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ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 43, No. 4 April 2019 Critical Review Cannabidiol as a Novel Candidate Use Disorder Pharmacotherapy: A Systematic Review

Jasmine Turna, Sabrina K. Syan, Benicio N. Frey, Brian Rush, Mary Jean Costello, Mark Weiss, and James MacKillop

There is substantial interest in the therapeutic potential of cannabidiol (CBD), a nonpsychoactive found in plants of the genus . The goal of the current systematic review was to characterize the existing literature on this topic and to evaluate the credibility of CBD as a candidate pharmacotherapy for alcohol use disorder (AUD). Using a comprehensive search strategy, 303 unique potential articles were identified and 12 ultimately met criteria for inclusion (8 using rodent models, 3 using healthy adult volunteers, and 1 using cell culture). In both rodent and cell culture models, CBD was found to exert a neuroprotective effect against adverse alcohol consequences on the hippocampus. In rodent models, CBD was found to attenuate alcohol-induced hepatotoxicity, specifically, alcohol- induced steatosis. Finally, findings from preclinical rodent models also indicate that CBD attenuates cue-elicited and stress-elicited alcohol seeking, alcohol self-administration, withdrawal-induced convul- sions, and impulsive discounting of delayed rewards. In human studies, CBD was well tolerated and did not interact with the subjective effects of alcohol. Collectively, given its favorable effects on alcohol- related harms and addiction phenotypes in preclinical models, CBD appears to have promise as a candi- date AUD pharmacotherapy. This is further bolstered by the absence of abuse liability and its general tolerability. A clear limitation to the literature is the paucity of human investigations. Human preclini- cal and clinical studies are needed to determine whether these positive effects in model systems substan- tively translate into clinically relevant outcomes. Key Words: Cannabidiol, Alcohol Use Disorder, CBD, Alcohol, Pharmacotherapy.

HERE IS BURGEONING interest in the therapeutic (CBD) are the most commonly studied. The eCB is an T potential of compounds found in plants of the genus important physiological system with broad activity impact- Cannabis. The cannabis plant contains more than 500 con- ing various functions of the human body, including brain stituents and over 100 phytocannabinoids that actively inter- plasticity, inflammation, appetite regulation, and learning act with the body’s (eCB), of which and memory among others (Aizpurua-Olaizola et al., 2017). delta-9- (THC) and cannabidiol It is comprised of at least 2 G protein–coupled receptors, the cannabinoid type 1 (CB1) and type 2 (CB2) receptors (Boggs et al., 2018). THC is a partial of CB and CB recep- From the Michael G. DeGroote Centre for Medicinal Cannabis 1 2 Research (JT, JM), McMaster University & St. Joseph’s Healthcare tors (Boggs et al., 2018), and studies using CB1 Hamilton, Hamilton, Ontario, Canada; Peter Boris Centre for Addictions antagonists attenuate the effects of THC suggesting responsi- Research (JT, SKS, JM), McMaster University & St. Joseph’s Health- bility for its psychoactive effects (e.g., Englund et al., 2016; care Hamilton, Hamilton, Ontario, Canada; Department of Psychology, Justinova et al., 2008; Klumpers et al., 2013). Unlike THC, Neuroscience, and Behavior (SKS, JM), McMaster University, Hamil- CBD is nonpsychoactive which may be attributed to its func- ton, Ontario, Canada; Department of Psychiatry and Behavioural Neuro- sciences (SKS, BNF, JM), McMaster University, Hamilton, Ontario, tion as a negative of CB1 and CB2 recep- Canada; Mood Disorders Program and Women’s Health Concerns Clinic tors (Laprairie et al., 2015; Mechoulam et al., 2007). Further (BNF), St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada; impact of CBD on the eCB involves blocking Centre for Addiction and Mental Health (BR), Toronto, Ontario, uptake and inhibiting its enzymatic hydrolysis (Pertwee, Canada; Homewood Research Institute (BR, MJC, JM), Guelph, Ontar- 2008; Thomas et al., 2007). There are also numerous nonen- io, Canada; and Addiction Service (MW), Homewood Health Centre, Guelph, Ontario, Canada. docannabinoid signaling systems that CBD may interact Received for publication December 22, 2018; accepted January 20, with, explaining its diverse biologic effects (Boggs et al., 2019. 2018). For instance, CBD can modulate 5-HT1A receptors Reprint requests: James MacKillop, PhD, Peter Boris Centre for (Russo et al., 2005), GPR55 (Ryberg et al., 2007), TRPV1 Addictions Research, McMaster University/St. Joseph’s Healthcare cation channels (Bisogno et al. 2001), and l-andd- Hamilton, 100 West 5th Street, Hamilton, ON L8P 3R2, Canada; E-mail: [email protected] receptors (Kathmann et al., 2006). © 2019 by the Research Society on Alcoholism. With numerous and diverse pharmacological effects on a DOI: 10.1111/acer.13964 wide variety of body systems, CBD has gained attention for

550 Alcohol Clin Exp Re, Vol 43, No 4, 2019: pp 550–563 CANNABIDIOL FOR ALCOHOL USE DISORDER 551 equally numerous health applications. It has demonstrated neurotransmission (Jesse et al., 2017), CBD’s anti-inflammatory and effects and reports also effects may have therapeutic potential. Second, preclinical suggest it may have , antiemetic, antioxidant, evidence suggests that the eCB plays important roles in moti- and anticonvulsant effects (Hampson et al., 1998; Parker vational properties of alcohol as demonstrated by studies et al., 2002; Zuardi et al., 2006). However, it is critical to examining CB1 receptor modulation. More specifically, CB1 note that this support is derived from a primarily preclinical receptor antagonism has been shown to suppress rodent literature. Despite the ubiquitous health claims of CBD, sub- alcohol consumption (Arnone et al., 1997; Colombo et al., stantive support only exists in a small number of conditions. 1998; Femenıa et al., 2010; Wang et al., 2003) and can block Ò In Canada, Sativex (an oromucosal spray of THC and the increased alcohol consumption noted with CB1 receptor CBD) has been approved as an adjunctive treatment for neu- agonist administration (Colombo et al., 2002). Given that ropathic in (Health Canada, 2007). CBD may decrease CB1 receptor activity (through negative Similarly, randomized controlled trials of CBD only provide allosteric modulation), and CB1 receptor antagonism has support for seizure disorders (Cunha et al., 1980; Devinsky been shown to decrease alcohol consumption in animal mod- et al., 2017, 2018a; Thiele et al., 2018). Reflecting these find- els, this evidence further supports the notion that CBD may ings, earlier this year CBD (Epidiolex©) was approved by be a promising treatment for AUD. the Food and Drug Administration (FDA) for Lennox–Gas- The preceding lines of research obliquely suggest that taut and , 2 rare and severe forms of CBD may be a viable AUD pharmacotherapy, but a number pediatric . of studies have also directly examined the potential role of Given the salutary effects of CBD in preclinical studies, a CBD. The goal of the current systematic review was to char- variety of clinical applications have been considered, includ- acterize the findings from those direct investigations of ing alcohol use disorder (AUD) and other substance use dis- CBD’s effects on alcohol-related dysfunction or AUD. The orders (SUDs). AUD is characterized by a problematic broad goal was to appraise the extent to which CBD may be pattern of alcohol use, which leads to significant impairment a credible AUD pharmacotherapy. Although a number of and distress (American Psychiatric Association, 2013). It is a existing pharmacotherapies exist for AUD, suboptimal treat- highly disabling condition and represents a serious public ment outcomes remain common and the development of health concern. The FDA has approved 3 medications for novel strategies remains a priority (Kranzler and Soyka, treating AUD including (both oral and intramus- 2018; Litten et al., 2012, 2016a,b). cular formulation), acamprosate, and disulfiram (Leggio and Lee, 2017); however, meta-analytic evidence only supports the use of acamprosate and naltrexone (Jonas et al., 2014). MATERIALS AND METHODS The European Agency has also approved nalme- Search Strategy fene for AUD (Paille and Martini, 2014). These medications We applied the relevant methods outlined in the Preferred have distinct mechanisms of action and are effective for some Reporting Items for Systematic Review and Meta-Analyses patients, but predicting treatment response is difficult (Jonas (PRISMA; Moher et al., 2009). Relevant articles on the effects of et al., 2014). Despite existing pharmacological or psychologi- CBD on different alcohol-related harms were identified using the cal therapies, substantial proportions of patients do not have Boolean search terms (“cannabidiol” or “CBD”) and (“ethanol” or “alcohol”). The search was conducted using PubMed/MEDLINE, successful outcomes (e.g., naltrexone number needed to EMBASE, and PsycINFO in September 2018, and the initial treat = 9; Aronson, 2015) and there is a clear need for addi- searches were downloaded to shared drives. Titles and abstracts tional treatments, particularly those targeting alternative resulting from the initial search were screened by 2 reviewers for novel mechanisms (Litten et al., 2012, 2016a,b), such as the suitability for full-text review and final inclusion. To be included, an eCB. article was required to meet the following criteria: (i) an original empirical research article published in a peer-reviewed journal; (ii) The rationale for CBD as an AUD pharmacotherapy written in (or available in) English; (iii) study design must include comes from both oblique and direct evidence. First, there is CBD as an experimental intervention or in an observational design; evidence that AUD leads to dysfunction in a number of the and (iv) the study outcomes must examine some aspect of alcohol- biologic systems for which CBD has favorable effects. For related harm. This systematic review was preregistered in PROS- example, alcohol is a potent modulator of the immune sys- PERO (registration number: CRD42018109578). tem, potentiating alcohol-induced inflammation and stimulating immune cells, like monocytes, macrophages, and RESULTS T lymphocytes, which in turn cause the release of proinflam- matory cytokines (reviewed in Neupane, 2016). To address Our initial search generated 303 results, of which 12 met these effects, CBD’s anti-inflammatory effects may prove inclusion criteria (see PRISMA flow diagram, Fig. 1). In the beneficial. Oxidative stress also plays a demonstrable role in following sections, we review findings of the effects of CBD potentiating alcohol-related harms (Hernandez et al., 2016; on alcohol-related harms in human participants (Belgrave Li et al., 2015) which may be alleviated by CBD’s antioxi- et al., 1979; Bird et al., 1980; Consroe et al., 1979), cell cul- dant properties. Further, based on the risk of seizures during ture (Brenneman et al., 2018), and animal models (Filev alcohol withdrawal and persistent disturbances in glutamate et al., 2017; Gonzalez-Cuevas et al., 2018; Hamelink et al., 552 TURNA ET AL.

