Rachel A. Rabin, MSc

Schizophrenia affects approximately 1% of the general population. It is characterized by positive symptoms, such as delusions, hallucinations, and disorganized speech, and negative symptoms, including blunted affect, reduced motivation, and poor social relationships.

 In addition, studies have consistently identified 

 as clinically relevant core features that affect 75% to 85% of schizophrenia patients and that may serve as critical indices of social functioning, treatment strategies, and functional outcomes.

 Neurocognitive dysfunction is observed across several domains, including working memory, attention, executive function, response inhibition, and 

Approximately 50% of patients with schizophrenia will have a comorbid lifetime substance use disorder.

 Tobacco and cannabis are the most commonly used substances among these patients.

 The presence of a substance use disorder has been associated with alterations in neurocognitive performance.

 While previous studies have found positive effects of nicotine and tobacco smoking on neurocognition in schizophrenia, the effects of cannabis on neurocognitive function in schizophrenia are inconsistent and inconclusive.

The aim of this article is to evaluate the effects of nicotine and cannabis on neurocognitive function in individuals with schizophrenia and to review potential pharmacological treatment strategies.

Persons with schizophrenia are more likely to smoke cigarettes and to begin smoking at a younger age, extract more nicotine from each cigarette, have a preference for higher-tar cigarettes, and have reduced 

 Hypotheses have been proposed to explain comorbid smoking behaviors in these patients. The self-medication hypothesis suggests that schizophrenia patients smoke, in part, to alleviate negative symptoms, dysphoric mood, and neurocognitive impairments by ameliorating a dysfunctional dopamine system.

 The addiction vulnerability hypothesis suggests that genetic and neurobiological factors associated with schizophrenia (ie, alterations in nicotinic acetylcholine receptors [nAChRs] and central dopamine systems) may predispose schizophrenia patients to nicotine addiction.

Examining the effects of tobacco smoking on neurocognition in schizophrenia is crucial because it may help clarify the rationale for high consumption of tobacco products and inform treatment interventions. 

 summarizes the significant findings on the effects of nicotine on neurocognition in persons with schizophrenia. A recent cross-sectional study by Wing and colleagues

 found smoking history and current smoking status to be associated with neurocognition in schizophrenia. Patients without any history of tobacco smoking performed worse than former and current smokers with schizophrenia on neurocognitive tasks that assess processing speed, attention, and response inhibition.

A study of the effects of prolonged (up to 10 weeks) smoking abstinence on visuospatial working memory in patients with schizophrenia and controls found that the patients had impaired visuospatial working memory.

 Subsequently, a study by Sacco and colleagues

 examined visuospatial working memory under conditions of overnight smoking abstinence. They found that smoking abstinence specifically impaired visuospatial working memory in schizophrenia patients but not in controls. Abstinence-induced neurocognitive deficits were restored following restart of smoking. The effects of restarting smoking were blocked by treatment with the nAChR antagonist mecamylamine, which suggests that these pro-neurocognitive effects were dependent on nAChR stimulation.

On the basis of these studies, there is consensus that cigarette smoking may transiently enhance visuospatial working memory and attention in schizophrenia. Whether these pro-neurocognitive effects extend to other domains has not been studied extensively in the literature. While a few studies of cigarette smoking in patients with schizophrenia have found positive effects on tasks that involve sensory gating, motor speed, processing speed, working memory, and executive function, other studies have demonstrated no significant differences in neurocognitive performance apart from modest improvements on attentional and spatial processing tasks.

 Interestingly, the studies that reported modest effects used brief, general neurocognitive batteries, which are not as sensitive as more comprehensive batteries.

Comparative analyses across studies may be difficult to interpret because of methodological differences. For instance, while some studies have participants abstain from smoking for 2 hours, other studies have 

 This may create discrepancies among samples because individuals with schizophrenia who can maintain abstinence for 7 days may represent a less neurocognitively vulnerable subgroup of patients, even more so than patients who are able to refrain from smoking for shorter periods, also hypothesized to be inherently less susceptible to neurocognitive deficits.

