Current Pharmaceutical Design - Volume 18, Issue 32, 2012

We conducted a systematic review on resting state cerebral blood flow activities found in first-episode psychosis (FEP) and during acute effects of cannabinoids and opioids, mental states that can be profoundly different from normal functioning. The main goal was to identify connections of cerebral blood flow measure and regional brain activity patterns associated with subjective experiences and to find out whether there are similarities between the three mental states. The present study reviewed systematically the current state of research with respect to cannabinoids and opioids on resting state activity patterns as investigated by different neuroimaging techniques. Twenty-two studies encompassing different neuroimaging techniques were selected. Cerebral perfusion and resting blood flow measure by single-photon emission computed tomography (SPECT), positron emission tomography (PET), perfusion-weighted imaging (PWI), arterial spin labeling (ASL), and resting-state functional magnetic resonance imaging (resting-state fMRI) during acute cannabinoids or opioids challenges were compared to findings in patients with FEP. The total number of subjects included in this review encompassed 279 FEP/controls (mean age = 28 ± 8.6 years, 40.1% females), 315 participants with cannabinoids (mean age = 29 ± 7.1 years, 31.8% females) and 113 participants with opioids (mean age = 30 ± 3.9 years, 17.3% females). We found that effects on regional activity were highly conflicting within the same condition group. However, we critical compared baseline acitivty patterns between FEP and acute cannabinoid or opioids effects. There was some consistent evidence suggesting positive symptoms of FEP and depersonalization experiences after cannabis administration both result in an increased anterior cingulate activity, an important area in the default mode network.

Background:Duration of untreated psychosis (DUP) is an important predictor of outcome in first-episode psychosis (FEP). Cannabis use is highly prevalent in FEP patients and it is important to evaluate the potential impact of cannabis use on DUP. Methods: A systematic review of the literature was conducted to identify articles reporting DUP in FEP cannabis users (CU+) and nonusers (CU-) respectively. Studies meeting inclusion criteria were entered into a meta-analysis. In addition, a comparative review was conducted of the relationship between substance use and DUP. Results: Nine studies were identified reporting DUP in CU+ versus CU- patients. Of the pooled sample of 1726 FEP patients, 39% were cannabis users. Although in most studies DUP was shorter in cannabis using patients, meta-analysis did not detect a significant relationship between DUP and cannabis use. A trend towards shorter DUP in substance users was also apparent in the comparative review; although in none of the studies did this association reach statistical significance. Discussion: This review and meta-analysis suggests a trend association between shorter DUP and cannabis use in FEP; especially when cannabis use is defined in terms of current or recent use (rather than lifetime use.) Further research should aim to clarify the relative effects of longstanding versus recent onset cannabis use on neurobiology, pathway to care and outcome in FEP.

Over the past years a growing research effort has investigated the relation between cannabis use and schizophrenia at a neurobiological, epidemiological and clinical level. A number of systematic reviews and meta analyses have summarized the available evidence in the field. Conversely the patient's perception of the link between cannabis use and psychosis has been under investigation. Since patient's beliefs and attitudes strongly correlate with adherence to all forms of treatment, we conducted a systematic PUBMED database search for any English and German-language articles published until January 2012 that addressed patient's perception of a cannabis psychosis link. Six studies including psychotic subjects met inclusion criteria yielding a total sample of 97. The vast majority of patients with either schizophrenia or a recent psychosis disagreed with a causal link between cannabis use and their mental illness. We qualitatively reviewed the explanatory models underlying their views, which were multi-factorial, psychological, social, biological, esoteric and irrational factors. Most patient's believed that the temporal sequence of events did not clearly indicate a causal relationship for them. They thus discarded the hypothesis of a causal link between cannabis use and psychosis. Despite the heterogeneity of the included studies, findings are comparable and support the robustness of this review. Limitations and implications for clinicians and psychosis research are discussed.

The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ 9-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein).

Δ 9-tetrahydrocannabinol (Δ 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ 9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.

