation, relapse, anxiety and impulsivity).
However, it should be noted that there are no available data on CBD efficacy in more relevant
animal models of AUD, such as binge drinking models (58,59) or in models that use more chronic
exposure to ethanol and behaviors linked to addiction (loss of control over intake, compulsive
use of ethanol, increased motivation) (60). Thus, whether CBD is effective in animal models
such as the post-dependent state, in which rats drink ethanol for months and are exposed to
ethanol vapors in order to induce dependence, is unknown.
4. Cannabidiol for reducing alcohol-related liver inflammation
Animal studies also demonstrated that CBD could significantly reduce liver steatosis and fibrosis
that are induced by both chronic and binge ethanol administrations, based on its antioxidant,
immunomodulatory, and lipid metabolic regulation properties.
In ethanol-fed rats and mice hepatic cells (61), CBD triggered the activation of an endoplasmic
reticulum stress response, leading to the selective death of activated hepatic stellate cells (HSC)
through activation of the inositol-requiring enzyme 1/Apoptosis signal-regulating kinase 1/c-Jun
N-terminal kinase (IRE1/ASK1/JNK) pathway. By contrast, CBD had no effect on HSC in
control rats. HSC are involved in the development and progression of liver cirrhosis. As the
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activation of HSC increases, there is an excessive production of type I collagen, leading to a
progressive hepatic fibrosis. The activation mechanism of this pathway was independent from
cannabinoid receptors, suggesting that the action of CBD on alcohol-induced liver steatosis is
not mediated by this specific pharmacological pathway.
In another study, CBD was demonstrated to reduce binge-alcohol-induced liver damage (62).
Mice were force-fed with ethanol (30% v/v in saline, 4g/kg) every 12 hours for five days. They
were then divided into two groups, and injected i.p. 30 minutes before each ethanol gavage with
either CBD (5mg/kg) or vehicle (tween 80 2%-saline). Eventually, mice were sacrificed, and
their serum and liver were collected. CBD prevented the increase in serum aspartate
aminotransferase (AST), a marker of liver injury, and significantly attenuated the increase in
hepatic triglycerides (TG) level. CBD also stimulated in vitro and in vivo autophagy, which
alleviated lipid accumulation. Finally, CBD decreased ethanol-induced oxidative stress in the
liver, and prevented c-Jun N-terminal kinases (JNK) pathway activation, by blocking the increase
in JNK phosphorylation. Interestingly, administration of CBD had no effect on control cells
injected with vehicle, suggesting a selective mechanism of regulation. Similarly, CBD did not
alter the activation of cytochrome P450 E21(CYP2E1), which is supposed to promote steatosis
induction. This raises the hypothesis that CBD does not act through this pharmacological
pathway.
In an animal model of chronic ethanol feeding and binge ethanol feeding (47), mice were fed
with a control Lieber-DeCarli diet for five days to acclimate them to a liquid diet. Subsequently,
a control group was fed with an isocaloric control diet while the other group was fed with a
Lieber-DeCarli diet containing 5% ethanol for ten days, to mimic a chronic ethanol intoxication.
On day 11, ethanol and pair-fed mice were respectively force-fed with a single dose of ethanol
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(5g/kg b.w.) or with isocaloric dextrin-maltose. During the eleven days of ethanol exposure,
ethanol-fed mice were injected with CBD (5 or 10 mg/kg) dissolved in a vehicle solution (one
drop of Tween 80 in 3 mL 2.5% dimethyl sulfide in saline) while control-mice were injected with
a vehicle solution. Both solutions were administered i.p. CBD reduced hepatic lipids and TG
accumulation, neutrophil infiltration and neutrophil-mediated oxidative injury and inflammation,
and attenuated the increase in serum ALT and serum aspartate aminotransferase (AST) levels in
ethanol-fed mice. In this group, CBD modulated the ethanol-induced dysregulation of numerous
genes and proteins involved in metabolism and liver steatosis, such as key genes of fatty acid
biosynthetic and oxidation pathway, mitochondrial pathway, and transcription factor PPAR-α.
