Canna~Fangled Abstracts

Cannabis and Alcohol: From Basic Science to Public Policy.

By July 2, 2019January 6th, 2022No Comments


About Author manuscripts Submit a manuscript HHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
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PMCID: PMC6721966
NIHMSID: NIHMS1039260
PMID: 31265135

Overview

The emergence of state-level approval of cannabis for both medical and recreational use is likely to increase the already prevalent co-use of alcohol and cannabis () and raise many important health and social concerns (). Cannabis research has lagged behind that of alcohol research, but important studies are emerging on the interactions between alcohol and cannabinoids. In this Virtual Issue, Cannabis and Alcohol: From Basic Science to Public Policy, we present nine leading-edge research publications spanning preclinical and epidemiological studies, as well as a critical review on the potential therapeutic use of cannabidiol (CBD) in the treatment of alcohol use disorder (AUD) (), which recently appeared in Alcoholism: Clinical and Experimental Research.

The Virtual Issue addresses the potential risks and benefits of alcohol and cannabis co-use, which may depend on the particular subgroup of individuals, and whether these drugs are used simultaneously (i.e., drug effects overlap) () or concurrently (i.e., drug effects do not overlap in time) (). Simultaneous drug use may be perceived as a means to complement or enhance the effects of each substance (), despite some individuals reporting negative effects (). The positive perception of complementary drug effects is concerning given the greater health risks associated with simultaneous use (). Another pattern of use has also developed that substitutes cannabis for alcohol use, particularly in individuals who are making efforts to reduce alcohol intake (). As summarized in the sections below, this Virtual Issue provides a current assessment of cannabis-alcohol interactions and shows patterns of drug use and risk profiles that may impact the prevalence of co-use and dependence.

Endocannabinoids, Exocannabinoids, and Alcohol Actions

Complex cannabinoid signaling systems are found throughout the body and are particularly important for brain, immune, and inflammatory signaling. Endogenous cannabinoids (endocannabinoids) shape neural circuits and affect many behaviors, including reward-driven behaviors such as addiction (). Unlike vesicle-secreted neurotransmitters, endocannabinoids are synthesized directly from plasma membrane phospholipids and their transient production generally follows a use-dependent signaling mechanism (). Tight control of this system depends heavily on specific enzymes to regulate synthesis and degradation (), and distinct metabolic processes in brain suggest differential mechanisms are in place for finely-tuned synaptic signaling (). The two main endocannabinoids (N-arachidonoylethanolamine and 2-arachidonoylglycerol) bind cannabinoid type 1 and 2 (CB1 and CB2) receptors and have additional targets, such as peroxisome proliferator-activated receptors, transient receptor potential cation channels, and other ligand- and voltage-gated ion channels (). Exocannabinoids such as CBD also act on CB1 and CB2 receptors and other endocannabinoid targets.

In general, chronic alcohol exposure increases endocannabinoid production, which may in turn downregulate CB1 receptor signaling in rodent models and perhaps also in human alcoholic brain as shown by positron emission tomography (). The overall reduction in these signaling pathways after chronic alcohol consumption may contribute to anxiety and relapse drinking (). In most preclinical studies, downregulation of CB1 signaling (e.g., by genetic deletion of CB1) reduced voluntary alcohol consumption and reward (conditioned place preference), whereas activation of cannabinoid signaling (e.g., by inhibition of fatty acid amino hydrolase, an enzyme that degrades endocannabinoids) increased alcohol consumption (). The cannabinoid signaling components and metabolic pathways offer multiple targets for regulating this complex system. It’s possible that compensatory cannabinoid-alcohol mechanisms could be used in the future to balance responses to mimic the favorable effects of cannabinoids while protecting against the deleterious effects of alcohol.

Chronic alcohol exposure is known to inhibit adult hippocampal neurogenesis, and in this Virtual Issue Khatri and colleagues used a rat binge-drinking model to show that acute alcohol inhibition of neurogenesis depends on activation of CB1 receptors and is exacerbated by further activation of these receptors (). This model suggests that acute activation of endocannabinoid signaling by alcohol is an important step in impairment of hippocampal neurogenesis. The acute and chronic effects of alcohol on CB1 receptor signaling indicate that the endocannabinoid system may be a viable target for alcohol-related behaviors or pathologies.