 Furthermore, several studies do not provide comprehensive information concerning confounders and use small samples, lack control groups, and employ cross-sectional designs without consideration of longitudinal outcomes. These limitations should be addressed in future studies to provide a more uniform picture about the effects of tobacco use and neurocognitive function in schizophrenia.

Epidemiological studies indicate high rates of cannabis use disorders among individuals with schizophrenia, with lifetime prevalence of 13% to 64%.

 Evidence from longitudinal studies shows an increased risk of schizophrenia and psychotic symptoms following heavy cannabis use.

 Previous studies have proposed self-medication with cannabis to remedy symptoms of schizophrenia.

 In contrast to these studies, recent data show that cannabis misuse often occurs before the onset of 

 and that psychotic and affective symptoms worsen after cannabis use.

 summarizes the significant findings on the effects of cannabis on neurocognition in persons with schizophrenia. Surprisingly, schizophrenia patients with a comorbid cannabis use disorder demonstrate superior neurocognitive performance compared with non–drug-using patients.

 This may be counterintuitive given that cannabis use among nonpsychiatric controls has been consistently shown to have a deteriorating effect on neurocognitive performance and has been associated with poorer prognosis among schizophrenia patients.

 Given that neurocognitive dysfunction is a core feature in patients with schizophrenia and the high rates of cannabis use in these patients, a closer look at the association between cannabis use and neurocognition is warranted.

Two recent meta-analyses have addressed the relationship between cannabis use and neurocognition in schizophrenia. 

 published a meta-analysis that focused on the effects of cannabis on neurocognition in patients with established schizophrenia. Our group recently examined the same relationship while controlling for the confounding influence of other substance use disorders. Findings from both meta-analyses show superior neurocognitive performance among cannabis-using patients versus non-using patients.

 investigated the impact of cannabis use disorders and patterns of consumption on neurocognition in a large sample of schizophrenia patients. The cannabis-using group performed better on tests of verbal and working memory, visuomotor speed (Digit Symbol Test), and executive function. More frequent cannabis use was associated with better performance in attention and working memory tasks. Jockers-ScherÃ¼bl and colleagues

 evaluated the effects of long-term cannabis consumption on neurocognition in schizophrenia patients and controls. Schizophrenia patients performed significantly better than controls on a test of psychomotor speed, while control cannabis users showed impaired performance. Results were even more pronounced when patients began regular cannabis consumption before the age of 17.

Indeed, patients with comorbid cannabis use disorders may belong to a subgroup of schizophrenia patients with better premorbid adjustment and socialization.

 Drug-seeking individuals may possess essential skills required in communicating with drug dealers and negotiating the subculture required to procure illicit drugs; such traits have been associated with higher neurocognitive capacities among those with schizophrenia.

Findings from other studies show no significant difference in neurocognitive performance between schizophrenic cannabis users and non-users across various cognitive domains, including decision making, while others report worse performance on tasks assessing verbal learning and memory, executive function, working memory, and semantic fluency among cannabis-using patients.

While positive effects of cannabis may be unexpected, they should also be interpreted with caution. The majority of studies assessing this relationship employed cross-sectional designs. Longitudinal studies that examine the effects of cannabis on neurocognition in schizophrenia are needed to determine the true effects of cannabis on core symptoms associated with the illness.

Future studies should control for potential confounding variables, such as premorbid IQ and other substance use, especially tobacco, given its modulating role on neurocognitive processes. How investigators define cannabis-using status should also be uniform across studies. Furthermore, the amount of cannabis used should be taken into account, by using indices that capture cumulative consumption, such as joint-years. Thus, both confounding factors and methodological differences between previous studies may be responsible for the discrepant findings across studies.

Pharmacotherapies that target the nAChRs, which mediate the reinforcing properties and neurocognitive effects of nicotine in smokers, may have therapeutic effects on neurocogni-tive dysfunction in schizophrenia.