Several lines of experimental and clinical evidence point to a close relationship between cannabis, the endogenous cannabinoid system, and schizophrenia. A variety of animal and human studies found a dysregulation of endocannabinoid signalling in psychosis. Elevated anandamide levels in schizophrenia patients that are negatively correlated with psychotic symptomatology indicate a protective role, whereas 2-arachidonoylglycerol appears to counteract psychosis-related cognitive impairments. Thus, pharmacological manipulation of the endogenous cannabinoid system might be associated with potential antipsychotic properties. In the present systematic review, both preclinical studies using different animal models of psychosis as well as clinical trials investigating the antipsychotic effects of both cannabidiol and rimonabant are presented together with the possible underlying mechanisms of action. The results predominantly confirm the hypothesis of an antipsychotic activity of both cannabinoids. In comparison, cannabidiol appears to be superior to rimonabant with a pharmacological profile similar to atypical antipsychotic drugs.

Background: Although neurological soft signs (NSSs) have been consistently associated with schizophrenia and a variety of risk factors, few studies have focused on the association between NSSs and environmental factors such as cannabis use, particularly in patients with first episode psychosis (FEP). Aims: To review studies that have specifically investigated the association between NSSs and cannabis use in subjects who suffer from psychosis, and more specifically in FEP. Methods: A review of studies investigating the associations between neurological function in psychotic patients and cannabis use. Results: A total of 5 studies met our inclusion criteria. Two of these included data only from patients with FEP. Four studies concluded that patients with psychosis and particularly FEP who consumed cannabis showed fewer NSSs. Conclusions: Four possible explanations are suggested for the paradoxical relationship between cannabis use and NSSs in FEP. First, heavy cannabis users present with different acute responses to cannabis use than do occasional cannabis users. Second, the psychoses developed by patients who consume cannabis follow different physio-pathological pathways that include fewer neurodevelopmental abnormalities. Third, the direct effect of cannabis on the Central Nervous System (CNS) may be responsible for the paradox. Finally,severe NSSsare associated with other clinical characteristics that would limit a subject's personal access to cannabis.

Objectives: This paper aimed to critically review the current literature concerning the possible association between cannabis use and suicidal behavior in patients with psychosis and in non-psychotic samples. Methods: We performed a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters focusing on the association between cannabis use, and suicidal behavior during the period between 1980 and 2011. Results: Most, but not all studies reported an association between suicidal behavior and cannabis use both in psychotic and non-psychotic samples. However, there were also some studies suggesting a weak (not direct) association between these two phenomena. Overall, those who attempt or complete suicide are characterized by additional risk factors such as mood disorders, stressful life events, interpersonal problems, poor social support, lonely lives, and feelings of hopelessness. Limitations: It was not possible to perform a meta-analysis due to the high heterogeneity of individual data. Conclusions: Cannabis use was a relevant risk factor associated with both suicidal attempts and behaviors in psychotic and non-psychotic samples. Preventive programs should be directed on reducing cannabis use, particularly in psychotic subjects. Evidence suggests that targeted suicide prevention programs can be also developed in specific at-risk subgroups such as those at genetic or clinical high risk of psychosis.

There is epidemiological evidence that frequent cannabis use in general and during puberty in particular increases the risk to suffer psychosis and psychotic symptoms. Based on these observations, there is growing interest in the role of the endogenous cannabinoid system (eCB system) - the point of action for psychoactive cannabinoids - in psychiatric disorders and schizophrenia in particular. It has been hypothesized nearly two decades ago that the eCB system may play a pathophysiological role in schizophrenia either in terms of an endogenous malfunction of the system itself and/or of a secondary malfunction as a result of the use of exogenous cannabinoids like Δ 9-tetrahydrocannabinol, the major psychoactive phytocannabinoid in Cannabis sativa. To test this hypothesis, several studies have been performed investigating endogenous ligands to cannabinoid CB1-receptors such as anandamide both in cerebrospinal fluid and plasma of patients and controls. Here a mini-review of the role of anandamide in schizophrenia is provided.