Furthermore, in the ethanol-fed mice group, CBD attenuated hepatic neutrophils infiltration,
oxidative and nitrative stress, decreased several markers of liver inflammation such as TNF-α,
the expression of adhesion molecule E-selectin, pro-inflammatory chemokine and cytokines, and
thus, attenuated liver injury induced by chronic plus binge ethanol exposure. None of these
effects were found in the pair-fed mice.
Consequently, in both previous studies, CBD reduced ethanol-induced TG accumulation in the
liver. The metabolic regulation properties of CBD were also demonstrated in a hepatosteatosis
model (63), both in vitro and in vivo. Human Hepatocyte Line 5 cells (HHL-5 cells) were exposed
to oleic acid for various periods of time, and co-incubated at different times with
tetrahydrocannabivarin (THCV) or CBD. CBD and THCV directly reduced accumulated lipids
and adipocytes levels in vitro. These results were subsequently demonstrated in vivo, as CBD (3
mg/kg) was administered for four weeks to mice, significantly reducing liver TG content. Neither
CB1 nor TRPV1 knockdown inhibited CBD activity, suggesting a mechanism independent from
these receptors.
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In summary, CBD seems to have valuable therapeutic properties for ethanol-induced liver
damage, through multiple mechanisms such as reduction of oxidative stress, modulation of
inflammation, death of activated HSC responsible for fibrosis, stimulation of autophagy and
reduction of lipid accumulation responsible for steatosis. These first results accumulating in
animal models call for further research in humans.
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5. Cannabidiol for reducing alcohol-related brain damage
Binge and chronic heavy alcohol use are responsible for neuronal damage in specific brain areas,
such as the frontal lobe, part of the limbic system and cerebellum (5). Moreover, alcohol induces
multiple cognitive deficits, including memory and executive dysfunction (6). Neuroprotective,
immunomodulatory and antioxidant properties of CBD could thus prevent or alleviate some
alcohol-related brain damage.
CBD was demonstrated to act as a neuroprotective antioxidant in a binge-ethanol rats model (64),
in which rats were fed with an alcohol-free diet for three days. On day four, they were
administered an ethanol diet (10 to 12% ethanol, 9-12g/kg/day) every eight hours for four days.
At the same time, rats received in a double-blind manner either CBD (20 or 40 mg/kg) twice a
day, or other tested neuroprotective substances such as antioxidants (butylated hydroxytoluene,
α-tocopherol), NMDA receptor antagonists (dizocilpine, nimodipine, memantine), or diuretics
(furosemide, bumetanide, L-644,711). Animals were then sacrificed and the number of
degenerating brain cells was determined for each brain tissue section. At the end of the
experiment, binge-ethanol-rats had lost a significant number of neurons in the hippocampus and
in the entorhinal cortex. CBD, at dose range 40mg/kg co-administered with ethanol, significantly
reduced ethanol-induced cell death for both hippocampal granular cells and entorhinal cortical
pyramidal cells. Furthermore, CBD was demonstrated to have an antioxidant effect comparable
to butylated hydroxytoluene and tocopherol, which significantly decreased ethanol-induced
neuronal death in the experiment.
In another study, CBD was delivered transdermally to rats as a treatment for ethanol-induced
neurodegeneration (65). Rats were either administered ethanol (25% w/v) or an isocaloric diet
every eight hours for four days by intragastric-gavage. Plasma levels of ethanol and CBD were
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measured on day three. CBD plasma concentration was also measured in trunk blood collected
after euthanasia. Fluoro-JadeB (FJB) was used to assess neurodegeneration on brains extracted
after euthanasia.
In a first experiment, rats received CBD by daily gel application with different concentrations of
CBD (1.0%, 2.5%, 5%) or vehicle, after the third dose of ethanol. Neurodegeneration was visible
by FJB+ staining in the entorhinal cortex after four days of binge-ethanol intoxication. The 5%-
CBD-gel-treated group showed a 48.8% reduction in the number of FJB+ cells, what trended to
statistical significance. In a second experiment, the same model of ethanol intoxication was used.
