Default Mode Network in the Effects of ¿9-Tetrahydrocannabinol (THC) on Human Executive Function

Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ¿9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADH

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

Methylone and mCPP, two new drugs of abuse?

Recently, two new ecstasy-like substances, methylone and mCPP, were found in street drugs in the Netherlands by the Drugs Information and Monitoring System (DIMS). Methylone (3,4-methylenedioxymethcathinone) is the main ingredient of a new liquid designer drug that appeared on the Dutch drug market, called. 'Explosion'. mCPP (meta-chloropheizylpiperazine) is a substance often used as a probe for the serotonin function in psychiatric research, and has now been found in street drugs, both in tablets and powders. Methylone as well as mCPP act oil monoantinergic systems, resembling MDAM (3,4-methylenedioxymethaniphetamine), with mCPP mainly affecting the serotonin system. The subjective effects of both new substances exhibit subtle differences with those of MDAM. Only little is known about the harmfulness of both methylone and mCPP. However, because of similarities between these substances and MDAM, risks common to MDMA cannot be excluded

Acute and Non-acute Effects of Cannabis on Human Memory Function: A Critical Review of Neuroimaging Studies

Smoking cannabis produces a diverse range of effects, including impairments in learning and memory. These effects are exerted through action on the endocannabinoid system, which suggests involvement of this system in human cognition. Learning and memory deficits are core symptoms of psychiatric and neurological disorders such as schizophrenia and Alzheimer's disease, and may also be related to endocannabinoid dysfunction in these disorders. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of psychiatric disorders. Here we review neuroimaging studies that investigated acute and non-acute effects of cannabis on human learning and memory function, both in adults and in adolescents. Overall, results of these studies show that cannabis use is associated with a pattern of increased activity and a higher level of deactivation in different memory-related areas. This could reflect either increased neural effort ('neurophysiological inefficiency') or a change in strategy to maintain good task performance. However, the interpretation of these findings is significantly hampered by large differences between study populations in cannabis use in terms of frequency, age of onset, and time that subjects were abstinent from cannabis. Future neuroimaging studies should take these limitations into account, and should focus on the potential of cannabinoid compounds for treatment of cognitive symptoms in psychiatric disorders

Methods of the Pharmacological Imaging of the Cannabinoid System (PhICS) study: towards understanding the role of the brain endocannabinoid system in human cognition

Various lines of (pre)clinical research indicate that cannabinoid agents carry the potential for therapeutic application to reduce symptoms in several psychiatric disorders. However, direct testing of the involvement of cannabinoid brain systems in psychiatric syndromes is essential for further development. In the Pharmacological Imaging of the Cannabinoid System (PhICS) study, the involvement of the endocannabinoid system in cognitive brain function is assessed by comparing acute effects of the cannabinoid agonist Δ9-tetrahydrocannabinol (THC) on brain function between healthy controls and groups of psychiatric patients showing cognitive dysfunction. This article describes the objectives and methods of the PhICS study and presents preliminary results of the administration procedure on subjective and neurophysiological parameters. Core elements in the methodology of PhICS are the administration method (THC is administered by inhalation using a vaporizing device) and a comprehensive use of pharmacological magnetic resonance imaging (phMRI) combining several types of MRI scans including functional MRI (fMRI), Arterial Spin Labeling (ASL) to measure brain perfusion, and resting-state fMRI. Additional methods like neuropsychological testing further specify the exact role of the endocannabinoid system in regulating cognition. Preliminary results presented in this paper indicate robust behavioral and subjective effects of THC. In addition, fMRI paradigms demonstrate activation of expected networks of brain regions in the cognitive domains of interest. The presented administration and assessment protocol provides a basis for further research on the involvement of the endocannabionoid systems in behavior and in psychopathology, which in turn may lead to development of therapeutic opportunities of cannabinoid ligands

The endocannabinoid system and emotional processing: A pharmacological fMRI study with Delta 9-tetrahydrocannabinol

Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist Delta 9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative ('fearful faces') or a positive content ('happy faces') were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression. (C) 2013 Elsevier B.V. and ECNP. All rights reserved

Proceedings of the entretiens of Institute International de Philosophie

Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using ¿9-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction

Effects of ¿9-Tetrahydrocannabinol on human working memory function

Background Evidence indicates involvement of the endocannabinoid (eCB) system in both the pathophysiology of schizophrenia and working memory (WM) function. Additionally, schizophrenia patients exhibit relatively strong WM deficits. These findings suggest the possibility that the eCB system is also involved in WM deficits in schizophrenia. In the present study, we examined if perturbation of the eCB system can induce abnormal WM activity in healthy subjects. Methods A pharmacological functional magnetic resonance imaging study was conducted with a placebo-controlled, cross-over design, investigating effects of the eCB agonist ¿9-tetrahydrocannabinol on WM function in 17 healthy volunteers, by means of a parametric Sternberg item-recognition paradigm with five difficulty levels. Results Performance accuracy was significantly reduced after ¿9-tetrahydrocannabinol. In the placebo condition, brain activity increased linearly with rising WM load. ¿9-Tetrahydrocannabinol administration enhanced activity for low WM loads and reduced the linear relationship between WM load and activity in the WM system as a whole and in left dorsolateral prefrontal cortex, inferior temporal gyrus, inferior parietal gyrus, and cerebellum in particular. Conclusions ¿9-Tetrahydrocannabinol enhanced WM activity network-wide for low loads, while reducing the load-dependent response for increasing WM loads. These results indicate that a challenged eCB system can induce both abnormal WM activity and WM performance deficits and provide an argument for the possibility of eCB involvement in WM deficits in schizophreni