Epidemiology: Prevalence and Developmental Course of Alcohol and Cannabis Use

As cannabis use is increasing worldwide (), there is an immediate need for universal guidelines to diagnose substance use disorders (SUD). The International Classification of Diseases, 11th edition (ICD-11) () was recently ratified by the 72nd World Health Assembly, and will go into effect on January 1, 2022. Despite attempts to bring the two main classification systems, ICD and the Diagnostic and Statistical Manual For Mental Disorders (DSM) () into closer alignment (), differences between the diagnostic systems remain. These differences highlight ongoing issues in conceptualizing SUD. In this Virtual Issue, a cross-sectional study of adolescents in addiction treatment (N = 339, ages 14–18) found a significantly higher prevalence of diagnoses of alcohol and cannabis dependence using the ICD-11 classification compared to the DSM-IV, DSM-5, and ICD-10 systems (). This is likely due to the radically simplified set of three dependence criteria (physical dependence, priority of substance use, and impaired control over substance use) found in ICD-11, only two of which need to be met for a diagnosis of dependence to be made. Notably, adolescents with an ICD-11 dependence diagnosis usually met only the criteria of tolerance and priority of substance use (e.g., much time spent using or recovering from the substance), rather than the criterion of impaired control over substance use. The absence of reports of impaired control, a hallmark of dependence, raises questions regarding the ICD-11 dependence algorithm when applied to alcohol and cannabis, particularly in adolescents. Field testing of ICD-11 in community and treatment samples internationally is underway (personal communication, J. B. Saunders, University of Queensland, Australia).

Beyond establishing the prevalence of AUD and cannabis use disorder (CUD), risk factors influencing the developmental course of use need to be identified to effectively guide substance use prevention efforts. In this regard, the role of lifetime cannabis use in elevating the risk for increasing alcohol use was examined in this Virtual Issue in adolescents and young adults from 901 high-risk families (). For each of four transitions leading to AUD (time to first drink, first drink to first alcohol-related problem, first drink to AUD onset, and first alcohol-related problem to AUD onset), lifetime cannabis use consistently elevated the likelihood of each transition, independent of externalizing psychopathology, which also predicted each transition. These results highlight the role of cannabis use as a consistent risk factor across multiple transitions in the development of AUD, although the underlying mechanisms remain to be determined.

Risks Associated with Co-use of Alcohol and Cannabis

In the United States, the effect of state-level laws on the prevalence of and attitudes toward cannabis use among adolescents is mixed (). In this issue, a cross-sectional online survey () compared college students (N = 1389) from three states with different cannabis laws (i.e., criminalized, decriminalized, and recreational cannabis use for ages 21+) on the prevalence, negative consequences, and perceived norms associated with simultaneous alcohol and cannabis use. Three-quarters of the students reported simultaneous use at least once in the past year. Contrary to expectation, students in the state with decriminalized use reported higher rates of simultaneous use, compared with states with legalized or criminalized use. This may be a reflection of a perceived norm for simultaneous use among their peers by students in the decriminalized state, compared with students at the other two colleges. In support of this interpretation, a student’s own simultaneous use was positively associated with perceptions of simultaneous use among peers (which were higher in the decriminalized state relative to the other two states). Furthermore, greater simultaneous use was found in Greek members and in non-varsity sports club athletes, suggesting the potential utility of targeted interventions for specific subgroups to reduce risk of simultaneous use ().

