Elsevier

Alcohol

Volume 46, Issue 3, May 2012, Pages 185-204
Alcohol

A review of the interactions between alcohol and the endocannabinoid system: Implications for alcohol dependence and future directions for research

https://doi.org/10.1016/j.alcohol.2012.01.002Get rights and content

Abstract

Over the past fifty years a significant body of evidence has been compiled suggesting an interaction between the endocannabinoid (EC) system and alcohol dependence. However, much of this work has been conducted only in the past two decades following the elucidation of the molecular constituents of the EC system that began with the serendipitous discovery of the cannabinoid 1 receptor (CB1). Since then, novel pharmacological and genetic tools have enabled researchers to manipulate select components of the EC system, to determine their contribution to the motivation to consume ethanol. From these preclinical studies, it is evident that CB1 contributes the motivational and reinforcing properties of ethanol, and chronic consumption of ethanol alters EC transmitter levels and CB1 expression in brain nuclei associated with addiction pathways. These results are augmented by in vitro and ex vivo studies showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the EC system. This report provides a current and comprehensive review of the literature regarding the interactions between ethanol and the EC system. We begin be reviewing the studies published prior to the discovery of the EC system that compared the behavioral and physiological effects of cannabinoids with ethanol in addition to cross-tolerance between these drugs. Next, a brief overview of the molecular constituents of the EC system is provided as context for the subsequent review of more recent studies examining the interaction of ethanol with the EC system. These results are compiled into a summary providing a scheme for the known changes to the components of the EC system in different stages of alcohol dependence. Finally, future directions for research are discussed.

Introduction

Alcohol use disorders (AUDs) affect an estimated 8.5% of the US population over the age of 18, and problems associated with AUDs cost the United States economy up to $185 billion per year (NIAAA, 2009). This enormous economic and public health problem is due to the addictive behaviors of alcohol abusing and dependent individuals. These behaviors are driven by two hallmark features of addiction: an overriding compulsion to seek and use alcohol and an inability to control or inhibit these actions even though they result in a negative outcome (e.g. loss of job, imprisonment, family problems, etc). These two features of addiction are thought to emerge from aberrant learning processes and plasticity in the striatum and frontal cortices (For review see Kalivas, 2008; Koob & Volkow, 2010) a subset of which are general mechanisms that participate in driving the addictive phenotype for all drugs of abuse. Historically, dopamine (DA) has been seen as a key neuromodulator driving reward processes, but an increasing amount of attention has been focused on other neuromodulatory and neurendocrine systems that may serve as more tenable sites for pharmacotherapy. Along these lines, it is often instructive to examine disorders that are frequently comorbid in the hopes of understanding a common underlying etiology, and in this regard, AUDs and cannabis use disorders (CUDs) share some similarity.

Since the early 1970's, a growing body of evidence has suggested a link between the neuropsychological effects of cannabis and ethanol consumption. Specifically, studies of the affective, cognitive, and psychomotor effects of these two substances in humans found evidence of a potential cross-tolerance to ethanol amongst cannabis users (Jones & Stone, 1970; MacAvoy & Marks, 1975). More recently, epidemiological studies of US populations indicate that for individuals with a CUD there is 45–81% lifetime prevalence of developing a comorbid AUD (Agosti, Nunes, & Levin, 2002; Regier et al., 1990; Stinson, Ruan, Pickering, & Grant, 2006). In a clinical study of adolescents with an AUD, over 70% reported use of cannabis within the past year, and the mean frequency of cannabis use for this group was between 16 and 20 days per month (Martin, Kaczynski, Maisto, & Tarter, 1996). In addition, data from a national computerized telephone survey show that individuals who responded as using marijuana and ethanol simultaneously engaged in significantly more binge drinking and were more likely to have alcohol dependence (Midanik, Tam, & Weisner, 2007). Together, these findings demonstrate a high prevalence of comorbidity between AUDs and CUDs.

One possible explanation for these findings is that these drugs may serve as a substitute for one another. Ethanol and cannabis both have depressant effects on central nervous system function. In laboratory rodents, administration of either ethanol or Δ9-tetrahydrocannabinol (THC; the main psychoactive compound in cannabis) produces hypolocomotion, hypothermia, and ataxia (Crabbe, Metten, Cameron, & Wahlsten, 2005; Martin et al., 1991). In human subjects acute administration of either compound produces euphoria and feelings of intoxication (Heishman, Arasteh, & Stitzer, 1997; Jones & Stone, 1970), and both substances decrease response time and accuracy on neuropsychological tests measuring memory, attention, and psychomotor performance (Chait & Perry, 1994; Heishman et al., 1997; Heishman, Stitzer, & Bigelow, 1988). In addition, daily cannabis users significantly increased self-reported ethanol craving and consumption during a two-week abstinence from marijuana (Peters & Hughes, 2010) and individuals in treatment for CUDs increased the frequency of ethanol use during 12 months following treatment (Stephens, Roffman, & Simpson, 1994). However, there are conflicting data with respect to combined ethanol and cannabis use. Findings from other studies of post-treatment outcomes for CUDs show a decrease (Stephens, Roffman, & Curtin, 2000) or no change (Kadden, Litt, Kabela-Cormier, & Petry, 2009) in ethanol consumption associated with decreased use of cannabis.

