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CORK Bibliography: Marijuana and Psychosis

85 citations. January 2012 to present

Prepared: December 2012

Baeza I; Graell M; Moreno D; Castro-Fornieles J; Parellada M; Gonzalez-Pinto A et al. Cannabis use in children and adolescents with first episode psychosis: Influence on psychopathology and short-term outcome (CAFEPS study). Schizophrenia Research 113(2-3): 129-137, 2009. (41 refs.)

Objective: To know the prevalence of substance use and its relationship with psychopathology at onset and after six months in children and adolescents with first episode psychosis (FEP). Method: 110 FEP patients, aged 9-17, were assessed for substance use, and with the Positive and Negative Syndrome Scale (PANSS) and other psychopathological and general functioning scales at baseline and after a six-month follow-up. Results: Patients' substance use at baseline was: tobacco (30.9%), cannabis (29.1%), alcohol (21.8%), cocaine (8.2%), amphetamines (2.7%), LSD (1.8%) and opiates (0.90%). Six months later, there was a decrease in patients' use of cannabis (p = 0.004) and other drugs, except tobacco. Patients were divided, according to their baseline cannabis use, into 32 cannabis users (CU) and 78 non-cannabis users (NCU). CU were older (p = 0.002) and had higher PANSS positive scores (p = 0.002) and lower PANSS negative (p<0.001), PANSS general (p = 0.002) and PANSS total (p = 0.007) scores than NCU. At six months, CU had significantly lower PANSS positive (p = 0.010), negative (p = 0.0001), general (p = 0.002) and total (p = 0.002) scores than NCU. When we divided CU at six months into previous CU (n = 16) and current CU (n = 15), previous CU had the best outcome, NCU the worst and current CU had an intermediate profile. Conclusions: Cannabis use may be related to higher positive symptom scores for FEP patients, with greater improvement after six months for those who cease using cannabis.

Baker AL; Hides L; Lubman DI. Treatment of cannabis use among people with psychotic or depressive disorders: A systematic review. (review). Journal of Clinical Psychiatry 71(3): 247-254, 2010. (36 refs.)

Objective: This article systematically reviews the evidence from randomized controlled trials (RCTs) for pharmacologic and psychological approaches to the treatment of cannabis use among individuals with psychotic or depressive disorders. Data Sources: A systematic literature search was conducted using the Pub Med and PsychINFO data-bases from inception to December 2008. Individual searches in cannabis use (search terms: marijuana, cannabis, marijuana abuse, cannabis abuse, marijuana usage, cannabis usage), mental disorders (search terms: mood disorders, affective disorders, anxiety disorders, anxiety, depressive disorder, depression, psychotic disorders, psychosis, mental disorders), and pharmacotherapy (search terms: medication, drug therapy, pharmacotherapy, psychopharmacology, clinical trials, drug trial, treatment trial) were conducted and limited to humans, adolescents and adults. Study Selection: A search combining the individual cannabis use, mental disorder and pharmacotherapy searches produced 1,713 articles (PubMed = 1,398; PsychINFO = 315). Combining the cannabis use and mental disorder searches while limiting them to English articles and RCTs produced a total of 286 articles (PubMed = 228; PsychINFO = 58). From this literature, there were 7 RCTs conducted among mental health clients that reported cannabis use outcomes using pharmacologic or psychological interventions. Data Synthesis: While few RCTs have been conducted, there is evidence that pharmacologic and psychological interventions are effective for reducing cannabis use in the short-term among people with psychotic disorders or depression. Conclusions: Although it is difficult to make evidence-based treatment recommendations due to the paucity of research in this area, available studies indicate that effectively treating the mental health disorder with standard pharmacotherapy may be associated with a reduction in cannabis use and that longer or more intensive psychological interventions rather than brief interventions may be required, particularly among heavier users of cannabis and those with more chronic mental disorders. Specific recommendations regarding the type and length of specific psychological treatments cannot be made at this time, although motivational interviewing and cognitive-behavioral therapy approaches appear most promising.

Barkus E; Murray RM. Substance use in adolescence and psychosis: Clarifying the relationship. (review). Annual Review of Clinical Psychology 6: 365-389, 2010. (246 refs.)

Adolescence is a time of exploration of the self, and this exploration may involve the use of alcohol and drugs. Sadly, for some, adolescence also marks the first signs of a psychosis. The temporal proximity between the onset of substance use and of psychosis has been the cause of much debate. Here we review the association of alcohol, cannabis, stimulants, and other drugs with psychosis, and we conclude that the use of cannabis and the amphetamines significantly contributes to the risk of psychosis.

Bhattacharyya S; Crippa JA; Allen P; Martin-Santos R; Borgwardt S; Fusar-Poli P et al. Induction of psychosis by delta 9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Archives of General Psychiatry 69(1): 27-36, 2012. (75 refs.)

Context: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. Objective: To examine the effects of Delta 9-tetrahydrocannabinol (Delta 9-THC) and cannabidiol (CBD) on regional brain function during salience processing. Design: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Delta 9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. Setting: University center. Participants: Fifteen healthy men with minimal previous cannabis use. Main Outcome Measures: Symptom ratings, task performance, and regional brain activation. Results: During the processing of oddball stimuli, relative to placebo, Delta 9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Delta 9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Delta 9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Delta 9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. Conclusions: Delta 9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Bossong MG; Niesink RJM. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. (review). Progress in Neurobiology 92(3): 370-385, 2010. (271 refs.)

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Delta 9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose-time-effect relationship should be central.

Buadze A; Stohler R; Schulze B; Schaub M; Liebrenz M. Do patients think cannabis causes schizophrenia? A qualitative study on the causal beliefs of cannabis using patients with schizophrenia. Harm Reduction Journal 7: article 22, 2010. (32 refs.)

Background: There has been a considerable amount of debate among the research community whether cannabis use may cause schizophrenia and whether cannabis use of patients with schizophrenia is associated with earlier and more frequent relapses. Considering that studies exploring patients' view on controversial topics have contributed to our understanding of important clinical issues, it is surprising how little these views have been explored to add to our understanding of the link between cannabis and psychosis. The present study was designed to elucidate whether patients with schizophrenia who use cannabis believe that its use has caused their schizophrenia and to explore these patients other beliefs and perceptions about the effects of the drug. Methods: We recruited ten consecutive patients fulfilling criteria for paranoid schizophrenia and for a harmful use of/dependence from cannabis (ICD-10 F20.0 + F12.1 or F12.2) from the in- and outpatient clinic of the Psychiatric University Hospital Zurich. They were interviewed using qualitative methodology. Furthermore, information on amount, frequency, and effects of use was obtained. A grounded theory approach to data analysis was taken to evaluate findings. Results: None of the patients described a causal link between the use of cannabis and their schizophrenia. Disease models included upbringing under difficult circumstances (5) or use of substances other than cannabis (e. g. hallucinogens, 3). Two patients gave other reasons. Four patients considered cannabis a therapeutic aid and reported that positive effects (reduction of anxiety and tension) prevailed over its possible disadvantages (exacerbation of positive symptoms). Conclusions: Patients with schizophrenia did not establish a causal link between schizophrenia and the use of cannabis. We suggest that clinicians consider our findings in their work with patients suffering from these co-occurring disorders. Withholding treatment or excluding patients from certain treatment settings like day-care facilities or in patient care because of their use of cannabis, may cause additional harm to this already heavily burdened patient group.

Burns JK; Jhazbhay K; Emsley R. Cannabis use predicts shorter duration of untreated psychosis and lower levels of negative symptoms in first-episode psychosis: A South African study. African Journal of Psychiatry 13(5): 395-399, 2010. (27 refs.)

Objective: Cannabis use/abuse is a common co-morbid problem in patients experiencing a first episode of psychotic illness (FEP). The relationship between the clinical presentation of FEP and cannabis abuse is complex and warrants further investigation, especially within the South African context. Method: We tested associations between recent/current cannabis use and duration of untreated psychosis (DUP), age of onset (AO), PANSS-rated (Positive and Negative Syndrome Scale) positive, negative and general psychopathology symptoms and depressive symptoms (Calgary Depression Scale for Schizophrenia) in a sample of 54 patients with FEP. Results: Mean DUP was 34.4 weeks, while mean AO was 24.7 years. Co-morbid cannabis use occurred in 35% of the sample and was significantly associated with shorter DUP (Mann-Whitney U, p=0.026). While not significant, there was also a trend association between cannabis use and lower negative symptoms (Mann-Whitney U, p=0.051). Conclusion: Current/recent cannabis use was associated with clinical features of psychosis onset that previously have been associated with better outcome. Medium and long-term outcome for cannabis users however, is likely to depend on whether or not cannabis use is ongoing.

Carr JAR; Norman RMG; Manchanda R. Substance misuse over the first 18 months of specialized intervention for first episode psychosis. Early Intervention In Psychiatry 3(3): 221-225, 2009. (21 refs.)

Aim: Examine substance misuse over the first 18 months of first-episode psychosis treatment. Method: Clinicians rated alcohol and drug (mostly cannabis) misuse for 243 individuals followed prospectively. Assessments were completed at baseline and after 3, 6 and 18 months. Interventions relating to substance misuse included ongoing assessment of use, education and counselling to avoid. Results: Alcohol and drug misuse declined significantly between baseline and 3 months, especially among patients with a substance abuse or dependence diagnosis at baseline. Overall, these reductions were maintained over the 18-month follow-up period. The exception was worsening alcohol misuse over time among patients with alcohol abuse or dependence on entry. Conclusions: With good usual care, education and support, alcohol and drug misuse declined significantly during the first months of psychosis treatment. The improvements in drug misuse were generally maintained over the 18-month follow-up, and worsening alcohol misuse over time may be the greater issue.

Casadio P; Fernandes C; Murray RM; Di Forti M. Cannabis use in young people: The risk for schizophrenia. (review). Neuroscience and Biobehavioral Reviews 35(8, special isssue): 1779-1787, 2011. (131 refs.)

Cannabis is one of the most commonly used illicit drugs, and despite the widely held belief that it is a safe drug, its long-term use has potentially harmful consequences. To date, the research on the impact of its use has largely been epidemiological in nature and has consistently found that cannabis use is associated with schizophrenia outcomes later in life, even after controlling for several confounding factors. While the majority of users can continue their use without adverse effects, it is clear from studies of psychosis that some individuals are more vulnerable to its effects than others. In addiction, evidence from both epidemiological and animal studies indicates that cannabis use during adolescence carries particular risk. Further studies are warranted given the increase in the concentration of the main active ingredient (Delta(9)-tetrahydrocannabinol) in street preparations of cannabis and a decreasing age of first-time exposure to cannabis.

Cassidy CM; Joober R; King S; Malla AK. Childhood symptoms of inattention-hyperactivity predict cannabis use in first episode psychosis. Schizophrenia Research 132(2-3): 171-176, 2011. (50 refs.)

Background: A history of childhood symptoms of inattention-hyperactivity is often reported in first episode psychosis (FEP) as is cannabis use. In the general population childhood ADHD predicts future cannabis use but the relationship has not been tested in FEP. Method: Parents of patients with a first episode of psychosis (n = 75) retrospectively assessed their affected child for symptoms of early-life disorders, namely, attention deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) using the Child Behaviour Checklist (CBCL). Assessments were made prospectively of cannabis use over two years following a FEP and of SCID diagnosis of cannabis-use disorder. Results: Childhood hyperactivity-inattention symptoms predicted inability to maintain abstinence from cannabis following treatment (Wald = 8.4, p = .004) and lifetime cannabis-use diagnosis (Wald = 5.3, p = .022) in a logistic regression controlling for relevant covariates including symptoms of CD and ODD from ages 12 to 18. When the symptom of inattention was considered in place of the hyperactivity-inattention syndrome it predicted cannabis-use diagnosis (Wald = 6.4, p = .011) and persistent abstinence from cannabis (Wald = 5.3, p = .021). Symptoms of CD and ODD did not predict cannabis use when hyperactivity-inattention symptoms were controlled for. Conclusions: Symptoms of childhood inattention-hyperactivity predict subsequent cannabis use in FEP.

Cassidy CM; Lepage M; Harvey PO; Malla A. Cannabis use and anticipatory pleasure as reported by subjects with early psychosis and community controls. Schizophrenia Research 137(1-3): 39-44, 2012. (50 refs.)

Background: There is evidence of decreased pleasure and deficits in the anticipation of reward in both psychotic illness and drug addiction. Individuals with low anticipatory pleasure may preferentially engage in behaviours associated with immediate reward such as cannabis use. Method: Ninety-one psychosis patients and 91 controls without history of psychosis were administered the Temporal Experience of Pleasure Scale (TEPS), a self report which measures anticipatory and consummatory pleasure. Cannabis use diagnosis was assessed using the Structured Clinical Interview for DSM IV (SCID). Subjects reported the frequency of cannabis consumption and time since last use. Results: Patients did not show a significant deficit in anticipatory or consummatory pleasure compared to controls; however, patients with an active cannabis-use disorder tended to have lower consummatory pleasure than controls with active cannabis disorder (p<.05). Patients who continued to use cannabis during treatment of their first episode of psychosis reported significantly lower anticipatory pleasure compared to those who had a lifetime cannabis diagnosis but were able to maintain abstinence (F(1,60) = 5.6, p =. 021). Frequency of cannabis use was negatively correlated to anticipatory and consummatory pleasure (Pearson R = -.46, -.48 respectively) in 37 patients currently using cannabis but not in 46 cannabis-using controls (partial R = -.04, -.07 respectively). Conclusion: Anticipatory pleasure may not be decreased in early psychosis patients. Lower hedonic response may be associated with persistent, heavy cannabis use in patients in the early phase of psychotic disorders.