 Several promising nAChR agents, including galantamine (an allosteric modulator of central nAChRs), DMXB-A (Î±

-selective agonist), TC-5619 (a selective Î±

 partial agonist), have been studied in patients with schizophrenia.

 found that varenicline treatment in stable, medication-compliant schizophrenia patients for 8 weeks (1 mg/d) improved sensory gating, startle reactivity, and executive function. However, there were no significant effects on other neurocognitive domains, such as spatial working memory, sustained attention, and processing speed.

Cannabinoid antagonists or partial agonists have also been suggested to improve neurocognition in patients with schizophrenia given that cannabinoids increase prefrontal norepinephrine, acetylcholine, dopamine, and glutamate levels. Verrico and colleagues

 established that acute administration of a synthetic CB1 receptor agonist selectively decreased medial prefrontal cortical dopamine turnover in rodents. Thus, caution needs to be used because cannabinoid agonism may increase neurocognitive deficits in patients with schizophrenia by exacerbating frontal cortical dopamine, a critical neurotransmitter involved in neurocognitive processes.

Although there are reports of improved attention, processing speed, and executive function with cannabis use in schizophrenia, negative effects on other domains of neurocognition, such as immediate memory, have also been reported.

 Are these probable benefits worth the trade-off for impairments across certain aspects of memory? Coulston and colleagues

 argue that indeed the trade-off may be beneficial because high-order prefrontal brain processes could, in turn, help patients compensate for other neurocognitive shortfalls (eg, memory). Future investigations are required to determine whether specific neurocognitive components are more beneficial to functioning in schizophrenia than other components.

The second most abundant cannabinoid, cannabidiol (CBD) constitutes up to 40% of cannabis extracts.

 Recently, CBD has been deemed as a safe and efficacious treatment option for schizophrenia.

 Comparable to typical neuroleptics and unlike tetrahydrocannabinol (THC), CBD has been found to induce proneurocognitive, anxiolytic, and antipsychotic effects.

 A recent functional MRI study showed that THC and CBD exerted opposite effects on activation in the striatum, hippocampus, amygdala, superior temporal cortex, and occipital cortex.

 The researchers also found that pretreatment with CBD averted the induction of psychotogenic effects typically produced by THC.

Understanding the mechanisms by which nicotine and cannabis influence neurocognition in schizophrenia may help guide future rehabilitation strategies. The best approach may be an integrative one that combines pharmacotherapy with psychosocial interventions (eg, neurocognitive enhancement therapies). The development of novel agents that target neurocognitive dysfunction in substance-dependent schizophrenia patients is an important endeavor, given the clinical importance of tobacco and cannabis use in schizophrenia.

Future research should consider comorbid substance dependence among persons with schizophrenia in order to eliminate confounding variables that distort the association between smoking (eg, nicotine or cannabis) and neurocognitive performance. It is also important to consider whether neurocognition is altered in a general manner or whether specific neuropsychological parameters are affected differently by nicotine and cannabis.

The general consensus on the effects of nicotine on neurocognition in schizophrenia seems to be that nicotine transiently improves spatial working memory and sustained attention. On the other hand, the effects of cannabis on other domains of neurocognition remain unclear. Future studies are required to evaluate the true nature of this relationship.

Clinicians who treat patients with schizophrenia need to be aware of several caveats. While the research suggests opposite effects of nicotine and cannabis on 

 in patients with schizophrenia, treating comorbid tobacco and cannabis dependence should be a priority, given their negative health effects. In addition, when neurocognitive assessments of patients with schizophrenia are conducted, knowledge of tobacco and cannabis use status is important in interpreting the test results. The findings that constituents of tobacco (nicotine) and cannabis (CBD) may have therapeutic effects on neurocognition in schizophrenia hold promise for the development of novel treatments for cognitive dysfunction in persons with schizophrenia.

The preparation of this manuscript was supported in part by grants from the Canadian Institutes of Health Research (MOP#115145), the Ontario Mental Health Foundation, and the Chair in Addiction Psychiatry at the University of Toronto to Dr George.