2005; Liput et al., 2013; Viudez-Martınez et al., 2018a,b; problem-solving, attention, information processing, and Wang et al., 2017; Yang et al., 2014). Table 1 provides a learning and memory (Liput et al., 2013). Further, reduced concise summary of the alcohol-related harm and associated gray cortical matter has been associated with a heightened outcomes of the studies included in this review. Below, the risk of relapse (Rando et al., 2011). Thus, treatments focus- results are according to the most commonly studied outcome ing on brain regeneration or compounds with neuroprotec- domains. tive abilities are attractive, given that they focus on a novel therapeutic target. CBD has demonstrated neuroprotective effects, preventing oxidative damage in an model of Protection of Cognition and Prevention of Neurodegeneration excitotoxicity (e.g., Hampson et al., 1998), making it a highly Existing approved pharmacological interventions for credible pharmacotherapy for reducing adverse alcohol- AUD focus on modifying the motivational properties of related cognitive consequences. Although the exact mecha- alcohol (Swift, 2007). However, excessive alcohol use can nism by which it elicits these actions remains unclear, 5HT1A give rise to neurodegeneration, which is a hypothesized cause or CB2 receptor mediation has been hypothesized (reviewed of the observed cognitive and behavioral impairments noted in Campos et al., 2016). in AUD (Crews and Boettiger, 2009). Previous studies have revealed that alcohol is particularly damaging to the frontal Preclinical Studies. Three studies were identified examin- and temporal lobes (Crews and Nixon, 2008) and the hip- ing the extent to which CBD was able to prevent alcohol- pocampus (Wilson et al., 2017), with induction of neuroin- induced neurodegeneration in the rat entorhinal cortex flammatory mediators and/or oxidative stress responsible for (Hamelink et al., 2005; Liput et al., 2013) and hippocampus such consequences. These brain regions are involved in (Brenneman et al., 2018; Hamelink et al., 2005). The first 2

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study flow diagram. Table 1. Summary of Outcomes Associated with Alcohol-Related Harms of All Studies Included in the Review DISORDER USE ALCOHOL FOR CANNABIDIOL

Study Group (n) Model/paradigm Assessed outcomes Human studies Consroe and Total n = 10 Healthy human (postgraduate volunteers) • Cancellation test: measure psychomotor processes of colleagues (1979) PBO; CBD; EtOH; CBD+EtOH Within-subject design, double-blind, attention and concentration 1 week between sessions • Differential Aptitude Test: visual-motor test measuring attention and concentration • Time production task: internal perceptual function • Finger tap test: undirected motor speed • Subjective Drug Reaction scale (DRS) • BAC Belgrave and Total n = 15 Healthy humans (primarily • Standing steadiness (eye open and closed) colleagues (1979) CBD + EtOH; PBO + EtOH; CBD + PBO; undergraduates) • Visual, auditory, and complex reaction time PBO + PBO Within-subjects design, double-blind, • Vienna Determination Apparatus: to measure coordination 1 week between sessions • The pursuit rotor • Arithmetic concentration and attention task • “Boggles” word construction task • BAC Bird and Total n = 161 Healthy humans • As described in Belgrave and colleagues (1979) colleagues (1980) CBD, , THC, and EtOH Double-blind administered in 16 combinations Cell culture Brenneman and CBD Dissociated hippocampal cell cultures • Fluorescent dye-based assays: propidium iodide (cell colleagues (2018) KLS-13019 Oxidative stress-related toxicity in death) and CFDA (neuronal viability) hepatic encephalopathy Animal studies Hamelink and N = 6/group Rats (male Sprague Dawley) • Quantification of hippocampal (ventral) and right/left colleagues (2005) CBD, antioxidants (a-tocopherol, butylated 4-day binge drinking entorhinal cortex neurodegeneration hydroxytoluene), NMDAR antagonists • BAC (, ), diuretics (furosemide, bumetanide, L-644,711) Liput and Experiment 1: EtOH+VEH; EtOH+ CBD Rats (male Sprague Dawley) • Experiment 1: Determine optimal CBD for neuropro- colleagues (2013) (either 1%, 2.5%, or 5%) Binge-drinking model tective effects (intoxication behavior, quantification of Experiment 2: EtOH; VEH i.p.; CBD i.p.; entorhinal cortex neurodegeneration) VEH gel; CBD gel; Total n = 148 • Experiment 2: Quantification of entorhinal cortex neurode- generation Yang and n = 4to6/group Mice (C57BL/6) • EtOH-induced hepatotoxicity (ATP levels, AST, triglyc- colleagues (2014) VEH + VEH; EtOH + VEH; VEH + CBD; Alcohol-induced liver steatosis model erides) EtOH + CBD (gavaged with EtOH for 5 days)—30% • Oxidative stress in liver EtOH • JNK activation Wang and n = 4to7/group Mice (C57BL/6) • Liver triglycerides, ALT, and AST levels colleagues (2017) Pair-fed; Pair-fed + CBD; EtOH; Hepatic failure-induced model of hepatic • Hepatic nitrotyrosine and hydroxynonenal content EtOH + CBD encephalopathy (Lieber-DeCarli diet— • Liver histology and immunochemistry 5% EtOH for 10 days) • Hepatic leukocytes and flow cytometry analysis Filev and Total n = 84 Male adult mice (DBA/2) • Effect on EtOH-induced locomotor sensitization colleagues (2017) Saline or EtOH plus, CBD, THC, or Model of locomotor sensitization THC + CBD Daily i.p. EtOH injections (2.5 g/kg, 12 days)

Continued. 553 554

Table 1. (Continued)

Study Group (n) Model/paradigm Assessed outcomes Viudez-Martınez and N = 10/group Male (C57BL/6) mice • BAC colleagues (2018b) CBD + EtOH; VEH + EtOH EtOH-induced relapse and acute EtOH • Hypothermia administration • Handling-induced convulsions with acute EtOH adminis- Oral EtOH self-administration paradigm tration • Two-bottle choice paradigm • Oral EtOH self-administration (3 dosages of CBD): Experi- ment 1: Reinforcement and motivation for EtOH; Experi- ment 2: Reinforcement and motivation for water; Experiment 3: EtOH-induced relapse • Gene expression: tyrosine hydroxylase in VTA and l- , CB1 and CB2 receptors, and GPR55 in NAcc Viudez-Martınez and Total n = 140 Male (C57BL/6) mice • Experiment 1: EtOH consumption and motivation to drink colleagues (2018a) Experiment 1: Oral EtOH self-administration paradigm (oral EtOH self-administration) VEH + VEH; VEH + NTX; CBD + VEH; • Gene expression CBD + NTX) • Experiment 2: Role of 5-HT1A receptors Experiment 2: VEH + VEH; WAY + VEH; WAY + CBD; WAY + CBD + NTX Gonzalez-Cuevas n = 9 to 12/group Rats (male Wistar) • Drug self-administration and reinstatement (context and and colleagues CBD or VEH Model of drug seeking and relapse stress related) (2018) • Delay discounting • Locomotor activity • Elevated plus maze • Plasma/brain CBD levels