Castle D; Murray RM; D'Souza DC. Marijuana and Madness, 2nd edition. Cambridge: Cambridge University Press, 2011. (5 refs.)

This second edition of an award-winning text provides a comprehensive overview of the psychiatry and neuroscience of Cannabis sativa (marijuana). It describes the research of the human cannabinoid system, and links this knowledge to clinical and epidemiological facts about the impact of cannabis on mental health. Clinically focused chapters review not only the direct psychomimetic properties of cannabis, but also the impact consumption has on the courses of evolving or established mental illnesses such as schizophrenia. With 44 contributors, the book is organized in 8 parties. Part I focuses upon the pharmacology of cannabis and the endocannabinoid system. Part II considers the "changing face" of cannabis, including chapters on epidemiology of use from an international perspective; examination of whether cannabis is become more potent; and cannabis-related health policy. Part III addresses cannabis and the brain, in three chapters dealing with the impact of cannabis and endocannabinoids on neurodevelopment; the impact of pbertal exposure, with insights from animal studies; the effects on cognition; and long-term impact on the brain. Part IV deals with cannabis, anxiety and mood, with chapters on acute and subacute psychiatric effects; the association with depression; the association with bipolar disorder. Part V considers the relationship of cannabis with psychosis. Separate chapters deal with the relationship of cannabis and proneness to psychosis; genetic factors that moderate the psychomimetic effects; its production of positive, negative and cognitive symptoms; and the neural basis for the acute effects. Part VI addresses cannabinoids and schizophrenia, it's role in etiology and treatment implications; post-mortum studies; the endogenous cannabinoid system in schizophrenia and as a target for drug therapies. Part VII focuses upon the impact of cannabis on schizophrenia, addressing the acute effects in established schizophrenia; motives that maintain use in schizophrenia; the implications of use for long-term course of schizophrenia; and clinical interventions. Part VIII provides a summary and integrates the material presented.

Clutterbuck R; Tobin D; Orford J; Copello A; Preece M; Birchwood M et al. Exploring the attitudes of staff working within mental health settings toward clients who use cannabis. Drugs: Education, Prevention and Policy 16(4): 311-327, 2009. (39 refs.)

Aims: This study aimed to explore the attitudes of staff working within mental health settings toward cannabis in general and cannabis use in individuals with severe mental-health problems. Method: Twenty members of staff working within community mental health teams in Birmingham, UK, were interviewed using qualitative research methods. The overarching themes within the staff accounts are described and the interrelationship between themes explored. Findings: Staff use an 'individualized' approach when working with cannabis-using clients dependent on a number of key components, including the positive and negative effects of use, wider evidence base, client vulnerability, engagement, professional and personal views and harm reduction. It is suggested that any approach staff may take toward cannabis use at any one time is greatly dependent upon the above factors and these factors are highly client specific. Conclusions: The findings may help to explain why interventions aimed at reducing substance use in people with psychosis might prove less successful when targeting cannabis use.

Compton MT; Broussard B; Ramsay CE; Stewart T. Pre-illness cannabis use and the early course of nonaffective psychotic disorders: Associations with premorbid functioning, the prodrome, and mode of onset of psychosis. Schizophrenia Research 126(1-3): 71-76, 2011. (47 refs.)

Introduction: Limited research indicates that pre-illness cannabis use may result in an earlier age at onset of psychosis, though little is known about the influence of prior cannabis use on the premorbid and prodromal phases. This study examined the effects of prior or concurrent cannabis (as well as nicotine and alcohol) use on: (1) early adolescent (12-15 years) premorbid functioning, (2) late adolescent (16-18 years) premorbid functioning, (3) two features of the prodrome, and (4) mode of onset of psychosis. Methods: Participants included 109 well-characterized first-episode patients hospitalized in public-sector settings. Assessments included ages at initiation of first, weekly, and daily use of substances, the Premorbid Adjustment Scale, the Symptom Onset in Schizophrenia inventory, and a consensus-based best estimate of mode of onset. Results: Participants having used cannabis at <= 15 years had better early adolescence social functioning than those who had not used cannabis (p = 0.02). Conversely, those who had used cannabis at <= 18 years had poorer late adolescence academic functioning (p < 0.001). Participants having used cannabis before onset of psychotic symptoms did not differ from those who had not in terms of having had an identifiable prodrome or the number of prodromal symptoms experienced. Whereas 42% of those having used cannabis daily had an acute mode of onset of psychosis, only 20% of those without prior daily cannabis use had an acute onset (p = 0.04). Conclusions: Findings suggest that cannabis use is associated with premorbid social and academic functioning and mode of onset. Further research is warranted to elucidate the complex associations between cannabis use and diverse early-course features.

Compton MT; Kelley ME; Ramsay CE; Pringle M; Goulding SM; Esterberg ML et al. Association of pre-onset cannabis, alcohol, and tobacco use with age at onset of prodrome and age at onset of psychosis in first-episode patients. American Journal of Psychiatry 166(11): 1251-1257, 2009. (57 refs.)

Objective: Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, although not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use, alcohol use, and tobacco use are associated with an earlier age at onset of prodromal and psychotic symptoms. Effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses. Method: First-episode patients (N=109) hospitalized in three public-sector inpatient psychiatric units underwent in-depth cross-sectional retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined by standardized methods, and analyses were conducted using Cox regression modeling. Results: Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness or prodromal symptoms was the outcome. A gender-by-daily-cannabisuse interaction was observed; progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males. Conclusions: Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.

Crippa JAS; Derenusson GN; Chagas MHN; Atakan Z; Martin-Santos R; Zuardi AW et al. Pharmacological interventions in the treatment of the acute effects of cannabis: A systematic review of literature. (review). Harm Reduction Journal 9: e-article 7, 2012. (55 refs.)

Background: Cannabis intoxication is related to a number of physical and mental health risks with ensuing social costs. However, little attention has been given to the investigation of possible pharmacological interactions in this condition. Objective: To review the available scientific literature concerning pharmacological interventions for the treatment of the acute effects of cannabis. Methods: A search was performed on the PubMedicine, Lilacs, and Scielo online databases by combining the terms cannabis, intoxication, psychosis, anxiety, and treatment. The articles selected from this search had their reference lists checked for additional publications related to the topic of the review. Results: The reviewed articles consisted of case reports and controlled clinical trials and are presented according to interventions targeting the physiological, psychiatric, and cognitive symptoms provoked by cannabis. The pharmacological interventions reported in these studies include: beta-blockers, antiarrhythmic agents, antagonists of CB 1 and GABA benzodiazepine receptors, antipsychotics, and cannabidiol. Conclusion: Although scarce, the evidence on pharmacological interventions for the management of cannabis intoxication suggests that propanolol and rimonabant are the most effective compounds currently available to treat the physiological and subjective effects of the drug. Further studies are necessary to establish the real effectiveness of these two medications, as well as the effectiveness of other candidate compounds to counteract the effects of cannabis intoxication, such as cannabidiol and flumazenil.

de la Serna E; Mayoral M; Baeza I; Arango C; Andres P; Bombin I et al. Cognitive functioning in children and adolescents in their first episode of psychosis differences between previous cannabis users and nonusers. Journal of Nervous and Mental Disease 198(2): 159-162, 2010. (19 refs.)

To investigate the relationship between cognition and prior cannabis use in children and adolescents presenting a first episode of psychosis. A total of 107 patients with first episode of psychosis and 96 healthy controls, aged 9 to 17 years, were interviewed about their previous substance use and to assess their cognitive functions. Patients were assessed while not using cannabis by means of a comprehensive neuropsychological battery. They were divided into 2 groups depending on the history of prior cannabis use: cannabis users (CU) and cannabis nonusers (CNU). Significant differences were found in all areas evaluated between the 3 groups. Both CU and CNU patients obtained lower scores than controls on verbal learning and memory and working memory. Patients with prior cannabis use performed better on some tests of attention (Continuous performance test (CPT) number of correct responses, p = 0.002; CPT average reaction time, p < 0.001) and executive functions (Trail Making Test, part B (TMT-B) number of mistakes, p < 0.001; Wisconsin Card Sorting Test (WCST) number of categories completed, p < 0.001) than CNU patients. CU patients performed better than CNU subjects on some cognitive measures. This may indicate lower individual vulnerability for psychosis in CU patients in whom cannabis use can be a precipitating factor of psychotic episodes.

Degenhardt L; Hall WD; Lynskey M; McGrath J; McLaren J; Calabria B et al. Should burden of disease estimates include cannabis use as a risk factor for psychosis? PLoS Medicine 6(9): e1000133, 2009. (66 refs.)

Comparative risk assessments estimate the proportion of a disease that can be attributed to a particular risk exposure and are important guides for health planning. In observational studies, there has been consistent evidence that cannabis use is associated with an increased risk of schizophrenia and more generally, psychosis. There is debate about whether such observational evidence is sufficient to infer that cannabis use is a contributory cause of psychosis. Given the controversy, should the comparative risk assessment in the current revision of the Global Burden of Disease (GBD) include an attribution of psychosis to cannabis use? We argue that the risk assessment should be included because the evidence is as good as that for many other risk factors included in the GBD, psychotic disorders are associated with substantial unavertable disability, and cannabis use is a potentially preventable exposure.

Dekker N; Meijer J; Koeter M; van den Brink W; van Beveren N; Kahn RS et al. Age at onset of non-affective psychosis in relation to cannabis use, other drug use and gender. Psychological Medicine 42(9): 1903-1911, 2012. (44 refs.)

Background. Cannabis use is associated with an earlier age at onset of psychotic illness. The aim of the present study was to examine whether this association is confounded by gender or other substance use in a large cohort of patients with a non-affective psychotic disorder. Method. In 785 patients with a non-affective psychotic disorder, regression analysis was used to investigate the independent effects of gender, cannabis use and other drug use on age at onset of first psychosis. Results. Age at onset was 1.8 years earlier in cannabis users compared to non-users, controlling for gender and other possible confounders. Use of other drugs did not have an additional effect on age at onset when cannabis use was taken into account. In 63.5% of cannabis-using patients, age at most intense cannabis use preceded the age at onset of first psychosis. In males, the mean age at onset was 1.3 years lower than in females, controlling for cannabis use and other confounders. Conclusions. Cannabis use and gender are independently associated with an earlier onset of psychotic illness. Our findings also suggest that cannabis use may precipitate psychosis. More research is needed to clarify the neurobiological factors that make people vulnerable to this precipitating effect of cannabis.

Dragt S; Nieman DH; Becker HE; van de Fliert R; Dingemans PM; de Haan L et al. Age of onset of cannabis use is associated with age of onset of high-risk symptoms for psychosis. Canadian Journal of Psychiatry 55(3): 165-171, 2010. (31 refs.)

Objective: Increasing interest in the prodromal stage of schizophrenia over the past decade led us to perform our study to monitor people at high risk for developing a psychosis. We hypothesized that cannabis use or a cannabis use disorder at a younger age relates to high-risk symptoms at a younger age. Method: People referred to the Academic Medical Centre in Amsterdam, the Netherlands, with an ultra-high risk (UHR) for psychosis were interviewed with the Composite International Diagnostic Interview to assess their cannabis consumption. The Interview for the Retrospective Assessment of the Onset of Schizophrenia was used to collect data about age of onset of high-risk or prodromal symptoms. Nine high-risk symptoms were selected and clustered because of their known relation with cannabis use. Results: Among the 68 included participants, 35 had used cannabis (51.5%), of whom 15 had used recently. Twenty-two participants had been cannabis abusers or cannabis-dependent (32.4%) in the past. Younger age at onset of cannabis use was related to younger age of onset of the cluster of symptoms (rho = 0.48, P = 0.003) and also to 6 symptoms individually (rho = 0.47 to 0.90, P < 0.001 to 0.04). Younger age at onset of a cannabis use disorder was related to younger age of onset of the cluster of symptoms (rho = 0.67, P = 0.001) and also to 6 symptoms individually (rho = 0.50 to 0.93, P = 0.007 to 0.03). Conclusion: Cannabis use or a cannabis use disorder at a younger age in a group with an UHR for transition to psychosis is related to onset of high-risk symptoms for psychosis at a younger age.

Dragt S; Nieman DH; Schultze-Lutter F; van der Meer F; Becker H; de Haan L et al. Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Acta Psychiatrica Scandinavica 125(1): 45-53, 2012. (43 refs.)

Objective: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early ( or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high-risk symptoms in subjects at clinical high risk for psychosis. Method: Prospective multicenter, naturalistic field study with an 18-month follow-up period in 245 help-seeking individuals clinically at high risk. The Composite International Diagnostic Interview was used to assess their cannabis use. Age at onset of high risk or certain early symptoms was assessed retrospectively with the Interview for the Retrospective Assessment of the Onset of Schizophrenia. Results: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r(s) < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. Conclusion: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals. Cannabis use in early adolescence should be discouraged.

Every-Palmer S. Synthetic cannabinoid JWH-018 and psychosis: An explorative study. Drug and Alcohol Dependence 117(2-3): 152-157, 2011. (53 refs.)

Background: Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms. Method: This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service. Results: All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms. Conclusion: It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids.

Fattore L; Fratta W. Beyond THC: The new generation of cannabinoid designer drugs. Frontiers in Behavioral Neuroscience 5: 60, 2011

Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC), the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in "head shops" under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as "Spice drugs" or "legal highs") do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis, and death have been recently reported after consumption, posing difficult social, political, and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naive individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology, and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a "dog chasing its tail" situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

Foti DJ; Kotov R; Guey LT; Bromet EJ. Cannabis use and the course of schizophrenia: 10-year follow-up after first hospitalitalization. American Journal of Psychiatry 167(8): 987-993, 2010. (40 refs.)