It is possible that shared physiological and biochemical mechanisms contribute to the comorbid abuse and substitution of ethanol and cannabis, but at first glance, these two substances seem remarkably different. On one hand, ethanol is a remarkably low affinity ligand for the many enzymes and receptors with which it interacts. Ethanol's low affinity is evidenced by the fact that it must be consumed in quantities sufficient to produce blood concentrations in the millimolar range before substantial behavioral effects can be observed. In contrast, THC produces the majority of its effects through high-affinity interactions with a small number of molecular targets. Almost all of the centrally mediated, behavioral effects of THC intoxication result from activation of the cannabinoid 1 (CB1) receptor. CB1 is a G-protein coupled receptor (GPCR) and is the main receptor for the endogenous cannabinoid (endocannabinoid; EC) system in the brain. ECs are a class of lipid-derived neuromodulators that serve as retrograde transmitters in central synapses. Research within the past decade has made it clear that ethanol interacts with the EC system, and a growing body of evidence suggests that the function of the EC system may be altered in alcohol dependence. In this review, we will begin by briefly discussing the early studies that demonstrated a link between the physiological and behavioral effects of cannabis and ethanol. Next we will cover the findings indicating that the EC system is a molecular target for ethanol and how the function of this neuromodulatory system is altered following chronic ethanol. Along these lines, we will attempt to place the behavioral ramifications of altered EC signaling in the context of circuitry associated with addictive processes. Finally, emerging topics in the fields of EC signaling and alcohol abuse will be discussed as future directions for research.

Section snippets

Comparative studies on the effects of cannabis and ethanol

The first study to directly compare the effects of ethanol and marijuana was conducted by Jones and Stone (1970). Participants who claimed a history of heavy marijuana use were administered cannabis orally or in a cigarette, and in separate sessions, they were given ethanol. The authors reported cannabis significantly increased pulse, time estimation, and low-voltage, high-frequency EEG activity. Ethanol, on the other hand, was observed to only decrease subjective time estimation. The opposing

Molecular targets of ethanol and cannabis

For many years, both ethanol and cannabinoid drugs were thought to exert the majority of their psychotropic effects through non-specific disruption of membrane lipids or alterations in the content of membrane lipids (Bruggemann & Melchior, 1983; Chin & Goldstein, 1981; Hillard, Harris, & Bloom, 1985; Hillard, Pounds, Boyer, & Bloom, 1990; Sun & Sun, 1985). Although there is currently not a specific receptor associated with the mechanism of action for ethanol, a robust data set has emerged in

Ethanol and the EC system

Despite the early flurry of research concerning the interactions between marijuana and ethanol in the 1970s, there was a marked paucity of studies examining the intersection of ethanol and cannabinoid substances through the 1980's and most of the 90's. Although it was not realized at the time, the first reports to implicate ethanol as a modulator of EC biosynthetic enzymes demonstrated that chronic exposure to ethanol in mice up-regulated the activity of PLA2 and that this effect persisted into

Future directions for research

As is evident from the preceding sections, a fundamental basis of knowledge exists for the changes to EC system function over the development of ethanol dependence, but much work needs to be done to establish a mechanism for how these changes contribute to addiction pathology. In particular, studies employing region specific modulation of EC signaling are needed to establish the brain nuclei important for EC-mediated contributions to the various phases of alcohol dependence, including: the

Conclusions

A retrospective examination of the early literature on the interactions between ethanol and cannabinoids finds clear evidence for the involvement of the EC system in the acute reinforcing properties of ethanol and the neuroadaptive changes that occur with its chronic abuse. However, it was not until the 1990's that the molecular constituents of the EC system were discovered, and only in the past decade has the interaction between ethanol and the EC system been directly investigated. From these

Acknowledgments

This work was supported by National Institutes of Health Grants P50AA10761 (Charleston Alcohol Research Center; JJW) and F31AA018908 (MJP).

References (211)

  • R.B.C. Clarke et al.

    Acute ethanol treatment prevents endocannabinoid-mediated long-lasting disinhibition of striatal output

    Neuropharmacology

    (2010)
  • J.C. Crabbe et al.

    An analysis of the genetics of alcohol intoxication in inbred mice

    Neuroscience & Biobehavioral Reviews

    (2005)
  • M. Davidson et al.

    Ethanol increases synaptosomal free calcium concentration

    Neuroscience Letters

    (1988)
  • D.G. Deutsch et al.

    The cellular uptake of anandamide is coupled to its breakdown by fatty-acid amide hydrolase

    Journal of Biological Chemistry

    (2001)
  • T.P. Dinh et al.

    A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation

    Chemistry and Physics of Lipids

    (2002)
  • D. Economidou et al.

    Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to Delta9-tetrahydrocannabinol

    Toxicology and Applied Pharmacology

    (2007)
  • L. Fattore et al.