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATP, adenosine triphosphate; BAC, blood alcohol concentration; CB, cannabinoid; CBD, cannabidiol; CFDA, 6-carboxyfluores- cein diacetate; EtOH, alcohol; i.p., intraperitoneal; NAcc, nucleus accumbens; NTX, naltrexone; PBO, placebo; THC, tetrahydrocannabinol; VEH, vehicle; VTA, central tegmental area; WAY, WAY 100635 (a drug). UN TAL. ET TURNA CANNABIDIOL FOR ALCOHOL USE DISORDER 555 studies utilized the Majchrowicz procedure (Majchrowicz, fluorescence to 76 Æ 4% for control culture. Both com- 1975), a widely used paradigm in studies examining AUD pounds revealed a protective ability compared to control, and alcohol-induced brain damage (Crews and Nixon, although KLS-13019 exhibited substantially higher potency. 2008). This model maintains intoxicating blood alcohol Specifically, 10 lM CBD and 100 to 700 nM KLS-13019 levels typical of AUD with minimal mortality and a clear were required for full protection in hippocampal cultures pattern of neurodegeneration during a 4-day binge period (Brenneman et al., 2018). (Hamelink et al., 2005; Liput et al., 2013). Compounds of Adverse functional cognitive performance is a potential interest, in this case neuroprotectants, are administered sequela of neurodegeneration observed in AUD. Our search between days 2 and 4 of alcohol treatment as neurodegenera- revealed 1 preclinical study that evaluated the impact of tion is not observed prior to day 3 or 4 of the binge (Hame- CBD in a neurocognitive domain, specifically impulsive link et al., 2005; Liput et al., 2013). choice, also referred to as delay discounting (i.e., preference In the first study, Hamelink and colleagues (2005) evalu- for small immediate rewards compared to larger delayed ated the effects of several compounds on hippocampal gran- rewards). Impairments in impulse control are related to both ular and entorhinal cortical pyramidal cell death, including alcohol use/AUD and risk of relapse (Amlung et al., 2017; intraperitoneal (i.p.) administration of CBD (20 or 40 mg/ MacKillop et al., 2011). In animals, impulsive choice is pre- kg/d), a-tocopherol, and butylated hydroxytoluene (antioxi- dictive of high alcohol intake and “loss of control” drinking dants); dizocilpine, memantine, and nimodipine (NMDA (Oberlin and Grahame, 2009; Wilhelm and Mitchell, 2009). receptor antagonists); and furosemide, bumetanide, and L- Gonzalez-Cuevas and colleagues (2018) utilized a 7-day 644,711 (diuretics). When 40 mg/kg/d of CBD was coadmin- dependence-inducing intragastric alcohol (or vehicle) intoxi- istered with alcohol, cell death was reduced by approxi- cation protocol, during which animals were treated with mately 60% in both areas compared to controls. Neuronal transdermal CBD (~15 mg/kg) or vehicle gel every 24 hours. rescue with both antioxidants and furosemide was compara- Effects on impulsive choice were examined after termination ble to the CBD group. Greater cell death was observed with of the intoxication protocol, and CBD was associated with dizocilpine, and there was no difference between the remain- significantly lower impulsive choice in the animals that ing NMDA receptor antagonists (Hamelink et al., 2005). received the alcohol dependence protocol. This finding pro- Subsequently, Liput and colleagues (2013) determined the vides evidence of CBD inhibiting the impaired impulse con- target CBD plasma concentration to achieve a neuroprotec- trol typically seen in AUD. tive effect, to be approximately 100 ng/ml. This concentra- tion was achieved on day 3 with transdermal application of a Human Studies. In contrast to preclinical studies, no 5.0% CBD gel (but not 1.0% or 2.5%). It also resulted in a studies examining the effects of CBD on AUD-related cogni- 48.8% reduction in neurodegeneration in the entorhinal cor- tive dysfunction were identified in humans. However, 3 stud- tex, a difference which approached significance. In a second ies were identified that examined the effects of concurrent experiment, an optimized CBD gel (2.5%) was evaluated in alcohol and CBD intake on cognitive function in healthy comparison with i.p. CBD and transdermal vehicle on day 3 humans. In the earliest study, Consroe and colleagues (1979) of binge treatment. During treatment, intoxication levels recruited 10 healthy adults and administered a dose of pla- were comparable between all groups, with each group receiv- cebo ( and orange juice with 4 ml alcohol), ing 380.4 Æ 7.8 mg/dL of alcohol, and evidence of cell death CBD only (200 mg CBD and orange juice with 4 ml alco- as a result. Compared to the alcohol control condition, i.p. hol), alcohol only (glucose capsule and orange juice with 1 g/ CBD was associated with a 50.6% reduction and transder- kg alcohol), or CBD + alcohol (200 mg CBD and orange mal CBD was associated with a 56.1% reduction in cell juice with 1 g/kg alcohol) in a double-blind within-subjects death of the entorhinal cortex, but they did not differ from design. Across all conditions (alcohol only and CBD + alco- one another (Liput et al., 2013). hol), alcohol was associated with detectable psychoactive Most recently, Brenneman and colleagues (2018) exam- effects and significant decrements in motor (finger tap test) ined the effect of CBD and a novel CBD-derived compound and cognitive (attention and concentration) performance (KLS-13019) on rat hippocampal cultures to evaluate treat- (Consroe et al., 1979). Thus, coadministration of CBD did ment of oxidative stress as it is relevant to hepatic not affect alcohol intoxication. Similarly, Belgrave and col- encephalopathy. Hippocampal cultures were cotreated with leagues (1979) examined the effect of CBD or placebo intake toxic levels of alcohol (30 mM) and ammonium acetate followed by consumption of an alcoholic (0.54 g/kg) or pla- (300 lM), and the protective effects of CBD (concentrations cebo beverage. Cognitive, perceptual, and motor function ranging from 0.1 to 10 lM) and KLS-13019 (concentrations tests revealed all noted deficits to be related to alcohol, while ranging from 1 nM to 10 lM) were assessed. Both cell death CBD was essentially inactive (Belgrave et al., 1979). Bird and neuronal viability were measured, and neuroprotection and colleagues (1980) evaluated the effects of CBD (320 lg/ specifically was observed as an increase in fluorescence for kg), THC (215 lg/kg), and cannabinol (320 lg/kg) alone or 5,6-carboxyfluorescein diacetate and succinimidyl ester in all possible combinations with alcohol (0.54 g/kg). Over- (CFDA), and decrease in fluorescence for propidium iodide all, only THC produced significant synergistic declines on all (PI). The combined toxin produced a decrease in CFDA performance measures, with no interaction effects by CBD 556 TURNA ET AL. or cannabinol pretreatment. Together, these findings provide effects on closed arm entries, a more common indicator of evidence that CBD is not associated with the same detrimen- , were not reported. In addition, CBD also did not tal cognitive effects as alcohol or THC, suggesting that it interfere with context-induced or stress–induced may be a well-tolerated treatment from the perspective of reward seeking of a glucose–saccharin sweet , sug- cognition. gesting that the behavioral changes associated with CBD were likely not due to or amotivational effects. Two studies investigated the effects of CBD on motivation Alcohol Motivation and Relapse for alcohol (Viudez-Martınez et al., 2018a,b) using a 3-stage Beyond excessive drug seeking, posttreatment relapse is a operant oral alcohol self-administration paradigm (Navar- primary driver of the chronicity of SUDs. Individuals with rete et al., 2014). In this paradigm, animals underwent 5 SUDs are at risk of relapse due to multiple factors including daily sessions on a fixed ratio (FR)1 reinforcement schedule susceptibility to stress, craving induced by drug contexts, and and then a FR3 schedule with a final session on a progressive heightened anxiety (MacKillop et al., 2010; Ramo and ratio (PR) schedule. Once alcohol intake was normalized, Brown, 2008; Sinha, 2012). Unlike existing AUD treatments, mice underwent FR1 (5 days), FR3 (5 days), and PR CBD is pointed to as a potential treatment as it targets multi- (1 day) again. The first study revealed decreased voluntary ple states associated with drug addiction and heightened alcohol consumption with i.p. CBD treatment (60 and relapse risk. Preclinical evidence has shown the potential of 120 mg/kg/d) using the 2-bottle choice test (Viudez-Martınez CBD in opioid and psychostimulant addiction, while human et al., 2018a,b). To examine the effects of CBD on relapse- studies present preliminary evidence of a beneficial impact of like behavior, a separate group of animals underwent a per- CBD on cannabis and dependence (reviewed in iod of deprivation (where food and water were still provided Prud’homme et al., 2015). ad libitum) following the oral alcohol self-administration protocol to normalize postalcohol exposure. In these animals Preclinical Studies. Four studies were identified examin- with a history of alcohol dependence, 60 mg/kg and 120 mg/ ing the effects of CBD on alcohol consumption or self- kg of i.p. CBD reduced alcohol-induced relapse behavior. In administration and processes associated with relapse and addition, less withdrawal (handling-induced convulsion addiction (Gonzalez-Cuevas et al., 2018; Viudez-Martınez score) was observed in CBD (+ saline or alcohol)-treated ani- et al., 2018a,b; Filev et al., 2017). One of these studies exam- mals following a single dose of i.p. alcohol (4 g/kg) than the ined the effects of CBD when combined with naltrexone vehicle + alcohol group. Furthermore, acute administration (Viudez-Martınez et al., 2018a). Some of the most com- of i.p. alcohol (30 mg/kg/d) did not alter basal temperatures pelling evidence for CBD’s therapeutic capacity is derived of CBD-treated mice, while those treated with vehicle from animal models of addiction and relapse. For example, revealed decreased temperature within 30 minutes. Subcuta- Gonzalez-Cuevas and colleagues (2018) systematically neous administration of a microparticle formulation of CBD demonstrated the potential of CBD treatment on a number via continuous controlled release (30 mg/kg/d) also signifi- of risk factors of relapse. Using an established protocol, rats cantly reduced alcohol self-administration and motivation to were trained to self-administer oral alcohol in daily 30-min- drink. Finally, CBD treatment significantly reduced relative ute sessions. Vehicle pretreatment for 4 days was followed gene expression of Th gene in the ventral tegmental area; by a 7-day treatment phase where groups were randomized Oprm1, Cnb1,andGpr55 on the nucleus accumbens (NAcc); to receive either CBD (15 mg/kg) or vehicle gel. Testing on and increased CB2 receptors in the NAcc. reinstatement (drug seeking) occurred during treatment and Another study examined the effects of combining a subcu- the posttreatment phase. Reinstatement was provoked by taneous controlled release microparticle CBD formulation exposure to drug-associated environmental stimuli (an olfac- (20 mg/kg) and naltrexone (0.7 mg/kg) in reducing alcohol tory and auditory component) and an acute stressor (yohim- self-administration and motivation compared to either com- bine administration). Compared to vehicle treatment, CBD pound alone (Viudez-Martınez et al., 2018a,b). In this case, reduced both context- and yohimbine-induced drug seeking the combined CBD and naltrexone group or either treatment when applied acutely (day 1) and with repeated treatment independently reduced operant response and reduced alcohol (day 7). The effect of CBD did not diminish with multiple self-administration on days 8 to 10 when compared to the administrations, implying no development of tolerance. control group (vehicle + vehicle). However, only the com- Rather, both forms of reinstatement remained significantly bined treatment was able to significantly reduce alcohol self- reduced up to 138 days after CBD treatment was discontin- administration in all phases of the alcohol administration ued. In contrast, vehicle treatment was associated with paradigm. Of note, the authors remarked that lowering the increased drug-seeking behaviors with yohimbine adminis- dose from the previous study (from 30 mg/kg/d to 20 mg/ tration. CBD also reduced experimental anxiety as demon- kg/d; Viudez-Martınez et al., 2018a,b) may have altered strated by greater duration of time CBD-treated animals CBD’s ability to reduce alcohol motivation. Combined spent in the open arms of the elevated plus maze compared treatment also revealed greater reduction of gene expression to vehicle treatment. Specifically, CBD did not alter open of Th and Oprm1 in the NAcc, dorsal raphe nucleus, and arm crossings (locomotor activity) compared to vehicle; ventral tegmental area. In addition, CBD alone or in CANNABIDIOL FOR ALCOHOL USE DISORDER 557 combination with naltrexone reduced 5HT1A receptor gene containing 5% alcohol for 10 days. CBD (or vehicle) was (Htr1a) expression and administration of a 5HT1A receptor administered by an i.p. injection (5 or 10 mg/kg/d) antagonist blocked the reduction in alcohol motivation throughout the alcohol exposure. On day 11, mice were induced by the alcohol administration paradigm. gavaged with a single dose of alcohol or isocaloric dex- Finally, 1 study examined the effect of CBD on an ani- trin-maltose. Yang and colleagues (2014) utilized a more mal model of locomotor sensitization (Filev et al., 2017). conventional approach, where mice were gavaged with The rationale for this model is that repeated administra- alcohol (or vehicle) every 12 hours for 5 days and CBD tion of substances of abuse (e.g., alcohol) typically (5 mg/kg) or vehicle was injected i.p. 30 minutes prior to induces progressive and persistent increase in locomotor alcohol administration. activity, even after withdrawal (Coelhoso et al., 2013). In both studies, alcohol led to elevated liver (AST Evaluating locomotor sensitization is a common tool as [Wang et al., 2017; Yang et al., 2014] and ALT [Wang et al., rodent sensitization to the rewarding effects of a drug of 2017]) and hepatic triglycerides (Wang et al., 2017; Yang abuse is directly related to the sensitization to its locomo- et al., 2014), demonstrating liver injury. CBD treatment tor effects (Vanderschuren and Pierce, 2010). Once reversed these effects with liver injury appearing at a level acquired, this effect is long-lasting and is temporally similar to vehicle + vehicle–treated mice (no alcohol expo- related to morphological and neurochemical changes in sure) and significantly less than alcohol + vehicle–treated the mesolimbic pathway and in the encephalic nuclei mice (no CBD exposure). Staining of liver sections (H&E interacting with this dopaminergic tract (Vanderschuren and Oil Red O) also revealed significant liver injury with and Pierce, 2010). Filev and colleagues (2017) examined alcohol exposure which was prevented in CBD-treated mice the effects of 4 days of pretreatment with only CBD (Wang et al., 2017; Yang et al., 2014). (2.5 mg/kg), THC (2.5 mg/kg), or the combination of Of particular interest, Wang and colleagues (2017) evalu- bothcomparedtovehicle.OnlytheTHCandTHC+ ated CBD’s role in modulating genes involved in CBD group revealed reduced expression of locomotor and liver steatosis, neutrophil accumulation, and liver sensitization; no effects were observed with CBD alone. inflammation. Alcohol enhanced expression of several genes This suggests CBD does not attenuate alcohol-induced involved in biosynthesis and decreased those locomotor sensitization. involved in fatty acid oxidation. Further significant hepatic neutrophil accumulation was noted with alcohol; however, Human Studies. No studies on human populations CBD treatment markedly attenuated such effects. CBD sup- examining the effects of CBD alcohol-related motivation or pressed the alcohol-induced increases in mRNA expression treatment response were identified. of chemokines (macrophage inflammatory protein-1 alpha, chemokine 2, and monocyte chemotactic protein-1 and cytokines (tumor necrosis factor alpha, interleukin-1 Hepatotoxicity beta, and adhesion molecules [E-selectin]). These findings Chronic alcohol consumption is a leading cause of liver suggest the protective effects of CBD were at least partially a disease worldwide (Leggio and Lee, 2017). Alcohol-related result of anti-inflammatory mechanisms (Wang et al., 2017). liver disease ranges in severity from mild and reversible fatty Beyond inflammation, findings from both studies also liver (steatohepatitis) to more severe forms including hepati- supported antioxidant activity of CBD, with CBD inhibit- tis, cirrhosis, or even hepatic failure (Leggio and Lee, 2017). ing hepatic increase in reactive oxygen species induced by In terms of mechanisms, both oxidative stress and inflamma- alcohol exposure. However, the proposed mechanisms of tion have been implicated in the induction of alcohol-related action differed. Yang and colleagues (2014) suggested that liver injury, including steatohepatitis. In this context, CBD CBD’s effects may be mediated by activation of autophagy, may be a credible pharmacotherapy based on existing evi- inhibition of the Jun N-terminal kinase/mitogen-activated dence regarding its effects as an anti-inflammatory and protein kinase pathway (which is active with acute alcohol antioxidant molecule. Specifically, in non–alcohol-related exposure), and direct inhibition of oxidative stress. How- liver injury, CBD has improved brain and liver function in a ever, Wang and colleagues (2017) isolated granulocytes fulminant hepatic failure-induced model of hepatic from human blood and noted that CBD, in a CB2 receptor- encephalopathy (Avraham et al., 2011) and hepatotoxicity independent manner, was able to inhibit the rapid release of resulting from cadmium (Fouad et al., 2013) and reactive oxygen species in human neutrophil cells exposed (Vilela et al., 2015). to alcohol. Furthermore, Wang and colleagues (2017) demonstrated that CBD’s actions attenuated an inflamma- Preclinical Studies. Our search revealed 2 studies tory response involving E-selectin and neutrophil recruit- examining the effects of CBD on alcohol-induced liver ment, and it was this anti-inflammatory effect that reduced steatosis (Wang et al., 2017; Yang et al., 2014). While oxidative stress. both studies utilized a “binge-drinking” animal model, the Wang and colleagues (2017) paradigm was unique in that Human Studies. No studies have examined the effect of it incorporated chronic alcohol consumption via a diet CBD intake on alcohol-related hepatic activity in humans. 558 TURNA ET AL.