Among adults with AUD, a study in this Virtual Issue by  replicated an intriguing result obtained from secondary analyses of the COMBINE study (), which found that, during alcohol treatment, “midlevel” cannabis use (i.e., average 1–2 times per month), compared with non-use, was associated with worse alcohol outcome (e.g., lower percent days abstinent), while there was no such association with “low” and “high” levels of cannabis use. In their follow-up study in this Virtual Issue,  selected adults from the U.S. National Alcohol Surveys who reported prior AUD treatment, and created four comparison groups: no cannabis use in the past year, light cannabis use (“less than monthly”), midlevel use (“more than monthly/less than weekly”), and heavy use (“weekly or more”). The cross-sectional analyses found, as in the prior COMBINE study, that only the midlevel cannabis use group (not the light or heavy use groups) significantly differed on alcohol outcomes from the group that reported no cannabis use in the past year, with the midlevel use group showing worse alcohol outcomes (e.g., average frequency of 5+ drinks, greater risk for alcohol-related harm). The authors speculate that the association between midlevel cannabis use and worse alcohol outcomes, particularly in the absence of an association between heavy cannabis use and worse alcohol outcomes, might be due to different motives and contexts of use for midlevel versus heavy cannabis use groups. For example, midlevel cannabis use might involve recreational motives, with intoxication as the main reason for use (e.g., significant associations with frequency of 5+ drinks), whereas high frequency cannabis consumption might involve medicinal use, or use of cannabis as a harm reduction substitute for alcohol use (). The authors’ interpretations remain speculative, however, since data on cannabis quantity, medicinal use of cannabis, simultaneous use of alcohol and cannabis (i.e., timing of using both substances within a day), and the motives and context of substance use were not collected.

Similar to the  report, a retrospective event-level study () in this Virtual Issue found less frequent heavy drinking (defined as > 4 and 5 drinks per occasion for females and males, respectively) among those with heavier (more frequent) cannabis use. This study, which examined daily patterns of alcohol and cannabis use among veterans based on Timeline Followback data, found that heavy drinking occurred on days when cannabis was consumed, and that this association was particularly strong among veterans with both AUD and CUD, or only AUD, but not among veterans with only CUD. The results were interpreted as support for possible complementary effects of alcohol and cannabis use, such that simultaneous use enhances the effects of each substance (). In contrast, veterans with only CUD were more likely to drink at moderate, not heavy, levels when using cannabis. The authors surmise that this might reflect a possible substitution effect, for example, in which medical marijuana replaces alcohol use among veterans with CUD only. In support of this possibility, daily or near daily medical marijuana use has been associated with a previous history of alcohol-related problems, but with a lower severity of current alcohol problems, compared with recreational cannabis use (). The study by Metrik and colleagues, however, did not assess medical use, cannabis quantity, or the timing of cannabis and alcohol use on a daily level. Among veterans with CUD only, the extent to which medical marijuana represents an effective harm reduction strategy as a potential substitute for alcohol remains to be determined ().

Possible Benefits of Co-use of Alcohol with Cannabis or Cannabidiol

Excessive alcohol consumption activates neuroimmune and inflammatory signaling and this contributes to organ damage and may promote further escalation of consumption (). In contrast, cannabis produces anti-inflammatory actions (), and it is of great interest to determine if any of the detrimental effects of alcohol can be ameliorated by exo- or endo-cannabinoids. As discussed in this Virtual Issue, studies in animal models report protective effects of CBD on alcohol-induced neurodegeneration and alcohol-induced liver steatosis, and human studies suggest a relationship between co-use of cannabis and alcohol on immune function and inflammation (). To further examine cannabis-alcohol interactions in humans, Karoly and colleagues determined if plasma levels of proinflammatory cytokines were associated with alcohol and cannabis use (). They found a positive association for interleukin 6 and alcohol use, and the association was stronger in cannabis non-use groups compared with use groups. Their findings suggest that cannabis use might blunt some of the adverse inflammatory consequences of alcohol abuse. Although certain peripheral cytokines may have the ability to penetrate the blood-brain barrier, this study did not directly measure neuroinflammation and more research is needed to determine the role of inflammatory responses in the periphery and the brain in cannabis and alcohol use groups. Considering the overall opposing effects of alcohol and cannabinoids on inflammatory responses and the effects of cannabinoids on alcohol-mediated inflammation, cannabinoid receptors are attractive anti-inflammatory targets for AUD ().