Each group received either ethanol only, or vehicle i.p, CBD transdermal delivery or CBD i.p.
CBD administered i.p and transdermally significantly reduced FJB+ cells in the entorhinal
cortex, compared to the ethanol-only group. However, this effect did not reach statistical
significance when compared with the vehicle group.
CBD was also studied in a model of chronic liver disease leading to hepatic encephalopathy (66).
Bile duct ligation (BDL) was conducted on mice, to mimic biliary liver disease causing elevation
of liver enzymes and liver fibrosis, responsible for cognitive and motor impairments. CBD
(5mg/kg) was injected i.p every day for four weeks, starting after surgery. An antagonist of A2a
adenosine receptors (A2aR), ZM241385, was injected i.p at a 1mg/kg dose. A2aR is thought to
modulate multiple inflammatory cells, and to be one of CBD’s target receptors. Cognitive and
motor functions, assessed three weeks after the beginning of ethanol intoxication, were markedly
impaired in BDL-mice. CBD significantly improved these BDL-induced impairments by down-
regulating TNF-α 1 receptor mRNA expression (up-regulated in BDL-mice), and restoring
BDNF mRNA expression (down-regulated in BDL mice). Interestingly, the effect of CBD on
TNF-α receptor 1 mRNA expression was blocked by ZM241385, suggesting a CBD reduction
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of cerebral inflammation by regulation of the adenosine system, while it had no effect on BDNF
mRNA expression.
Finally, in a hepatic encephalopathy model (67), a single dose of thiocetamide (TAA) was
administered i.p (200mg/kg) to mice, to induce a fulminant hepatic failure (FHF), while vehicle
was injected in the control group. A single dose of either CBD (5mg/kg) or vehicle was injected
one day after TAA. Neurological and motor functions were assessed on day two and day three
respectively. A first group of mice was sacrificed on day four, their brain and liver were removed
for histopathological analyses, and plasma liver enzymes levels were measured. Cognitive
functions were tested in a second group of mice eight days after liver failure induction, and brain
5-hydroxytryptamine (5-HT) levels were measured 12 days after the beginning of the experiment.
In TAA-mice, CBD restored neurological and cognitive functions impaired by the FHF model,
and partially restored motor functions. CBD restored ammonia, bilirubin and liver enzymes
levels, increased by FHF, as well as 5-HT levels in the brain (increased by FHF).
In conclusion, CBD significantly reduces alcohol-induced neuronal loss after binge and chronic
ethanol exposure in preclinical studies, possibly through immunomodulatory properties
involving regulation of the cerebral adenosine system, and antioxidant properties. Effects of CBD
on ethanol-induced clinical impairments were also associated with significant improvement in
cognitive functions.
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6. Discussion
The aim of this review was to highlight, based on preclinical literature, the promising therapeutic
applications of CBD in the reduction of drinking in AUD, and for improving or preventing
alcohol-related damage on the liver and the brain. The main findings on these different topics are
displayed in Figure 1. First, CBD was able to reduce motivation for alcohol, relapse, and the
global level of alcohol intake in mice. Next, CBD reduced alcohol-induced liver damage, by
reducing liver fibrosis via its immunomodulatory and antioxidant properties, as well as its action
on activated HSC, stimulation of autophagy, and via regulation of lipid accumulation in the liver.
Last, CBD acts as a multimodal neuroprotective agent that could decrease alcohol-induced
neuronal damage leading to cognitive and motor impairment in animals. This latter effect could
be associated with CBD antioxidant properties and immunomodulatory action, possibly
correlated with the cerebral adenosine system.
Although fewer studies are available to assess the effects of CBD on cannabinoid type 2
receptors (CB2), there could be another mechanism involved in its protective effects on the
liver and the brain. CB2 receptors are cannabinoid receptors that are mainly expressed in the
immune system (68). CBD seems to have complex interactions with CB2 receptors, acting as a
negative allosteric modulator (69).