DISCUSSION Finally, 2 small preclinical studies suggest that CBD may have therapeutic potential in alcohol-induced steato- The purpose of the current systematic review was to con- hepatitis (Wang et al., 2017; Yang et al., 2014). There sider the viability of CBD as a novel prospective pharma- was clear consensus among findings from both studies, cotherapy for AUD or specific adverse alcohol-related revealing that markers of liver damage consequent to medical consequences. Overall, the literature was limited to a binge drinking are prevented by CBD (Wang et al., 2017; small number of primarily preclinical studies, and there was Yang et al., 2014). This is promising with the suggestion an absence of studies in human clinical samples. Nonetheless, that perhaps CBD treatment may slow the development the results were consistently supportive of the potential ther- of more complicated and severe hepatic problems conse- apeutic benefits of CBD for AUD, particularly in the areas quenttoalcoholoveruse. of neurodegeneration, hepatotoxicity, cognition, and risk of The prior findings were restricted to preclinical models, relapse. Arguably of greatest promise was consistent evi- and studies with human participants were restricted to dence that CBD is neuroprotective against alcohol-induced healthy volunteers, not clinical samples. This work revealed brain insults in preclinical models, specifically in the hip- that CBD does not alter the acute cognitive effects of alcohol pocampus and entorhinal cortex (Brenneman et al., 2018; (Belgrave et al., 1979; Bird et al., 1980; Consroe et al., Hamelink et al., 2005; Liput et al., 2013). The selective vul- 1979), which does not directly speak to CBD as a treatment nerability of these 2 brain regions is notable given that it may for AUD given the single-dose nontherapeutic nature of the lead to the significant behavioral sequelae which go on to studies. On the other hand, these findings provide oblique impact daily functioning and cognitive ability (Hamelink insights into drug interactions if AUD patients drink while et al., 2005). Aptly, this leads to the suggestion that neuro- taking CBD, suggesting a relatively tolerable side-effect pro- protective compounds may prevent the cognitive deficits that file of CBD. Ultimately, translational studies in humans contribute to relapse in some (Stevens et al., 2015). exploring these candidate mechanisms identified by the exist- Direct evidence regarding CBD’s effect on cognition in the ing preclinical literature are critical to evaluate the potential context of alcohol-related harms was specific to a favorable of CBD as an AUD pharmacotherapy. effect on impulsive behavior in animal model of alcohol The potential therapeutic benefit of CBD can be further dependence (Gonzalez-Cuevas et al., 2018). This is a critical derived from the substantial evidence supporting its use in finding given that diminished impulse control is thought to seizure disorders. While the relevance of this indication play a significant role in the relapsing nature of AUD (Ste- may seem obscure, other , specifically topi- vens et al., 2015), and this specific form of impulsivity (delay ramate, have shown substantial promise in AUD (Johnson discounting) has been robustly associated with AUD and et al., 2003, 2007). In addition to seizure prevention during other forms of addictive behavior (Amlung et al., 2017; alcohol withdrawal, has a large effect on absti- MacKillop et al., 2011). Furthermore, precipitous delay dis- nence (g = 0.468) and heavy drinking (g = 0.406) in AUD counting has been found to predict formal addiction treat- as demonstrated by meta-analytic evidence (Blodgett et al., ment outcome (e.g., MacKillop and Kahler, 2009; Sheffer 2014). Moreover, a recent meta-analysis suggested that et al., 2012) and natural resolution of alcohol problems topiramate was superior to , baclofen, naltrex- (Tucker et al., 2002, 2008). one, and acamprosate on alcohol consumption outcomes More generally, the literature examining relapse-like (Palpacuer et al., 2018). Despite the moderate effect size of behaviors highlighted the potential benefit of CBD in this topiramate therapy in AUD, side effects (i.e., cognitive domain, particularly in animals that underwent a depen- impairment, paresthesia, abnormalities) reduce topira- dence induction protocol (Gonzalez-Cuevas et al., 2018; mates’ tolerability clinically. This has led to evaluations of Viudez-Martınez et al., 2018a,b). Although the mechanism other anticonvulsants in AUD. For instance, , by which CBD elicits these effects is unclear, CBD prevented another anticonvulsant that shares structural features with reinstatement of alcohol seeking in contexts that trigger topiramate, has revealed promising preclinical (Knapp relapse while also limiting risk factors associated with relapse et al., 2007; Sarid-Segal et al., 2008), open-label (Knapp (i.e., high anxiety and low impulse control). These findings et al., 2010; Rubio et al., 2010), and randomized controlled suggest that CBD may attenuate cue-elicited craving or trial evidence (Arias et al., 2010). However, cognitive stress-elicited craving in humans, although that is clearly a impairment of zonisamide may be comparable to topira- hypothesis to be tested. Another preclinical study illustrated mate, excluding mental slowing which is only increased in that combined CBD and naltrexone was more effective at topiramate (Knapp et al., 2015). is another reducing alcohol consumption than CBD or naltrexone anticonvulsant that has been examined in AUD. Although alone (Viudez-Martınez et al., 2018a,b). They illustrated it produces fewer adverse effect on cognition (Gomer et al., down-regulated gene expression in brain regions responsible 2007), research on its efficacy in AUD is not consistent for reward and habit formation, relevant to AUD, suggest- (Fertig et al., 2012; Richter et al., 2012; Sarid-Segal et al., ing a shared putative as demonstrated 2008). Other anticonvulsants that have shown promise in by the additive effect on treatment outcome (Viudez- AUD include divalproex (Brady et al., 2002) and gabapen- Martınez et al., 2018a,b). tin (Leung et al., 2015). CANNABIDIOL FOR ALCOHOL USE DISORDER 559