Objective: The authors examined the relationship between cannabis use and the course of illness in schizophrenia over 10 years of follow-up after first psychiatric hospitalization. Method: The authors assessed 229 patient S with a schizophrenia spectrum disorder five times: during the first admission and 6 months, 2 years, 4 years, and 10 years later. Ratings of cannabis use and psychiatric symptoms (psychotic, negative, disorganized, and depressive) were made at each assessment. Results: The lifetime rate of cannabis use was 66.2%, and survival analysis revealed that lifetime use was associated with an earlier onset of psychosis. The rates of current use ranged from 10% to 18% across assessments. Cannabis status was moderately stable, with tetrachoric correlation coefficients between waves ranging from 0.48 to 0.78. Mixed-effects logistic regression revealed that changes in cannabis use were associated with changes in psychotic symptoms over time even after gender, age, socioeconomic status, other drug use, antipsychotic medication use, and other symptoms were controlled for. Structural equation modeling indicated that the association with psychotic symptoms was bidirectional. Conclusions: Cannabis use is associated with an adverse course of psychotic symptoms in schizophrenia, and vice versa, even after taking into account other clinical, substance use, and demographic variables.

Galvez-Buccollini JA; Proal AC; Tomaselli V; Trachtenberg M; Coconcea C; Chun J et al. Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis. Schizophrenia Research 139(1-3): 157-160, 2012. (14 refs.)

Introduction: Several studies have associated cannabis use with the development of schizophrenia. However, it has been difficult to disentangle the effects of cannabis from that of other illicit drugs, as previous studies have not evaluated pure cannabis users. To test whether the onset of cannabis use had an effect on the initiation of psychosis, we examined the time relationship between onset of use and onset of psychosis, restricting our analysis to a cohort of individuals who only used cannabis and no other street drugs. Methods: Fifty-seven subjects with non-affective psychoses who used cannabis prior to developing a psychosis were interviewed using the Diagnostic Interview for Genetic Studies (DIGS). The Family Interview for Genetic Studies (FIGS) was also used to interview a family informant about psychiatric illness in the patient and the entire family. Multiple linear regression techniques were used to estimate the association between variables. Results: After adjusting for potential confounding factors such as sex, age, lifetime diagnosis of alcohol abuse or dependence, and family history of schizophrenia, the age at onset of cannabis was significantly associated with age at onset of psychosis (beta=0.4, 95% CI=0.1-0.7, p=0.004) and age at first hospitalization (beta=0.4, 95% CI=0.1-0.8, p=0.008). The mean time between beginning to use cannabis and onset of psychosis was 7.0 +/- 4.3. Age at onset of alcohol use was not associated with age at onset of psychosis or age at first hospitalization. Conclusion: Age at onset of cannabis is directly associated with age at onset of psychosis and age at first hospitalization. These associations remain significant after adjusting for potential confounding factors and are consistent with the hypothesis that cannabis could cause or precipitate the onset of psychosis after a prolonged period of time.

Goldberger C; Dervaux A; Gourion D; Bourdel MC; Loo H; Laqueille X et al. Variable individual sensitivity to cannabis in patients with schizophrenia. International Journal of Neuropsychopharmacology 13(9): 1145-1154, 2010. (54 refs.)

There is now compelling evidence that cannabis consumption might precipitate psychosis onset. The objective of the present study was to assess the role of individual sensitivity to the psychotogenic effect of cannabis in male patients with schizophrenia. The lifetime diagnosis, disease and substance-use history were determined using a standardized interview in 190 patients with schizophrenia. Of patients with lifetime cannabis use (n=121), 44 were characterized as Cannabis-sensitive (CS) patients if the onset of psychotic symptoms occurred within 1 month following the initiation of cannabis consumption, or following a marked rise of cannabis consumption, or marked aggravation of psychotic symptoms each time the subject used cannabis. Age at onset of psychosis was not different in patients with lifetime cannabis use compared to non-users. By contrast, the first psychotic episode occurred 2.6 yr earlier in CS compared to Non-cannabis-sensitive (NCS) patients (p=0.006). Moreover, a specific excess of family history of psychotic disorder was found in CS patients, but not of any other psychiatric disorder, as well as an earlier age at exposure to cannabis (16.7 +/- 2.5 yr, p=0.03). Sensitivity to psychotogenic effects of cannabis in schizophrenia patients could be related to both genetic vulnerability to schizophrenia and the influence of cannabis on brain maturation and could modulate the influence of cannabis on the onset of schizophrenia.

Gunderson EW; Haughey HM; Ait-Daoud N; Joshi AS; Hart CL. "Spice" and "K2" herbal highs: A case series and systematic review of the clinical effects and biopsychosocial implications of synthetic cannabinoid use in humans. (review). American Journal on Addictions 21(4): 320-326, 2012. (39 refs.)

Cannabis, the most commonly used illicit substance, exerts its primary psychoactive effect via delta-9 tetrahydrocannabinol (Delta(9)-THC) agonism of cannabinoid receptor type 1 (CB1). Some users develop a cannabis use disorder and physical dependence manifested by withdrawal symptoms during abstinence. Hence, there is growing public health concern about increasing use of a new generation of synthetic cannabinoid (SC) agonists (eg, JWH-018, CP 47,497) marketed as natural herbal incense mixtures under brand names such as "Spice" and "K2." Anecdotal reports suggest overlapping effects with marijuana when the mixtures are smoked, however, systematic evaluation of SC-related psychoactive properties and adverse effects is lacking. We conducted a systematic review of published reports on SC clinical effects in humans. Most highlight potential toxicity such as acute anxiety and psychosis. In addition, we carefully document three cases in which experienced marijuana users meeting criteria for cannabis dependence with physiologic dependence smoked SC products regularly. The SC mixture effects were reportedly similar to marijuana and well tolerated. The individuals all reported that SC product use effectively alleviated cannabis withdrawal. Biopsychosocial factors associated with SC initiation and usage by the cases help to shed light on psychopharmacologic, clinical, and public health aspects of SC product consumption.

Hall W. Does a lack of specificity rule out a causal relationship between cannabis use and schizophrenia? (editorial). Addiction Research & Theory 18(6): 606-608, 2010. (10 refs.)

In this article, the author discusses a study on the causal relationship between cannabis use and schizophrenia. He stresses that cannabis use cannot be a contributory cause of psychoses because the same type of evidence also exists for a causal relationship between cigarette smoking and psychosis. He emphasizes that the argument that a contributory causal role for cannabis in psychosis is weakened because tobacco smoking satisfies many of the same criteria for casual inference as cannabis use.

Harley M; Kelleher I; Clarke M; Lynch F; Arseneault L; Connor D et al. Cannabis use and childhood trauma interact additively to increase the risk of psychotic symptoms in adolescence. Psychological Medicine 40(10): 1627-1634, 2010. (54 refs.)

Background. Adolescent cannabis use has been shown in many studies to increase the risk of later psychosis. Childhood trauma is associated with both substance misuse and risk for psychosis. In this study our aim was to investigate whether there is a significant interaction between cannabis use and childhood trauma in increasing the risk for experiencing psychotic symptoms during adolescence. Method. Psychiatric interviews using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) semi-structured instrument were carried out with 211 adolescents aged between 12 and 15 years and their parents as part of a population-based study. The interview enquired about early traumatic events, cannabis use and psychiatric symptoms in adolescence. Results. In separate analyses both cannabis use and childhood trauma were significantly associated with risk of experiencing psychotic symptoms. However, the presence of both childhood trauma and early cannabis use significantly increased the risk for psychotic symptoms beyond the risk posed by either risk factor alone, indicating that there was a greater than additive interaction between childhood trauma and cannabis use. Conclusion. Our finding of a greater than additive interaction between childhood trauma and cannabis use may have implications for the identification of individuals at high risk of experiencing psychotic symptoms. For example, measures to actively discourage or intensively treat cannabis use in children and adolescents who have experienced abuse may help to prevent the development of psychosis in this vulnerable group. Our findings require replication in larger samples to confirm this interaction effect.

Henquet C; van Os J; Kuepper R; Delespaul P; Smits M; Campo JA et al. Psychosis reactivity to cannabis use in daily life: An experience sampling study. British Journal of Psychiatry 196(6): 447-453, 2010. (47 refs.)

Background: Little is known about the experiential dynamics of the interaction between cannabis and vulnerability to psychosis. Aims To examine the effects of cannabis on psychotic symptoms and mood in patients with psychosis and healthy controls. Method: Patients with a psychotic disorder (n = 42) and healthy controls (n = 38) were followed in their daily lives using a structured time-sampling technique. Results Daily life cannabis use predicted subsequent increases in positive affect and in patients, but not in controls, decreases in negative affect. In patients, but not in controls, cannabis use predicted increased levels of hallucinatory experiences. Mood-enhancing properties of cannabis were acute, whereas psychosis-inducing effects were sub-acute. There was no direct evidence for self-medication effects in daily life. Conclusions: Patients with psychosis are more sensitive to both the psychosis-inducing and mood-enhancing effects of cannabis. The temporal dissociation between acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the vicious circle of deleterious use in these patients.

Hickman M; Vickerman P; Macleod J; Lewis G; Zammit S; Kirkbride J et al. If cannabis caused schizophrenia: How many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction 104(11): 1856-1861, 2009. (24 refs.)

Background: We consider how many cannabis users may need to be prevented in order to prevent one case of schizophrenia or psychosis [defined as number needed to prevent (NNP)]. Method: Calculation for England and Wales using best available estimates of: incidence of schizophrenia; rates of heavy and light cannabis use; and risk that cannabis causes schizophrenia. Results: In men the annual mean NNP for heavy cannabis and schizophrenia ranged from 2800 [90% confidence interval (CI) 2018-4530] in those aged 20-24 years to 4700 (90% CI 3114-8416) in those aged 35-39. In women, mean NNP for heavy cannabis use and schizophrenia ranged from 5470 (90% CI 3640-9839) in those aged 25-29 to 10 870 (90% CI 6786-22 732) in 35-39-year-olds. Equivalent mean NNP for heavy cannabis use and psychosis were lower, from 1360 (90% CI 1007-2124) in men aged 20-24 and 2480 (90% CI 1408-3518) in women aged 16-19. The mean and median number of light cannabis users that would need to be prevented in order to prevent one case of schizophrenia or psychosis per year are four to five times greater than among heavy users. Conclusions: The number of young people who need to be exposed to an intervention to generate NNP and prevent one case of schizophrenia will be even larger. The public health importance of preventing cannabis to reduce schizophrenia or psychosis remains uncertain. More attention should be given to testing the hypothesis that cannabis is related causally to psychotic outcomes, and to considering what strategies will be the most effective in reducing heavy cannabis use among young people.

Hides L; Cotton SM; Berger G; Gleeson J; O'Donnell C; Proffitt T et al. The reliability and validity of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in first-episode psychosis. Addictive Behaviors 34(10, Special Issue): 821-825, 2009. (30 refs.)

Aims: The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is a brief, easily administered, valid and reliable screening instrument for all psychoactive substances in drug treatment and primary care settings. This study aims to determine the reliability and validity of the ASSIST for detecting substance use disorders in first-episode psychosis. Participants: Participants were 214 first-episode psychosis patients attending the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia. Measurements: Participants were administered the ASSIST. Alcohol Use Disorders Identification Test (AUDIT), the Severity of Dependence Scale (SDS) and the Brief Psychiatric Rating Scale (BPRS). Presence of DSM-IV Substance abuse and dependence disorders in the previous 12 months was assessed using the Structured Clinical Interview for DSM-IV (SCID-W). Findings: The ASSIST total substance involvement (TSI) score and Specific Substance involvement (SSI) scores for cannabis, alcohol and amphetamine use demonstrated high levels of internal consistency and acceptable levels of concurrent and discriminative validity. Individuals with cutoff scores of 2, 4 and I on the ASSIST cannabis, alcohol and amphetamine SSI scores were 5 to 6 times more likely to meet the diagnostic criteria for these Substance use disorders. Conclusions: The ASSIST is a psychometrically sound measure of cannabis, alcohol and amphetamine use disorders in first-episode psychosis.

Hides L; Kavanagh DJ; Dawe S; Young RM. The influence of cannabis use expectancies on cannabis use and psychotic symptoms in psychosis. Drug and Alcohol Review 28(3): 250-256, 2009. (43 refs.)

Introduction and Aims. Little is known about motives or expectancies for cannabis use in psychotic populations, despite these cognitive factors being a central focus of the treatment for substance misuse in psychosis. This study examined the relationship between cannabis use expectancies, cannabis use and psychotic symptoms among cannabis using psychotic inpatients. A secondary aim was to determine if there were significant differences in the cannabis use expectancies of psychotic patients with and without Diagnostic and Statistical Manual version IV (DSM-IV) cannabis dependence. Design and Methods. Participants consisted of 101 in-patients with psychosis who had used cannabis more than five times in the past year. Expectancies were assessed using the Cannabis Expectancy Questionnaire (CEQ). The frequency of cannabis use, severity of cannabis dependence, presence of DSM-IV cannabis dependence and severity of psychotic symptoms were also assessed using standardised measures. Results and Conclusions. Results suggested that cannabis use expectancies were associated with cannabis use but not symptom variables. Expectances for cannabis use predicted recent cannabis use and the presence and severity of cannabis dependence. Psychotic patients with DSM-IV cannabis dependence had significantly higher expectancies for negative effects from cannabis use. Prospective research examining the influence of motives and expectancies for cannabis use on cannabis use and psychotic symptoms is required to obtain a greater understanding of substance use in psychosis and assist with the development of innovative treatment interventions.