Ms Sharif-Razi is a research analyst at the Centre for Addiction and Mental Health (CAMH), Toronto. Ms Rabin is a PhD student at the Institute of Medical Sciences at the University of Toronto. Dr George is Professor of Psychiatry at the University of Toronto and Chief of the Schizophrenia Division at the CAMH. Ms Sharif-Razi and Ms Rabin report no conflicts of interest concerning the subject matter of this article; Dr George reports that in the past 3 years he has been a consultant to Novartis, Bristol-Myers Squibb, and Pfizer, and has had investigator-initiated and industry-sponsored grant support from Pfizer.

 Saha S, Chant D, Welham J, McGrath J. A systematic review of the prevalence of schizophrenia. 

 Kuperberg G, Heckers S. Schizophrenia and cognitive function. 

 Keefe RS, Harvey PD. Cognitive impairment in schizophrenia. 

 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. 

 Green AI, Brown ES. Comorbid schizophrenia and substance abuse. 

 Wing VC, Bacher I, Sacco KA, George TP. Neuropsychological performance in patients with schizophrenia and controls as a function of cigarette smoking status. 

 Sacco KA, Termine A, Seyal A, et al. Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms. 

Rabin RA, Zakzanis KK, George TP. The effects of cannabis use on neurocognition in schizophrenia: a meta-analysis. 

Smoking habits, current symptoms, and premorbid characteristics of schizophrenic patients in Nithsdale, Scotland.

 Kumari V, Postma P. Nicotine use in schizophrenia: the self medication hypotheses. 

 de Leon J. Smoking and vulnerability for schizophrenia. 

 George TP, Vessicchio JC, Termine A, et al. Effects of smoking abstinence on visuospatial working memory function in schizophrenia. 

 Zabala A, Eguiluz JI, Segarra R, et al. Cognitive performance and cigarette smoking in first-episode psychosis. 

 Harris JG, Kongs S, Allensworth D, et al. Effects of nicotine on cognitive deficits in schizophrenia. 

Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia

 Sevy S, Robinson DG, Napolitano B, et al. Are cannabis use disorders associated with an earlier age at onset of psychosis? A study in first episode schizophrenia. 

 Hall W, Degenhardt L, Teesson M. Cannabis use and psychotic disorders: an update. 

 Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence for an association? [published correction appears in 

 LÃ¸berg EM, Hugdahl K. Cannabis use and cognition in schizophrenia. 

 Schnell T, Koethe D, Daumann J, Gouzoulis-Mayfrank E. The role of cannabis in cognitive functioning of patients with schizophrenia. 

 DeRosse P, Kaplan A, Burdick KE, et al. Cannabis use disorders in schizophrenia: effects on cognition and symptoms. 

 Solowij N, Stephens RS, Roffman RA, et al; Marijuana Treatment Project Research Group. Cognitive functioning of long-term heavy cannabis users seeking treatment [published correction appears in 

 D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. 

Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent-onset schizophrenic disorders. 

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

 Jockers-ScherÃ¼bl MC, Wolf T, Radzei N, et al. Cannabis induces different cognitive changes in schizophrenic patients and in healthy controls. Prog 

 Leeson VC, Sharma P, Harrison M, et al. IQ trajectory, cognitive reserve, and clinical outcome following a first episode of psychosis: a 3-year longitudinal study. 

 Silverstein ML, Mavrolefteros G, Turnbull A. Premorbid factors in relation to motor, memory, and executive functions deficits in adult schizophrenia. 

 Sevy S, Burdick KE, Visweswaraiah H, et al. Iowa gambling task in schizophrenia: a review and new data in patients with schizophrenia and co-occurring cannabis use disorders. 

 Ringen PA, Vaskinn A, Sundet K, et al. Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia. 

 Sacco KA, Creeden C, Reutenauer EL, George TP. Effects of galantamine on cognitive deficits in smokers and non-smokers with schizophrenia. 

Freedman R, Olincy A, Buchanan RW, et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. 

 Lieberman JA, Dunbar G, Segreti AC, et al. A randomized exploratory trial of an alpha-7 nicotinic receptor agonist (TC-5619) for cognitive enhancement in schizophrenia. 