Taken together, the literature signals that CBD may be term effects of CBD are present in 1 or more of these efficacious in the context of alcohol-related harms by way of domains, there would be a strong basis for randomized con- its neuroprotective, antirelapse, and anticonvulsant mecha- trolled trials in individuals with AUD. However, rather than nisms. Despite these potential therapeutic effects, this review prioritizing 1 specific mechanism or phase of treatment, the highlights the need for further translational studies given that existing literature suggests investigations that broadly screen the current literature is limited to a small number of preclini- the effects in these domains are warranted. cal studies using animal models of AUD phenotypes. It has Dosing and present some of the been previously suggested that CBD may influence specific primary challenges in designing clinical trials to evaluate the phases of addiction for different substances of abuse (Prud’- therapeutic benefit of CBD. For instance, a majority of the homme et al., 2015). Considering the AUD literature, there animal studies reviewed above administered CBD transder- is merit to exploring CBD’s effects on relapse (Gonzalez- mally or by injection. This may be relevant as the bioavail- Cuevas et al., 2018; Viudez-Martınez et al., 2018a,b). More- ability of oral CBD in humans is relatively low, over, it may prove particularly beneficial in the early stages approximately 6% (Agurell et al., 1981). However, recent of treatment given its neuroprotective ability in hippocampal trials of CBD in the form of Epidiolex© (an oral solution) to and entorhinal cortical cells (Brenneman et al., 2018; Hame- treat pediatric seizure disorders may inform dosing and route link et al., 2005; Liput et al., 2013), potential benefit to cog- of administration. These studies revealed that 14 weeks of nitive function (Gonzalez-Cuevas et al., 2018), and 10 mg/kg/d or 20 mg/kg/d of Epidiolex© was efficacious in prevention of alcohol-related liver problems (Wang et al., reducing seizure frequency (Devinsky et al., 2017, 2018a; 2017; Yang et al., 2014). Although the animal studies Thiele et al., 2018). As a recently approved indication, the included in this review used robust paradigms for investigat- FDA recommends a titration schedule involving a starting ing alcohol-related harms, the promise of this literature is dose of 5 mg/kg/d (administered as doses of 2.5 mg/kg twice from a purely preclinical standpoint. In order to appropri- a day [b.i.d.]), and after 1 week, the dosage may be increased ately appraise the utility of a pharmacotherapy, human labo- to 10 mg/kg/d (5 mg/kg b.i.d.). In those tolerating this dose ratory and clinical studies (and integrated bench-to-bedside but requiring further seizure reduction, a maximum recom- studies) in humans are imperative. More specifically, there is mended maintenance dose of 10 mg/kg b.i.d. is recom- a need for studies that evaluate whether these mechanisms mended (20 mg/kg/d; FDA, 2018). When considering a identified in preclinical work will translate to clinical popula- target dose for AUD, 10 mg/kg/d may be more appropriate tions. Figure 2 concisely articulates the candidate mecha- for a number of reasons. First, only 1 of the Epidiolex© sei- nisms by which CBD may be useful in the treatment of AUD zure trials examined efficacy of both 10 mg/kg/d and 20 mg/ that warrants direct empirical investigation. If positive short- kg/d and the higher dose provided limited additional benefit