Hjorthoj CR; Fohlmann A; Larsen AM; Arendt M; Nordentoft M. Correlations and agreement between delta-9-tetrahydrocannabinol (THC) in blood plasma and timeline follow-back (TLFB)-assisted self-reported use of cannabis of patients with cannabis use disorder and psychotic illness attending the CapOpus randomized clinical trial. Addiction 107(6): 1123-1131, 2012. (37 refs.)

Aims: To assess correlations and agreement between timeline follow-back (TLFB)-assisted self-report and blood samples for cannabis use. Design Secondary analysis of a randomized trial. Setting Copenhagen, Denmark. Participants One hundred and three patients from the CapOpus trial with cannabis use disorder and psychosis, providing 239 self-reports of cannabis use and 88 valid blood samples. Measurements: Delta-9-tetrahydrocannabinol (THC), 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) detected in plasma using high-performance liquid chromatography with tandem mass spectrometry detection. Self-report of cannabis-use last month by TLFB. Pearson's r, sensitivity and specificity calculated as measures of correlation or agreement. Findings: Correlations were strong; r = 0.75 for number of days and r = 0.83 for number of standard joints in the preceding month when excluding outliers. Including outliers, coefficients were moderate to strong (r = 0.49). There were differences in subgroups, mainly inconsistent, depending on inclusion or exclusion of outliers. Sensitivity and specificity for TLFB detecting the presence or absence of cannabis use were 95.7% [95% confidence interval (CI) 88.099.1%) and 72.2% (95% CI 46.590.3%), respectively. Using 19 days as cut-off on TLFB, they were 94.3% (95% CI 86.098.4%) and 94.4% (95% CI 72.299.9%), respectively. Area under the receiver operating characteristic (ROC) curve was 0.96. Conclusions: Timeline follow-back (TLFB)-assisted self-report of cannabis use correlates highly with plasma-delta-9-tetrahydrocannabinol in patients with comorbid cannabis use disorder and psychosis. Sensitivity and specificity of timeline follow-back appear to be optimized with 19 days as the cut-off point. As such, timeline follow-back may be superior to analysis of blood when going beyond 19 days of recall.

Houston JE; Murphy J; Shevlin M; Adamson G. Cannabis use and psychosis: Re-visiting the role of childhood trauma. Psychological Medicine 41(11): 2339-2348, 2011. (54 refs.)

Background. Cannabis consumption continues to be identified as a causal agent in the onset and development of psychosis. However, recent findings have shown that the effect of cannabis on psychosis may be moderated by childhood traumatic experiences. Method. Using hierarchical multivariate logistic analyses the current study examined both the independent effect of cannabis consumption on psychosis diagnosis and the combined effect of cannabis consumption and childhood sexual abuse on psychosis diagnosis using data from the Adult Psychiatric Morbidity Survey 2007 (n=7403). Results. Findings suggested that cannabis consumption was predictive of psychosis diagnosis in a bivariate model; however, when estimated within a multivariate model that included childhood sexual abuse, the effect of cannabis use was attenuated and was not statistically significant. The multivariate analysis revealed that those who had experienced non-consensual sex in childhood were over six times [odds ratio (OR) 6.10] more likely to have had a diagnosis of psychosis compared with those who had not experienced this trauma. There was also a significant interaction. Individuals with a history of non-consensual sexual experience and cannabis consumption were over seven times more likely (OR 7.84) to have been diagnosed with psychosis compared with those without these experiences; however, this finding must be interpreted with caution as it emerged within an overall analytical step which was non-significant. Conclusions. Future studies examining the effect of cannabis consumption on psychosis should adjust analyses for childhood trauma. Childhood trauma may advance existing gene-environment conceptualisations of the cannabis-psychosis link.

Johnson LA; Johnson RL; Alfonzo C. Spice: A legal marijuana equivalent. Military Medicine 176(6): 718-720, 2011. (21 refs.)

Spice, an herbal mixture containing synthetic cannabinoids, is a legal drug increasingly abused by adolescents and young adults for its narcotic-like effects. A paucity of English language literature exists on the clinical effects of Spice use. A case report of substance-induced psychosis and a summary of available literature follows later.

Kahn RS; Linszen DH; van Os J; Wiersma D; Bruggeman R; Cahn W et al. Evidence that familial liability for psychosis is expressed as differential sensitivity to cannabis an analysis of patient-sibling and sibling-control pairs. Archives of General Psychiatry 68(2): 138-147, 2011. (61 refs.)

Context: Individual differences in cannabis sensitivity may be associated with genetic risk for psychotic disorder. Objectives: To demonstrate and replicate, using 2 conceptually different genetic epidemiological designs, that (familial) liability to psychosis is associated with sensitivity to cannabis. Design, Setting, and Participants: Sibling-control and cross-sibling comparisons using samples of patients with a psychotic disorder (n=1120), their siblings (n=1057), and community controls (n=590) in the Netherlands and Flanders. Main Outcome Measures: Positive and negative schizotypy using the Structured Interview for Schizotypy-Revised (for siblings and controls) and self-reported positive and negative psychotic experiences using the Community Assessment of Psychic Experiences (for siblings and patients). Cannabis use was assessed as current use (by urinalysis) and lifetime frequency of use (by Composite International Diagnostic Interview). Results: In the sibling-control comparison, siblings displayed more than 15 times greater sensitivity to positive schizotypy associated with particularly current cannabis use by urinalysis (adjusted B=0.197, P<.001) than controls (adjusted B=0.013, P=.86) (P interaction=.04) and a similar difference in sensitivity to its effect on negative schizotypy (siblings: adjusted B=0.120, P<.001; controls: B=-0.008, P=.87; P interaction=.03). Similarly, siblings exposed to cannabis resembled their patient relative nearly 10 times more closely in the positive psychotic dimension of the Community Assessment of Psychic Experiences (adjusted B=0.278, P<.001) compared with nonexposed siblings (adjusted B=0.025, P=.12) (P interaction<.001). No significant effect was apparent for the Community Assessment of Psychic Experiences negative domain, although the association was directionally similar (2 times more resemblance; P interaction=.17). Crosssibling, cross-trait analyses suggested that the mechanism underlying these findings was moderation (familial risk increasing sensitivity to cannabis) rather than mediation (familial risk increasing use of cannabis). Conclusions: Genetic risk for psychotic disorder may be expressed in part as sensitivity to the psychotomimetic effect of cannabis. Cannabis use may synergistically combine with preexisting psychosis liability to cause positive and negative symptoms of psychosis.

Khan MK; Usmani MA; Hanif SA. A case of self amputation of penis by cannabis induced psychosis. Journal of Forensic and Legal Medicine 19(6): 355-357, 2012. (14 refs.)

Self-mutilation, self-injuring or self-harming behaviour has been defined as deliberate destruction or alteration of body tissue in the absence of conscious suicidal intention. Persons suffering from mental disorder may inflict hundred of small wounds upon themselves which may be added to the actual cause of death. Another recognized syndrome is self mutilation of genitals almost invariably in males suffering from paranoid schizophrenia and often with strong religious flavour to their delusion. Here we present a case of a 35-year-old male who self mutilated his penis due to dependence on cannabis for the past few years that led to a condition called cannabis induced psychosis.

Kivimies K; Repo-Tiihonen E; Tiihonen J. Substance use among forensic psychiatric patients. American Journal of Drug and Alcohol Abuse 38(4): 273-277, 2012. (24 refs.)

Objectives: The primary goal of this study was to examine the relative differences in the use of illegal substances (i.e., amphetamine, cannabis, opiates) among forensic patients who have committed a violent crime compared with the general population. The aim was also to find out if there were differences in substance use among forensic versus nonforensic patients with psychosis diagnosis. Methods: The study population consisted of 190 persons, who were involuntarily ordered to hospital treatment as forensic patients in Finland. The information was compared with data from the national hospital discharge register. These results were also compared with national statistics from the general population. Results: Among forensic patients, the lifetime prevalence of cannabis use was 2-fold, amphetamine use 40-fold, and opiate use over 60-fold higher than estimated from the general population in Finland. Cannabis use was 1.5-fold more common than amphetamine use among forensic patients and 1.3-fold more common among nonforensic patients. The prevalences of cannabis-related diagnoses were 4.7- and 3.7-fold more common than opiate use among forensic and nonforensic patients, respectively. Conclusions: Cannabis, amphetamine, and opiate use are associated with an increased risk of becoming a forensic psychiatric patient, but no substantial differences were observed among patients with psychosis diagnosis in the relative risk increase for cannabis versus amphetamine versus opiate use, indicating that none of these drugs are uniquely associated with violent offending among mentally ill.

Kolliakou A; Fusar-Poli P; Atakan Z. Cannabis abuse and vulnerability to psychosis: Targeting preventive services. (review). Current Pharmaceutical Design 18(4): 542-549, 2012. (91 refs.)

Cannabis is the most widely used illicit substance in the world and due to the high levels of use observed among young people with psychosis, most research has focused on the causal relationship between cannabis use and mental health problems. Despite a large interest in developing intervention models to target this group, there are as yet no established and effective methods of prevention and intervention focusing on cannabis use. In this paper we present the available evidence for the effectiveness of substance use treatments in patients with co-morbid severe mental illness, as well as exploring the prevention and early intervention initiatives for substance use in the general population.

Kolliakou A; Joseph C; Ismail K; Atakan Z; Murray RM. Why do patients with psychosis use cannabis and are they ready to change their use? International Journal of Developmental Neuroscience 29(3, special issue): 335- 346, 2011. (121 refs.)

Numerous studies have shown that patients with psychosis are more likely to use illicit drugs than the general population, with cannabis being the most popular. There exists overwhelming evidence that cannabis use can contribute to the onset of schizophrenia and poor outcome in patients with established psychosis. Therefore, understanding why patients use cannabis and whether they are motivated to change their habits is important. The evidence is that patients with psychosis use cannabis for the same reasons the general population does, to 'get high', relax and have fun. There is little support for the 'self-medication' hypothesis, while the literature points more towards an 'alleviation of dysphoria' model. There is a lack of research reporting on whether psychotic patients are ready to change their use of cannabis, which has obvious implications for identifying which treatment strategies are likely to be effective.

Kuepper R; Morrison PD; van Os J; Murray RM; Kenis G; Henquet C. Does dopamine mediate the psychosis-inducing effects of cannabis? A review and integration of findings across disciplines. (review). Schizophrenia Research 121(1-3): 107-117, 2010. (163 refs.)

General population epidemiological studies have consistently found that cannabis use increases the risk of developing psychotic disorders in a dose-dependent manner. While the epidemiological signal between cannabis and psychosis has gained considerable attention, the biological mechanism whereby cannabis increases risk for psychosis remains poorly understood. Animal research suggests that delta-9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) increases dopamine levels in several regions of the brain, including striatal and prefrontal areas. Since dopamine is hypothesized to represent a crucial common final pathway between brain biology and actual experience of psychosis, a focus on dopamine may initially be productive in the examination of the psychotomimetic effects of cannabis. Therefore, this review examines the evidence concerning the interactions between THC, endocannabinoids and dopamine in the cortical as well as subcortical regions implicated in psychosis, and considers possible mechanisms whereby cannabis-induced dopamine dysregulation may give rise to delusions and hallucinations. It is concluded that further study of the mechanisms underlying the link between cannabis and psychosis may be conducted productively from the perspective of progressive developmental sensitization, resulting from gene-environment interactions.

Kuepper R; van Os J; Lieb R; Wittchen HU; Henquet C. Do cannabis and urbanicity co-participate in causing psychosis? Evidence from a 10-year follow-up cohort study. Psychological Medicine 41(10): 2121-2129, 2011. (49 refs.)

Background. Cannabis use is considered a component cause of psychotic illness, interacting with genetic and other environmental risk factors. Little is known, however, about these putative interactions. The present study investigated whether an urban environment plays a role in moderating the effects of adolescent cannabis use on psychosis risk. Method. Prospective data (n = 1923, aged 14-24 years at baseline) from the longitudinal population-based German Early Developmental Stages of Psychopathology cohort study were analysed. Urbanicity was assessed at baseline and defined as living in the city of Munich (1562 persons per km(2); 4061 individuals per square mile) or in the rural surroundings (213 persons per km(2); 553 individuals per square mile). Cannabis use and psychotic symptoms were assessed three times over a 10-year follow-up period using the Munich version of the Composite International Diagnostic Interview. Results. Analyses revealed a significant interaction between cannabis and urbanicity [10.9% adjusted difference in risk, 95% confidence interval (CI) 3.2-18.6, p = 0.005]. The effect of cannabis use on follow-up incident psychotic symptoms was much stronger in individuals who grew up in an urban environment (adjusted risk difference 6.8%, 95% CI 1.0-12.5, p = 0.021) compared with individuals from rural surroundings (adjusted risk difference -4.1%, 95% CI -9.8 to 1.6, p = 0.159). The statistical interaction was compatible with substantial underlying biological synergism. Conclusions. Exposure to environmental influences associated with urban upbringing may increase vulnerability to the psychotomimetic effects of cannabis use later in life.

Kuepper R; van Os J; Lieb R; Wittchen HU; Hofler M; Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. British Medical Journal 342: article d738, 2011. (46 refs.)