 Smith RC, Lindenmayer JP, Davis JM, et al. Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder. 

Hong LE, Thaker GK, McMahon RP, et al. Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder. 

 Verrico CD, Jentsch JD, Roth RH. Persistent and anatomically selective reduction in prefrontal cortical dopamine metabolism after repeated, intermittent cannabinoid administration to rats. 

 Coulston CM, Perdices M, Tennant CC. The neuropsychological correlates of cannabis use in schizophrenia: lifetime abuse/dependence, frequency of use, and recency of use. 

 Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. 

 Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. 

Articles

The authors evaluate the effects of nicotine and cannabis on neurocognitive function in individuals with schizophrenia and review potential pharmacological treatment strategies.

Schizophrenia, Neurocognitive Dysfunction, and Substance-Related Disorders: A Review

Marijuana doesn’t count, does it?” Clinicians are familiar with this common reply when screening for drug use. Cannabis-the most common illicit substance-has managed to exempt itself from the hazardous reputation held by other illicit drugs.

As mental health practitioners, it is our duty to educate our patients about the potential harms and consequences of cannabis use. This important task is complicated by the disagreement and uncertainty surrounding the nature of the interaction between cannabis and psychotic disorders.

While research suggests that cannabis use can induce an acute psychotic state, there is controversy about whether it may precipitate psychotic disorders, such as schizophrenia. In this article, we provide an update on the literature on this important issue, emphasize areas in need of research, and provide clinically useful recommendations.

More than 16 million Americans use cannabis on a regular basis, typically beginning in adolescence. Notably, it is estimated that approximately 4% of the population has a diagnosis of either cannabis abuse or dependence.

 A history of cannabis misuse is even more common in patients who are schizophrenic than in the general population; 25% of patients with schizophrenia have a comorbid cannabis use disorder. Cannabis use disorders are especially common in younger and first-episode patient samples and in samples with high proportions of males.

Marijuana contains more than 400 chemical compounds, including over 60 cannabinoids that contribute to its psychopharmacological effects. The primary psychoactive constituent of cannabis is delta-9-tetrahydrocannabinol (THC). Other plant cannabinoids include delta-8-tetrahydrocannabinol; cannabinol; and cannabidiol (CBD); CBD is the second major psychoactive constituent of cannabis.

 The ratios of these and other cannabinoids vary enormously in preparations of cannabis, and little information exists about the concentration of each of the particular cannabinoids in commonly used cannabis products. Concerns have been expressed regarding the large increase in the potency of cannabis and the surrounding health implications. In the 1960s, the THC content was thought to be in the range of 1% to 3%; today it can reach up to 20%.

The endogenous cannabinoid system consists of 2 types of G-protein-coupled receptors: cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. CB1 receptors are the most abundant in the brain, while CB2 receptors predominate on immune cells. CB1 receptors are highly concentrated in brain regions implicated in the putative neural circuitry of psychosis and cognitive function. These include the hippocampus, prefrontal cortex, anterior cingulate, basal ganglia, cerebellum, and cortex, with lower levels present in the thalamus, hypothalamus, and amygdala. Activation of CB1 receptors mediates the behavioral and physiological effects of both endogenous and exogenous cannabinoids in the brain.

An important role of the CB1 receptor is to modulate neurotransmitter release in a manner that maintains homeostasis by preventing excessive neuronal activity in the CNS.

 CB1 receptors are localized on presynaptic neuron terminals on both inhibitory and excitatory neurons, yet they predominate on Î³-aminobutyric acid interneurons.

 It is the inhibitory neurons that are thought to mediate most of the effects of cannabinoids. In addition, the action of cannabinoids includes interactions, albeit indirectly, with the dopaminergic system.

THC is a partial agonist at the CB1 receptors, where it has modest affinity and low intrinsic activity. In contrast, CBD shows very little affinity for CB1 receptors. Moreover, the precise molecular mechanism of action of CBD remains unclear. The main endocannabinoids are anandamide and 2-arachidonylglycerol. In contrast to classic neurotransmitters, endocannabinoids can function as retrograde synaptic messengers-they are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release.

