Current Pharmaceutical Design - Volume 18, Issue 32, 2012

Although cannabis use disorder is strongly related to schizophrenia and treatment of patients with double diagnosis provides serious problem, specific pharmacological, molecular and therapeutical data on this subgroup are poorly available. In this paper we present a critical review on psychopharmacological boundaries of schizophrenia with concurrent cannabis use. The relevant data available in the literature suggest that a weaker compliance, poorer therapy response and higher sensitivity for extrapyramidal side effects are key features of schizophrenia and comorbid cannabis use disorder and represent a clinical challenge. Because of paucity of available research in the field there is not enough evidence to clearly depict the exact psychopharmacological profile of cannabis related schizophrenia. Further investigations are needed to assess phenotypic characteristics of this entity and to tailor effective treatment options accordingly.

Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures. In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced. Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity. Especially direct THC effects (or via endocannabinoids) may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. In particular, cannabidiol (CBD) was shown to prevent THC associated hippocampal volume loss in a small pilot study. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors. We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD.

Cannabis is widely used recreationally and for symptomatic relief in a number of ailments. However, cannabis has been implicated as a risk factor for the development of psychotic illness. For forty years researchers have utilised intravenous preparations of Δ9- THC, as well as several other phytocannabinoids, in a laboratory setting. The intravenous route has the most reliable pharmacokinetics, reducing inter-individual variation in bioavailability and is well suited for the delivery of synthetic compounds containing a sole pharmacological moiety. Given the association between cannabinoids and psychotic illness, there has been a resurgence of interest in experimental studies of cannabinoids in humans, and the intravenous route has been employed. Here in a critical review, we appraise the major findings from recent intravenous cannabinoid studies in humans and trace the historical roots of this work back to the 1970's.

The survival of any organism, animal or human, relies on the ability to accurately process, sense or tell time. Emerging evidence shows that timing is a crucial element in most, if not all, cognitive functioning and motor behaviour. Advances made by timing researchers provide valuable information on the neural substrates of interval timing, which indicate the involvement of certain brain areas and networks, most of which have not only been implicated in conditions such as schizophrenia, but are also abundant with cannabinoid receptors. A distorted sense of time is one of the most common effects of cannabis reported by users. In this paper, we present a critical review of the existing research on the topic. The findings are inconclusive, mainly due to methodological variations and the paucity of research. Even though 70% of time estimation studies report over-estimation, the findings of time production and time reproduction studies remain inconclusive. More research with robust methods is required to reach conclusions about the precise effect of cannabis and its active compounds on time perception. Such studies may also lead towards a better understanding of the mechanisms involved in brain functioning.

There is growing and converging evidence that cannabis may be a major risk factor in people with psychotic disorders and prodromal psychotic symptoms. The lack of available pharmacological treatments for cannabis use indicates that psychological interventions should be a high priority, especially among people with psychotic disorders. However, there have been few randomised controlled trials (RCTs) of psychological interventions among this group. In the present study we critically overview RCTs of psychological and pharmacologic interventions among people with psychotic disorders, giving particular attention to those studies which report cannabis use outcomes. We then review data regarding treatment preferences among this group. RCTs of interventions within “real world” mental health systems among adults with severe mental disorders suggest that cannabis use is amenable to treatment in real world settings among people with psychotic disorders. RCTs of manual guided interventions among cannabis users indicate that while brief interventions are associated with reductions in cannabis use, longer interventions may be more effective. Additionally, RCTs reviewed suggest treatment with antipsychotic medication is not associated with a worsening of cannabis cravings or use and may be beneficial. The development of cannabinoid agonist medication may be an effective strategy for cannabis dependence and suitable for people with psychotic disorders. The development of cannabis use interventions for people with psychotic disorders should also consider patients' treatment preferences. Initial results indicate face-to-face interventions focussed on cannabis use may be preferred. Further research investigating the treatment preferences of people with psychotic disorders using cannabis is needed.