In an experimental study with cultured hepatic myofibroblasts and activated HSC from human
liver biopsy (70), CB2 receptors were not detected in normal human liver whereas they were
highly up-regulated in cirrhotic liver. Activation of CB2 receptor led to antifibrogenic effects
by growth inhibition that probably involved cyclooxygenase-2 (COX-2), and to the increase in
apoptosis by regulating oxidative stress. In the same study, mice invalidated for CB2 receptor
developed enhanced liver fibrosis.
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Hepatoprotective properties of CB2 receptors were also shown in a mice model of carbon
tetrachloride-induced acute hepatitis (71). Activation of CB2 receptors reduced liver injury and
accelerated liver regeneration by immunomodulation involving TNF-α, IL-6, Matrix metallo-
proteinase-2 (MMP-2) and reduction of oxidative stress.
In another animal model (72) of alcohol-fed mice, CB2 receptors regulated Kupffer cells
polarization by provoking a switch from a classical pro-inflammatory program of activation
(M1) to an alternative anti-inflammatory one (M2). This eventually protected the liver from the
deleterious effects of alcohol. Moreover, in the same study, CB2 receptors were shown to
reduce steatosis based on paracrine effects of Kupffer cells on hepatocytes.
Finally, as far as the brain is concerned, specific pharmacological activation of CB2 receptors
in a forced-alcohol-consumption rat model rescued alcohol-induced impaired neural progenitor
cells (NPC) proliferation, thus counteracting alcohol-induced neuronal damage (73).
However, all these promising findings come from animal models only, and there are currently no
results from clinical trials studying CBD in human AUD. It should be noted, however, that one
double-blind randomized clinical trial is currently being conducted in the United States. In this
ongoing study, CBD is administered versus placebo to patients with AUD, with the aim of
reducing the overall level of alcohol drinking (NCT03252756).
Having a similar effect as drugs such as nalmefene (74), baclofen (75), or topiramate (76), CBD
might thus be another good candidate molecule for reducing drinking in subjects with AUD.
Furthermore, the antioxidant and immunomodulatory properties of CBD constitute additional
and valuable features in the achievement of harm reduction in subjects with AUD, via a reduction
or even a prevention of alcohol-related liver or brain damage. While specific pharmacological
strategies of harm reduction have previously been developed in other substance use disorders, in
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particular in opioid use disorder, no other drug has been used in AUD for the specific purpose of
reducing alcohol-related damage, even without drinking reduction.
Moreover, CBD seems to have other interesting harm reduction properties, which have not been
assessed in AUD models so far, and thus, could not be investigated in this review. CBD has well-
known antiepileptic properties: in 2018, the Food Drug Administration (FDA) granted an
approval to CBD (EPIDIOLEX®, GW Pharmaceuticals), for Dravet and Lennox-Gastaut
syndromes. Given that patients with AUD are at increased risk to exhibit alcohol-induced or
withdrawal-related seizures, CBD could prevent the occurrence or reduce the severity of seizures
in this population. CBD also possesses anxiolytic and analgesic properties (38,39,77). Since
subjects with AUD display anxious symptoms or chronic pain more frequently than subjects
without AUD (78,79), CBD could reduce the overall level of anxiety and pain in subjects with
AUD, which could improve overall outcomes such as stress and quality of life. Indeed, 5-HT
receptors, which are known to regulate anxiety (80–82), are one of CBD’s targets (48,83), and
were studied in AUD (84). For example, ondansetron, a 5-HT3 receptor antagonist, showed some
efficacy in both preclinical and clinical studies on AUD (13,85,86). More recently, a preclinical
study in mice (55) showed that the 5-HT1a receptor antagonist WAY100635, blocked the
positive effect of a cannabidiol-plus-naltrexone combination on motivation and ethanol intake.