Objective To determine whether use of cannabis in adolescence increases the risk for psychotic outcomes by affecting the incidence and persistence of subclinical expression of psychosis in the general population (that is, expression of psychosis below the level required for a clinical diagnosis). Design Analysis of data from a prospective population based cohort study in Germany (early developmental stages of psychopathology study). Setting Population based cohort study in Germany. Participants 1923 individuals from the general population, aged 14-24 at baseline. Main outcome measure Incidence and persistence of subthreshold psychotic symptoms after use of cannabis in adolescence. Cannabis use and psychotic symptoms were assessed at three time points (baseline, T2 (3.5 years), T3 (8.4 years)) over a 10 year follow-up period with the Munich version of the composite international diagnostic interview (M-CIDI). Results In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021). Furthermore, continued use of cannabis increased the risk of persistent psychotic symptoms over the period from T2 to T3 (2.2, 1.2 to 4.2; P=0.016). The incidence rate of psychotic symptoms over the period from baseline to T2 was 31% (152) in exposed individuals versus 20% (284) in non-exposed individuals; over the period from T2 to T3 these rates were 14% (108) and 8% (49), respectively. Conclusion Cannabis use is a risk factor for the development of incident psychotic symptoms. Continued cannabis use might increase the risk for psychotic disorder by impacting on the persistence of symptoms.

Latt N; Jurd S; Tennant C; Lewis J; Macken L; Joseph A et al. Alcohol and substance use by patients with psychosis presenting to an emergency department: Changing patterns. Australasian Psychiatry 19(4): 354-359, 2011. (14 refs.)

Objectives: The aim of this study was to determine the incidence of alcohol and other substance use in patients presenting to an emergency department with acute psychiatric illnesses and to clarify the role of urine drug screens. Method: This was an unblinded prospective (observational) cohort study incorporating retrospective review of patient medical records, history of alcohol and substance use, results of urine drug screens and blood alcohol concentrations. Results: Of 196 acute psychotic patients, 104 were diagnosed with schizophrenia and 92 with "other psychosis". Results of urine drug screens were consistent with self-reported use of substances and only identified an additional 5% of substance users. Cannabis was the commonest illicit substance used by both groups of patients, followed by psychostimulants, mainly amphetamines. Younger males were more likely to use psychostimulants and to present with violence. Conclusions: Patients with co-existing mental health problems and substance use present a major problem for our emergency departments. Cannabis was the most common substance used. Youth, male gender and psychostimulant use are associated with violent presentations. A comprehensive history of alcohol and substance use is important to implement appropriate dual diagnosis treatment. Urine drug screening is recommended for patients who do not admit to substance use.

Leeson VC; Harrison I; Ron MA; Barnes TRE; Joyce EM. The effect of cannabis use and cognitive reserve on age at onset and psychosis outcomes in first-episode schizophrenia. Schizophrenia Bulletin 38(4): 873-880, 2012. (40 refs.)

Objective: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use. Methods: Ninety-nine patients without alcohol or substance abuse other than cannabis were divided into lifetime users and never-users of cannabis and compared on measures of premorbid function, cognition, and clinical outcome. Results: Cannabis users demonstrated better cognition at psychosis onset, which was explained by higher premorbid IQ. They also showed better social function and neither measure changed over the subsequent 15 months. Cannabis users had an earlier age at onset of psychosis, and there was a strong linear relationship between age at first cannabis use and age at onset of both prodromal and psychotic symptoms. Cannabis use spontaneously declined over time with 3-quarters of users giving up altogether. Later age at first cannabis use predicted earlier cessation of use and this in turn was linked to fewer positive psychotic symptoms and days in hospital during the first 2 years. Conclusions: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.

Loberg EM; Hugdahl K. Cannabis use and cognition in schizophrenia. Frontiers in Human Neuroscience 3: article 53, 2009. (79 refs.)

People with schizophrenia frequently report cannabis use, and cannabis may be a risk factor for schizophrenia, mediated through effects on brain function and biochemistry. Thus, it is conceivable that cannabis may also influence cognitive functioning in this patient group. We report data from our own laboratory on the use of cannabis by schizophrenia patients, and review the existing literature on the effects of cannabis on cognition in schizophrenia and related psychosis. Of the 23 studies that were found, 14 reported that the cannabis users had better cognitive performance than the schizophrenia non-users. Eight studies reported no or minimal differences in cognitive performance in the two groups, but only one study reported better cognitive performance in the schizophrenia non-user group. Our own results confirm the overall impression from the literature review of better cognitive performance in the cannabis user group. These paradoxical findings may have several explanations, which are discussed. We suggest that cannabis causes a transient cognitive breakdown enabling the development of psychosis, imitating the typical cognitive vulnerability seen in schizophrenia. This is further supported by an earlier age of onset and fewer neurological soft signs in the cannabis-related schizophrenia group, suggesting an alternative pathway to psychosis.

Lubman DI; Baker A. Cannabis and mental health: Management in primary care. Australian Family Physician 39(8): 554-557, 2010. (35 refs.)

Background: Cannabis is the most widely used illicit drug in Australia. Regular use has been associated with increased risk for a range of harms, including the development and exacerbation of mental disorders. Objective: This article reviews current evidence relating to the neuropharmacology of cannabis and its impact on mental health, as well as strategies related to the assessment and management of cannabis and co-occurring mental disorders within the primary care setting. Discussion: Early and heavy use of cannabis has been associated with the onset of psychosis and depression, while chronic use results in poorer treatment outcomes among those with co-occurring mental disorders. Effective management involves the development of therapeutic engagement and an ongoing relationship, with monitoring of cannabis use and mental health problems. Standard pharmacotherapeutic treatment of the mental disorder may be associated with a reduction in cannabis use, although adjunctive psychological intervention is also likely to be required.

Machielsen M; van der Sluis S; de Haan L. Cannabis use in patients with a first psychotic episode and subjects at ultra high risk of psychosis: Impact on psychotic and pre-psychotic symptoms. Australian and New Zealand Journal of Psychiatry 44(8): 721-728, 2010. (25 refs.)

Objectives: Co-morbidity with cannabis use disorder is common in patients with a psychotic disorder and is associated with adverse outcome. This study aimed to determine prevalence of cannabis use disorder among patients with a psychotic disorder and subjects at ultra high risk of psychosis and to study the influence of cannabis use on severity of (pre-) psychotic symptomatology, psychosocial functioning and variables related to the course of the disorder in these patients Methods: In this study 169 consecutively assessed patients with a psychotic disorder were included as well as 59 consecutively assessed subjects at ultra high risk of psychosis Results: 45% of the patients with a psychotic disorder and 27% of the UHR patients were diagnosed with a co-morbid cannabis use disorder. Patients with cannabis use disorders did not differ from patients without cannabis use disorder in severity of psychotic symptoms. However, excluding patients with substance use disorder other than cannabis use disorder resulted in higher scores on positive symptom levels for patients with cannabis use disorder compared to patients without any substance use disorder Regarding ultra high risk patients, subjects with cannabis use disorder did not differ from subjects without cannabis use disorder on severity of pre-psychotic symptomatology. However, a negative correlation was found between the amount of cannabis used recently and scores on the pre-psychotic negative subscale Conclusion: Our results suggest a specific association between cannabis abuse and psychotic symptomatology.

Malcolm CP; Picchioni MM; DiForti M; Sugranyes G; Cooke E; Joseph C et al. Pre-morbid Conduct Disorder symptoms are associated with cannabis use among individuals with a first episode of psychosis. Schizophrenia Research 126(1-3): 81-86, 2011. (39 refs.)

Background: Early cannabis use has consistently been associated with an increased risk for the later development of psychosis. Studies suggest that Conduct Disorder (CD) is more common amongst young people who later go on to develop psychosis. CD has been associated with greater and earlier cannabis use in general population samples. Based on this evidence, we hypothesised that among patients experiencing their first episode of psychosis, the presence of CD symptoms prior to age 15 would be associated with cannabis use. Method: 102 patients experiencing a first episode of psychosis were interviewed to assess CD symptoms prior to age 15 and use of cannabis and other substances. Results: The number of CD symptoms was significantly associated with lifetime cannabis use (odds ratio = 5.41 (1.76-16.57), p = 0.03) and with first use of cannabis before age 14 (odds ratio = 1.46 (1.12-1.92), p = 0.006), after controlling for stimulant/hallucinogen use and level of education. Conclusions: Among patients experiencing a first episode of psychosis, CD symptoms were significantly associated with use of cannabis and with use by age 14. Among individuals vulnerable for psychosis, CD symptoms may independently increase the likelihood of cannabis use which in turn increases the risk of psychosis.

Martinotti G; Di Iorio G; Tedeschi D; De Berardis D; Niolu C; Janiri L et al. Prevalence and intensity of basic symptoms among cannabis users: An observational study. American Journal of Drug and Alcohol Abuse 37(2): 111-116, 2011. (53 refs.)

Background: It is difficult to establish whether people who are prone to psychosis are drawn to cannabis use or whether cannabis use truly increases the incidence of psychotic experiences. Objectives: The aim of our study was to evaluate, in a sample of healthy high school and university students, the presence and level of subjective experiences (SEs) and their relation to cannabis use. Methods: A total of 502 voluntary subjects were recruited; an anamnestic interview was administered to obtain socio-demographic information, cannabis use data, and psychiatric familial history. SEs were assessed using the Italian version of the Frankfurt Complaint Questionnaire (FCQ). Results: One hundred and fourteen subjects declared the use of cannabis: 20.5%% smoked more than 1 joint per week, and 71.9%% used cannabis for a period of more than 1 year. Cannabis users did not differ from the cannabis-free group in any of the 10 FCQ dimensions. Higher FCQ total scores were found in cannabis users with a familial history of psychiatric disorders respective to those without a psychiatric load (p < .05). Conclusions and scientific significance: In our study, SE intensity was not influenced by the use of cannabis. With regard to familial data, this is the first study to explore the relationship between SE and the presence of psychiatric problems in first-degree relatives. The association between FCQ intensity and psychiatric familial load may confirm the independence of these phenomena from the use of cannabis.

Mason O; Morgan CJA; Dhiman SK; Patel A; Parti N; Patel A et al. Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis. Psychological Medicine 39(6): 951-956, 2009. (20 refs.)

Background. Epidemiological evidence suggests a link between cannabis use and psychosis. A variety of factors have been proposed to mediate an individual's vulnerability to the harmful effects of the drug, one of which is their psychosis proneness. We hypothesized that highly psychosis-prone individuals would report more marked psychotic experiences under the acute influence of cannabis. Method. A group of cannabis users (n = 140) completed the Psychotomimetic States Inventory (PSI) once while acutely intoxicated and again when free of cannabis. A control group (n = 144) completed the PSI on two parallel test days. All participants also completed a drug history and the Schizotypal Personality Questionnaire (SPQ). Highly psychosis-prone individuals from both groups were then compared with individuals scoring low on psychosis proneness by taking those in each group scoring above and below the upper and lower quartiles using norms for the SPQ. Results. Smoking cannabis in a naturalistic setting reliably induced marked increases in psychotomimetic symptoms. Consistent with predictions, highly psychosis-prone individuals experienced enhanced psychotomimetic states following acute cannabis use. Conclusions. These findings suggest that an individual's response to acute cannabis and their psychosis-proneness scores are related and both may be markers of vulnerability to the harmful effects of this drug.

McGuinness TM. Update on marijuana. Journal of Psychosocial Nursing and Mental Health Services 47(10): 19-22, 2009. (17 refs.)

Marijuana, the illicit drug most widely used by adolescents, is not a benign substance. Inhalation of marijuana smoke is more harmful than tobacco smoke; cannabis smoke delivers 50% to 70% more carcinogens. Other physiological effects include decreased immune function, higher rates of cardiac arrhythmias, and documented cases of cerebellar infarction. Mood and cognitive effects of marijuana include exacerbation of depression and anxiety (including panic attacks), as well as memory problems that may persist for a month after last use. Cannabis abuse is a risk factor for psychosis in genetically predisposed people and may lead to a worse outcome of schizophrenia. The cumulative respiratory, cardiovascular, metabolic, and mental health risks of marijuana are significant and should be emphasized by nurses who work with adolescents.

McLaren JA; Silins E; Hutchinson D; Mattick RP; Hall W. Assessing evidence for a causal link between cannabis and psychosis: A review of cohort studies. (review). International Journal of Drug Policy 21(1): 10-19, 2010. (75 refs.)

Over the past five years, the release of cohort studies assessing the link between cannabis and psychosis has increased attention on this relationship. Existing reviews generally conclude that these cohort studies show cannabis has a causal relationship to psychosis, or at least that one cannot be excluded. Few studies have evaluated the relative strengths and limitations of these methodologically heterogeneous cohort studies, and how their relative merits and weaknesses might influence the way the link between cannabis use and psychosis is interpreted. This paper reviews the methodological strengths and limitations of major cohort studies which have looked at the link between cannabis and psychosis, and considers research findings against criteria for causal inference. Cohort studies that assessed the link between cannabis and psychosis were identified through literature searches using relevant search terms and MEDline, PsycINFO and EMBASE. Reference lists of reviews and key studies were hand searched. Only prospective studies of general population cohorts were included. Findings were synthesised narratively. A total of 10 key studies from seven general population cohorts were identified by the search. Limitations were evident in the measurement of psychosis, consideration of the short-term effects of cannabis intoxication, control of potential confounders and the measurement of drug use during the follow-up period. Pre-existing vulnerability to psychosis emerged as an important factor that influences the link between cannabis use and psychosis. Whilst the criteria for causal association between cannabis and psychosis are supported by the studies reviewed, the contentious issue of whether cannabis use can cause serious psychotic disorders that would not otherwise have occurred cannot be answered from the existing data. Further methodologically robust cohort research is proposed and the implications of how evidence informs policy in the case of uncertainty is discussed.

Meijer JH; Dekker N; Koeter MW; Quee PJ; Beveren NJM; Meijer CJ. Cannabis and cognitive performance in psychosis: A cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings. Psychological Medicine 42(4): 705-716, 2012. (69 refs.)