As reported in two studies in this Virtual Issue, mining of large hospital datasets provides evidence that cannabis use reduces risk of alcoholic pancreatitis and gastritis (). The authors discussed the possibility that the anti-inflammatory actions of cannabis may lessen the inflammatory effects of these alcohol-associated conditions. It will be of interest to determine which components of cannabis are most important and if the non-psychoactive CBD component may also be beneficial. Although such cross-sectional studies have limitations, they show the power of using large databases to detect potentially important alcohol-cannabis interactions.

CBD has become widely available in many forms from a rapidly increasing number of online and retail suppliers. Preclinical studies reviewed by  in this Virtual Issue report diverse beneficial effects of CBD, such as neuroprotection from adverse alcohol effects in the hippocampus and reduced alcohol-mediated liver damage, as well as reduced alcohol-dependent phenotypes (e.g., alcohol self-administration, craving, acute withdrawal). While only a few studies have examined the effects of CBD and alcohol in humans, the clinical evidence indicates that CBD was well tolerated and did not interact with the subjective effects of alcohol ().

Although not directly assessed, two studies in this issue () suggest that frequent cannabis use in some subgroups may be related to medical marijuana use and might represent a possible harm reduction strategy to substitute marijuana for alcohol (). The effectiveness of medical marijuana as a harm reduction strategy for AUD is not known, but in light of the beneficial evidence that is emerging for some alcohol-cannabis interactions, this is an intriguing area of research.

Conclusions

The articles presented in this Virtual Issue provide an important advance in understanding the combined effects of alcohol and cannabis use. They, however, also highlight significant gaps in research, particularly in humans, that need to be considered in the future. Information is lacking on the actions (molecular, physiological, behavioral) of specific cannabis-derived compounds and how they may be used for specific health conditions (). This is particularly true of CBD, which is now in popular use despite little information about its mechanism of action or therapeutic effects (). An attractive anti-inflammatory treatment approach is to amplify endocannabinoid signaling to mimic the favorable actions of exocannabinoids and perhaps correct problems caused by reduced endocannabinoid signaling, such as is observed following chronic alcohol exposure. The considerable interest in fatty acid amino hydrolase inhibitors has not yet led to therapeutic advances, but a successful strategy to harness endocannabinoid pathways may be realized in the future.

Other gaps in our knowledge include understanding the effects of the quantity of cannabis consumed, route of administration (e.g., smoke, vapor, edible), timing of cannabis and alcohol intake to distinguish simultaneous versus concurrent use, cannabis strain (e.g., indica, sativa), tetrahydrocannabinol/cannabidiol (THC/CBD) ratio, use of cannabis for medical purposes, and the impact of state-level cannabis regulatory policies. The article in this Virtual Issue that examined state-level differences in cannabis legislation found limited effects on cannabis use and simultaneous cannabis-alcohol use, relative to perceived peer norms for substance use (). However, increased implementation of cannabis legislation and continued monitoring of substance use prevalence may have a future impact on patterns of substance co-use and dependence diagnoses.

A key point made in this Virtual Issue is that some of the associations between alcohol and cannabis use were specific to subgroups, such as those diagnosed with SUD (), particular groups of college students (), or an individual’s frequency of (and possible motives for) cannabis use (). These subgroup-specific associations may explain some of the inconsistencies in previous research findings and emphasize the importance of identifying more homogeneous populations that demonstrate specific use patterns and risk profiles.

Collectively, the Virtual Issue calls our attention to the paradoxical interactions of cannabis and alcohol found in studies ranging from basic science to epidemiology. This paradox arises because the anti-inflammatory actions of cannabinoids likely ameliorate some actions of alcohol, particularly those where alcohol has an inflammatory component. Yet cannabis and alcohol can interact in other domains to produce enhanced effects (both positive and negative) of both substances. Better understanding of the CBD/THC ratio in relation to anti-inflammatory and psychoactive effects, together with studies of dose, patterns of drug co-use, and other external factors mentioned above will begin to close the research gaps. This Virtual Issue shows the progress in delineating the complex interactions, but also emphasizes that these are early days of cannabinoid-alcohol studies and much remains to be investigated.

