Cannabis Use and Neuroadaptation: A Call for Δ 9 -Tetrahydrocannabinol Challenge Studies

Abstract

Currently, the assessment of the neurobehavioral consequences of repeated cannabis use is restricted to studies in which brain function of chronic cannabis users is compared to that of non-cannabis using controls. The assumption of such studies is that changes in brain function of chronic users are caused by repeated and prolonged exposure to acute cannabis intoxication. However, differences in brain function between chronic cannabis users and non-users might also arise from confounding factors such as polydrug use, alcohol use, withdrawal, economic status, or lifestyle conditions. We propose a methodology that highlights the relevance of acute Δ⁹-tetrahydrocannabinol (THC) dosing studies for a direct assessment of neuroadaptations in chronic cannabis users. The approach includes quantification of neurochemical, receptor, and functional brain network changes in response to an acute cannabis challenge, as well as stratification of cannabis using groups ranging from occasional to cannabis-dependent individuals. The methodology allows for an evaluation of THC induced neuroadaptive and neurocognitive changes across cannabis use history, that can inform neurobiological models on reward driven, compulsive cannabis use.

Keywords: cannabis; cannabis abuse; mesocorticolimbic circuit; neuroadaptation; neurocognition.

FIGURE 1

Schematic representation of neurotransmission and functional connectivity in the mesocorticolimbic circuit in the normal brain (32) (left panel) and multimodal imaging measures (right panel) that can be employed to assess dynamics within this circuit during an acute challenge with THC and when sober. Magnetic Resonance Spectroscopy (MRS) has been successfully used to quantify frontal and striatal glutamate concentrations in cannabis users during intoxication and when sober (33, 34). fMRI measures of functional connectivity (FC) have provided functional associations within and between neural networks in cannabis users during intoxication (33, 35, 42) and when sober (–17, 42), and can be used as an indirect marker of striatal dopamine release during cannabis intoxication (33, 81). Positron emission tomography (PET) can be used to determine CB1 receptor density at glutamatergic and GABAergic neurons in the striatum of cannabis users (60, 62) and to determine dopamine displacement at D2/D3 receptors as a measure of dopamine transmission during cannabis intoxication (36). NAc, nucleus accumbens; PFC, prefrontal cortex.

FIGURE 2

Schematic representation of the dynamics of the neuroadaptive state of the mesocorticolimbic circuit when challenged with placebo (PLA) and THC as users proceed from occasional to chronic cannabis use and into abstinence. In occasional users, an acute THC challenge increases striatal levels of dopamine and glutamate (–35) through stimulation of CB1 receptors at presynaptic GABAergic and glutamatergic receptors, leading to hypoconnectivity of the mesocorticolimbic circuit (here shown superimposed on brain) and neurocognitive dysfunction (33, 35). With repeated cannabis use, CB1 receptors are downregulated as a neuroadaptive response to CB1 receptor overstimulation (60, 62). In chronic users, this leads to reduced striatal dopamine (40, 41) and glutamate (–22), as well as hyperconnectivity within the mesocorticolimbic circuit (9, 42, 82) and neurocognitive dysfunction when sober (13, 24, 27, 28). In these users, stimulation of CB1 receptors normalizes striatal dopamine and glutamate concentrations, functional connectivity and neurocognitive function during acute THC intoxication (35). With prolonged abstinence of cannabis, CB1 receptors upregulate (60, 62) and potentially normalize the neuroadaptive and neurocognitive state (63, 64, 66). NAc, nucleus accumbens; PFC, prefrontal cortex.