Cannabinoids produce an increase in the dopaminergic activity in the mesolimbic reward pathway, which plays a pivotal role in mediating the reinforcing effects of most drugs of abuse. The increased dopaminergic drive elicited by the cannabinoids could underlie the abusive property of the drug and increases in positive psychotic symptoms induced by THC.

 Recurrent cannabis use produces prolonged and excessive stimulation of the CB1 receptor, and this is thought to disrupt endocannabinoid system function.

 Several lines of evidence exist to suggest a role for cannabinoids and their receptors in the pathophysiology of schizophrenia. It has also been proposed that this CB1 receptor overstimulation may be a contributing factor in triggering THC-induced psychosis.


Summary of key studies linking cannabis and psychosis

Many studies have explored the link between cannabis and psychosis (

. In a systematic review, Moore and colleagues

 surveyed the literature on this topic. They looked at population-based longitudinal studies as well as nested case-control studies that assessed the impact of cannabis use on the later development of psychosis. The “psychosis” outcomes required the diagnosis of a primary psychotic disorder or affective psychosis, or the occurrence of delusions, hallucinations, or thought disorder during the study period. Results from 7 cohort studies showed a 40% increased risk of psychosis in cannabis users compared with nonusers. The data also revealed a dose-response effect-the risk of psychotic symptoms was increased approximately 50% to 200% in those who used cannabis frequently compared with nonusers.

Critics of this hypothesis believe that cohort studies have inherent limitations that prevent any clear conclusions from being drawn. McLaren and colleagues

 evaluated the methodological strength of the existing cohort studies. The definition of psychosis was a recurrent limitation in the studies. Many studies used psychotic symptoms, not diagnoses, as their outcome, which may not be of clinical significance. Moore and colleagues

 also noted this limitation and attempted to correct for it by separately analyzing the 2 studies that required the diagnosis of a primary psychotic disorder. Interestingly, they found an odds ratio of 2.6 for the development of psychotic disorders in those who had ever used cannabis compared with nonusers. Important confounding factors, such as noncannabis drug use, a family history of psychosis, and unmeasured vulnerability to psychosis, were not adequately controlled in these studies.

Age at onset of psychosis and cannabis use

Certain risk factors have been reported to interact with cannabis use to increase vulnerability to developing psychosis. One suspected important variable is the age at which cannabis use is started. The age effect was first noted in a Swedish conscript cohort study that demonstrated that cannabis use by age 18 led to a 6-fold increase in the risk of schizophrenia later in life.

 It is unclear, however, whether the psychotic symptoms predated the cannabis use.

To clarify this issue, the Dunedin Multidisciplinary Health and Development Study conducted a prospective longitudinal study of adolescent cannabis use, taking into account psychotic symptoms that occurred before cannabis use.

 The data were compiled from a birth cohort that consisted of 1037 individuals born in Dunedin, New Zealand. Information about psychotic symptoms was obtained at age 11, and drug use was assessed by self-reports at ages 15 and 18 and by a standardized interview schedule at age 26. Two psychosis-related outcomes were measured-the presence of symptoms of schizophrenia and the diagnosis of schizophreniform disorder.

The results showed that those who had used cannabis by ages 15 and 18 had more schizophrenia symptoms than controls, a finding that remained significant after controlling for the presence of psychotic symptoms at age 11. However, the increased likelihood of schizophreniform disorder at age 26 was no longer significant after controlling for psychotic symptoms at age 11. Taken together, this suggests that early cannabis use confers higher risk of psychosis.

These findings may be explained as follows: Adolescence represents a sensitive period of neurodevelopment, during which the brain is more vulnerable to the effects of cannabis. Alternatively, the heightened risk may simply be a consequence of greater cumulative cannabis use, since these subjects began using it at a younger age. These theories are not mutually exclusive, and the latter explanation is consistent with the previously mentioned dose-response relationship observed in many studies.