It is widely accepted that there is a close relationship between cannabis use, the endocannabinoid system, and psychosis. In particular, cannabis use has the potential to trigger the onset of psychosis in vulnerable individuals and to exacerbate psychotic symptomatology in schizophrenia patients, including positive, negative, and cognitive symptoms. With regard to the cognitive dysfunctions as a core feature of schizophrenia, overlapping deficits in the domains of attention, memory, and executive functioning have been observed between chronic cannabis use and the disease. In this overview, we report on human clinical and experimental studies investigating the acute and chronic effects of cannabinoids on specific neurophysiological measures, i.e., the P50 suppression, the mismatch negativity, and the P300 potential, that consistently showed characteristic abnormalities in schizophrenia. Based on the results, we discuss some explanations on the putative mechanisms involving the endocannabinoid system and its interactions with other neuromodulators that might form the neural substrates underlying cannabis-induced cognitive impairments and help understand the neurobiology underpinning the development of cognitive deficits in schizophrenia.

The rate of substance use, particularly cannabis, among patients with psychosis is high and much greater than in the general population. Persistent cannabis use by patients with an established psychotic disorder adversely affects prognosis and recovery. Little agreement has been reached on the reasons that sustain cannabis use in patients with psychosis although self-report studies have shown that patients appear to use cannabis largely for the same reasons as the general population i.e. to ‘get high’ or reduce negative states such as depression and boredom. The aim of this series is to explore 5 individual cases of patients with psychosis reporting cannabis use. Full clinical assessment for each patient as well as cannabis use history, reasons for use and implications for effective treatment are explored.

Objectives: Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR). Methods: Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2). Results: In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. Discussion: Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.

Rationale: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied separately. Objective: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. Methods: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. Results: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p<0.01), an increase in heart rate (p<0.05). There were no differences between CBD and placebo on any symptomatic, physiological variable. Conclusions: In healthy volunteers, THC has marked acute behavioural and physiological effects, whereas CBD has proven to be safe and well tolerated.

Cannabis derivatives produce their CNS effect through activation of the endocannabinoid system, a recently discovered signalling system comprising specific receptors, their intrinsic lipid ligands and the associated enzymatic machinery (transporters, biosynthetic and degradative enzymes). This review provides the latest preclinical and clinical breakthroughs on the endocannabinoid system's role in psychotic disorders such as schizophrenia. Data reported so far clearly indicate the presence of a dysregulation in the endocannabinoid system (both in term of cannabinoid receptors and endocannabinoid ligands) in animal models of psychosis as well as in schizophrenic patients. Based on these observations, the pharmacological modulation of the endocannabinoid system has been taken into account as a new therapeutic possibility for psychotic disorders. However, preclinical studies have not provided straightforward results, with both agonists and antagonists exhibiting positive, negative or even no effect. At human level, only cannabidiol, a non psychotropic phytocannabinoid, and the antagonist/inverse agonist rimonabant were tested, however additional controlled trials are required to confirm the therapeutic exploitation of these compounds. Another important aspect in studying the relationship between the endocannabinoid system and schizophrenia is the impact of Cannabis consumption on psychotic disorders, especially when this occurs at vulnerable ages such as adolescence. In fact literature from animal models support adolescence as a highly vulnerable age for the consequences of cannabis exposure on different domains (such as cognition and social behaviour) that are altered in psychotic disorders.

Cannabis is among the most widely used illicit substances. Epidemiological and neuroscientific evidence, though poorly integrated, have established a strong association between cannabis use and increased risk of psychosis. Chronic cannabis use, especially of new synthetic varieties, may trigger psychosis and precipitate schizophrenia in vulnerable individuals. However, the specific pathways by which cannabis affects brain function are unclear. It seems likely that a complex genetic-environmental interaction may underlie the link between cannabis exposure and psychosis onset, with multiple genetic variations and several environmental factors (i.e., trauma or maltreatment during childhood) involved. Also, the possible role of basic symptoms in cannabis users is still not fully acknowledged. Basic symptoms may possibly be a marker for the development of full schizophrenia in cannabis users and their recognition may play a role in prevention strategies. Moreover, the differential impact of different types of cannabis has been generally overlooked and little is known about possible pharmacological treatment approaches (with antipsychotics, cannabis agonists, cannabis antagonists) for cannabis users at risk of psychosis. The aim of the present review is to open this issue with a broad introduction on the clinical and pathophysiological link between cannabis abuse and psychosis onset.