Background. The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings. In individuals at genetic high risk for psychosis, information is sparse. The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings. Method. We conducted a cross-sectional study in 956 patients with non-affective psychosis, 953 unaffected siblings, and 554 control subjects. Participants completed a cognitive test battery including assessments of verbal learning, set shifting, sustained attention, processing speed, working memory, acquired knowledge, reasoning and problem solving and social cognition. Cannabis use was assessed by urinalysis and by the Composite International Diagnostic Interview. Using random-effect regression models the main effects of cannabis (recency and frequency) and the interaction with status (patient, sibling, control) on cognitive functioning were assessed. Results. Current cannabis use was associated with poorer performance on immediate verbal learning, processing speed and working memory (Cohen's d -0.20 to -0.33, p<0.005). Lifetime cannabis use was associated with better performance on acquired knowledge, facial affect recognition and face identity recognition (Cohen's d+0.17 to +0.33, p<0.005). There was no significant interaction between cannabis and status on cognitive functioning. Conclusions. Lifetime cannabis-using individuals might constitute a subgroup with a higher cognitive potential. The residual effects of cannabis may impair short-term memory and processing speed.

Mihalca AM; Gherasim LR; Chendran LA. Research Note: Adolescents' perception of psychosis risk following cannabis consumption. Substance Use & Misuse 47(4): 396-402, 2012. (25 refs.)

Cannabis consumption during adolescence has been associated with the onset of psychosis. In 2010, we examined adolescents' perception of this association. Adolescents (N = 583) from four Romanian urban high schools filled in psychosis proneness scales according to the risk they assigned to hypothetical adolescents described in vignettes. Target adolescent's frequency and age of first consumption were manipulated. Analysis of variance indicated a main effect of target's consumption frequency, but no effect of age of first consumption on psychosis risk perception. Participants' own consumption status acted as moderator. Results highlight the discrepancy between clinical research results and adolescents' perception of psychosis risk. The study's limitations are noted.

Miller R; Ream G; McCormack J; Gunduz-Bruce H; Sevy S; Robinson D. A prospective study of cannabis use as a risk factor for non-adherence and treatment dropout in first-episode schizophrenia. Schizophrenia Research 113(2-3): 138-144, 2009. (36 refs.)

Introduction: Although several studies have reported on cannabis use and adherence for first episode of psychosis patients, the findings remain unclear as to whether cannabis use is a risk factor for poor adherence in young people with first-episode schizophrenia. This study was designed to follow patients' use of cannabis and adherence in a naturalistic setting during the first 12 months of treatment. It examines whether cannabis use is a risk factor for two distinct types of non-adherence: non-adherence to medication and treatment dropout. Methods: Participants were 112 first-episode schizophrenia patients of diverse backgrounds a two community hospitals, enrolled in a study of differential effectiveness of two second generation antipsychotic medications. Multiple indicators were used to assess cannabis use and adherence to medication. Patients were encouraged to continue in the study even after period of treatment refusal or change from study to standardized medication. Study hypotheses were tested using Cox proportional hazards models with cannabis use as a time-varying covariate. Results: After 12 months, 23 had dropped out and 37 had at some point been non-adherent to medication. Of 34 participants who used cannabis during treatment, 32 had a prior diagnosis of cannabis abuse/dependence and 30 were male. Independently of age, race, socioeconomic status, gender, site, and medication assignment, cannabis use significantly increased hazard of non-adherence by a factor of 2.4 (p<.001) and hazard of dropout by a factor of 6.4 (p =.034) Conclusion: Results indicate that cannabis use is a risk factor for non-adherence to medication and dropout from treatment. Treatment for first-episode schizophrenia may be more effective if providers address the issue of cannabis use with patients throughout the early years of treatment, especially for those with existing cannabis abuse/dependence.

Moreno M; Estevez AF; Zaldivar F; Montes JMG; Gutierrez-Ferre VE; Esteban L et al. Impulsivity differences in recreational cannabis users and binge drinkers in a university population. Drug and Alcohol Dependence 124(3): 355-362, 2012. (99 refs.)

Background: Recreational cannabis use and alcohol binge drinking are the most common drug consumption patterns in young adults. Impulsivity and several psychopathological signs are increased in chronic drug users, but the implications of recreational use are still poorly understood. Methods: We evaluated impulsivity, sensation-seeking traits, impulsive decision-making, inhibitory control and possible symptoms of depression, anxiety and psychosis in three groups of young university adults: recreational cannabis users (N = 20), alcohol binge drinkers (N=22) and non-drug users (N=26). Results: The cannabis and binge drinking groups had increased scores for impulsivity and sensation-seeking traits. Both groups also exhibited increased impulsive decision-making on the two-choice task and the Iowa Gambling task; however, only the cannabis group was significantly different from the non-drug group regarding inhibitory control (Go/No-Go and Stop tasks). The cannabis and binge drinking groups did not show differences in the psychopathological symptoms evaluated. Conclusions: Our observations of this population of non-dependent drug users are consistent with the increased impulsivity traits and behaviors that have been described previously in chronic drug abusers. In this study, compared to no drug use, the recreational use of cannabis was associated with a major dysfunction of the different facets of impulsive behaviors. However, alcohol binge drinking was related only to impulsive decision-making. These results suggest that impulsivity traits and behaviors are present not only in chronic drug abusers but also in recreational drug users. Future work should continue to investigate the long-term effects of these common consumption patterns on various impulsive behaviors and psychopathological symptoms.

Ongur D; Lin L; Cohen BM. Clinical characteristics influencing age at onset in psychotic disorders. Comprehensive Psychiatry 50(1): 13-19, 2009. (43 refs.)

Background: Age at onset of psychosis may carry clinical significance across psychotic disorders and appears to be associated with specific genetic abnormalities. Methods: We used the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) to examine clinical characteristics contributing to age at onset variability in patients with schizophrenia (n = 80), schizoaffective disorder (n = 61), and bipolar disorder with psychotic features (n = 92). Results: Age at onset did not differ across DSM-IV diagnostic groups. Multiple regression analyses revealed that comorbid lifetime cannabis, but not alcohol, abuse/dependence was associated with a statistically significant 3 years earlier age at onset of psychosis. Patients developed cannabis abuse/dependence an additional 3 years before psychosis. Patients with comorbid lifetime panic disorder also had a 4-year earlier age at onset of psychosis. The effects of panic disorder and cannabis abuse/dependence were independent of one another. Conclusions: Early onset of psychosis, regardless of the specific DSM-IV diagnosis, is characterized by differential clinical features, notably a history of lifetime cannabis abuse/dependence. Panic disorder comorbidity is also associated with earlier age at onset of psychosis. Our findings indicate that examination of clinical and biological characteristics of patients with psychosis regardless of DSM-TV diagnosis can uncover relevant information.

Pedersen K; Waal H; Kringlen E. Patients with nonaffective psychosis are at increased risk for heroin use disorders. European Addiction Research 18(3): 124-129, 2012. (21 refs.)

Background/Aim: It is well-established knowledge that persons with nonaffective psychotic disorders often have problematic use of alcohol, cannabis and stimulants, but heroin use is usually not included. Our aim was to investigate the prevalence of heroin use disorders in patients with nonaffective psychosis. Methods: As the combination of heroin use and nonaffective psychosis is infrequent, epidemiological studies have to include large populations. The present study is a case count study using information from all psychiatric and social services in Oslo. Prevalence was calculated for four possible scenarios of minimum and maximum case counts and prevalences of nonaffective psychosis. Odds ratios were calculated for the resulting prevalences compared to the minimum and maximum prevalence of heroin use disorder in the general population. Results: We found between 39 and 56 subjects with nonaffective psychoses and comorbid heroin use disorder. The number of individuals with nonaffective psychosis was estimated to be between 692 and 1, 730. This corresponds to a prevalence of heroin use disorder of between 2.3 and 8.1%. The odds ratio compared to the general population will range from 1.83 with a prevalence of heroin use disorder in the general population of 1.2% to 9.43 with a prevalence of 0.9%. Conclusion: Individuals with non-affective psychosis are at increased risk of heroin use.

Pesa N; Hermens DF; Battisti RA; Kaur M; Hickie IB; Solowij N. Delayed preattentional functioning in early psychosis patients with cannabis use. Psychopharmacology 222(3): 507-518, 2012. (87 refs.)

Cannabis use is prevalent among the early psychosis (EP) population. The event-related potentials, mismatch negativity (MMN) and P3a are reduced in EP. Cannabinoids have been shown to modulate N-methyl-D-aspartate receptors which are involved in MMN generation. This study is the first to investigate the effects of cannabis use on MMN/P3a in EP. EP was defined as a history of psychosis or psychotic symptoms with no progression to date to chronic schizophrenia. Twenty-two EP patients with cannabis use (EP + CANN), 22 non-cannabis-using EP patients (EP-CANN) and 21 healthy controls participated in this study. MMN/P3a was elicited using a two-tone, auditory paradigm with 8% duration deviants. As expected, EP-CANN showed marked reductions in MMN/P3a amplitudes compared to controls. However, EP + CANN showed evidence of a different pattern of neurophysiological expression of MMN/P3a compared to non-using patients, most notably in terms of delayed frontal MMN/P3a latencies. This study provides further evidence that MMN/P3a deficits are present during early psychosis and suggests that this biomarker may have utility in differentiating substance- from non-substance-related psychoses.

Ramirez N; Arranz B; Salavert J; Alvarez E; Corripio I; Duenas R et al. Predictors of schizophrenia in patients with a first episode of psychosis. Psychiatry Research 175(1-2): 11-14, 2010. (37 refs.)

Early identification of schizophrenia in patients with a first episode of psychosis (FEP) may help to avoid inappropriate treatment and may enhance long-term outcome by addressing issues such as family network, treatment adherence and functional and symptomatic outcome. It was the aim of the study to determine baseline variables that significantly predicted a diagnosis of schizophrenia in patients with FEP The sample consisted of 133 FEP patients hospitalized for at least 6 weeks, in whom a DSM-IV diagnosis was confirmed after 1 year follow-up. Patients were divided into two groups, those with a diagnosis of schizophrenia (Schizophrenia group, n=63; 47.8%), and those with other psychosis, who were grouped under Non-Schizophrenic Psychosis (NSP, n=70; 52.2%). Sociodemographic (marital status, educational level) and clinical variables were recorded for each patient. Substance use (alcohol, cannabis and cocaine) did not statistically differ between the two groups. Absence of characteristics defined as criteria for good prognosis, lack of >= 20% improvement in the total Positive and Negative Syndrome Scale score at 6 weeks, and a poor premorbid adjustment as determined by the Premorbid Adjustment Scale score significantly predicted the presence of schizophrenia. The regression model including these three variables achieved a predictive value of 76.3%, with a sensitivity of 74.6% and a specificity of 77.9%.

Reece AS. Chronic toxicology of cannabis. (review). Clinical Toxicology 47(6): 517-524, 2009. (154 refs.)

Introduction. Cannabis is the most widely used illicit drug worldwide. As societies reconsider the legal status of cannabis, policy makers and clinicians require sound knowledge of the acute and chronic effects of cannabis. This review focuses on the latter. Methods. A systematic review of Medline, PubMed, PsychInfo, and Google Scholar using the search terms "cannabis," "marijuana," "marihuana," "toxicity," "complications," and "mechanisms" identified 5,198 papers. This list was screened by hand, and papers describing mechanisms and those published in more recent years were chosen preferentially for inclusion in this review. Findings. There is evidence of psychiatric, respiratory, cardiovascular, and bone toxicity associated with chronic cannabis use. Cannabis has now been implicated in the etiology of many major long-term psychiatric conditions including depression, anxiety, psychosis, bipolar disorder, and an amotivational state. Respiratory conditions linked with cannabis include reduced lung density, lung cysts, and chronic bronchitis. Cannabis has been linked in a dose-dependent manner with elevated rates of myocardial infarction and cardiac arrythmias. It is known to affect bone metabolism and also has teratogenic effects on the developing brain following perinatal exposure. Cannabis has been linked to cancers at eight sites, including children after in utero maternal exposure, and multiple molecular pathways to oncogenesis exist. Conclusion. Chronic cannabis use is associated with psychiatric, respiratory, cardiovascular, and bone effects. It also has oncogenic, teratogenic, and mutagenic effects all of which depend upon dose and duration of use.

Richardson TH. Cannabis use and mental health: A review of recent epidemiological research. (review). International Journal of Pharmacology 6(6): 796-807, 2010. (117 refs.)

Cannabis is the most commonly used drug in the world. This review examines recent epidemiological research on the relationships between cannabis use and mental health problems. Relationships with depression, anxiety disorders, mania and psychosis are examined, with relevant issues such as the effect of confounding variables, temporal directions and causality being discussed. Factors which influence the relationship such as dose-response effects, age of first cannabis use and risk of mental health problems are also examined. Causality is often difficult to establish, as cannabis is often used by those with mental illness for self-medication. However, there is substantial evidence to suggest that cannabis may induce or exacerbate a number of mental health problems.

Rodrigo C; Welgama S; Gunawardana A; Maithripala C; Jayananda G; Rajapakse S. A retrospective analysis of cannabis use in a cohort of mentally ill patients in Sri Lanka and its implications on policy development. Substance Abuse Treatment, Prevention and Policy 5: article 16, 2010. (65 refs.)