    The endocannabinoid system and nondrug rewarding behaviours

    Experimental Neurology

    (2010)
  • F. Fezza et al.

    Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues

    FEBS Letters

    (2002)
  • J.E. Gallate et al.

    Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist

    European Journal of Pharmacology

    (1999)
  • S. González et al.

    Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine

    Brain Research

    (2002)
  • S. Gonzalez et al.

    Chronic exposure to morphine, cocaine or ethanol in rats produced different effects in brain cannabinoid CB(1) receptor binding and mRNA levels

    Drug and Alcohol Dependence

    (2002)
  • S.J. Heishman et al.

    Comparative effects of alcohol and marijuana on mood, memory, and performance

    Pharmacology, Biochemistry, and Behavior

    (1997)
  • S.J. Heishman et al.

    Alcohol and marijuana: comparative dose effect profiles in humans

    Pharmacology, Biochemistry, and Behavior

    (1988)
  • B.L. Hungund et al.

    Ganglioside GM1 reduces ethanol induced phospholipase A2 activity in synaptosomal preparations from mice

    Neurochemistry International

    (1994)
  • M. Kaczocha et al.

    Anandamide uptake is consistent with rate-limited diffusion and is regulated by the degree of its hydrolysis by fatty acid amide hydrolase

    Journal of Biological Chemistry

    (2006)
  • R.M. Kadden et al.

    Increased drinking in a trial of treatments for marijuana dependence: substance substitution?

    Drug and Alcohol Dependence

    (2009)
  • M. Karlsson et al.

    cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases

    Journal of Biological Chemistry

    (1997)
  • M. Karlsson et al.

    Expression, purification, and characterization of histidine-tagged mouse monoglyceride lipase from baculovirus-infected insect cells

    Protein Expression and Purification

    (2000)
  • I.B. Adams et al.

    Cannabis: pharmacology and toxicology in animals and humans

    Addiction

    (1996)
  • C.L. Adams et al.

    Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors

    British Journal of Pharmacology

    (2010)
  • V. Agosti et al.

    Rates of psychiatric comorbidity among U.S. residents with lifetime cannabis dependence

    American Journal of Drug and Alcohol Abuse

    (2002)
  • F. Alén et al.

    Converging action of alcohol consumption and cannabinoid receptor activation on adult hippocampal neurogenesis

    International Journal of Neuropsychopharmacology

    (2010)
  • M. Arnone et al.

    Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors

    Psychopharmacology

    (1997)
  • B.K. Atwood et al.

    CB2: a cannabinoid receptor with an identity crisis

    British Journal of Pharmacology

    (2010)
  • B.S. Basavarajappa et al.

    Chronic ethanol increases the cannabinoid receptor agonist anandamide and its precursor N-arachidonoylphosphatidylethanolamine in SK-N-SH cells

    Journal of Neurochemistry

    (1999)
  • B.S. Basavarajappa et al.

    Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons

    Journal of Neurochemistry

    (2008)
  • B.S. Basavarajappa et al.

    Activation of arachidonic acid-specific phospholipase A2 in human neuroblastoma cells after chronic alcohol exposure: prevention by GM1 ganglioside

    Alcoholism: Clinical and Experimental Research

    (1997)
  • P. Bech et al.

    Cannabis and alcohol: effects on estimation of time and distance

    Psychopharmacology (Berl)

    (1973)
  • H. Begleiter et al.

    Event-related brain potentials in boys at risk for alcoholism

    Science

    (1984)
  • Y.A. Blednov et al.

    Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase

    Neuropsychopharmacology

    (2007)
  • K.J. Brower

    Alcohol's effects on sleep in alcoholics

    Alcohol Research & Health

    (2001)
  • S. Caillé et al.

    Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration

    Journal of Neuroscience

    (2007)
  • L.D. Chait et al.

    Acute and residual effects of alcohol and marijuana, alone and in combination, on mood and performance

    Psychopharmacology (Berl)

    (1994)
  • J.F. Cheer et al.

    Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats

    Journal of Neuroscience

    (2004)
  • J.F. Cheer et al.

    Phasic dopamine release evoked by abused substances requires cannabinoid receptor activation

    Journal of Neuroscience

    (2007)
  • J.H. Chin et al.

    Membrane-disordering action of ethanol: variation with membrane cholesterol content and depth of the spin label probe

    Molecular Pharmacology

    (1981)
  • A. Cippitelli et al.

    The anandamide transport inhibitor AM404 reduces ethanol self-administration

    European Journal of Neuroscience

    (2007)
  • A. Cippitelli et al.

    Cannabinoid CB1 receptor antagonism reduces conditioned reinstatement of ethanol-seeking behavior in rats

    European Journal of Neuroscience

    (2005)
  • A. Cippitelli et al.

    Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat

    Psychopharmacology (Berl)

    (2008)
  • G. Colombo et al.

    Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716

    Alcohol and Alcoholism

    (1998)
  • Cited by (0)

    View full text