Cannabis use and cannabis use disorder

Abstract

Cannabis use disorder (CUD) is an underappreciated risk of using cannabis that affects ~10% of the 193 million cannabis users worldwide. The individual and public health burdens are less than those of other forms of drug use, but CUD accounts for a substantial proportion of persons seeking treatment for drug use disorders owing to the high global prevalence of cannabis use. Cognitive behavioural therapy, motivational enhancement therapy and contingency management can substantially reduce cannabis use and cannabis-related problems, but enduring abstinence is not a common outcome. No pharmacotherapies have been approved for cannabis use or CUD, although a number of drug classes (such as cannabinoid agonists) have shown promise and require more rigorous evaluation. Treatment of cannabis use and CUD is often complicated by comorbid mental health and other substance use disorders. The legalization of non-medical cannabis use in some high-income countries may increase the prevalence of CUD by making more potent cannabis products more readily available at a lower price. States that legalize medical and non-medical cannabis use should inform users about the risks of CUD and provide information on how to obtain assistance if they develop cannabis-related mental and/or physical health problems.

Fig. 1 |. Distribution of cannabinoid CB1 and CB2 receptors.

a | The concentration of CB1 receptors is higher in the brain than the rest of the body, whereas CB2 receptors are primarily found in immune cells and are less prevalent in the brain. b | Some brain regions have high CB1 receptor concentrations; these regions have diverse functions. Part a is adapted from REF., CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Part b, image courtesy of the Canadian Consortium for the Investigation of Cannabinoids.

Fig. 2 |. CB1 receptor signalling.

The endocannabinoid neurotransmitters anandamide (AEA) and 2-arachidonoylglycerol (2-AG) activate cannabinoid CB1 and CB2 receptors. 2-AG and AEA are synthesized from diacylglycerol (DAG) and N-arachidonoyl phosphatidylethanolamine (NAPE), respectively. Plant-derived exogenous cannabinoids such as Δ⁹-tetrahydrocannabinol (THC) and their synthetic counterparts stimulate the endocannabinoid system through binding to CB1 and CB2 receptors. Endocannabinoids released into the synaptic area act as a brake on the firing of presynaptic neurons, thereby inhibiting the release of neurotransmitters such as glutamate and γ-aminobutyric acid (GABA). Cannabinoid signalling is terminated by a family of intracellular degradative enzymes including fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Gq, guanine nucleotide-binding protein; NMDA, N-methyl-D-aspartate. Adapted with permission from REF..

Fig. 3 |. The reward circuitry.

Acute exposure to cannabinoids results in a cascade within the reward circuitry that resembles that of other drugs of abuse. The best characterized component of the circuit is the dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), which are crucial for the recognition of reward in the environment and the initiation of consumption behaviour. Additionally, dopaminergic neurons from the VTA innervate the hippocampus (HIPP) and prefrontal cortex (PFC), amongst other regions, allowing for the regulation of these regions. Beyond these dopaminergic projections, the NAc receives dense glutamatergic innervations from the PFC, the basolateral amygdala (BLA), the HIPP and the bed nucleus of the stria terminalis (BNST). There exist rich glutamatergic interconnections between the amygdala, PFC and HIPP, enabling the execution of complex affective and cognitive behaviours such as the formation and retrieval of associative and contextual fear- and reward-related memories. In addition, there are GABAergic neurons within the VTA, and projecting from the NAc to the VTA through a direct pathway and an indirect pathway via the ventral pallidum (VP). These GABAergic neurons provide a potent regulator of the dopaminergic activity of the VTA, thereby acting to regulate reward and aversive behaviour. Adapted with permission from REF.. CB1R, CB1 receptor; CeA, central nucleus of the amygdala; dlStr, dorsolateral striatum; GP: globus pallidus.

Fig. 4 |. PET imaging of CB1 receptors and FAAH.

a | PET imaging of CB1 receptors using [¹⁸F]FMPEP-d₂. Statistical parametric mapping (SPM) analysis showed lower distribution volume V_T (a measure of receptor density) in chronic daily cannabis smokers (n = 30) than in control subjects (n = 28) at baseline as a large single cluster that includes cortical regions. Bar represents t-values in each voxel within the significant cluster. b | PET imaging of fatty acid amide hydrolase (FAAH) using [¹¹C]CURB in transaxial (top) and coronal (bottom) views of an individual used as control (left) and a subject with cannabis use disorder (CUD) (right) following overnight abstinence. The subject with CUD had lower uptake of PET tracer in striatum, thalamus and cortical regions. Panel a reprinted from REF., Springer Nature Limited. Panel b reprinted with permission from REF., American Chemical Society.

Fig. 5 |. A multifactorial model for cannabis use disorders.

A range of biological factors, psychological factors and social factors shape an individual’s vulnerability. Repeated exposure to sufficiently high doses of Δ⁹-tetrahydrocannabinol (THC) for an extended period (months to years) can result in adverse acute and long-term mental, physical and social consequences. Chemical alterations of nervous system function can occur in the brain. Learning mechanisms (such as cue reactivity and operant learning) further explain long-lasting behavioural changes. The disease model involves dynamic changes over the lifespan. Stressors and protective factors can modify the severity of dependence. Many changes in the direction of a pathway over the lifespan are possible. Vulnerability and risk factors vary across populations. CBD, cannabidiol; CUD, cannabis use disorder.

Fig. 6 |. The hierarchy of substance use disorders across diagnostic systems.

Cannabis use and misuse form a spectrum of severity. Most individuals do not use cannabis. Individuals who do use cannabis typically use infrequently. However, in a smaller percentage of cannabis users, frequent use increases risk of harm (that is, hazardous cannabis use according to the International Classification of Diseases (ICD)) or actual harm (ICD Harmful Cannabis Use). These are the thresholds for health professionals to intervene. At the most severe end of the spectrum is ICD-11 Cannabis Dependence, which is defined as a disorder of substance regulation. The most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) replaced the previous categories of ‘Cannabis dependence’ and ‘Cannabis abuse’ with a single category of ‘Cannabis use disorder’. Adapted with permission from REF..