Abstract
Cannabis use is associated with psychosis, particularly in those with expression of, or vulnerability for, psychotic illness. The biological underpinnings of these differential associations, however, remain largely unknown. We used Positron Emission Tomography and 18F-fallypride to test the hypothesis that genetic risk for psychosis is expressed by differential induction of dopamine release by Δ9-THC (delta-9-tetrahydrocannabinol, the main psychoactive ingredient of cannabis). In a single dynamic PET scanning session, striatal dopamine release after pulmonary administration of Δ9-THC was measured in 9 healthy cannabis users (average risk psychotic disorder), 8 patients with psychotic disorder (high risk psychotic disorder) and 7 un-related first-degree relatives (intermediate risk psychotic disorder). PET data were analyzed applying the linear extension of the simplified reference region model (LSRRM), which accounts for time-dependent changes in 18F-fallypride displacement. Voxel-based statistical maps, representing specific D2/3 binding changes, were computed to localize areas with increased ligand displacement after Δ9-THC administration, reflecting dopamine release. While Δ9-THC was not associated with dopamine release in the control group, significant ligand displacement induced by Δ9-THC in striatal subregions, indicative of dopamine release, was detected in both patients and relatives. This was most pronounced in caudate nucleus. This is the first study to demonstrate differential sensitivity to Δ9-THC in terms of increased endogenous dopamine release in individuals at risk for psychosis.
Highlights
The use of cannabis has long been associated with an increased risk of developing psychotic symptoms in healthy individuals, and with poor outcome in patients with psychotic disorder [1,2]
The present study revealed the novel finding of differential striatal DA release following inhalation of D9-THC in individuals displaying different levels of psychosis risk
Behind Cannabis-induced Psychosis? Numerous animal studies suggest that exogenous cannabinoids such as D9-THC stimulate burst firing of midbrain DA neurons and, as a consequence, facilitate striatal DA release through activation of CB1Rs, e.g. [16,17]
Summary
The use of cannabis has long been associated with an increased risk of developing psychotic symptoms in healthy individuals, and with poor outcome in patients with psychotic disorder [1,2]. Patients with psychotic disorder as well as individuals at risk for psychosis seem to express increased sensitivity to cannabis [3,4,5,6,7,8]. Long-term heavy cannabis use, in particular when started during early adolescence, is associated with structural brain changes such as impaired structural integrity of the corpus callosum [10], alterations in white and gray matter [11], and decreased hippocampal and amygdala volumes [12]. It has been argued that the use of cannabis is unlikely to increase the risk of psychosis by mechanisms that manifest themselves as major structural brain changes. Neurochemical interactions between cannabis and neurotransmitters such as dopamine (DA)
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