Fig. 2. Candidate mechanisms by which cannabidiol may be an efficacious pharmacotherapy for alcohol use disorder. Mechanisms are denoted by rounded rectangles, with titles indicating domains and italics indicating specific processes or measures. 560 TURNA ET AL. in reducing seizure severity (median reduction À42% vs. research. Fundamentally, empirical studies are needed to À37%) (Devinsky et al., 2018a), although these groups were determine whether these effects translate into favorable out- not compared statistically. Moreover, while CBD presents a comes in human preclinical and clinical models and, ulti- good safety profile (Bergamaschi et al., 2011), the FDA has mately, to inform the appropriateness of CBD as a potential recommended a dose adjustment in those with hepatic pharmacotherapy for AUD. impairment based on transaminase elevations observed in patients receiving 20 mg/kg/d (FDA, 2018). Liver damage is commonly seen in AUD patients (Leggio and Lee, 2017), ACKNOWLEDGMENTS and the FDA recommends a maximum dosage of 10 mg/kg/ This work was supported by the Michael G. DeGroote d for patients with moderate hepatic impairment making this Centre for Medicinal Cannabis Research, the Peter Boris an appropriate target for AUD. Interestingly, the studies on Chair in Addictions Research, and NIH grants AA025849 hepatotoxicity as discussed in the current review revealed and AA025911. The content is solely the responsibility of the that CBD was able to prevent development of signs of liver authors and does not necessarily represent the official views pathology noted with excessive alcohol exposure (Wang of the National Institutes of Health. et al., 2017; Yang et al., 2014), and safety data from Devin- sky and colleagues (2018b) also revealed that patients with elevated transaminase levels received concomitant . CONFLICT OF INTEREST An alternative candidate route of administration is inhala- tion of combusted or vaporized plant material of high CBD Benicio N. Frey has received research support from Pfizer composition. However, none of the studies identified in this and consultant fees from Otsuka. James MacKillop is a prin- review used as a route of administration; all used cipal in BEAM Diagnostics, Inc. No other potential conflicts , which was tolerated well by partici- of interest to report. pants. Furthermore, variation in topography (e.g., number of puffs, puff duration, inhalation volume, and duration) has REFERENCES the potential to create substantial differences in dosing and heterogeneity of effects. Collectively, oral route of adminis- Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H, Hollister L tration appears to be most appropriate at this stage. (1981) Assay of cannabinol and cannabidiol by mass fragmentography. – In addition to the parameters outlined above, the literature Experientia 37:1090 1092. Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, discussed in this review identifies target outcomes that would Usobiaga A (2017) Targeting the endocannabinoid system: future thera- be of interest, including the effects of CBD on alcohol con- peutic strategies. Drug Discov Today 22:105–110. sumption, liver pathology, and cognition. First, measuring American Psychiatric Association (2013) Diagnostic and Statistical Manual abstinence or change in heavy drinking could be quantified of Mental Disorders. 5th ed. American Psychiatric Association, Arlington, by self-report (e.g., timeline followback interview) and could VA. Amlung M, Vedelago L, Acker J, Balodis I, MacKillop J (2017) Steep delay be complemented with more objective biomarkers of alcohol discounting and addictive behavior: a meta-analysis of continuous associa- consumption or heavy drinking (e.g., ethyl glucuronide or tions. Addiction 112:51–62. carbohydrate-deficient transferrin) (Jastrzezbska et al., 2016). Arias A, Feinn R, Oncken C, Covault J, Kranzler HR (2010) Placebo-con- While serum liver enzymes have low specificity for detecting trolled trial of zonisamide for the treatment of alcohol dependence. J Clin – alcohol use, they would be reliable markers of liver damage. Psychopharmacol 30:318 322. Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, SoubrieP, Studies on hepatotoxicity revealed that CBD treatment pre- Le Fur G (1997) Selective inhibition of and ethanol intake by SR vented increases in ALT and AST that were noted in 141716, an antagonist of central cannabinoid (CB1) receptors. Psy- response to heavy alcohol consumption in animals (Wang chopharmacol 132:104–106. et al., 2017; Yang et al., 2014). As such, measuring baseline Aronson M (2015) Psychosocial treatment of alcohol use disorder UpTo- to end point change in these liver enzymes would not only Date. Available at:. https://www.uptodate.com/contents/psychosocial-trea tment-of-alcohol-use-disorder. Accessed September 29, 2018. describe the effects of CBD on liver function in AUD Avraham Y, Grigoriadis NC, Poutahidis T, Vorobiev L, Magen I, Ilan Y, patients, but also provide safety data regarding the hepatic Mechoulam R, Berry EM (2011) Cannabidiol improves brain and liver impairment noted in Epidiolex© trials. Finally, given the function in a fulminant hepatic failure-induced model of hepatic neuroprotective effects of CBD on the hippocampus and encephalopathy in mice. Br J Pharmacol 162:1650–1658. entorhinal cortex (Brenneman et al., 2018; Hamelink et al., Belgrave BE, Bird KD, Chesher GB, Jackson DM, Lubble KE, Starmer GA, Teo RKC (1979) The effect of cannabidiol, alone and in combination with 2005; Liput et al., 2013), and benefits in impulsive choice ethanol, on human performance. Psychopharmacology 64:243–246. (Gonzalez-Cuevas et al., 2018), general changes in neurocog- Bergamaschi M, Costa Queiroz R, Zuardi AW, Crippa AS (2011) Safety and nitive function throughout treatment would be of interest. side effects of cannabidiol, a constituent. Curr Drug In sum, this systematic review suggests that CBD may be a Safety 6:237–249. credible therapeutic for a wide variety of alcohol-related Bird KD, Boleyn T, Chesher GB, Jackson DM, Starmer GA, Teo RKC (1980) Intercannabinoid and cannabinoid-ethanol interactions and their harms based on the preclinical literature. Several candidate effects on human performance. Psychopharmacology 71:181–188. mechanisms by which CBD may produce therapeutic effects Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, in AUD were identified, providing clear avenues for future Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular CANNABIDIOL FOR ALCOHOL USE DISORDER 561

targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 Filev R, Engelke DS, Da Silveira DX, Mello LE, Santos-Junior JG (2017) receptors and on the cellular uptake and enzymatic hydrolysis of anan- THC inhibits the expression of ethanol-induced locomotor sensitization in damide. Br J Pharmacol 134:845–852. mice. Alcohol 65:31–35. Blodgett JC, Del Re AC, Maisel NC, Finney JW (2014) A meta-analysis of Fouad AA, Al-Mulhim AS, Gomaa W (2013) Protective effect of cannabid- topiramate’s effects for individuals with alcohol use disorders. Alcohol iol against cadmium hepatotoxicity in rats. J Trace Elem Med Biol 27:355– Clin Exp Res 38:1481–1488. 363. Boggs DL, Nguyen JD, Morgenson D, Taffe MA, Ranganathan M (2018) Gomer B, Wagner K, Frings L, Saar J, Carius A, Harle€ M, Steinhoff BJ, Clinical and preclinical evidence for functional interactions of cannabidiol Schulze-Bonhage A (2007) The influence of antiepileptic drugs on cogni- and D 9-tetrahydrocannabinol. Neuropsychopharmacology 43:142–154. tion: a comparison of levetiracetam with topiramate. Epilepsy Behav Brady KT, Myrick H, Henderson S, Coffey SF (2002) The use of divalproex 10:486–494. in alcohol relapse prevention: a pilot study. Drug Alcohol Depend 67:323– Gonzalez-Cuevas G, Martin-Fardon R, Kerr TM, Stouffer DG, Parsons 330. LH, Hammell DC, Banks SL, Stinchcomb AL, Weiss F (2018) Unique Brenneman DE, Petkanas D, Kinney WA (2018) Pharmacological compar- treatment potential of cannabidiol for the prevention of relapse to drug isons between cannabidiol and KLS-13019. J Mol Neurosci 66:121–134. use: preclinical proof of principle. Neuropsychopharmacology 43:2036– Campos AC, Fogaca MV, Sonego AB, Guimaraes FS (2016) Cannabidiol, 2045. neuroprotection and neuropsychiatric disorders. Pharmacol Res 112:119– Hamelink C, Hampson A, Wink DA, Eiden LE, Eskay RL (2005) Compar- 127. ison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol- Coelhoso CC, Engelke DS, Filev R, Silveira DX, Mello LE, Santos-Junior induced neurotoxicity. J Pharmacol Exp Ther 314:780–788. JG (2013) Temporal and behavioral variability in Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (À) expression in outbred mice submitted to ethanol-induced locomotor sensi- D9-tetrahydrocannabinol are neuroprotective antioxidants. PNAS tization paradigm. Alcohol Clin Exp Res 37:1516–1526. 95:8268–8273. Colombo G, Agabio R, Fa M, Guano L, Loche A, Reali R, Gessa GL Health Canada (2007) Fact Sheet – Sativex [Health Canada website]. (1998) Reduction of voluntary ethanol intake in ethanol-preferring sP August 1. Available at: https://www.canada.ca/en/health-canada/service rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol 33:126– s/drugs-health-products/drug-products/notice-compliance/conditions/fac 130. t-sheet-sativex-tetranabinex-nabidiolex.html. Accessed November 10, Colombo G, Serra S, Brunetti G, Gomez R, Melis S, Vacca G, Carai MA, 2018. Gessa G (2002) Stimulation of voluntary ethanol intake by cannabinoid Hernandez JA, Lopez-S anchez RC, Rendon-Ram ırez A (2016) Lipids and receptor in ethanol-preferring sP rats. Psychopharmacol 159:181– oxidative stress associated with ethanol-induced neurological damage. 187. Oxid Med Cell Longev 2016:1–15. Consroe P, Carlini EA, Zwicker AP, Lacerda LA (1979) Interaction of Jastrzezbska I, Zwolak A, Szczyrek M, Wawryniuk A, Skrzydło-Rado- cannabidiol and alcohol in humans. Psychopharmacol 66:45–50. manska B, Daniluk J (2016) Biomarkers of alcohol misuse: recent Crews FT, Boettiger CA (2009) Impulsivity, frontal lobes and risk for addic- advances and future prospects. Prz Gastroenterol 11:78–89. tion. Pharmacol Biochem Beh 93:237–247. Jesse S, Brathen G, Ferrara M, Keindl M, Ben-Menachem E, Tanasescu R, Crews FT, Nixon K (2008) Mechanisms of neurodegeneration and regenera- Brodtkorb E, Hillbom M, Leone MA, Ludolph AC (2017) Alcohol with- tion in alcoholism. Alcohol Alcohol 44:115–127. drawal syndrome: mechanisms, manifestations, and management. Acta Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gagliardi R, Neurol Scand 135:4–16. Sanvito WL, Lander N, Mechoulam R (1980) Chronic administration of Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Law- cannabidiol to healthy volunteers and epileptic patients. Pharmacology son K, Javors MA, Ma JZ (2003) Oral topiramate for treatment of alcohol 21:175–185. dependence: a randomised controlled trial. Lancet 361:1677–1685. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, Thiele EA, Wright S (2017) Trial of cannabidiol for drug-resistant seizures McKay A, Ait-Daoud N, Anton RF, Ciraulo DA, Kranzler HR (2007) in the Dravet syndrome. N Engl J Med 376:2011–2020. Topiramate for treating alcohol dependence: a randomized controlled Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, trial. JAMA 298:1641–1651. Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, Kim SM (2018a) Effect of cannabidiol on drop seizures in the Lennox-Gastaut MM, Shanahan E, Gass CE, Rowe CJ, Garbutt JC (2014) Pharmacother- syndrome. N Engl J Med 378:1888–1897. apy for adults with alcohol use disorders in outpatient settings: a system- Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, atic review and meta-analysis. JAMA 311:1889–1900. Greenwood S, Morrison G, Sommerville K; GWPCARE1 Part A Study Justinova Z, Munzar P, Panlilio LV, Yasar S, Redhi GH, Tanda G, Gold- Group (2018b) Randomized, dose-ranging safety trial of cannabidiol in berg SR (2008) Blockade of THC-seeking behavior and relapse in mon- Dravet syndrome. 90: e1204–e1211. keys by the cannabinoid CB 1-receptor antagonist . Englund A, Atakan Z, Kralj A, Tunstall N, Murray R, Morrison P (2016) Neuropsychopharmacology 33:2870–2877. The effect of five day dosing with THCV on THC-induced cognitive, psy- Kathmann M, Flau K, Redmer A, Trankle€ C, Schlicker E (2006) Cannabid- chological and physiological effects in healthy male human volunteers: a iol is an allosteric modulator at mu-and delta-opioid receptors. Naunyn placebo-controlled, double-blind, crossover pilot trial. J Psychopharmacol Schmiedebergs Arch Pharmacol 372:354–361. 30:140–151. Klumpers LE, Fridberg M, de Kam ML, Little PB, Jensen NO, Kleinloog FDA (2018) Epidiolex – Prescribing information. June. Available at: https:// HD, Elling CE, van Gerven JM (2013) Peripheral selectivity of the novel www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. cannabinoid receptor antagonist TM38837 in healthy subjects. Br J Clin Accessed on November 11, 2018. Pharmacol 76:846–857. Femenıa T, Garcıa-Gutierrez MS, Manzanares J (2010) CB1 receptor block- Knapp CM, Ciraulo DA, Sarid-Segal O, Richardson MA, Devine E, Streeter ade decreases ethanol intake and associated neurochemical changes in CC, Oscar-Berman M, Surprise C, Colaneri L, Putnam M, Waters M fawn-hooded rats. Alcohol Clin Exp Res 34:131–141. (2015) Zonisamide, topiramate, and levetiracetam: efficacy and neuropsy- Fertig JB, Ryan ML, Falk DE, Litten RZ, Mattson ME, Ransom J, Rick- chological effects in alcohol use disorders. J Clin Psychopharmacol 35:34– man WJ, Scott C, Ciraulo D, Green AI, Tiouririne NA (2012) A double- 42. blind, placebo-controlled trial assessing the efficacy of levetiracetam Knapp CM, Mercado M, Markley TL, Crosby S, Ciraulo DA, Kornetsky C extended-release in very heavy drinking alcohol-dependent patients. Alco- (2007) Zonisamide decreases ethanol intake in rats and mice. Pharmacol hol Clin Exp Res 36:1421–1430. Biochem Behav 87(1):65–72. 562 TURNA ET AL.