A subsequent study conducted with the Dunedin cohort investigated whether specific genes increase the risks associated with early cannabis use.

 The researchers examined the role of the catechol-

) gene, whose link with psychosis has been the focus of many studies. The 

 gene encodes the enzyme responsible for the synaptic metabolism of dopamine. A functional polymorphism of this gene, Val158Met, has been shown to slow the breakdown of dopamine, which potentially increases the risk of psychosis.

 The results of the study showed that the presence of the valine polymorphism was not significant unless coupled with adolescent cannabis use.

Persons with Val/Val or Val/Met genotypes and adolescent cannabis use were at increased risk for schizophreniform disorder (with respective odds ratios of 10.9 and 2.5), while individuals with Met/Met genotypes were not. These findings implicate genetic factors as important contributors to the cannabis-psychosis link, but they are in need of replication.

Impact of cannabis use on the course of schizophrenia

The extent to which cannabis use might alter the clinical course of schizophrenia remains a point of contention within the literature. Intuitively, one may expect cannabis to have a negative impact on the expression and course of schizophrenia. Findings suggest that patients with schizophrenia who use cannabis experience increased psychotic symptoms, are more likely to have relapses, have a greater likelihood of rehospitalization, and experience poorer therapeutic response to antipsychotic medication than patients who are cannabis-naive.

 Furthermore, pre-onset cannabis use may trigger an earlier age of onset of psychosis, which is of critical importance given the negative prognostic features associated with earlier onset.

 These effects have been reported to be dose-dependent.

It is interesting to note that other studies have been unable to confirm these adverse findings after controlling for potential confounding factors, which include but are not limited to alcohol and drug use, premorbid functioning, and family history. Moreover, it has been suggested that patients with comorbid cannabis use constitute a clinically distinct subgroup of schizophrenia patients.

In this respect, cannabis use may trigger the onset of psychosis in vulnerable individuals in whom a psychotic disorder otherwise may not have developed. As a result, these patients have a better prognosis, exhibit fewer negative symptoms, have better social skills, and have an enhanced treatment response compared with nonusers. In addition, a recent meta-analysis demonstrated that patients with lifetime cannabis use disorders have superior cognitive function compared with nonuser counterparts.

These conflicting findings may be due to the varying levels of THC/CBD found in street cannabis. The fact that these constituents have divergent properties may explain the manifestation of different psychological symptoms among users. In fact, CBD may actually attenuate some of the unwanted psychopharmacological effects of THC, because it may have anxiolytic and antipsychotic properties.

 Furthermore, CBD has been shown to have neutral or even procognitive effects.

Despite all of the uncertainties surrounding the cannabis-psychosis link, we are left with the task of translating these results into clear recommendations for our patients. The evidence suggests that cannabis is associated with an increased risk of psychosis when it is used frequently. Whether cannabis can trigger a primary psychotic disorder that would not have otherwise occurred is unclear. However, in most individuals who use cannabis, psychosis does not develop, which suggests that the increased risk must be related to other vulnerability factors (genetics, frequency, or age of onset of cannabis misuse).

Cannabis also seems to alter the clinical course of schizophrenia negatively. While meta-analyses suggest better cognitive function among cannabis-using patients, this may be a reflection of a higher-functioning subgroup of schizophrenia patients. Accordingly, cannabis-using patients who achieve abstinence may demonstrate improved symptoms and cognitive performance.

The first step in communicating this information to our patients consists of screening for cannabis use and obtaining a thorough substance use history. Psychoeducation and early interventions for young patients who may be vulnerable to psychosis should be used, and motivational interviewing and cognitive-behavioral therapy should be considered to encourage reduction and cessation of use.

There are no accepted pharmacological treatments for cannabis use disorders, yet several potential agents are under investigation. Future studies that control for both environmental and biological risk factors are needed to more clearly elucidate the mechanisms linking cannabis misuse to psychosis.

Editor’s Note: Our Category 1 CME articles are on hiatus for the summer. 

In the meantime, we invite you to test yourself: read the article, take the posttest below, and then check the answer key on the last page of this article for the correct answers.

