The influence of cocaine and cannabis on impulsivity.

Genetic variations may affect drug induced changes in impulsivity and vulnerability to drug abuse. Two prime genes linking loss of impulse control, prefrontal dopamine (DA) and drug addiction are catechol O-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH). Yet, the precise role of genetic variations on prefrontal DA and vulnerability to drug abuse is largely unknown. The current research proposal is designed to assess the influence of cocaine and cannabis on impulse control and to define the modulating role of the COMT and DBH genotypes on prefrontal DA and impulsive behaviours in cannabis and cocaine abusers. The research program consists of two major studies in regular users of cannabis and cocaine (N=60 in both studies) that will be conducted in parallel at Maastricht University and Radboud University Nijmegen Medical Centre. In each study, subjects will receive single doses of placebo, a THC dose of maximal 20mg and cocaine HCl 300mg according to a double blind, cross-over design. Impulsivity will be assessed objectively after administration of cannabis and cocaine with several performance models of impulse control (e.g. stop signal task, Cued Go/NoGo task) as well as with event related potentials and fMRI. Performance data will be analyzed separately for each centre but also combined in a meta-analysis over 120 subjects. It is expected that acute challenges with cocaine and cannabis will induce two opposing dopaminergic states in the brain. That is, cocaine will stimulate dopamine release leading to hyperdopaminergia whereas cannabis will reduce central dopamine levels resulting in hypodopaminergia. At present the common assumption is that a state of hypodopaminergia will lead to an increase in impulsive and risky behaviours such as drug use. Yet, the present studies are expected to demonstrate that drug induced impulsive behaviours can occur during both dopaminergic states depending on COMT and DBH genotypes and type of drug.

Acute challenges with cocaine and cannabis will induce two opposing dopaminergic states in the brain. Cocaine will stimulate dopamine release leading to hyperdopaminergia whereas cannabis will reduce central dopamine levels resulting in hypodopaminergia. Drug induced impulsive behaviours can occur during both dopaminergic states depending on COMT and DBH genotypes and type of drug.

Timepoint: 1 day.

1. Cocaine HCl 300mg as capsule;

2. Cannabis 20mg by inhalation;

3. Placebo.