Cannabis use disorder: from neurobiology to treatment

Abstract

Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.

Figure 1. Signaling by endogenous and exogenous cannabinoids modifies synaptic activity at multiple levels.

(A) There are two known endocannabinoids, called anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Cannabis contains exogenous cannabinoids, including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). (B) Endogenous cannabinoid release prevents overstimulation of neurons, modulates the release of various neurotransmitters such as GABA and glutamate, and has downstream effects, notably on dopaminergic transmission. The enzyme fatty acid amide hydrolase (FAAH) degrades anandamide. The enzyme MAGL regulates 2-AG. THC stimulates the cannabinoid system by binding to CB₁ and CB₂ receptors. Compared with signaling by endogenous cannabinoids (normal state), chronic cannabis use likely results in changes in various components of the endocannabinoid system (e.g., CB₁ and FAAH).

Figure 2. Selected pharmacological strategies under investigation for treatment of CUD.

(A) CB₁ antagonists have demonstrated efficacy in preclinical models, with variable tolerability profiles. (B) CBD is the main nonpsychomimetic cannabis-derived compound. It has shown promising results in treatment of CUD. (C) Nabiximol (a 1:1 mixture of THC and CBD) may facilitate abstinence from cannabis in treatment-seeking patients, possibly by reducing withdrawal. (D) AEF0117, which blocks the intracellular signaling of CB₁, showed promise in decreasing cannabis use in a phase IIA study of volunteers with CUD.