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Role of the endocannabinoid system in human brain functions relevant for psychiatric disorders

Impaired cognitive function is a fundamental characteristic of many psychiatric and neurological disorders such as schizophrenia or Alzheimer’s disease. The endocannabinoid (eCB) system, consisting of cannabinoid receptors and accompanying ligands, has been implicated in these disorders. In addition, behavioral evidence from healthy subjects indicates that modulation of the eCB system by administration of eCB agonists such as Δ9-tetrahydrocannabinol (THC) impairs performance on cognitive paradigms. However, the neurophysiological mechanisms underlying these effects are unknown. In this thesis, results of functional MRI (fMRI) studies are presented in which we investigated the effects of THC on cognitive brain function of healthy volunteers. Healthy males participated in double-blind, randomized, placebo-controlled, cross-over pharmacological fMRI studies. All subjects underwent two fMRI sessions, separated by two weeks, receiving THC (6 mg) or placebo using a Volcano vaporizer. Effects of THC administration on brain function and task performance were assessed using different cognitive tasks. The first study included a memory task that consisted of separate encoding and recall conditions. Findings suggest involvement of the endocannabinoid system in encoding of information. In addition, recall activity was increased, which may be a compensatory mechanism to maintain normal levels of task performance. In the second study, subjects performed a Sternberg item-recognition task with increasing difficulty. After THC administration, a profile of working memory load, task performance and brain activity was shown that corresponds with current concepts of working memory inefficiency, and that resembles that of schizophrenia patients. In the third study, task performance on an executive function task (CPT-IP) was impaired after THC administration. This was associated with reduced deactivation in the default mode network, whereas activity in brain regions activated by the task was unaffected. These results suggest a role for the eCB system in executive function through modulation of the default mode network, which may be a common brain system that is affected in a broad range of psychiatric disorders. The fourth study included an emotional processing task. THC administration reduced both task performance and brain activity for negative emotions, without effects on processing of positive emotions. This indicates that THC administration changed emotional bias in healthy subjects, mainly reflected in decreased reactivity towards negative stimuli, which may suggest a role of the eCB system in symptoms of depression. Together, these results provide compelling support for endocannabinoid involvement in the control of higher cognitive functions. In addition, similarities in brain function between healthy volunteers after THC administration and psychiatric patients provide indirect evidence for possible involvement of the endocannabinoid system in psychiatric disorders. With these results, the endocannabinoid system becomes a promising candidate for novel therapies to target symptoms in psychiatric disorders such as schizophrenia or depression.