Cannabis is the most prevalent illicit substance used among schizophrenia patients. The effects of cannabis are mediated through the endocannabinoid system, which is a major regulator of neurotransmission and may be disturbed in schizophrenia. Though cognitive impairment in schizophrenia is well established, the effects of cannabis on cognition in schizophrenia patients are still unclear. This paper reviews 19 studies that examine the cognitive effects of cannabis on schizophrenia by comparing cognitive functioning of cannabis-using and non-using schizophrenia patients across a vast range of domains (memory, attention and processing speed, executive functions, visuospatial, psychomotor and language). Of the studies included in the review, 11 reported better cognitive functions among cannabis-using schizophrenia patients compared to non-users, 5 found minimal or no difference between the groups and 3 found poorer cognitive functions among cannabis-using schizophrenia patients compared to non-users. The inconsistencies in the studies reviewed may stem from significant methodological variance between the studies regarding patient selection, adequate controls, cognitive measures used, measures of cannabis use, additional drugs used, and clinical aspects of schizophrenia. These methodological issues are discussed, as well as possible explanations for the results presented and suggestions for future research in this field.

Cannabis use is associated with a spectrum of effects including euphoria, relaxation, anxiety, perceptual alterations, paranoia, and impairments in attention and memory. Cannabis is made up of approximately 80 different cannabinoid compounds, which have synergistic or antagonistic effects on the principle active ingredient in cannabis, delta-9-tetrahydrocannabinol (THC). The net overall effect of cannabis is thought to be related to the ratio of its composite constituents; in particular, the ratio of THC to cannabidiol (CBD). Since cannabinoids induce subjective and cognitive changes that share qualitative similarities with schizophrenia, cannabinoids have been used to model psychosis. Some limitations of cannabinoid models of psychosis include the relatively high variability in experiences between different individuals, the potential for inducing unwanted effects, such as toxic psychosis in study subjects, and the lack of data showing that effective anti-psychotic treatments can reverse the behavioural and cognitive/motor effects of cannabinoids. Nabiximols (Sativex®) is an oromucosal spray containing THC and CBD in an approximate 1:1 ratio. While not extensively studied, most studies confirm that nabiximols, despite the different route of administration and presence of CBD, have similar or slightly reduced subjective/cognitive effects compared to similar doses of oral THC. While the presence of CBD may have utility in some models, it is likely that the concentrations are not high enough to meaningfully affect those aspects important for psychosis research. This review suggests that while it may present an alternative to the use of oral THC, oromucosal nabiximols may not present substantial advantages for use in psychosis research.

Cannabis use is associated with an increased risk for psychotic disorder, yet most cannabis users do not develop psychosis, suggesting that other factors are also involved. This paper reviews the available evidence suggesting that differential sensitivity to the psychosis-inducing effects of cannabis may be related to underlying genetic liability. There is robust evidence that persons at psychometric risk for psychosis are most vulnerable to display psychotic symptoms subsequent to the use of cannabis. Multiple studies have also found that persons at familial risk for psychosis have an increased sensitivity to the effects of cannabis. Together, these findings support the concept of a biological interaction between cannabis use and one's underlying genetic vulnerability. At the molecular-genetic level, however, few (if any) interactions have been consistently replicated, although a reported interaction with variation in AKT1 is promising and deserves further follow-up. The apparent lack of consistent replication can be ascribed to problems of initial gene selection, statistical power, a bias towards positive results and insufficient attempts at true replication, leading to the conclusion that increased sample sizes, greater density of genetic markers and a stronger focus on true replication are necessary. The major challenge for molecular-genetic geneenvironment interaction research will be to combine the agnostic detection of disorder-associated genetic variants from genome-wide studies with the hypothesis-based approach from epidemiological and neurobiological studies. Possible strategies for future cannabis interaction studies are discussed.

Cannabis use may be considered as an additional risk factor in a diathesis-stress model of schizophrenia where the risk of developing the illness would be higher in genetic vulnerable people. In this regard, much of the research on cannabis and psychosis is currently focusing on gene-environment interactions. The present review will focus on the interaction between genes and cannabis exposure in the development of psychotic symptoms and schizophrenia and the biological mechanisms of cannabis. Cannabis use has been shown to act together with other environmental factors such as childhood trauma or urbanicity producing synergistic dopamine sensitization effects. Studies on gene-environment interaction have mainly included genetic variants involved in the regulation of the dopaminergic system. The most promising genetic variants in this field are COMT, CNR1, BDNF, AKT1 and NRG1. Additionally, the interaction with other environmental factors and possible gene-gene interactions are considered in the etiological model.