Background: Several epidemiological studies have shown that cannabis; the most widely used illegal drug in the world, is associated with schizophrenia spectrum disorders (SSD). Aims: To assess the characteristics of cannabis use and its association with SSD in a cohort of psychiatrically ill patients and discuss the implications for policy development Methods: This is a retrospective analytical study of a cohort of psychiatric patients who received treatment in the psychiatry unit of the Provincial General Hospital, Ratnapura, Sri Lanka over five years (2000 - 2004). The schizophrenia spectrum disorders defined in this article include schizophrenia and the schizoaffective disorders. Results: A total of 3644 patient records were analyzed. The percentage of self reported life time cannabis (LTC) use was 2.83% (103, all males). Sixteen percent (576) of the total cohort was diagnosed with SSD by 2009. Male sex and LTC use were significantly associated with SSD (p < 0.01 and 0.001 respectively). In the majority (91.5%), cannabis use preceded the diagnosis. There were 17(16.5%) patients diagnosed as cannabis induced psychosis and 7 (41.2%) of them were subsequently diagnosed as SSD. This group was significantly more likely to have had a past psychiatric consultation, but other demographic and clinical correlates did not differ from the rest of the LTC users. Conclusions: Self reported LTC use was strongly associated with being diagnosed with SSD. However we could not identify a particular subgroup of users that are at increased risk to recommend targeted primary prophylaxis. The policy implications of this observation are discussed.

Rodriguez-Sanchez JM; Ayesa-Arriola R; Mata I; Moreno-Calle T; Perez-Iglesias R; Gonzalez-Blanch C et al. Cannabis use and cognitive functioning in first-episode schizophrenia patients. Schizophrenia Research 124(1-3): 142-151, 2010. (76 refs.)

Cannabis is one of the most widely used illicit drugs in the world In healthy individuals cannabis is associated with cognitive impairments. Research into the effect of cannabis use in schizophrenia has yielded contradictory findings. Our aim has been to explore the correlates of cannabis use in cognitive and psychopathological features both cross-sectional and longitudinally in early phases of schizophrenia 104 patients with a first episode of non-affective psychosis and 37 healthy controls were studied Patients were classified according to their use of cannabis prior to the onset of the illness (47 users vs 57 non-users). They were cross-sectionally and longitudinally studied and compared on clinical and cognitive variables and also on their level of premorbid adjustment. Cannabis user patients had better attention and executive functions than non-cannabis user patients at baseline and after 1 year of treatment. Both groups showed similar improvement in their cognitive functioning during the 1-year follow-up period. We also found that users had a better social premorbid adjustment particularly during the early periods of life. The amount of cannabis consumed and the length of time of consumption did not significantly relate to cognitive performance. The use of cannabis does not seem to be associated with a negative effect on cognition in a representative sample of first-episode schizophrenia patients. Cannabis user patients appear to comprise a subgroup of patients with a better premorbid adjustment and premorbid frontal cognitive functions.

Ruiz-Veguilla M; Gurpegui M; Barrigon ML; Ferrin M; Marin E; Rubio JL et al. Fewer neurological soft signs among first episode psychosis patients with heavy cannabis use. Schizophrenia Research 107(2-3): 158-164, 2009. (62 refs.)

Background: Although neurological soft signs (NSS) have been consistently associated with schizophrenia and a variety of risk factors, few studies have focused on the association between NSS and environmental factors such as cannabis use, particularly in patients with first episode psychosis. Methods: We administered the Neurological Evaluation Scale (NES) to 92 patients during their first episode of functional psychosis. Psychopathology was assessed with the Positive And Negative Syndrome Scale (PANSS) and the family history of psychotic disorder was established on the basis of the Family Interview for Genetic Studies (FIGS). We also assessed lifetime cannabis and cocaine use utilizing that specific section of the Composite International Diagnostic Interview. The outcome variable was the presence of high NSS, defined by a score above the median split of the NES score (>21). Results: Most patients (80/92, 87%) presented a non-affective psychosis. The presence of high NSS showed a significant independent association with not having been a heavy cannabis user (OR=83; 95% CI, 2.4-33.3), family history of psychosis (OR=4.3; 95% CI, 1.2-14.9), male sex (OR=4.0; 95% CI,1.2-14.0), lower score in verbal fluency and higher score in negative symptoms (both p<0.01). Conclusion: Our cross-sectional results support the hypothesis that potentially different pathways associated with the emergence of first episode psychosis may exist, including neurological premorbid alteration and environmental cannabis abuse.

Saddichha S; Sur S; Sinha BNP; Khess CRJ. How Is substance use linked to psychosis? A study of the course and patterns of substance dependence in psychosis. Substance Abuse 31(1): 58-67, 2010. (63 refs.)

Substance use in mentally ill patients is now a major problem that influences the course and outcome of psychosis. With prevalence ranging up to 60%, several theories were postulated to explain the link. It would be interesting to know if substances have different effects in persons with psychosis than in those without. This study aimed to explore patterns of symptomatology of dependence and comorbid psychiatric illness by comparing and contrasting it with a group suffering from pure substance dependence. Consecutively admitted patients who were matched for age, sex, and tobacco use were divided into 3 groups. These were substance dependence without any comorbid psychiatric disorder (SD; n = 32), schizophrenia with substance dependence (SC; n = 31), and bipolar disorder with substance dependence (BD; n = 31). Patients were administered the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Mini International Neuropsychiatric Inventory (MINI) to evaluate the chronology of criterion of International Classificiation of Diseases (ICD)-10 dependence. Results showed that cannabis was the most common substance used by both the SC (100%) and BD (80%) groups. This was followed by alcohol as the most common substance used, with prevalence of 87% in SC and 77% in BD groups. There was a significant difference in the pattern of use of cannabis in patients with psychosis, who developed tolerance much faster (P = .018) and had longer durations of cannabis use (P = .001) than the SD group. The presence of "loss of control" over drug use criterion seems to be a specific marker predicting development of dependence and psychosis. Cannabis use is more strongly associated with development of psychosis than any other substance.

Schafer G; Feilding A; Morgan CJA; Agathangelou M; Freeman TP; Curran HV. Investigating the interaction between schizotypy, divergent thinking and cannabis use. Consciousness and Cognition 21(1): 292-298, 2012. (35 refs.)

Cannabis acutely increases schizotypy and chronic use is associated with elevated rates of psychosis. Creative individuals have higher levels of schizotypy, however links between cannabis use, schizotypy and creativity have not been investigated. We investigated the effects of cannabis smoked naturalistically on schizotypy and divergent thinking, a measure of creativity. One hundred and sixty cannabis users were tested on 1 day when sober and another day when intoxicated with cannabis. State and trait measures of both schizotypy and creativity were administered. Quartile splits compared those lowest (n = 47) and highest (n = 43) in trait creativity. Cannabis increased verbal fluency in low creatives to the same level as that of high creatives. Cannabis increased state psychosis-like symptoms in both groups and the high creativity group were significantly higher in trait schizotypy, but this does not appear to be linked to the verbal fluency change. Acute cannabis use increases divergent thinking as indexed by verbal fluency in low creatives.

Scherr M; Hamann M; Schwerthoffer D; Frobose T; Vukovich R; Pitschel-Walz G et al. Environmental risk factors and their impact on the age of onset of schizophrenia: Comparing familial to non-familial schizophrenia. Nordic Journal of Psychiatry 66(2): 107-114, 2012. (82 refs.)

Background and aims: Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder). Methods: Aside from the age of onset of psychosis, we examined the risk factors for schizophrenia including obstetric complications, birth during winter or spring, behavioral deviances or delayed motor and speech development, exposure to adverse life events and exposure to substance use within a group of 100 patients (45 female, 55 male) with a mean age (+/- standard deviation) of 35.15 +/- 13.21. Results: Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified. Conclusions: Certain environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, they do not seem to have an impact on familial schizophrenia.

Schimmelmann BG; Conus P; Cotton S; Kupferschmid S; McGorry PD; Lambert M. Prevalence and impact of cannabis use disorders in adolescents with early onset first episode psychosis. European Psychiatry 27(6): 463-469, 2012. (35 refs.)

Background. - Previous studies on the impact of cannabis use disorders (CU) on outcome in psychosis were predominantly based on non representative samples, often have not controlled for confounders and rarely focused on adolescent patients. Thus, the aims of the present study were to assess: (i) prevalence of CU; (ii) baseline and pretreatment differences between CU and those without CU (NCU); (iii) the impact of baseline and course of CU on 18-month outcomes in a representative cohort of adolescents with early onset first episode psychosis (EOP). Methods. - The sample comprised 99 adolescents (age 14 to 18) with EOP (onset age 14 to 17), admitted to the Early Psychosis Prevention and Intervention Centre in Australia. Data were collected from medical files using a standardized questionnaire. Results. - Prevalence of lifetime CU was 65.7%, of current CU at baseline 53.5%, and of persistent CU throughout treatment 26.3%. Baseline CU compared to NCU had significantly higher illness-severity, lower psychosocial functioning, less insight, lower premorbid functioning and longer duration of untreated psychosis. Compared to all other groups, only persistent CU was linked to worse outcomes and more service disengagement. Effect sizes were medium controlling for relevant confounders. Medication non-adherence did not explain the association between persistent CU and worse outcome. Conclusions. - Baseline CU was associated with worse baseline characteristics, but only persistent CU was linked with worse outcome. About half of those with baseline CU reduced cannabis during treatment. For these, effectively treating the psychotic disorder may already be beneficial. However, future research is necessary on the reasons for persistent CU in EOP and its treatment.

Schubart CD; van Gastel WA; Breetvelt EJ; Beetz SL; Ophoff RA; Sommer IEC et al. Cannabis use at a young age is associated with psychotic experiences. Psychological Medicine 41(6): 1301- 1310, 2011. (60 refs.)

Background. Cannabis use is associated with psychosis and a range of subclinical psychiatric symptoms. The strength of this association depends on dosage and age at first use. The current study investigates whether level of cannabis exposure and starting age are associated with specific profiles of subclinical symptoms. Method. We collected cross-sectional data from a young adult population sample by administering an online version of the Community Assessment of Psychic Experiences (CAPE). Cannabis exposure was quantified as the amount of Euros spent on cannabis per week and the age of initial cannabis use. The primary outcome measure was the odds ratio (OR) to belong to the highest 10% of scores on the total CAPE and the positive-, negative- and depressive symptom dimensions. Results. In 17 698 adolescents (mean age 21.6, S.D. = 4.2 years), cannabis use at age 12 years or younger was strongly associated with a top 10% score on psychotic experiences [OR 3.1, 95% confidence interval (CI) 2.1-4.3] and to a lesser degree with negative symptoms (OR 1.7, 95% CI 1.1-2.5). The OR of heavy users (>(sic)25/week) for negative symptoms was 3.4 (95% CI 2.9-4.1), for psychotic experiences 3.0 (95% CI 2.4-3.6), and for depressive symptoms 2.8 (95% CI 2.3-3.3). Conclusions. Early start of cannabis use is strongly associated with subclinical psychotic symptoms and to a lesser degree with negative symptoms, while smoking high amounts of cannabis is associated with increased levels of all three symptom dimensions : psychotic, negative and depressive. These results support the hypothesis that the impact of cannabis use is age specific.

Sewell RA; Ranganathan M; D'Souza DC. Cannabinoids and psychosis. (review). International Review of Psychiatry 21(2): 152-162, 2009. (101 refs.)

Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Case series, autobiographical accounts, and surveys of cannabis users in the general population suggest an association between cannabis and psychosis. Cross-sectional studies document an association between cannabis use and psychotic symptoms, and longitudinal studies suggest that early exposure to cannabis confers a close to two-fold increase in the risk of developing schizophrenia. Pharmacological studies show that cannabinoids can induce a full range of transient positive, negative, and cognitive symptoms in healthy individuals that are similar to those seen in schizophrenia. There is considerable evidence that in individuals with an established psychotic disorder such as schizophrenia, exposure to cannabis can exacerbate symptoms, trigger relapse, and worsen the course of the illness. Only a very small proportion of the general population exposed to cannabis develop a psychotic illness. It is likely that cannabis exposure is a 'component cause' that interacts with other factors to 'cause' schizophrenia or other psychotic disorder, but is neither necessary nor sufficient to do so alone. Further work is necessary to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk.

Shapiro GK; Buckley-Hunter L. What every adolescent needs to know: Cannabis can cause psychosis. Journal of Psychosomatic Research 69(6): 533-539, 2010. (73 refs.)

Objective: Cannabis is a widely used substance that may be becoming more socially accepted, legally tolerated, and utilized by younger individuals. This review explores the relationship between cannabis and the onset of psychosis as well as the policy ramifications of current research. Method: This article synthesizes published work that was considered by the author to be relevant to the discussion of cannabis and the onset of psychosis. Results: The evidence suggests that, along with other harms, cannabis is a significant risk factor in the etiology of psychosis. Adolescents are more vulnerable to using cannabis, and because of their stage of mental development, the cognitive effects are more pronounced. The mechanism for this change is thought to be neuro-chemical with a stronger effect in those with a diathesis for psychosis. Conclusion: The risk that cannabis poses to adolescent health should not be neglected. Policy measures should use a multifaceted and strategic perspective in order to prevent adolescents from using this drug.

Simon AE; Cattapan-Ludewig K; Gruber K; Ouertani J; Zimmer A; Roth B et al. Subclinical hallucinations in adolescent outpatients: An outcome study. Schizophrenia Research 108(1-3): 265-271, 2009. (36 refs.)