1. What percentage of patients with schizophrenia have a comorbid cannabis use disorder?

2. The primary psychoactive constituent of cannabis is:

3. It has been suggested that early cannabis use confers a higher risk of psychosis, which may be explained by the fact that

A. The brain is more vulnerable during adolescence

B. There is greater cumulative cannabis use

4. The presence of the Val allele polymorphism of the catechol-

) gene may be responsible for increased risk of psychosis in cannabis users.

5. The link between cannabis use and psychosis may be attributable to actions on which of the following on the G-protein-coupled receptors:

6. Which of the following is true of patients with schizophrenia who use cannabis?

A. They experience increased psychotic symptoms

C. They have a greater likelihood of rehospitalizations

7. Cannabis has been found to be associated with psychosis no matter the frequency of use.

8. The results of a multisite US epidemiological study of the relationship between self-reported psychotic experiences and cannabis use showed that any cannabis use was associated with a _____ increased risk of psychotic experiences.

9. The enhanced cognitive function in schizophrenia patients who use cannabis may be due to the effects of which of the following?

10. Currently there is only one accepted pharmacological treatment for cannabis use disorders.

Answer key to the Mine Your Mind posttest:

1, D;   2, C;   3, C;   4, A;   5, A;   6, D;   7, B;   8, C;   9, A;   10, B. 

 United Nations Office on Drugs and Crime (UNODC). 

 Koskinen J, LÃ¶hÃ¶nen J, Koponen H, et al. Rate of cannabis use disorders in clinical samples of patients with schizophrenia: a meta-analysis. 

 2nd ed. New York: Oxford University Press; 2008.


 Ameri A. The effects of cannabinoids on the brain. 

 Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. 

 Eggan SM, Lewis DA. Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. 

 Szabo B, Siemes S, Wallmichrath I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. 

 Murray RM, Morrison PD, Henquet C, Di Forti M. Cannabis, the mind and society: the hash realities. 

 Morrison PD, Murray RM. From real-world events to psychosis: the emerging neuropharmacology of delusions. 

 Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. 

 McLaren JA, Silins E, Hutchinson D, et al. Assessing evidence for a causal link between cannabis and psychosis: a review of cohort studies. 

 AndrÃ©asson S, Allebeck P, EngstrÃ¶m A, Rydberg U. Cannabis and schizophrenia. A longitudinal study of Swedish conscripts. 

 Arseneault L, Cannon M, Poulton R, et al

 Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. 

 Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-

methyltransferase gene: longitudinal evidence of a gene X environment interaction. 

 Lachman HM, Papolos DF, Saito T, et al. Human catechol-

-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. 

 Bilder RM, Volavka J, Lachman HM, Grace AA. The catechol-

methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. 

 Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. 

 Bowers MB Jr, Mazure CM, Nelson JC, Jatlow PI. Psychotogenic drug use and neuroleptic response. 

 Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent-onset schizophrenic disorders. 

 Rabin RA, Zakzanis KK, George TP. The effects of cannabis use on neurocognition in schizophrenia: a meta-analysis. 

 Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a 

 Fadda P, Robinson L, Fratta W, et al. Differential effects of THC- or CBD-rich cannabis extracts on working memory in rats. 

 Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. 

Evidence suggests that cannabis is associated with an increased risk of psychosis when it is used frequently. Marijuana doesn't count, does it?

The Cannabis-Psychosis Link: Mind Your Mind

"Marijuana doesn’t count, does it?” Clinicians are familiar with this common reply when screening for drug use. Cannabis-the most common illicit substance-has managed to exempt itself from the hazardous reputation held by other illicit drugs.

 As mental health practitioners, it is our duty to educate our patients about the potential harms and consequences of cannabis use. This important task is complicated by the disagreement and uncertainty surrounding the nature of the interaction between cannabis and psychotic disorders.

While research suggests that cannabis use can induce an acute psychotic state, there is controversy about whether it may precipitate psychotic disorders, such as schizophrenia. These authors offer an update on this important issue and provide clinically useful recommendations.