Keep off the grass?:Cannabis, cognition and addiction

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.This work was supported by grants from the US National Institutes of Health to L.H.P. (AA020404, AA006420, AA022249 and AA017447) and by grants from the UK Medical Research Council to H.V.C. and C.J.A.M. (G0800268; MR/K015524/1)

Functional interaction between opioid and cannabinoid receptors in drug self-administration

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence

Pharmacogenetics of Methadone Response

The efficacy of methadone maintenance treatment (MMT) in opioid use disorder is well established but responses vary. The influence of methadone pharmacodynamics and pharmacokinetics on dose requirements and program outcomes remains controversial despite the increasing number of studies evaluating genetic influences on response to methadone treatment. Furthermore, patients require different doses (usually between 60 and 100 mg/day), and there are no clear data on a plasma concentration associated with treatment success. We review the evidence regarding the influence of genetics on pharmacokinetic and pharmacodynamic factors in terms of MMT outcome. We also analyse the influence of genetics on the occurrence of severe adverse events such as respiratory depression and ventricular arrhythmia in methadone treatment. The outcomes of MMT may be influenced by a combination of environmental, drug-induced, and genetic factors. The influence of pharmacokinetic genetic variability can be clinically managed by modifying the posology. A better understanding of pharmacodynamic factors could help in selecting the best opioid for substitution treatment, but patient phenotype must still be considered when establishing a maintenance treatment. Pharmacogenetic studies represent a promising field that aims to individualize treatments according to genetic backgrounds, adapting medication and doses according to possible outcomes and the risk of adverse events