Acknowledgements

This work was supported by grants R01 DA012237 (TC) from the National Institute on Drug Abuse and U24 AA025479 (RAH) from the National Institute on Alcohol Abuse and Alcoholism. The authors thank Jody Mayfield for editing the article.

Footnotes

Conflict of interest

The authors have no conflicts of interest to declare.

 

References

  • Adejumo AC, Akanbi O, Adejumo KL, Bukong TN (2019a) Reduced risk of alcohol-induced pancreatitis with cannabis use. Alcohol Clin Exp Res 43:277–286. [PubMed[]
  • Adejumo AC, Li J, Akanbi O, Adejumo KL, Bukong TN (2019b) Reduced prevalence of alcoholic gastritis in hospitalized individuals who consume cannabis. Alcohol Clin Exp Res 43:270–276. [PubMed[]
  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, Fifth Edition, American Psychiatric Association, Washington, DC. []
  • Augustin SM, Lovinger DM (2018) Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chem Neurosci 9:2146–2161. [PMC free article] [PubMed[]
  • Blevins CE, Marsh E, Banes KE, Stephens RS, Walker DD, Roffman RA (2018) The implications of cannabis policy changes in Washington on adolescent perception of risk, norms, attitudes, and substance use. Subst Abuse: Research and Treatment 12:1178221818815491. [PMC free article] [PubMed[]
  • Bucholz KK, McCutcheon VV, Agrawal A, Dick DM, Hesselbrock VM, Kramer JR, Kuperman S, Nurnberger JI Jr., Salvatore JE, Schuckit MA, Bierut LJ, Foroud TM, Chan G, Hesselbrock M, Meyers JL, Edenberg HJ, Porjesz B (2017) Comparison of parent, peer, psychiatric, and cannabis use influences across stages of offspring alcohol involvement: Evidence from the COGA prospective study. Alcohol Clin Exp Res 41:359–368. [PMC free article] [PubMed[]
  • Chung T, Cornelius J, Clark D, Martin C (2017) Greater prevalence of proposed ICD-11 alcohol and cannabis dependence compared to ICD-10, DSM-IV, and DSM-5 in treated adolescents. Alcohol Clin Exp Res 41:1584–1592. [PMC free article] [PubMed[]
  • Degenhardt L, Charlson F, Ferrari A, Santomauro D, Erskine H, Mantilla-Herrara A, Whiteford H, Leung J, Naghavi M, Griswold M, Rehm J, Hall W, Sartorius B, Scott J, Vollset SE, Knudsen AK, Haro JM, Patton G, Kopec J, Carvalho Malta D, Topor-Madry R, McGrath J, Haagsma J, Allebeck P, Phillips M, Salomon J, Hay S, Foreman K, Lim S, Mokdad A, Smith M, Gakidou E, Murray C, Vos T (2018) The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Psychiatry 5:987–1012. []
  • Erickson EK, Grantham EK, Warden AS, Harris RA (2019) Neuroimmune signaling in alcohol use disorder. Pharmacol Biochem Behav 177:34–60. [PMC free article] [PubMed[]
  • Friedman D, French JA, Maccarrone M (2019) Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. Lancet Neurol 18:504–512. [PubMed[]
  • Henderson-Redmond AN, Guindon J, Morgan DJ (2016) Roles for the endocannabinoid system in ethanol-motivated behavior. Prog Neuropsychopharmacol Biol Psychiatry 65:330–339. [PMC free article] [PubMed[]
  • Karoly HC, Bidwell LC, Mueller RL, Hutchison KE (2018) Investigating the relationships between alcohol consumption, cannabis use, and circulating cytokines: A preliminary analysis. Alcohol Clin Exp Res 42:531–539. [PMC free article] [PubMed[]
  • Khatri D, Laroche G, Grant ML, Jones VM, Vetreno RP, Crews FT, Mukhopadhyay S (2018) Acute ethanol inhibition of adult hippocampal neurogenesis involves CB1 cannabinoid receptor signaling. Alcohol Clin Exp Res 42:718–726. [PMC free article] [PubMed[]
  • Lee CM, Cadigan JM, Patrick ME (2017) Differences in reporting of perceived acute effects of alcohol use, marijuana use, and simultaneous alcohol and marijuana use. Drug Alcohol Depend 180:391–394. [PMC free article] [PubMed[]
  • Lin LA, Ilgen MA, Jannausch M, Bohnert KM (2016) Comparing adults who use cannabis medically with those who use recreationally: Results from a national sample. Addict Behav 61:99–103. [PMC free article] [PubMed[]
  • Mason WA, Fleming CB, Ringle JL, Hanson K, Gross TJ, Haggerty KP (2016) Prevalence of marijuana and other substance use before and after Washington State’s change from legal medical marijuana to legal medical and nonmedical marijuana: Cohort comparisons in a sample of adolescents. Subst Abus 37:330–335. [PMC free article] [PubMed[]
  • Metrik J, Gunn RL, Jackson KM, Sokolovsky AW, Borsari B (2018) Daily patterns of marijuana and alcohol co-use among individuals with alcohol and cannabis use disorders. Alcohol Clin Exp Res 42:1096–1104. [PMC free article] [PubMed[]
  • Nair MP, Figueroa G, Casteleiro G, Muñoz K, Agudelo M (2015) Alcohol versus cannabinoids: A review of their opposite neuro-immunomodulatory effects and future therapeutic potentials. J Alcohol Drug Depend 3:184. [PMC free article] [PubMed[]
  • National Academies of Sciences (2017) The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research, The National Academies Press, Washington, DC. []
  • Pakula B, Macdonald S, Stockwell T (2009) Settings and functions related to simultaneous use of alcohol with marijuana or cocaine among clients in treatment for substance abuse. Subst Use Misuse 44:212–226. [PubMed[]
  • Patrick ME, Fairlie AM, Lee CM (2018) Motives for simultaneous alcohol and marijuana use among young adults. Addict Behav 76:363–369. [PMC free article] [PubMed[]
  • Sartorius N (2010) Revision of the classification of mental disorders in ICD–11 and DSM–V: Work in progress. Adv Psychiatr Treat 16:2–9. []
  • Serrano A, Pavon FJ, Buczynski MW, Schlosburg J, Natividad LA, Polis IY, Stouffer DG, Zorrilla EP, Roberto M, Cravatt BF, Martin-Fardon R, Rodriguez de Fonseca F, Parsons LH (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840–1850. [PMC free article] [PubMed[]
  • Subbaraman MS (2016) Substitution and complementarity of alcohol and cannabis: A review of the literature. Substance Use Misuse 51:1399–1414. [PMC free article] [PubMed[]
  • Subbaraman MS, Barnett SB, Karriker-Jaffe KJ (2019) Risks associated with mid level cannabis use among people treated for alcohol use disorder. Alcohol Clin Exp Res 43:690–694. [PMC free article] [PubMed[]
  • Subbaraman MS, Metrik J, Patterson D, Swift R (2017) Cannabis use during treatment for alcohol use disorders predicts alcohol treatment outcomes. Addiction (Abingdon, England) 112:685–694. [PMC free article] [PubMed[]
  • Turna J, Syan SK, Frey BN, Rush B, Costello MJ, Weiss M, MacKillop J (2019) Cannabidiol as a novel candidate alcohol use disorder pharmacotherapy: A systematic review. Alcohol Clin Exp Res 43:550–563. [PMC free article] [PubMed[]
  • Volkow ND, Baler RD, Compton WM, Weiss SRB (2014) Adverse health effects of marijuana use. N Engl J Medicine 370:2219–2227. [PMC free article] [PubMed[]
  • White H, Kilmer J, Fossos-Wong N, Hayes K, Sokolovsky A, Jackson K (2019) Simultaneous alcohol and marijuana use among college students: Patterns, correlates, norms and consequences. Alcohol Clin Exp Res 43:1545–1555. [PMC free article] [PubMed[]
  • World Health Organization (2018) International classification of diseases, 11th edition, World Health Organization, Geneva. []
  • Yurasek AM, Aston ER, Metrik J (2017) Co-use of alcohol and cannabis: A review. Curr Addict Rep 4:184–193. []

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