Anxiolytic properties of CBD could also be explained by its potential ability to regulate
endocannabinoid levels. FAAH is an enzyme responsible for the degradation of
endocannabinoids such as anandamide and 2-Arachidonoylglycerol (35,37,87,88), after they
have bound to fatty acid binding protein (FABP). CBD inhibits FAAH and thus, prevents
anandamide from being degraded (37,89–91). Facilitation of endocannabinoid signaling by
repeated administration of CBD led to a decrease of chronic stress in mice (92). In a human study
with a simulated public speaking test in patients suffering from social phobia, CBD was found
to significantly reduce anxiety (93). Contrasting with these results, a preclinical study in rats
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showed an impaired FAAH function in the alcohol-preferring phenotype compared to the non-
preferring phenotype, causing an over-reactive endocannabinoid transmission and a
compensatory downregulation of CB1 signaling (94). However, extrapolating all these results in
humans seems quite premature : for example, an experimental study on human cells found that
CBD had no action on FAAH but rather targeted several types of FABPs (95).
Finally, in addition to hepatic and brain damage, alcohol induces many other noxious effects on
the body, for example by inducing alcohol-related myocarditis, or various types of cancers.
Because of its immunomodulatory properties, protective effects of CBD against these other
harms should be further investigated in both animals and humans. Overall, CBD safety aspects
appear to be good, which is another important criterion for extending human research to patients
with AUD. So far, no severe clinical states resulting from CBD intoxication have been reported,
neither in animal nor in human use. Similarly, to our knowledge, no pharmacological tolerance,
withdrawal syndrome, abuse, or addictive behaviors, have been reported hitherto. This is an
important factor to consider before using CBD in AUD or other addictive disorders.
Despite the multiple prospects of CBD in AUD that have been emphasized in this review, many
issues and unsolved questions remain. The current literature only pertains to animal models, and
the translational aspects of the findings listed in this review are yet to be established. Moreover,
CBD effective dose range observed in animals is unlikely to be similar in humans. This point is
important because the dose-effect relationship of CBD depends on the type of effect and is not
always linear. For example, some effects of CBD seem to have an inverted U-shaped dose-
response curve. Regarding anxiety, while a dose superior to 20 mg/kg appears to be ineffective
in animals (96), a human study with a Simulating Public Speaking Test confirmed this U-shaped
dose-response, with an efficacy observed with 300 mg of CBD, but not with 150mg or 900 mg
(97). However, other animal studies found an anxiolytic effect with repetitive doses of 30 mg/kg,
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which may activate different pathways (92,98). In animal models of depression, a dose of
30mg/kg of CBD was found to be as effective as tricyclic antidepressants whereas a 100mg/kg
one was ineffective (99). With higher doses, activation of TRPV1 reduced the
anxiolytic/antidepressant effect (100). Higher doses of CBD (800mg/kg, 1000mg/day) seem to
be needed to obtain antipsychotic effect with reduction of positive psychotic score in clinical
studies (37) (101). Consistent with its large therapeutic target spectrum, sometimes with opposite
effects, the therapeutic dose range of CBD should be defined specifically for the various
symptoms that clinicians want to alleviate, in connection with hypothetical receptors or
secondary pathways.
In conclusion, experimental data underline that CBD offers multiple therapeutic prospects in
patients with AUD. CBD seems to facilitate drinking reduction, making CBD an interesting
pharmacological option in AUD treatment. Moreover, CBD might provide idiosyncratic
protection to the liver and the brain, which could reduce the development and impact of both
ARLD and ARBI. In this perspective, CBD treatment could be proposed to subjects who are
unable to reduce or to stop alcohol consumption, in order to prevent or reduce the effects of
alcohol on the brain and the liver, thus opening new and original therapeutic options for harm
reduction in AUD. CBD could have many more positive effects in subjects with AUD, including
antiepileptic, cardioprotective, anxiolytic, or analgesic ones. Human studies are thus crucially
needed to explore the many prospects of CBD in AUD and related conditions.
Conflict of Interest: The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest.
Funding: Funds for open access publication fees were provided by CH le Vinatier.
Author Contributions Statement: BR conceived the presented idea and supervised the
project. MN, MNO, BR and JD wrote the manuscript. All authors provided critical feedback
and helped shape the manuscript. All authors approved the final version for submission.
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