Knapp CM, Sarid-Segal O, Richardson MA, Colaneri LS, Afshar M, Devine Parker LA, Mechoulam R, Schlievert C (2002) Cannabidiol, a non-psy- E, Streeter CC, Piechniczek-Buczek J, Ciraulo DA (2010) Open label trial choactive component of cannabis and its synthetic dimethylheptyl homo- of the tolerability and efficacy of zonisamide in the treatment of alcohol log suppress nausea in an experimental model with rats. NeuroReport dependence. Am J Drug Alcohol Abuse 36:102–105. 13:567–570. Kranzler HR, Soyka M (2018) Diagnosis and pharmacotherapy of alcohol Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of use disorder: a review. JAMA 320:815–824. three plant : D9-tetrahydrocannabinol, cannabidiol and D9- Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM (2015) . Br J Pharmacol 153:199–215. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 Prud’homme M, Cata R, Jutras-Aswad D (2015) Cannabidiol as an interven- receptor. Br J Pharmacol 172:4790–4805. tion for addictive behaviors: a systematic review of the evidence. Subst Leggio L, Lee MR (2017) Treatment of alcohol use disorder in patients with Abuse 9:33–38. alcoholic liver disease. Am J Med 130:124–134. Ramo DE, Brown SA (2008) Classes of substance abuse relapse situa- Leung JG, Hall-Flavin D, Nelson S, Schmidt KA, Schak KM (2015) The tions: a comparison of adolescents and adults. Psychol Addict Behav role of in the management of alcohol withdrawal and depen- 22:372–379. dence. Ann Pharmacother 49:897–906. Rando K, Hong KI, Bhagwagar Z, Li CSR, Bergquist K, Guarnaccia J, Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The Sinha R (2011) Association of frontal and posterior cortical gray matter role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci volume with time to alcohol relapse: a prospective study. Am J Psychiatry 16:26087–26124. 168:183–192. Liput DJ, Hammell DC, Stinchcomb AL, Nixon K (2013) Transdermal Richter C, Effenberger S, Bschor T, Bonnet U, Haasen C, Preuss UW, Heinz delivery of cannabidiol attenuates binge alcohol-induced neurodegenera- A, Forg€ A, Volkmar K, Glauner T, Schaefer M (2012) Efficacy and safety tion in a rodent model of an alcohol use disorder. Pharmacol Biochem of levetiracetam for the prevention of alcohol relapse in recently detoxified Behav 111:120–127. alcohol-dependent patients: a randomized trial. J Clin Psychopharmacol Litten RZ, Egli M, Heilig M, Cui C, Fertig JB, Ryan ML, Falk DE, 32:558–562. Moss H, Huebner R, Noronha A (2012) Medications development to Rubio G, Lopez-Mu noz~ F, Ferre F, Martınez-Gras I, Ponce G, Pascual treat alcohol dependence: a vision for the next decade. Addict Biol JM, Jimenez-Arriero MA, Alamo C (2010) Effects of zonisamide in 17:513–527. the treatment of alcohol dependence. Clin Neuropharmacol 33:250– Litten RZ, Falk DE, Ryan ML, Fertig JB (2016a) Discovery, develop- 253. ment, and adoption of medications to treat alcohol use disorder: goals Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of for the phases of medications development. Alcohol Clin Exp Res cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043. 40:1368–1379. Ryberg E, Larsson N, Sjogren€ S, Hjorth S, Hermansson NO, Leonova Litten RZ, Wilford BB, Falk DE, Ryan ML, Fertig JB (2016b) Potential J, Elebring T, Nilsson K, Drmota T, Greasley PJ (2007) The orphan medications for the treatment of alcohol use disorder: an evaluation of receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol clinical efficacy and safety. Subst Abus 37:286–298. 152:1092–1101. MacKillop J, Amlung MT, Few LR, Ray LA, Sweet LH, MunafoMR Sarid-Segal O, Knapp CM, Burch W, Richardson MA, Bahtia S, DeQuattro (2011) Delayed reward discounting and addictive behavior: a meta-analy- K, Afshar M, Richambault C, Sickels L, Devine E, Ciraulo DA (2008) sis. Psychopharmacology 216:305–321. The anticonvulsant zonisamide reduces ethanol self-administration by MacKillop J, Kahler CW (2009) Delayed reward discounting predicts treat- risky drinkers. Am J Drug Alcohol Abuse 35:316–319. ment response for heavy drinkers receiving cessation treatment. Sarid-Segal O, Piechniczek-Buczek J, Knapp C, Afshar M, Devine E, Sickles Drug Alcohol Depend 104:197–203. L, Uwodukunda E, Richambault C, Koplow J, Ciraulo D (2008) The MacKillop J, Miranda JR, Monti PM, Ray LA, Murphy JG, Rohsenow DJ, effects of levetiracetam on alcohol consumption in alcohol-dependent sub- McGeary JE, Swift RM, Tidey JW, Gwaltney CJ (2010) Alcohol demand, jects: an open label study. Am J Drug Alcohol Abuse 34:441–447. delayed reward discounting, and craving in relation to drinking and alco- Sheffer C, MacKillop J, McGeary J, Landes R, Carter L, Yi R, Jones B, hol use disorders. J Abnorm Psychol 119:106–114. Christensen D, Stitzer M, Jackson L, Bickel W (2012) Delay discounting, Majchrowicz E (1975) Induction of physical dependence upon ethanol and locus of control, and cognitive impulsiveness independently predict the associated behavioral changes in rats. Psychopharmacologia 43:245– tobacco dependence treatment outcomes in a highly dependent, lower 254. socioeconomic group of smokers. Am J Addict 21:221–232. Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (2007) Cannabid- Sinha R (2012) How does stress lead to risk of alcohol relapse? Alcohol Res- iol—recent advances. Chem Biodivers 4:1678–1692. Curr Rev 34:432–440. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group Stevens L, Goudriaan AE, Verdejo-Garcia A, Dom G, Roeyers H, Vander- (2009) Preferred reporting items for systematic reviews and meta-analyses: plasschen W (2015) Impulsive choice predicts short-term relapse in sub- the PRISMA Statement. PLoS Med 6: e1000097. stance-dependent individuals attending an in-patient detoxification Navarrete F, Rubio G, Manzanares J (2014) Effects of naltrexone plus topi- programme. Psychol Med 45:2083–2093. ramate on ethanol self-administration and tyrosine hydroxylase gene Swift R (2007) Emerging approaches to managing alcohol dependence. Am J expression changes. Addict Biol 19:862–873. Health Syst Pharm 64:S12–S22. Neupane SP (2016) Neuroimmune interface in the comorbidity between Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis alcohol use disorder and major depression. Front Immunol 7:655– SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K, Gunning B 666. (2018) Cannabidiol in patients with seizures associated with Lennox-Gas- Oberlin BG, Grahame NJ (2009) High-alcohol preferring mice are more taut syndrome (GWPCARE4): a randomised, double-blind, placebo-con- impulsive than low-alcohol preferring mice as measured in the delay dis- trolled phase 3 trial. Lancet 391:1085–1096. counting task. Alcohol Clin Exp Res 33:1294–1303. Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG Paille F, Martini H (2014) Nalmefene: a new approach to the treatment of (2007) Cannabidiol displays unexpectedly high potency as an antagonist of alcohol dependence. Subst Abuse Rehabil 5:87–94. CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623. Palpacuer C, Duprez R, Huneau A, Locher C, Boussageon R, Laviolle Tucker JA, Foushee HR, Black BC (2008) Behavioral economic analysis of B, Naudet F (2018) Pharmacologically controlled drinking in the natural resolution of drinking problems using IVR self-monitoring. Exp treatment of alcohol dependence or alcohol use disorders: a system- Clin Psychopharmacol 16:332–340. atic review with direct and network meta-analyses on nalmefene, Tucker JA, Vuchinich RE, Rippens PD (2002) Predicting natural resolution naltrexone, acamprosate, baclofen and topiramate. Addiction 113:220– of alcohol-related problems: a prospective behavioral economic analysis. 237. Exp Clin Psychopharmacol 10:248–257. CANNABIDIOL FOR ALCOHOL USE DISORDER 563

Vanderschuren LJ, Pierce RC (2010) Sensitization processes in drug addic- Wang Y, Mukhopadhyay P, Cao Z, Wang H, Feng D, HaskoG,Mechou- tion. Curr Top Behav Neurosci 3:179–195. lam R, Gao B, Pacher P (2017) Cannabidiol attenuates alcohol-induced Vilela LR, Gomides LF, David BA, Antunes MM, Diniz AB, Moreira liver steatosis, metabolic dysregulation, inflammation and neutrophil- FDA, Menezes GB (2015) Cannabidiol rescues acute hepatic toxicity and mediated injury. Sci Rep 7:1–12. seizure induced by cocaine. Mediators Inflamm 2015:1–12. Wilhelm CJ, Mitchell SH (2009) Strain differences in delay discounting using Viudez-Martınez A, Garcıa-Gutierrez MS, Fraguas-Sanchez AI, Torres- inbred rats. Genes Brain Behav 8:426–434. Suarez AI, Manzanares J (2018a) Effects of cannabidiol plus naltrex- Wilson S, Bair JL, Thomas KM, Iacono WG (2017) Problematic alcohol use one on motivation and ethanol consumption. Br J Pharmacol and reduced hippocampal volume: a meta-analytic review. Psychol Med 175:3369–3378. 47:2288–2301. Viudez-Martınez A, Garcıa-Gutierrez MS, Navarron CM, Morales-Calero Yang L, Rozenfeld R, Wu D, Devi LA, Zhang Z, Cederbaum A (2014) MI, Navarrete F, Torres-Suarez AI, Manzanares J (2018b) Cannabidiol Cannabidiol protects liver from binge alcohol-induced steatosis by mecha- reduces ethanol consumption, motivation and relapse in mice. Addict Biol nisms including inhibition of oxidative stress and increase in autophagy. 23:154–164. Free Radical Bio Med 68:260–267. Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G (2003) Endocannabi- Zuardi AW, Crippa JAS, Hallak JEC, Moreira FA, Guimaraes FS (2006) noid signaling via cannabinoid receptor 1 is involved in ethanol preference Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz and its age-dependent decline in mice. PNAS 100:1393–1398. J Med Biol Res 39:421–429.