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