Familial analysis of MMN in cannabis users: A case study

Abstract presented at the 23rd Australasian Society for Psychophysiology Conference, 20-22 Nov 2013, Wollongong, Australi

Involvement of the endocannabinoid system in reward processing in the human brain

Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Δ9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction

PsyCog:A computerised mini battery for assessing cognition in psychosis

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) ( N = 135), Clinical High Risk (CHR) ( N = 233), and First Episode Psychosis (FEP) ( N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design. </p

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort

[Background] We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN).[Method] Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study.[Results] The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period.[Conclusions] This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.PSYSCAN was supported as part of the European Funding 7th Framework Programme (grant number 603196).Peer reviewe

Supplements to: A naturalistic cohort study of first-episode schizophrenia spectrum disorder: a description of the early phase of illness in the PSYSCAN cohort

Suppl. Figure 1. Percentage of FES patients in symptomatic remission throughout the study.Suppl. Figure 2. Percentage of FES patients in functional remission throughout the study.Suppl. Figure 3. Clustered boxplot displaying the mean depression scores per time point (measured using the Hamilton Depression Rating Scale) in the subgroup meeting criteria for a depressive episode at baseline (assessed through the SCID-I) versus the subgroup without a depressive episode at baseline.Suppl. Table 1. Baseline demographics and clinical characteristics of study completers and drop-outs.Suppl. Table 2. Number of patients in symptomatic and functional remission throughout the period of follow-up.Suppl. Table 3. Generalized linear mixed models: pairwise contrasts for symptomatic and functional remission.Suppl. Table 4. Linear mixed models: estimated marginal means for PANSS, GAF, SOFAS, CGI, GF-S, GF-R and HAM-D.Suppl. Table 5. Linear mixed models: estimates of fixed effect time on PANSS, GAF, SOFAS, CGI, GF-S, GF-R and HAM-D.Suppl. Table 6. Number of patients admitted to the hospital since the previous visit due to psychotic symptoms and due to psychiatric reasons in general.Suppl. Table 7. Substances used at least once in the past three months (WHO-ASSIST).Suppl. Table 8. Number of patients reporting daily or almost daily substance use in the past three months, separated per time point and substance category (WHO-ASSIST).Suppl. Table 9. Number of patients reporting daily or almost daily substance use in the past three months, separated for the group of symptomatic remitters and non-remitters at month 12.Suppl. Table 10. Baseline demographics and clinical characteristics of symptomatic remitters and non-remitters at month 12.Suppl. Table 11. Summary of sociodemographics and baseline clinical characteristics of FES participants, separated per country.Suppl. Table 12. Number of FES patients in symptomatic remission throughout the period of follow-up, separated per country.Suppl. Table 13. Number of FES patients in functional remission throughout the period of follow-up, separated per country.Suppl. Table 14. Number of FES patients admitted to the hospital for psychiatric reasons throughout the period of follow-up, separated per country.Suppl. Table 15. Number of FES patients admitted to the hospital for psychosis throughout the period of follow-up, separated per country.Suppl. Table 16. Number of FES patients using antipsychotic medication throughout the period of follow-up, separated per country.Suppl. Table 17. Overview of subjects not meeting eligibility criteria.Suppl. Table 18. Number of patients in symptomatic and functional remission throughout the period of follow-up when using alternative definitions.Suppl. Table 19. Generalized linear mixed models: pairwise contrasts for symptomatic and functional remission when using alternative definitions.Peer reviewe

A protocol for the delivery of cannabidiol (CBD) and combined CBD and ∆9-tetrahydrocannabinol (THC) by vaporisation

Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with Δ9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. Methods:Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano® vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230°C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. Results:THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. Conclusions:While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD

Acute and chronic effects of cannabinoids on human cognition-a systematic review

Cannabis use has been associated with impaired cognition during acute intoxication as well as in the unintoxicated state in long-term users. However, the evidence has been mixed and contested, and no systematic reviews of the literature on neuropsychological task-based measures of cognition have been conducted in an attempt to synthesize the findings. We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. We summarize the findings into the major categories of the cognitive domains investigated, considering sample characteristics and associations with various cannabis use parameters. Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains underresearched. Associations between poorer performance and a range of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm

Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study

The main reason for recreational use of cannabis is the \u27high\u27, the primary psychotropic effect of Δ9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of \u27feeling high\u27. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function

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

Schizotypy and auditory mismatch negativity in a non-clinical sample of young adults.

Schizophrenia may be conceptualised using a dimensional approach to examine trait-like expression such as schizotypy within non-clinical populations to better understand pathophysiology