Objective: We assessed the continued prevalence at one year and association with clinical variables of subclinical hallucinations ascertained at baseline in a cohort of adolescent outpatients referred to a specialized early psychosis service. We further assessed the prevalence of psychiatric disorders in adolescents presenting subclinical hallucinations. Method: 84 adolescent patients were sampled from a longitudinal, prospective study that assesses the course of clinical and neuropsychological measures in patients identified as at high clinical risk for psychosis. Subclinical hallucinations were measured using the Scale of Prodromal Symptoms (SOPS) with its companion interview manual (Structured Interview for Prodromal Symptoms, SIPS) [Miller, T.J., McGlashan, T.H., Woods, S.W., Stein, K., Driesen, N., Corcoran, C.M., Hoffman, R., Davidson, L, 1999. Symptom assessment in schizophrenic prodromal states. Psychiatr. Q 70, 273-287; McGlashan, TH., Miller, T.J., Woods, S.W., Rosen, J.L., Hoffman, R.E., Davidson, L, 2001. Structured Interview for Prodromal Syndromes (Version 3.0, unpublished manuscript). PRIME Research Clinic, Yale School of Medicine New Haven, Connecticut 1, and the Schizophrenia Proneness Instrument -Adult Version (SPI-A) [Schultze-Lutter, F., Addington, J., Ruhrmann, S., Klosterkotter, J., 2007. Schizophrenia Proneness Instrument (SPI-A). Giovanni Fioriti, Rome, Italy]. At one-year follow-up, only patients reporting subclinical hallucinations at initial assessment were studied. Results: Full remission of subclinical hallucinations occurred in over half and at least partial remission in two thirds of these patients at one-year follow-up. Mood disorders were present in 62.5% of adolescents with subclinical hallucinations at initial assessment. SOPS measures for depression, deficient attention and for unusual/delusional thought were significantly associated with subclinical hallucinations at baseline. However, sustained experience of subclinical hallucinations at one-year follow-up was only predicted by the global level of functioning at baseline, while cannabis abuse, psychiatric and psychopharmacological treatment were not predictors. Conclusions: Subclinical hallucinations occur across a wide range of mental states in adolescents and show high rates of remission. Our results warrant that the clinical meaning of such phenomena needs to be carefully weighed against the specific developmental phenomena in this particular age range.

Tofighi B; Lee JD. Internet highs: Seizures after consumption of synthetic cannabinoids purchased online. Journal of Addiction Medicine 6(3): 240-241, 2012. (18 refs.)

Background: Since 2004, a new wave of synthetic cannabinoids (SCs) known as "Spice drugs" has come under scrutiny because of their suspected link to neurological and psychiatric sequelae. These "herbal incense" or "potpourri blends" have gained popularity as a result of being more potent than natural cannabinoids, are not detected with current screening tests, and are easily modified by manufacturers to bypass legal restrictions. Unfortunately, cases of withdrawal phenomena, nausea, hypertension, and psychosis are now being reported in the medical literature. In addition, after reports in lay media of seizures and coma attributed to the consumption of the drug, anecdotal reports have emerged of similar findings in the medical literature. Case Description: We report on a 48-year-old man who, after consuming the herbal blend, lost consciousness and suffered several episodes of seizures. Despite a complicated ICU stay, the patient recovered well with no subsequent neurological sequelae. Conclusions: The authors interpreted the history and findings consistent with the consumption of a large amount of synthetic cannabinoids leading to new-onset seizures and coma. However, at the time of admission, the lack of routine laboratory testing and treatment options delayed the diagnosis and delivery of appropriate therapy.

van Os J; Linscott RJ; Myin-Germeys I; Delespaul P; Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. (review). Psychological Medicine 39(2): 179-195, 2009. (137 refs.)

A systematic review of all reported incidence and prevalence Studies of population rates of subclinical psychotic experiences reveals a median prevalence rate of around 5%, and a median incidence rate of around 3%. A meta-analysis of risk factors reveals associations with developmental stage, child and adult social adversity, psychoactive drug use, and also male sex and migrant status. The small difference between prevalence and incidence rates, together with data from follow-up studies, indicates that approximately 75-90% of developmental psychotic experiences are transitory and disappear over time. There is evidence, however, that transitory developmental expression of psychosis (psychosis proneness) may become abnormally persistent (persistence) and subsequently clinically relevant (impairment), depending on the degree of environmental risk the person is additionally exposed to. The psychosis proneness-persistence-impairment model considers genetic background factors impacting on a broadly distributed and transitory population expression of psychosis during development, poor prognosis of which, in terms of persistence and clinical need, is predicted by environmental exposure interacting with genetic risk.

van Winkel R. Family-based analysis of genetic variation underlying psychosis-inducing effects of cannabis sibling analysis and proband follow-up. Archives of General Psychiatry 68(2): 148-157, 2011. (60 refs.)

Context: Individual differences exist in sensitivity to the psychotomimetic effect of cannabis; the molecular genetic basis underlying differential sensitivity remains elusive. Objective: To investigate whether selected schizophrenia candidate single-nucleotide polymorphisms (SNPs) moderate effects of cannabis use. Design: Interactions between recent cannabis use, determined by urinalysis results, and 152 SNPs in 42 candidate genes were examined in 740 unaffected siblings of 801 patients with psychosis to examine genetic moderation of the association between Structured Interview for Schizotypy-Revised positive schizotypy and recent cannabis use (at-risk paradigm). The SNPs showing Bonferroni-adjusted association in the at-risk paradigm were used in a case-only analysis in the 801 patients, as well as in a case-sibling and case-control analysis (using 419 controls) focusing on genetic moderation of developmental effects of cannabis on later psychotic disorder. Setting: The Netherlands and Flanders, Belgium. Participants: Eight hundred one patients with psychosis and their 740 unaffected siblings. Main Outcome Measure: Significant interaction between any of the selected SNPs and cannabis in the at-risk paradigm, followed by selective case-only, casesibling, and case-control analyses. Results: In the unaffected siblings, 16 SNPs in 12 genes showed significant interaction at P<.05, 3 of which survived correction for multiple testing (P<.0003), situated in AKT1 (rs2494732 and rs1130233) and LRRTM1 (rs673871). Follow-up analysis supported AKT1 rs2494732 X cannabis interaction in the case-only (beta=0.20; P=.007), case-sibling (interaction P=.040), and case-control (interaction P=.057) analyses, with individuals with C/C genotypes having an approximately 2-fold odds of being diagnosed with a psychotic disorder when having used cannabis. In the unaffected siblings, the AKT1 X cannabis interaction explained 2.2% additional variance in schizotypy in the whole sample and 19.0% additional variance in the exposed siblings with recent cannabis use. Conclusions: Genetic variation in AKT1 may mediate both short-term as well as longer-term effects on psychosis expression associated with use of cannabis, possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D-2 receptor.

Weissenborn R; Nutt DJ. Popular intoxicants: What lessons can be learned from the last 40 years of alcohol and cannabis regulation? Journal of Psychopharmacology 26(2): 213, 2012. (53 refs.)

In this paper we discuss the relative physical, psychological and social harms of the two most frequently used intoxicant drugs in the UK, namely cannabis and alcohol. Over the past 40 years, the use of both drugs has risen significantly with differential consequences. It is argued that increased policing of cannabis use under the current drug classification system will lead to increased criminalization of young people, but is unlikely to significantly reduce the rates of schizophrenia and psychosis. In comparison, increases in alcohol drinking are related to significant increases in liver cirrhosis hospital admissions and mortality, at a time when mortality rates from other major causes are on the decline. A recent expert-led comparison of the health and social harms to the user and to others caused by the most commonly used drugs in the UK showed alcohol to be more than twice as harmful as cannabis to users, and five times as harmful as cannabis to others. The findings underline the need for a coherent, evidence-based drugs policy that enables individuals to make informed decisions about the consequences of their drug use.

Welch KA; McIntosh AM; Job DE; Whalley HC; Moorhead TW; Hall J et al. The impact of substance use on brain structure in people at high risk of developing schizophrenia. Schizophrenia Bulletin 37(5): 1066-1076, 2011. (49 refs.)

Ventricular enlargement and reduced prefrontal volume are consistent findings in schizophrenia. Both are present in first episode subjects and may be detectable before the onset of clinical disorder. Substance misuse is more common in people with schizophrenia and is associated with similar brain abnormalities. We employ a prospective cohort study with nested case control comparison design to investigate the association between substance misuse, brain abnormality, and subsequent schizophrenia. Substance misuse history, imaging data, and clinical information were collected on 147 subjects at high risk of schizophrenia and 36 controls. Regions exhibiting a significant relationship between level of use of alcohol, cannabis or tobacco, and structure volume were identified. Multivariate regression then elucidated the relationship between level of substance use and structure volumes while accounting for correlations between these variables and correcting for potential confounders. Finally, we established whether substance misuse was associated with later risk of schizophrenia. Increased ventricular volume was associated with alcohol and cannabis use in a dose-dependent manner. Alcohol consumption was associated with reduced frontal lobe volume. Multiple regression analyses found both alcohol and cannabis were significant predictors of these abnormalities when simultaneously entered into the statistical model. Alcohol and cannabis misuse were associated with an increased subsequent risk of schizophrenia. We provide prospective evidence that use of cannabis or alcohol by people at high genetic risk of schizophrenia is associated with brain abnormalities and later risk of psychosis. A family history of schizophrenia may render the brain particularly sensitive to the risk-modifying effects of these substances.

Wisdom JP; Manuel JI. Prevalence of substance use in people with first-episode psychosis. Journal of Dual Diagnosis 7(1-2): 39- 49, 2011. (59 refs.)

Objective: People experiencing a first episode of psychosis often have co-occurring substance use, which increases risk of prolonged psychosis and impairs recovery. This article examines the prevalence of substance use in people with first-episode psychosis. Methods: The authors searched MEDLINE and other databases for articles published between 1990 and 2009 that described current or lifetime prevalence of substance use, misuse, abuse, or dependence in individuals with first-episode psychosis. Results: Forty-four unique studies provided information. More than 25% of individuals with first-episode psychosis in reviewed studies indicated current or lifetime alcohol use, lifetime alcohol abuse/dependence, current or lifetime cannabis use, or lifetime cannabis abuse or dependence. For all substances, lifetime prevalence of abuse/dependence was higher than current abuse/dependence. Conclusions: Despite variation in assessment methods, findings were generally consistent. Individuals with first-episode psychosis have lower current substance prevalence than lifetime prevalence, suggesting cessation of some substance use prior to seeking treatment for psychosis.

Wisdom JP; Manuel JI; Drake RE. Substance use disorder among people with first-episode psychosis: A systematic review of course and treatment. Psychiatric Services 62(9): 1007-1012, 2011. (54 refs.)

Objective: People experiencing a first episode of psychosis frequently have co-occurring substance use disorders, usually involving alcohol and cannabis, which put them at risk for prolonged psychosis, psychotic relapse, and other adverse outcomes. Yet few studies of first-episode psychosis have addressed the course of substance use disorders and the response to specialized substance abuse treatments. Methods: The authors searched MEDLINE, PsycINFO, and other medical databases for English-language articles published between 1990 and 2009. Included studies addressed two research questions. First, do some clients become abstinent after a first episode of psychosis without specialized substance abuse treatments? Second, for clients who continue to use substances after a first episode of psychosis, does the addition of specialized substance abuse treatment enhance outcomes? Results: Nine studies without specialized substance abuse treatment and five with specialized substance abuse treatment assessed the course of substance use (primarily cannabis and alcohol) after a first episode of psychosis. Many clients (approximately half) became abstinent or significantly reduced their alcohol and drug use after a first episode of psychosis. The few available studies of specialized substance abuse treatments did not find better rates of abstinence or reduction. Conclusions: Experience, education, treatment, or other factors led many clients to curtail their substance use disorders after a first episode of psychosis. Specialized interventions for others need to be developed and tested.

Yap MBH; Reavley NJ; Jorm AF. Young people's beliefs about the harmfulness of alcohol, cannabis and tobacco for mental disorders: Findings from two Australian national youth surveys. Addiction 107(4): 838-847, 2012. (35 refs.)

Aims: Using cross-sectional national survey data, we assessed young peoples' beliefs about the role of alcohol, tobacco and marijuana in the prevention and treatment of mental disorders as well as the predictors of these beliefs. We also compared these findings with those from a similar survey carried out in 2006. Design, setting and participants Between January and May 2011, a national computer-assisted telephone survey was conducted on a representative sample of Australian youths aged 15-25 years. A total of 3021 young people were presented with a case vignette portraying depression, depression with suicidal thoughts, psychosis, social phobia, depression with alcohol misuse or post-traumatic stress disorder in a young person. Measurements Respondents were asked about their beliefs regarding the role of using alcohol, tobacco and marijuana in preventing or dealing with the mental disorders described in the vignettes. Level of psychological distress was assessed by the Kessler 6 scale (K6). Findings More than 75% of respondents agreed that the three substances were harmful for the young people in the vignettes, and that not using marijuana or drinking alcohol in excess is preventive. Males, young adults and more distressed respondents were less likely to endorse these beliefs. No significant changes were observed between surveys. Conclusions: Most young people in Australia are aware of the negative impact of substance use on mental disorders, but a few high-risk groups remain: males, young adults and those with more psychological distress. Future public health campaigns need to target these groups and focus on translating young people's substance use beliefs into behavioural change.

Yucel M; Bora E; Lubman DI; Solowij N; Brewer WJ; Cotton SM et al. The impact of cannabis use on cognitive functioning in patients with schizophrenia: A meta-analysis of existing findings and new data in a first-episode sample. Schizophrenia Bulletin 38(2): 316-330, 2012. (79 refs.)

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use.

Zuardi AW; Crippa JAS; Hallak JEC; Pinto JP; Chagas MHN; Rodrigues GGR et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. Journal of Psychopharmacology 23(8): 979-983, 2009. (33 refs.)

The management of psychosis in Parkinson's disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson's Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.