Original Article

Citation: Translational Psychiatry (2016) 6, e738; doi:10.1038/tp.2015.219
Published online 16 February 2016

AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers

C J A Morgan1,2, T P Freeman1, J Powell3 and H V Curran1

  1. 1Clinical Psychopharmacology Unit, University College London, London, UK
  2. 2Psychopharmacology and Addiction Research Centre, University of Exeter, Exeter, UK
  3. 3Basic and Clinical Neurosciences, Institute of Psychiatry, Kings College London, London, UK

Correspondence: Professor CJA Morgan, Psychopharmacology and Addiction Research Centre, Washington Singer Laboratories, Department of Psychology, University of Exeter, Perry Road, Exeter EX4 4QG, UK. E-mail: celia.morgan@exeter.ac.uk

Received 23 July 2015; Revised 20 October 2015; Accepted 9 November 2015



Smoking cannabis daily doubles an individual’s risk of developing a psychotic disorder, yet indicators of specific vulnerability have proved largely elusive. Genetic variation is one potential risk modifier. Single-nucleotide polymorphisms in the AKT1 and catechol-O-methyltransferase (COMT) genes have been implicated in the interaction between cannabis, psychosis and cognition, but no studies have examined their impact on an individual’s acute response to smoked cannabis. A total 442 healthy young cannabis users were tested while intoxicated with their own cannabis—which was analysed for delta-9-tetrahydrocannbinol (THC) and cannabidiol content—and also ±7 days apart when drug-free. Psychotomimetic symptoms and working memory were assessed on both the sessions. Variation at the rs2494732 locus of the AKT1 gene predicted acute psychotic response to cannabis along with dependence on the drug and baseline schizotypal symptoms. Working memory following cannabis acutely was worse in females, with some suggestion of an impact of COMT polymorphism on working memory when drug-free. These findings are the first to demonstrate that AKT1 mediates the acute response to cannabis in otherwise healthy individuals and implicate the AKT1 pathway as a possible target for prevention and treatment of cannabis psychosis.