Background: The relation between cannabis use and psychotic disorders has been investigated extensively. A series of metaanalytic reviews reveal a robust association between cannabis use and the development of psychosis and schizophrenia. However, the actual impact of cannabis use in subjects at high clinical risk for psychosis (CHR) is still unclear. Method: We conducted a systematic review of publications measuring the impact of cannabis use on CHR symptomatology and transition to a first psychotic episode. Results: Of 729 potentially relevant papers, 11 met inclusion criteria. The results of these studies were mixed. In some studies, cannabis use was associated with more severe symptoms at baseline, increased pre-psychotic symptoms immediately after intoxication, and earlier onset of certain high-risk symptoms. In others, no significant association between cannabis use and baseline symptomatology was found. In one study, cannabis use was even significantly associated with a decrease in pre-psychotic negative symptoms, and with fewer symptoms of depression and anxiety. Four out of 5 studies reported no significant effect of cannabis use on transition to psychosis. Conclusions: Cannabis use seems to provoke and enhance subclinical symptoms in CHR subjects. However, the results provide no consistent evidence for an association between cannabis use and transition to a first psychosis in CHR subjects.

Pharmacological challenge in conjunction with neuroimaging techniques has been employed for over two decades now to understand the neural basis of the cognitive, emotional and symptomatic effects of the main ingredients of cannabis, the most widely used illicit drug in the world. This selective critical review focuses on the human neuroimaging studies investigating the effects of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD), the two main cannabinoids of interest present in the extract of the cannabis plant. These studies suggest that consistent with the polymorphic and heterogeneous nature of the effects of cannabis, THC and CBD have distinct and often opposing effects on widely distributed neural networks that include medial temporal and prefrontal cortex and striatum, brain regions that are rich in cannabinoid receptors and implicated in the pathophysiology of psychosis. They help elucidate the neurocognitive mechanisms underlying the acute induction of psychotic symptoms by cannabis and provide mechanistic understanding underlying the potential role of CBD as an anxiolytic and antipsychotic. Although there are ethical and methodological caveats, pharmacological neuroimaging studies such as those reviewed here may not only help model different aspects of the psychopathology of mental disorders such as schizophrenia and offer insights into their underlying mechanisms, but may suggest potentially new therapeutic targets for drug discovery.

A recent meta-analysis showed that the mean age of onset of psychosis among cannabis users was almost three years earlier than that of non-cannabis users. However, because cannabis users usually smoke tobacco, the use of tobacco might independently contribute to the earlier onset of psychosis. We aimed to use meta-analysis to compare the extent to which cannabis and tobacco use are each associated with an earlier age at onset of schizophrenia and other psychoses. We also examined other factors that might have contributed to the finding of an earlier age of onset among cannabis users, including the proportion of males in the samples, the diagnostic inclusion criteria and aspects of study quality. The electronic databases MEDLINE, EMBASE, PsycINFO and ISI Web of Science, were searched for English-language peer-reviewed publications that reported age at onset of schizophrenia and other psychoses separately for cannabis users and non-users, or for tobaccosmokers and non-smokers. Meta-analysis showed that the age at onset of psychosis for cannabis users was 32 months earlier than for cannabis non-users (SMD=- 0.399, 95%CI -0.493 – -0.306, z=-8.34, p<0.001), and was two weeks later in tobacco smokers compared with non-smokers (SMD=0.002, 95%CI -0.094 - 0.097, z=0.03, p=0.974). The main results were not affected by subgroup analyses examining studies of a single sex, the methods for making psychiatric diagnoses and measures of study quality. The results suggest that the association between cannabis use and earlier onset of psychosis is robust and is not the result either of tobacco smoking by cannabis using patients or the other potentially confounding factors we examined. This supports the hypothesis that, in some patients, cannabis use plays a causal role in the development of schizophrenia and raises the possibility of treating schizophrenia with new pharmacological treatments that have an affinity for endo-cannabinoid receptors.

It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms. We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis. Studies with schizophrenia (SCZ) and first episode psychosis (FEP) patients as well as individuals at genetic (GHR) or clinical high risk for psychosis (ARMS) were included. We identified 15 structural magnetic resonance imaging (MRI) (12 cross sectional / 3 longitudinal) and 4 post mortem studies. The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients, 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls. We found evidence for consistent brain structural abnormalities in cannabinoid 1 (CB1) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum. As these effects have not consistently been reported in studies examining nonpsychotic and healthy samples, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure.